Treatment of mental disorders

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof for use in the treatment of a psychiatric or nervous system disorder in a mother having a child aged 18 months or less.

Description

[Technical Field]

[0001] The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating patients who are mothers, particularly nursing mothers, diagnosed with a psychiatric or neurological disorder.

[0002] Psychiatric disorders are amenable to treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. This treatment also improves maternal function.

[0003] The present invention further allows for the treatment of psychiatric or neurological disorders in nursing mothers without substantially interrupting breastfeeding. [Background technology]

[0004] Mental or neurological disorders in nursing mothers can have a variety of adverse effects on the affected mother, her infant(s), and her family. For example, women suffering from mental or neurological disorders may develop thoughts of harming themselves or their child and are at increased risk of suicide.

[0005] Mental or neurological disorders may also lead to disruptions in maternal-infant interactions, such as higher rates of unengaged behavior and lower rates of visual and vocal communication between mother and child. There is also evidence suggesting an association between maternal mental or neurological disorders and child development, as shown by the increased risk of cognitive developmental abnormalities in children of patients with mental or neurological disorders.

[0006] Despite these problems, treatment options are quite limited: very generally, known treatments for psychiatric or neurological disorders are often associated with only limited success, especially in patients who do not merely suffer from mild symptoms of the disease.

[0007] If the patient is a nursing mother, one aggravating factor is that for many medications, lactating women are advised to discontinue breastfeeding while taking the medication and for a period thereafter, as the medication is excreted in breast milk and may put the nursing baby at risk.

[0008] Furthermore, studies have shown that nursing mothers may be reluctant to initiate pharmacological treatment due to a variety of concerns.

[0009] As a result, lactating patients suffering from psychiatric or neurological disorders may be faced with the decision to discontinue breastfeeding or to discontinue / withhold therapy.

[0010] Against this background, there is a need for improved treatments for psychiatric or nervous system disorders, particularly treatments that not only effectively address the symptoms of the disorder and result in a rapid clinical response, but also do not interfere with the patient's daily activities, particularly those related to caring for the infant(s). This treatment should improve maternal function. Furthermore, there is a need for treatments for psychiatric or nervous system disorders that do not require substantial interruption of breastfeeding.

[0011] In recent years, there has been great interest in hallucinogens for the treatment of psychiatric disorders, but to date this has not led to the use of such substances in the treatment of nursing mothers, due not only to specific concerns that the administration of hallucinogens may be inappropriate for nursing mothers, but also to a general lack of meaningful clinical data that would allow conclusions to be drawn about the clinical usefulness of hallucinogens.

[0012] Hallucinogens, including psychedelics, are compounds, both naturally occurring and synthetic, defined by their ability to induce sensory alterations, such as changes in hearing and vision, as well as mood and cognitive changes, in humans after ingestion. The term hallucinogen encompasses a fairly broad group of psychoactive molecules with various mechanisms of action. It has been suggested that several psychiatric disorders may, in principle, be amenable to treatment with psychoactive molecules such as psychedelics.

[0013] However, no psychedelic drugs have been approved by regulatory agencies, and indeed clinical experience with such molecules remains quite limited.

[0014] One compound already investigated in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO 2020 / 169850 reports on clinical trials that included testing in healthy volunteers as well as patients with treatment-resistant depression (TRD), a form of major depressive disorder. Patients with PPD were not included in the study.

[0015] Against this background, it is an object of the present invention to provide a therapy that is more effective than previously reported therapies, i.e., a) a greater proportion of patients experience 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.

[0016] It is a further object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens therefor that have a better safety profile and / or are better tolerated than previously reported therapies. Another object of the present invention is to provide compounds for improved psychoactive therapies and dosing regimens therefor that are more convenient than previously reported therapies. Another object of the present invention is to provide compounds for improved psychoactive therapies and dosing regimens therefor that are associated with higher patient compliance rates (including higher treatment initiation rates) than previously reported therapies. Yet another object of the present invention is to identify specific disease conditions and specific subgroups of disease conditions for which such improved psychoactive therapies are effective.

[0017] Yet another object of the present invention is to improve maternal function in patients suffering from psychiatric or neurological disorders, especially in nursing mothers diagnosed with a psychiatric disorder. Summary of the Invention

[0018] The present invention provides 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating mothers, particularly nursing mothers, diagnosed with a psychiatric or neurological disorder, including, among others, disorders characterized by depressive episodes, such as major depressive disorder (MDD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), including bipolar I and II disorders; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); and post-traumatic stress disorder. The mental and behavioral disorders may be 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 (SUDs); psychotic disorders, such as schizophrenia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; HIV-related, post-COVID related or traumatic brain injury-related psychiatric or nervous system disorders.

[0019] In one aspect, the patient may suffer from a sleep disorder.

[0020] This treatment allows for improved maternal function.

[0021] Patients to be treated are especially nursing mothers.

[0022] The present invention also allows for the treatment of nursing mothers without substantial interruption of breastfeeding.

[0023] The present invention also provides dose ranges and dosing regimens useful for the above treatments. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition As used in the context of the present invention, unless otherwise noted, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, where 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.

[0025] As used in the context of the present invention, a "patient" to be treated is a mother having a child under 18 months of age, particularly under 12 months of age, who has been diagnosed with a mental or nervous system disorder by a qualified professional in accordance with accepted medical practice.

[0026] Diagnosis of mental or nervous system disorders may be according to, for example, the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) published by the American Psychiatric Association. In some cases, as will be apparent from the description of specific conditions below, the criteria may be modified or supplemented to better define patients or groups of patients for whom treatment according to the present invention may be particularly effective. In any case, the diagnosis is made by a physician or psychologist. It is not sufficient for the subject to self-identify as suffering from a disorder.

[0027] As used in the context of the present invention, unless otherwise noted, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and include the provision 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.

[0028] The patient may suffer from treatment-resistant disease. Treatment-resistant means that the patient has not been adequately improved after at least two courses of appropriate therapy. In particular, the patient has not been adequately improved after at least two courses of appropriate therapy, and at least one of the two courses is drug therapy. For example, the patient has not been adequately improved after at least two courses of appropriate drug therapy. The at least two courses of prior therapy are particularly those administered during the current disease episode, for example, those administered during the current depressive episode if the patient suffers from a disorder characterized by depressive episodes.

[0029] As used in the context of the present invention, "suicidal ideation" refers to thinking, considering, or planning about suicide. The presence or absence 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 a patient to self-identify as 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 "intent to commit suicide."

[0030] As used in the context of the present invention, unless otherwise noted, the term "therapeutically effective amount" is intended to mean the amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is sought by a researcher, physician or other clinician, including alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0031] "Clinical response" includes, but is not limited to, improvement on a rating scale.

[0032] The severity and change in severity of the condition can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, treatment response, and treatment effectiveness.

[0033] The CGI rating scale was developed to provide a brief, independent assessment of clinicians' views of a patient's global functioning before and after treatment (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0034] The CGI-Severity Scale (CGI-S) is based on a single question to be answered by the clinician: "Considering your overall clinical experience with this particular population, how mentally ill is the patient at this time?" This is rated on a 7-point scale: 1 = normal, not at all ill; 2 = becoming mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = significantly ill; 6 = severely ill, 7 = among the most severely ill patients.

[0035] The CGI-S can be used to assess the success of treatment by comparing pre- and post-treatment scores.

[0036] Alternatively, treatment success can be assessed using a similarly brief form, the CGI-Improvement (CGI-I). After treatment, clinicians compare the patient's overall clinical status with that before treatment (the so-called baseline value). Again, only one question is rated on a 7-point scale: "Compared to the patient's condition at the time of entry into the project [before medication began], this patient's condition has: 1 = very much improved since the start of treatment; 2 = much improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worse; 6 = much worse; 7 = very much worse since the start of treatment."

[0037] The Patient Global Impression (PGI) scale, also known as the Subject Global Impression (SGI), is the counterpart of the Clinical Global Impression (CGI) scale. It consists of a single item adapted for patients based on the CGI. It can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0038] The severity and change in severity of the condition may further be assessed using a rating scale applicable to the particular psychiatric or neurological disorder from which the patient suffers.

[0039] Individual items of the scales described herein, as well as subcombinations of individual items, can be used to assess specific disease aspects.

[0040] Maternal functioning can be assessed using the Barkin Index of Maternal Functioning (BIMF).

[0041] When clinical response at an early time point after drug administration (e.g., 2 hours) is assessed based on endpoints developed for longer recall periods (e.g., typically 7 days for the MADRS), rational modifications of such endpoints (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration) may be applied.

[0042] The considerations outlined apply to early time points because, on the one hand, the influence of the patient's pre-treatment state on the scores recorded after treatment should be kept as low as possible in order to assess the clinical response, and, on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0043] At later time points, e.g., Day 1 or later, all items on the applicable scale for assessing clinical response can typically be assessed using an adapted recall period as needed, so that pre-treatment scores do not need to be carried forward. For example, if BIMF is assessed on Day 7, a 7-day recall period is used (instead of the standard 2-week recall period).

[0044] As used in the context of the present invention, unless otherwise noted, the term "administration" (or "application") shall mean the introduction of an active compound or pharmaceutical ingredient, which may be a predetermined amount, into a patient by any route. Preferably, the active compound is administered by inhalation, nasally, bucally, or sublingually.

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

[0046] As used herein, "aerosol" refers to a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and finely suspended solid and / or liquid particles. The term "degradation products" refers to compounds resulting from chemical modification of an active agent as a result of chemical reactions during aerosol formation. Such reactions include, but are not limited to, oxidation. When a percentage of "degradation products" is described in the context of the present invention, it refers to the amount of active agent degradation products present in a sample divided by the sum of the amount of active agent and active agent degradation products present in the sample, multiplied by 100%, i.e., (sum of the amount of all active agent degradation products present in the sample) / ((amount of active agent present in the sample)+(sum of the amount of all active agent degradation products present in the sample)) × 100%. As used herein, the term "impurities" refers to unwanted compounds that contaminate a sample of an active agent. Impurities may be present in the starting material prior to aerosol formation or may be degradation products.

[0047] The term "purity" refers to 100% minus the percentage of all active agent degradation products and all other impurities present, i.e., 100% - (the sum of the amounts of all active agent degradation products present + the sum of the amounts of all other impurities present) / (the amount of active agent present + the sum of the amounts of all active agent degradation products present + the sum of the amounts of all other impurities present) x 100%.

[0048] The term "mass median aerodynamic diameter" (MMAD) is the diameter at which 50% of the particles present in an aerosol are larger and 50% are smaller than the calculated diameter. The term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle formation rate" refers to the aerosolized mass of active agent per unit of aerosolization time.

[0049] Mental and nervous system disorders The psychiatric and neurological disorders treated according to the present invention have in common that they are associated with one or more symptoms from the symptom groups described below, including sleep disorders, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0050] In one aspect, the present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient who is a nursing mother diagnosed with a psychiatric or neurological disorder.

[0051] Psychiatric or neurological disorders are suitable for treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof, particularly major depressive disorder, persistent depressive disorder, bipolar disorder, anxiety disorder, post-traumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorders, or psychoactive substance abuse.

[0052] In a preferred embodiment, the psychiatric disorder is major depressive disorder.

[0053] In another preferred embodiment, the psychiatric disorder is a bipolar disorder, such as bipolar II disorder. In particular, patients diagnosed with bipolar disorder suffer from a current major depressive episode.

[0054] Various aspects of bipolar disorder can be improved, such as sleep disturbance, psychomotor retardation (reduced energy and activity and reduced motivation), negative thoughts (feelings of worthlessness, helplessness and hopelessness, guilt), anxiety, cognitive dysfunction (concentration and memory impairment), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal, and flat affect). Additional aspects of the disease that can be improved include suicidal ideation and mixed symptoms (psychotic symptoms, irritability, instability, increased motor urges, increased speech, agitation). The improvement that can be achieved is reflected in a clinically meaningful scale.

[0055] Scales for assessing mental and nervous system disorders Many scales have been proposed to assess the severity of psychiatric or neurological disorders. These scales are based on tests that may be self-administered or administered by a clinician.

[0056] Scales for the assessment of psychiatric or neurological disorders that may be used in accordance with the present invention include those known in the art for diagnosing and / or monitoring psychiatric or neurological disorders, which are described in more detail below.

[0057] Treatment outcomes are assessed by using one or more indicators or scales at one or more time points after the completion of the course of treatment.

[0058] This assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is generally about 2-3 hours after the final dose. Early assessments can generally be performed, for example, about 2 hours or about 3 hours after the final dose.

[0059] However, assessment of the effect on sleep disturbances, or on mental or nervous system disorders related to the effect on sleep disturbances, may be conducted at the earliest on the day after treatment (i.e., Day 1) so that the treated patient has had an opportunity to get at least one night's sleep.

[0060] Thus, evaluation on or at day 1 refers to evaluation on the day after administration. Evaluation is performed at least 12 hours after the final administration, and in any case, at least overnight after the final administration and within 36 hours after the final administration. Evaluation may also be performed about 24 hours later.

[0061] Assessment on or at day 7 means assessment at day 7 after dosing (day of dosing is day 0). Similar definitions apply to other assessment timings measured in days.

[0062] For example, when using one of the scales for assessing the severity of psychiatric or nervous system disorders to evaluate the clinical response at an early time point (e.g., 2 hours) after drug administration based on an endpoint established for a longer recall period (e.g., typically 7 days for the MADRS), reasonable modifications of such endpoints (e.g., changing the MADRS recall period to 2 hours and carrying forward the sleep items recorded at baseline before drug administration) may be applied. The same applies to all other scales used herein to evaluate the therapeutic effect on psychiatric or nervous system disorders, unless a recall period is specifically indicated.

[0063] The considerations outlined apply to early time points because, on the one hand, the influence of the patient's pre-treatment state on the scores recorded after treatment should be kept as low as possible in order to assess the clinical response, and, on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0064] At later time points, e.g., Day 1 or later, all items on the applicable scale for assessing clinical response can typically be assessed using an adapted recall period on demand, so that pre-treatment scores do not need to be carried forward.

[0065] Active Agent Psychiatric or neurological disorders are characterized by several aspects, which present a significant disease burden and require appropriate treatment, particularly pharmacological intervention, to improve not only the overall disease score but also specific aspects of the disease.

[0066] The inventors believed that a carefully selected hallucinogen may lead to improved treatment and may also lead to an overall improvement in disease and maternal function.

[0067] The inventors further believed that in the case of treatment of nursing mothers suffering from psychiatric or neurological disorders, a carefully selected hallucinogen may allow for continuation of nursing without substantial interruption.

[0068] 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 "psychedelics," emphasizing that their primary ability is to induce qualitatively altered states of consciousness, such as euphoria, trance, 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.

[0069] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, the indoleamine class being divided into two subsets, the ergolines and tryptamines, the latter being derived from tryptamine.

[0070] Various serotonergic psychedelics 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 trace amine-associated receptors.

[0071] Recently published clinical trials using serotonergic psychedelic drugs such as LSD, psilocybin, and DMT (using ayahuasca brews used by shamans, which contain DMT) in 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 with depressive symptoms, which may hinder their clinical use.

[0072] 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 oral ingestion of LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication, which resolved, but within approximately 3 weeks, a typical manic episode of psychotic severity followed. 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 oral ingestion of 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) report a switch to mania after ingestion of ayahuasca, a brew containing DMT, in a man with bipolar disorder.

[0073] Further case reports are available 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.

[0074] The inventors have considered that in order to avoid the induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound to be administered must be appropriately selected and preferably administered in a specific dosage regimen.

[0075] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic of particular interest for therapeutic use. 5-MeO-DMT has a unique pharmacological profile that differs from other psychedelic compounds.

[0076] 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 greater affinity for the 5-HT1A receptor subtype compared to other classical psychedelics.

[0077] The inhibition constants (K) for psilocin (the dephosphorylated form of psilocybin formed after uptake of psilocybin), DMT, and 5-MeO-DMT are further detailed in the Examples section below. i The K values ​​at the 5-HT1A receptor in the hippocampus of postmortem human brain are 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while psilocin and DMT exhibit moderate affinity. The inhibition constants (K iThe agonist activity (Ap) of psilocin at 5-HT2A receptors in the frontal cortex of postmortem human brains is 37, 117, and 122 nM, respectively. Thus, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0078] Relative to the other psychoactive compounds mentioned above, 5-MeO-DMT exhibits enhanced affinity for the 5-HT1A receptor and acts as a potent agonist. In the case of psilocin and DMT, the contribution of 5-HT2A binding is increased relative to 5-MeO-DMT, with the latter exhibiting the greatest differential affinity for 5-HT1A compared to 5-HT2A of the three compounds. Thus, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT relative to 5-HT2A binding compared to the other two compounds.

[0079] It has been reported that 5-HT1A agonism reduces impulsivity and aggression, while 5-HT2A agonism can result in a short-term increase in these same traits. Furthermore, the dopamine system has been implicated in mania, with increased dopamine drive being associated with mania. LSD, psilocybin, and DMT all exhibit increased affinity for various dopamine receptors relative to 5-MeO-DMT.

[0080] Compared to other psychedelics such as LSD, psilocybin, or DMT, 5-MeO-DMT, preferably using the dosing 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., bipolar disorders (BD) such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar I and II disorders; psychotic disorders such as schizophrenia; or personality disorders such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders who are treated according to the present invention do not experience treatment-emergent mania or hypomania.

[0081] 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).

[0082] Our approach of sequential uptitration of 5-MeO-DMT significantly reduces the risk of overdose with its attendant potential adverse events.

[0083] Furthermore, antidepressants have been reported to induce isolated episodes of hypomania 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.

[0084] 5-MeO-DMT can induce a peak experience (i.e., an experience characterized by a shift in emotional perspective described as a "loss of self" and often culminating in an overwhelming "sense of oneness with the universe") more rapidly than other psychedelics, and the duration of acute psychedelic effects is short (e.g., 5-30 minutes after inhalation, compared with several hours for oral psilocybin and oral LSD). These characteristics 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.

[0085] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. To estimate nonspecific binding, the present inventors investigated the effect of 5-MeO-DMT on recombinant human 5-HT7 receptors and the effect of 5-MeO-DMT on the radioligand [ 3 H]LSD, and serotonin were used to i was determined to be 2.3 nM.

[0086] Thus, in addition to the 5-HT1A and 5-HT2A receptors mentioned above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0087] 5-HT7 receptors are involved in neurogenesis, synaptogenesis, and dendritic spine formation, and are associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

[0088] 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.

[0089] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system, which synchronizes circadian rhythms in various brain regions. Disruption of this synchronization leads to pathological conditions, particularly those involving sleep disorders. In patients with sleep disorders, resting-state functional connectivity analysis reveals altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0090] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the function of this receptor in regulating the sleep / wake cycle, and we therefore believe that 5-MeO-DMT, which acts on this receptor, may be able to treat patients suffering from sleep disorders.

[0091] 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, which results in a "resetting" of functional network connectivity and neuroplastic effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0092] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 and 5-HT1A receptors, as two mediators of the effects produced by 5-MeO-DMT, including the "resetting" of functional network connectivity and neuroplasticity effects, may also enable beneficial effects to be achieved in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results shown in the studies referred to herein.

[0093] Another characteristic of 5-MeO-DMT is its short half-life.

[0094] 5-MeO-DMT is primarily inactivated via a deamination pathway mediated by monoamine oxidase A and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0095] We investigated the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after administration.

[0096] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid decline in plasma concentrations. Already 10 minutes after administration, concentrations fall to less than 10% of Cmax, 2 hours later to less than 1% of Cmax, and 3 hours later, 5-MeO-DMT is no longer detectable in plasma. This applies across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation is observed with repeated dosing within the 1-4 hour time frame. Uptitration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0097] The inventors further identified that 5-MeO-DMT offers a variety of properties that make it an attractive PPD treatment. Unlike SSRIs, it is a fast-acting drug (in the 5-MeO-DMT-TRD study, 5 / 8 TRD patients achieved remission within 2 hours of dosing, 8 / 8 patients achieved remission on day 1, and 7 / 8 patients maintained remission on day 7). The use of 5-MeO-DMT to treat PPD patients may achieve rapid improvement in not only depressive symptoms but also maternal functioning. Furthermore, 5-MeO-DMT is administered during a single treatment session with optional infrequent re-dosing, which differentiates it from SSRIs, which require chronic daily dosing regimens associated with poor compliance (and, in the case of brexanolone, require long-term infusions and hospitalization).

[0098] Thus, the present invention also addresses compliance and patient convenience.

[0099] Furthermore, the present inventors have determined that treatment of PPD with 5-MeO-DMT or a pharmaceutically acceptable salt thereof allows breastfeeding to be continued with only a short interruption for treatment.

[0100] Isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used in accordance with the present invention. Where reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0101] These variants are in particular deuterated forms of 5-MeO-DMT, and pharmaceutically acceptable salts of such forms.

[0102] A deuterated form of 5-MeO-DMT is one that has a higher deuterium content than would be expected based on the natural abundance of this isotope.

[0103] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium has been introduced at one or more defined hydrogen positions.

[0104] 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.

[0105] Further examples include forms of 5-MeO-DMT in which deuterium is introduced at one or more hydrogen positions of the N-linked methyl group. Yet other examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms on the indole ring system. Note that combinations of the above substitution patterns are also contemplated.

[0106] Methods for preparing these compounds are known in the art.

[0107] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated and non-deuterated 5-MeO-DMT may also be used.

[0108] Furthermore, according to 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.

[0109] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs can also be used. Such prodrugs of 5-MeO-DMT can be metabolically converted to 5-MeO-DMT. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, this can be replaced with a 5-MeO-DMT prodrug or a salt thereof.

[0110] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced by an organic moiety that can be cleaved after administration.

[0111] Examples of suitable organic moieties include -C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 where R 1 , R 2 , R 3 , and R 4is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, where each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0112] Preferred examples of organic moieties include -CH(R 3 )OC(O)R 4 and -C(O)OR 1 where R 1 , R 3 , and R 4 is defined as above.

[0113] Prodrugs, particularly those having the above structure, may also be used in the form of pharmaceutically acceptable salts.

[0114] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate di-trifluoroacetate), and 5-MeO-DMT methylpivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methylpivalate).

[0115] Methods for preparing prodrugs as described herein are known in the art.

[0116] According to the present invention, the T of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of 10 mg / kg of the prodrug. max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0117] 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.

[0118] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered by inhalation, nasal administration, buccal administration, or sublingual administration. Administration via these routes can ensure a rapid onset of action. The most preferred route of administration is by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in one breath.

[0119] For nasal administration, 5-MeO-DMT can be used as the substance itself or in the form of a formulation for nasal administration, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably hydrobromide, or in the form of a formulation of a pharmaceutically acceptable salt, preferably hydrobromide.Examples of suitable devices are known in the art.

[0120] For buccal or sublingual administration, a pharmaceutically acceptable salt of 5-MeO-DMT, preferably the hydrobromide salt, may be utilized either neat or in formulations such as tablets, films, sprays, creams, and the like, as are well known in the art.

[0121] Administration is typically by inhalation of an aerosol. Such aerosols comprise (a) a pharmaceutically acceptable gas; and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, the aerosol having an aerosol particle mass density of about 0.5 mg / L to about 18 mg / L, for example, about 0.5 mg / L to about 12.5 mg / L, preferably about 1.3 mg / L to about 10 mg / L, particularly about 2 mg / L to about 9 mg / L. The pharmaceutically acceptable gas is preferably air.

[0122] The aerosol particles preferably contain less than 1 wt.% impurities, in particular less than 0.5 wt.% impurities, and preferably further contain less than 0.5 wt.% 5-MeO-DMT degradation products, in particular less than 0.2 wt.% 5-MeO-DMT degradation products resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0123] In a further preferred embodiment, the aerosol consists essentially of: (a) air; and (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0124] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0125] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular a mass median aerodynamic diameter of less than 2 μm and greater than 0.1 μm.

[0126] Aerosols can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to create aerosol particles. The thin layer can have a thickness of less than about 10 μm, particularly less than about 7.5 μm. The thin layer can have a thickness in the range of about 0.1 μm to about 10 μm, particularly in the range of about 0.3 μm to about 7.5 μm.

[0127] A thin layer of 5-MeO-DMT formed on a solid support may be exposed to thermal energy via air passing over the thin layer. Alternatively, a thin layer of 5-MeO-DMT formed on a solid support may be exposed to thermal energy via the solid support.

[0128] The air passing over the thin layer may have a temperature in the range of about 180° C. to about 260° C. The air passing over the thin layer may in particular have a temperature of about 210° C. and may be passed over the thin layer at a rate of about 12 1 / min for about 15 seconds.

[0129] The aerosol particles may be contained in a volume of about 3 liters or less, particularly about 1 to about 3 liters, for example about 2 to about 3 liters, and are preferably delivered to a patient via a single inhalation.

[0130] 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharmaceutically acceptable salt thereof are provided in the form of an aerosol. These aerosols have a suitable aerosol particle mass density so that a therapeutically effective dose of the aerosol can be administered to a patient in a single inhalation.

[0131] Aerosols useful in the present invention can be formed using thermal energy. When using thermal energy to form aerosols of compounds, it is very difficult to predict the conditions suitable for safe, efficient, and predictable aerosolization, especially when the aerosol is used for systemic delivery of the compound to a patient via the lungs. Important variables in this regard include: a) the dose of the compound; b) the morphological state of the compound when used for aerosolization (e.g., crystalline form or thin layer form); c) the amount of thermal energy to which the compound is exposed (defined by temperature and duration of exposure); and d) the volume of air introduced to create the aerosol (defined by flow rate and duration of airflow).

[0132] The compositions and methods described herein are for the safe, efficient, and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient via inhalation. "Safe" means that the aerosol particles should contain only small amounts of impurities and 5-MeO-DMT degradation products; "efficient" means that the dose is aerosolized to a specified extent, preferably nearly completely or completely, such that the aerosol has desirable physical properties for systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof via the lungs, primarily via alveolar absorption, and that the aerosol can be inhaled by a patient in a single inhalation (i.e., one deep breath); and "predictable" means that there should be little or no variability in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0133] A suitable aerosol can be achieved by a) providing a therapeutically effective amount of 5-MeO-DMT as a thin layer on a solid support, b) exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature for a short period of time, and c) supplying a controlled amount of air so that the aerosol is formed.

[0134] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a thin layer of 5-MeO-DMT configured on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT, the aerosol having one or more of the following characteristics: 1) containing aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns; 2) containing aerosol particles characterized by less than 1% by weight impurities and less than 0.5% 5-MeO-DMT degradation products; and 3) being capable of being delivered to a patient via a single inhalation.

[0135] The generation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, containing less than 1% by weight of impurities and less than 0.5% by weight of 5-MeO-DMT drug degradation products, and in an aerosol volume that can be delivered to a patient via a single inhalation is achieved by defining a) the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by air flow rate and duration of air flow).

[0136] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, where the air is heated. The heated air passing over the thin layer can have a temperature ranging from about 180°C to about 260°C. In particular, the air passing over the thin layer can have a temperature of about 210°C.

[0137] Alternatively, the thin layer of 5-MeO-DMT can be exposed to thermal energy through a solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The heated solid support can have a temperature ranging from about 180°C to about 420°C.

[0138] Preferably, the 5-MeO-DMT used to form a thin layer on a solid support is highly pure, at least 99%, preferably at least 99.5% pure.

[0139] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT formed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Useful specific amounts include, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts include, for example, about 6 mg, about 12 mg, and about 18 mg.

[0140] Solid supports for providing 5-MeO-DMT or a pharmaceutically acceptable salt thereof can have a variety of shapes. Examples of such shapes include, but are not limited to, cylinders having a diameter of less than 1.0 mm, boxes having a thickness of less than 1.0 mm, and virtually any shape penetrated by small (e.g., less than 1.0 mm in size) holes. Preferably, the solid support has a high surface area to volume ratio (e.g., greater than 100 per meter) and a high surface area to mass ratio (e.g., greater than 1 cm per gram). 2 We provide super

[0141] A solid support of one shape can also be converted into another shape with different properties. For example, a flat sheet 0.25 mm thick has a surface area to volume ratio of about 8,000 per meter. Rolling the sheet into a hollow cylinder 1 cm in diameter creates a support with a reduced surface area to volume ratio (about 400 per meter) while retaining the high surface area to mass ratio of the original sheet.

[0142] Several different materials are used to construct solid supports. Such material classes include, but are not limited to, metals, inorganic materials, carbonaceous materials, and polymers. The following are example material classes: aluminum, silver, gold, stainless steel, copper, and tungsten; silica, glass, silicon, and alumina; graphite, porous carbon, carbon yarn, and carbon felt; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated versions of materials are also used.

[0143] When aluminum is used as the solid support, aluminum foil is a suitable material. Examples of silica, alumina, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (Aldrich, St. Louis, Mo., 2 m 2Carbon yarns and felts are available from American Kynol, Inc., New York, NY.

[0144] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, particularly less than about 7.5 μm. The thin layer can have a thickness in the range of about 0.1 μm to about 10 μm, particularly in the range of 0.3 μm to 7.5 μm.

[0145] Preferably, the total amount of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of about 6 liters per minute to about 40 liters per minute, preferably about 8 liters per minute to about 16 liters per minute, and the duration of the air flow is selected so that the total aerosol volume does not exceed about 3 liters, preferably about 1 liter to 3 liters, for example, 2 liters to 3 liters. For example, at an air flow rate of about 6 liters per minute, the duration of the air flow should be less than about 30 seconds. A useful specific air flow rate and duration is about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another useful specific air flow rate and duration is about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another useful specific air flow rate and duration is about 8 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful specific air flow rate and duration is about 10 liters per minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0146] The aerosol formation rate is greater than 0.1 mg / sec.

[0147] The aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, for example about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, particularly about 2 mg / l to about 9 mg / l.

[0148] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and more than 0.1 microns, preferably less than 2.5 microns and more than 0.1 microns, and most preferably less than 2 microns and more than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% impurities by weight, preferably less than 0.5% impurities by weight.

[0149] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% by weight of 5-MeO-DMT decomposition products, preferably less than 0.2% by weight of 5-MeO-DMT decomposition products.

[0150] A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise: a) an aerosol formed by exposing a 12 mg dose of 5-MeO-DMT, configured as a thin layer less than 5 microns thick on a solid support, to a temperature of 210°C by passing heated air over the thin layer for 15 seconds, the aerosol having one or more of the following characteristics: 1) containing aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns; 2) containing aerosol particles characterized by less than 1% impurities and less than 0.5% by weight of 5-MeO-DMT degradation products; and 3) capable of being delivered to a patient via a single inhalation.

[0151] Those skilled in the art can identify suitable vaporization devices or systems that provide the required aerosol characteristics, given the aerosol characteristics and aerosolization conditions defined in the present invention. Examples of such suitable vaporization devices or systems include the Volcano Medic Vaporization System (Storz & Bickel, Germany; for example, as disclosed in EP0933093B1 and EP1884254B1 and registered Community design 003387299-0001) with an associated dosing capsule with a drip pad, and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA; for example, as disclosed in US7,458,374B2, US9,370,629B2 and US9,687,487B2). The generated aerosol can be collected in a balloon and inhaled by the patient from the balloon.

[0152] Medication regimen The present invention also provides dose ranges, specific doses, and dosing regimens (administration schemes).

[0153] The present invention is based in part on the inventors' conclusion that the occurrence of a peak psychedelic experience in the acute phase following administration of 5-MeO-DMT may, whether causally or not, at least serve as a surrogate behavioral marker for the underlying unknown therapeutic mechanisms that contribute to its therapeutic benefit in patients suffering from psychiatric or neurological disorders, particularly one or more of the aspects defined above.

[0154] Thus, compared to previously tested psychedelic agents and dosing regimens, the peak experience is achieved more rapidly in a higher percentage of patients and with better reproducibility within individual patients, resulting in a better therapeutic profile.

[0155] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., the psychedelic effect does not fade or disappear after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., twice or more times daily or daily) designed to increase the incidence of peak experiences and thereby increase therapeutic benefit. Such short-term repeated administration also allows for individualized dose optimization, reducing the risk of overdose, which may otherwise result in physical side effects such as serotonin syndrome, negative psychological reactions such as flashbacks at later points in the experience, the induction of mania or hypomania, or, less significantly, a psychedelic experience with little or no recollection of the altered state (so-called "whiteout"). Furthermore, starting with a low dose allows patients to become accustomed to the overall psychedelic experience and prepares them for the more intense symptoms that occur at higher doses, which favorably impact the experience at those higher doses. Additionally, the prospect of initiating treatment at lower doses may increase patient acceptance of the treatment approach, improving overall compliance rates at the patient population level.

[0156] Frequent re-administration of serotonergic psychedelics to increase the rate and adjust its reproducibility of peak experiences, as well as to improve therapeutic efficacy, reduce side effects, and improve compliance rates, may not be possible with other psychedelics due to the slow onset and long duration of psychedelic effects and the rapid development of tolerance (i.e., the attenuation or disappearance of the psychedelic effects after re-administration), which can last for several days.

[0157] Patients as defined herein who have been diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorders, including those associated with suicidal ideation) are treated by administration of 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as monotherapy, i.e., the patient is not receiving any other treatment for their psychiatric or nervous system disorder or symptoms associated therewith.

[0158] The dosage of 5-MeO-DMT administered to a patient, as defined herein, diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorders, including those associated with suicidal ideation) ranges from about 1 mg to about 25 mg, or any amount within that range, preferably from about 2 mg to about 20 mg, and more preferably from about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, e.g., the hydrobromide salt. It should be noted that when a range, such as "about 1 mg to about 25 mg," is specified herein, the inventors contemplate all individual values ​​within that range, some of which are specifically recited, but not all of which are recited solely for the sake of brevity.

[0159] In a preferred embodiment, the improved method for treating a patient as defined herein who has been diagnosed with a disorder as defined herein (including treatment-resistant forms of the disorder, including disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises the occurrence of a clinical response within about 2 hours after administration of 5-MeO-DMT.

[0160] In a preferred embodiment, the improved method for treating a patient as defined herein who has been diagnosed with a disorder as defined herein (including treatment-resistant forms of the disorder, including disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises a sustained clinical response, including a clinical response that occurs within about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0161] In a preferred embodiment, the improved method for treating a patient as defined herein who has been diagnosed with a disorder as defined herein (including treatment-resistant forms of the disorder, including disorders associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0162] In a preferred embodiment, this greater 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 at least about 1 hour and not more than about 24 hours between doses in each treatment block, and with at least about 6 days between the end of one treatment block and the start of the next treatment block.

[0163] In a more preferred embodiment, the greater than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of one to three doses, separated by about 24 hours between each treatment block, and separated by about 6 days or more between the end of one treatment block and the start of the next treatment block.

[0164] In a most preferred embodiment, this greater 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, separated by about 1 to 4 hours, preferably about 1 to 2 hours, and separated by about 6 days or more between the end of one treatment block and the start of the next treatment block.

[0165] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient at each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Useful specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0166] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and thereafter increases with each subsequent administration within each treatment block until 20 mg is reached or all administrations within that treatment block have been administered, whichever occurs first.

[0167] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and thereafter increases with each subsequent administration within each treatment block until 20 mg is reached, all administrations within that treatment block have been administered, the patient experiences a peak psychedelic experience, or the supervising clinician determines that further dose increases are inappropriate based on observed side effects, whichever occurs first.

[0168] In embodiments where the dosage is increased during subsequent administrations, the dosage of the next administration is determined by adding about 2 mg for every about 10 mg, preferably about 4 mg for every about 8 mg, and most preferably about 6 mg to the dosage of the previous administration. For example, if the dosage of the first administration is 6 mg and the dosage increase is 6 mg, the dosage of the second administration will be 12 mg unless one of the above-mentioned discontinuation criteria is reached. Preferably, the dosage of the third administration is 18 mg.

[0169] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient within each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increases to a dosage selected from about 8 mg to about 14 mg for the second administration and about 14 mg to about 20 mg for the third administration, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising clinician determines that further dose increases are inappropriate based on observed side effects. Particular amounts useful for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0170] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration in a first treatment block, and thereafter increases with each subsequent administration in that first treatment block until 20 mg is reached, all administrations in that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the supervising clinician determines that further dose increases are inappropriate based on observed side effects, whichever occurs first, with the highest dosage in that first treatment block being used for all subsequent treatment blocks and administrations therein. For example, if a patient experiences a peak psychedelic experience at 18 mg and therefore that dose was the highest dosage in the first treatment block, then the dosage for all subsequent treatment blocks and administrations therein will be 18 mg.

[0171] In a most preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration in a first treatment block, and thereafter increases to a dosage selected from about 8 mg to about 14 mg for the second administration in the first treatment block and about 14 mg to about 20 mg for the third administration in the first treatment block, unless the patient has already experienced a peak psychedelic experience within that treatment block or unless the supervising clinician determines that subsequent 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. Particular amounts useful for the first, second, and third administrations in a first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0172] Of course, pharmaceutically acceptable salts of 5-MeO-DMT can also be used in all of the above dosing regimens, and the appropriate weight of the salt to be administered can be calculated from the stated weight of free base, assuming an equimolar amount is used.

[0173] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0174] The occurrence of a "peak psychedelic experience" in a patient can be determined 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 inexpressibility) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described by Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0175] The occurrence of a "peak psychedelic experience" in a patient may also be determined 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).

[0176] In accordance with the present invention, the occurrence of a "peak psychedelic experience" in a patient is preferably determined by achieving a score of at least 75 on the Peak Experience Scale (PES) total score, which is also known as the Peak Psychedelic Experience Questionnaire (PPEQ) and is calculated by averaging the patient's responses on a scale of 0 to 100 to three questions: 1. How intense was the experience? 2. How lost control did they feel? 3. How profound (i.e., deep and significant) was the experience?

[0177] Sleep disorders There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing depths of sleep. Non-REM and REM sleep alternate in each of four to five cycles each night in normal human sleep. Early in the night, non-REM sleep is deeper, accounting for a disproportionate amount of time, especially in 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.

[0178] Normal, healthy sleep consists of different phases, as outlined above, that proceed sequentially in a tightly regulated order throughout the night.

[0179] Disruption of this tight regulation leads to sleep disorders.

[0180] A sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in association with a medical condition, such as a psychiatric or nervous system disorder, which affects a person's ability to function adequately while awake.

[0181] Common forms of sleep disorders include disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial arousal (parasomnia), disorders characterized by abnormal breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0182] Insomnia is a sleep disorder in which an individual has difficulty falling asleep or staying asleep. Insomniacs have difficulty falling asleep due to poor sleep; frequent awakenings during the night and difficulty falling asleep again; awakenings too early in the morning; inability to get good quality sleep; and / or at least one daytime problem, such as fatigue, sleepiness, mood problems, concentration problems, or accidents at work or while driving.

[0183] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. This is difficulty transitioning from sleep to wakefulness. Individuals experiencing sleep drunkenness report waking in a state of confusion, disorientation, sluggishness, and frequent relapses into sleep.

[0184] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances resulting from alterations in an individual's internal circadian rhythm or from a mismatch between that circadian rhythm and desired or required work or social schedules. This dyssynchronization can be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are typically shortened and disrupted, desired wakefulness performance is impaired, and intermittent attempts to return to a regular sleep schedule are unsuccessful.

[0185] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (such as sleepwalking or nightmares) experienced by individuals before sleep onset, during sleep, or during brief arousals between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0186] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that depends heavily on the coordinated action of the respiratory muscles and the brain (the control center within the brain). One form of sleep-related breathing disorder is central sleep apnea. This occurs when the brain stops sending signals that control breathing, for example, due to an underlying disease. Central sleep apnea can seriously affect sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, which leads to sleep fragmentation by microarousals or awakenings. This can result in excessive daytime sleepiness.

[0187] In sleep-related movement disorders, repetitive, relatively simple, usually stereotyped movements interfere with sleep or its onset. The most common of these are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0188] Not getting adequate sleep in adequate quantity or quality can alter personality and may exacerbate existing psychiatric disorders or even precipitate the onset of new ones. Sleep disorders can also impair cognitive function, leading to memory impairment. Sleep-deprived subjects may experience difficulty making decisions, irritability, performance problems, and slowed reaction times. Sleep deprivation can also negatively impact quality of life by contributing to the development of obesity, diabetes, and cardiovascular disease.

[0189] 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 that is unsuccessful, treatment may also include medication or psychotherapy.

[0190] Available treatments are not successful in all patients, may be associated with side effects, and / or may require long-term treatment to achieve meaningful therapeutic benefit.

[0191] For patients suffering from sleep disorders associated with psychiatric or nervous system disorders, known treatments for the psychiatric or nervous system disorder do not always improve the sleep disorder.

[0192] For example, sleep disorders are frequently 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 dysfunction.

[0193] Although sleep disorders may be considered a condition that merits treatment regardless of other conditions, disorders, or symptoms that an individual may suffer from, several psychiatric and neurological disorders are associated with sleep disorders. Notably, the relationship between sleep and psychiatric or neurological disorders is often bidirectional. Not only can psychiatric or neurological disorders adversely affect healthy sleep patterns, but sleep disorders may also be a contributing factor to the onset, progression, and prognosis of mental health or neurological disorders.

[0194] Treatment according to the present invention reduces or eliminates sleep disorders and preferably also improves associated psychiatric or nervous system disorders.

[0195] Measurement of sleep disturbances Sleep can be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and frequency and duration of awakenings throughout the night. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency assessment, or by self-report measures (questionnaires).

[0196] Polysomnography is a technique that requires overnight monitoring of a patient in a specialized clinic. Various functions are measured throughout the night, including eye movement, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body posture and movement, snoring, and heart rate.

[0197] Another quantitative measurement is actigraphy, which uses a worn actimetry sensor to measure motor activity, which is continuously recorded and used to assess the sleep-wake cycle. This technique allows patients to continue their normal routine while recording the necessary data in a natural sleep environment.

[0198] Sleep latency can be measured by the multiple sleep latency test (MSLT). This test provides an objective measure to determine how long it takes a subject to fall asleep during multiple test naps. A mean sleep latency of approximately 10 minutes is considered normal, while less than 8 minutes indicates a sleep disorder (excessive daytime sleepiness). Accompanying brain activity analysis can aid in further diagnosis of sleep disorders.

[0199] Sleep assessment questionnaires obtain ratings of components of sleep quality such as perceived depth of sleep, difficulty waking, and feeling refreshed after sleep, in addition to other factors that may affect sleep quality such as comorbid conditions and medication use. Assessment of qualitative aspects of the sleep experience is important because sleep complaints often persist even when quantitative measures of sleep are normal.

[0200] Questionnaires may not only facilitate rapid and accurate assessment of complex clinical problems, but also help track patient progress.

[0201] Various indices of sleep quality are known. The following indices include examples of questionnaires for assessing overall sleep, as well as questionnaires for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias in particular. However, the present invention is not limited to the use of any particular indices or questionnaires.

[0202] Some questionnaires rely on a recall period (recall window) of several days or even weeks. This may be appropriate for diagnosing sleep disorders, but is not necessarily appropriate for assessing the rapid onset of treatment effects, especially post-treatment effects. In some questionnaires, the recall period can be modified so that the resulting score reflects the post-treatment period. The questionnaires specifically described herein for assessing the treatment effects on sleep in patients suffering from certain conditions rely on a recall period that does not begin before the time when the acute psychedelic experience has subsided after the last administration. To meet this criterion, the normally applied recall period is modified as necessary.

[0203] Overall sleep quality can be assessed, for example, with the Sleep-50 questionnaire.

[0204] 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 some of the most common sleep-related disorders and complaints and diagnostic factors, including sleep apnea, insomnia, narcolepsy, restless legs / periodic limb movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep-related complaints on daily functioning. For each item, respondents are asked to indicate on a scale from 1 ("not at all true") to 4 (very true") how well the statement matches their experience over the past month or another appropriate recall window.

[0205] To diagnose a sleep disorder, not only must certain subscales (e.g., insomnia) exceed certain cutoff points, but respondents must also meet cutoffs of at least 3 or 4 ("very true" or "extremely true," respectively) on subscales assessing the impact of sleep-related complaints on daily functioning (Spoormaker et al., Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0206] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0207] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other measures include the Insomnia Severity Index, the Espie Sleep Disorders Questionnaire, and the PROMIS® (Patient Reported Outcomes Measurement Information System) Sleep Disorders Scale.

[0208] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and abnormalities. The PSQI is a self-rating questionnaire containing 19 questions. Respondents are asked to indicate how often they have experienced specific sleep difficulties over the past month or another appropriate recall window.

[0209] The 19 self-rated items assess a wide variety of factors related to sleep quality, including sleep duration and latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are grouped into seven component scores: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) habitual sleep efficiency, (5) sleep disturbances, (6) use of sleep medications, and (7) daytime dysfunction.

[0210] Each component is given a score of 0 to 3. Higher scores indicate more acute sleep disturbances. A detailed description of the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0211] The seven component scores are then summed to obtain a global score ranging from 0 to 21, with 0 indicating no difficulty and 21 indicating severe difficulty in all areas. A global score cutoff of 5 distinguishes poor from good sleepers. A global score >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in four or more areas.

[0212] When treatment outcome is assessed using the PSQI, treatment success is indicated by (i) a reduction in score, preferably (ii) a reduction to 5 or less.

[0213] The Insomnia Severity Index (ISI) is a short questionnaire assessing subjective sleep quality, symptom severity, subjective sleep satisfaction, the degree to which insomnia interferes with daily functioning, the degree to which the respondent perceives their insomnia as significantly worse than others, and the overall level of distress caused by sleep difficulties. Individual responses can be scored from 0 (none) to 4 (very much), with higher total scores corresponding to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 indicates "subthreshold insomnia," 15–21 indicates "moderate clinical insomnia," and 22–28 indicates "severe clinical insomnia" (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012). The recall window is 2 weeks. Other appropriate recall windows may also be used.

[0214] Successful treatment is indicated by (i) a reduction in score, for example, a reduction of more than 7 points, particularly a reduction of more than 8 points, and preferably (ii) a reduction below the cut-off for clinically significant insomnia.

[0215] The Espie Sleep Disturbance Questionnaire (SDQ) assesses the subjective experience of insomnia. The SDQ assesses restlessness / agitation, mental hyperactivity, consequences of insomnia, and lack of sleep readiness, specifically regarding beliefs about the causes of sleep difficulties. Respondents use a 5-point scale to indicate how frequently specific statements about insomnia describe their experience, with 1 meaning "never true" and 5 meaning "very often true." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., loc.cit.;).

[0216] Successful treatment is indicated by a decrease in score.

[0217] The PROMIS® (Patient-Reported Outcomes Information System) Sleep Disorders Instrument is a universal scale for assessing sleep disorders. Available as an extended version and four different short versions (e.g., 4-item, 6-item, and 8-item), the instrument assesses self-reported perceptions of sleep quality, sleep depth, and difficulty falling asleep and staying asleep over a 7-day period.

[0218] Each item in this scale is rated on a 5-point scale. A total raw score is obtained by summing the item raw scores. A conversion table is then used to convert the total raw score into a standardized T-score.

[0219] Successful treatment is indicated by a decrease in T-score.

[0220] Hypersomnolence or hypersomnolence can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0221] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. This questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stalled in traffic. Respondents rate their likelihood of falling asleep using a scale of 0 to 3 (0 meaning "never sleepy" and 3 meaning "likely sleepy"). Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (A. Shahid et al., loc.cit.).

[0222] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0223] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific moment. The scale consists of only one item and asks respondents to select one of seven statements that best describes their current level of sleepiness. Sleepiness levels are assessed using a scale ranging from 1 (= feeling active and lively; alert; wide awake) to 7 (= drowsy; falling asleep immediately; unable to stay awake) (A. Shahid et al., loc.cit.;).

[0224] Successful treatment is indicated by a decrease in score.

[0225] Parasomnias can be assessed by the Paris Arousal Disorders Severity Scale (PADSS).

[0226] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists abnormal sleep behaviors, assesses their frequency, and includes an assessment of their consequences (Arnulf et al., A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0227] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0228] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., loc.cit.;). An appropriate recall period can also be selected.

[0229] Successful treatment is indicated by a decrease in score.

[0230] A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group's rating scale. This 10-item questionnaire uses a Likert-type rating system to ask respondents to indicate how severely affected they have been by the disorder during the past week. Questions can be categorized into one of two categories: the disorder's symptoms (nature, intensity, and frequency) and their impact (sleep problems, interference with daily functioning, and resulting mood changes). For each of the 10 questions, respondents are asked 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. Total scores can range from 0 to 40. As a brief scale with good psychometric quality, this instrument may be suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes (A. Shahid et al., loc.cit.).

[0231] Treatment response can be assessed by a reduction in score.

[0232] Resting-state networks and sleep disorders Brain processes can be examined by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0233] 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 areas containing correlated and anticorrelated fluctuations.

[0234] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit synchronized activity in the absence of any explicit cognitive task (i.e., the resting state). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0235] Various resting-state networks have been identified and named primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0236] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0237] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks are known to be impaired in various pathological conditions, 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.

[0238] Alterations in the resting-state network can be observed in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0239] The primary network involved in sleep is the default mode network (DMN). Generally, the DMN is deactivated during tasks and activated during rest. It is involved in multiple cognitive processes, including higher-order cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given the importance of the DMN to sleep physiology, changes in DMN activity are particularly significant in the context of sleep disorders.

[0240] Dysfunction of the resting-state network may also be observed in psychiatric or neurological disorders, as further described herein.

[0241] Resting-state networks involved in sleep disorders are also affected by psychiatric or neurological pathologies that are the consequence of certain medical conditions.

[0242] In patients with insomnia, connectivity dysfunction is observed within the default mode network (DMN) and within the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Studies suggest that these networks contain important regions that integrate emotional and physical states, and that connectivity dysfunction within and / or between these networks and other brain regions may contribute to patients' vigilance, subjective distress, and poor sleep continuity.

[0243] The default mode network is affected in patients with hypersomnia: for example, in idiopathic hypersomnia, different DMN hubs (precuneus and medial prefrontal cortex) show significant alterations, and functional connectivity within the DMN correlates with the severity of self-reported sleepiness.

[0244] A study investigating differences between night-shift and day-shift nurses found that circadian rhythm dysregulation contributes to altered resting-state function in the cerebellum, which is involved in sleep regulation and cognitive functions such as responsiveness and attention. 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 brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various disorders associated with circadian rhythm disorders.

[0245] Although it is technically difficult to perform functional brain imaging during a parasomnia event, differences in the precuneus have been observed in arousal disorders representing non-REM parasomnias.

[0246] The precuneus is involved in analyzing and integrating visual, auditory, and somatosensory information, as well as monitoring movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnia, the default mode network is affected.

[0247] Resting-state fMRI studies in patients with sleep-related breathing disorders, such as central sleep apnea, show significant global and local connectivity deficits, particularly in the default mode network (DMN) and regions involved in the arousal and sensorimotor systems.

[0248] 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. Cerebellar and thalamic activity can also be observed, with increased activation of the red nucleus and brainstem.

[0249] In many cases, abnormal functional connectivity of resting-state networks involved in sleep disorders is also involved in the above pathologies, and therefore, according to the present invention, influencing these networks by the therapy of the present invention will lead to an improvement in the sleep disorder and, if the treated patient suffers from a psychiatric or nervous system disorder, also to an improvement in that disorder.

[0250] Treatment of sleep disorders and mental and nervous system disorders According to the present invention, idiopathic sleep disorders and sleep disorders in patients suffering from psychiatric or nervous system disorders can be treated. In patients suffering from sleep disorders associated with psychiatric or nervous system disorders, treatment of sleep disorders according to the present invention leads to improvement of the pathology associated with the sleep disorder.

[0251] Resting-state networks, which are often involved in sleep disorders, are also involved in the above pathologies.

[0252] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption leads to a reset of pathologically abnormal brain connections as the networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0253] The long-lasting effects may be explained by the neuroplasticity-promoting properties of 5-MeO-DMT. In particular, 5-MeO-DMT enhances the structural and functional plasticity of synapses (i.e., the sites where neurons connect and communicate with each other). 5-MeO-DMT regulates the morphogenesis and maturation of dendritic spines, initiating the formation of new synaptic connections. These new connections can be strengthened, weakened, or even lost, depending on the activity.

[0254] The resulting new synapses subsequently influence patterns of neuronal activity, and we conclude that such reciprocal alterations in structure and function contribute to the proper establishment of networks and sustained effects following 5-MeO-DMT administration.

[0255] From a biochemical point of view, 5-MeO-DMT interacts specifically with the 5-HT receptor.

[0256] 5-HT receptors, receptors for the neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), are found throughout the central and peripheral nervous systems. A wide range of physiological and pathological functions are mediated by these receptors.

[0257] Seven types of 5-HT receptors are expressed in the brain, which can be further divided into several subtypes. The different types and subtypes show unique spatial distributions.

[0258] 5-MeO-DMT interacts with several 5-HT receptors, which are involved in mediating 5-MeO-DMT effects on resting-state networks and neuronal plasticity.

[0259] In addition to the 5-HT1A and 5-HT2A receptors, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0260] 5-HT7 receptors are involved in neurogenesis, synaptogenesis, and dendritic spine formation, and are associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

[0261] 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.

[0262] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system, which synchronizes circadian rhythms in various brain regions. Disruption of this synchronization leads to pathological conditions, particularly those involving sleep disorders. In patients with sleep disorders, resting-state functional connectivity analysis reveals altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0263] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the function of this receptor in regulating the sleep / wake cycle, and we therefore believe that 5-MeO-DMT, which acts on this receptor, may be able to treat patients suffering from sleep disorders.

[0264] 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, which results in a "resetting" of functional network connectivity and neuroplastic effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0265] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 and 5-HT1A receptors, as two mediators of the effects produced by 5-MeO-DMT, including the "resetting" of functional network connectivity and neuroplasticity effects, may also enable beneficial effects to be achieved in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results shown in the studies referred to herein.

[0266] Treatment according to the present invention leads to an improvement in sleep disorders and, if the patient being treated suffers from a psychiatric or nervous system disorder, also to an improvement in that disorder.

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

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

[0269] The MADRS item "Decreased Sleep" describes the experience of sleep that is reduced in duration or depth compared to the subject's own normal pattern when well. A score of 0 is given if the subject's sleep is normal. A score of 2 reflects slight difficulty falling asleep or slightly reduced, light, or intermittent sleep. A score of 4 means sleep is reduced or interrupted by at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0270] In the study group receiving the individualized medication regimen, the overall score for the MADRS item "Decreased Sleep" for all eight patients was 25 at baseline. By post-treatment day 1, the earliest time point for assessing the effect of treatment on sleep, it had decreased to 12, representing a 13-point or 52% improvement. By post-treatment day 7, it had decreased to 9, representing a 16-point or 64% improvement.

[0271] In the 12 mg group, the MADRS "Decreased Sleep" composite score for all four patients was 12 at baseline. It decreased to 10 on post-treatment day 1, corresponding to a 2-point or 17% improvement. It decreased to 6 on post-treatment day 7, corresponding to a 6-point or 50% improvement.

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

[0273] Cognitive dysfunction Cognition includes the skills required for thinking, remembering, paying attention and problem solving.The loss or decline of these skills leads to cognitive dysfunction, and this term is used herein to refer to the defect or dysfunction of any domain of cognition.Cognitive dysfunction can be one of the symptoms of the patient's underlying disease.

[0274] DSM-5 defines six major domains of cognitive function: complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0275] Cognitive dysfunction can affect one or more of these domains; indeed, cognitive abilities are highly interrelated and it is not uncommon for multiple domains to be affected.

[0276] For example, the domain of complex attention includes the subdomains of sustained attention (commonly referred to as "concentration" or "focus"), divided attention, selective attention, and processing speed.

[0277] Thus, complex attention clearly includes aspects that are important for various cognitive tasks, such as executive function and learning and memory. Cognitive control or executive function is essentially related to attention, and perception and decision-making are greatly influenced by attentional abilities.

[0278] Therefore, attention is not only tested in isolation, but also, for example, by cognitive control tasks / executive functions. Abnormalities in attention are likely to be present in other types of cognitive abilities as well. To understand language, perceive visuo-spatial relationships, remember information, or solve problems, one must first pay attention to a stimulus.

[0279] Cognitive dysfunction (a term used herein to refer to an acquired condition and thus represents a decline from a previously achieved level of functioning) can be associated with a variety of processes.

[0280] In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained with aging and may even improve over time. However, even in the absence of any pathology, aging leads to declines in abilities such as abstract thinking, reasoning, and decision-making. These deteriorations are linked to underlying age-related problems in processing speed, attention, memory, and executive function, which are indicative of cognitive aging.

[0281] Independent of normal aging, cognitive dysfunction may be associated with a psychiatric or nervous system disorder or some other medical condition.

[0282] The psychiatric or neurological disorders described herein result in or are associated with cognitive dysfunction.

[0283] Cognitive dysfunction also occurs in disorders that exhibit symptoms characteristic of neurocognitive disorders, which cause clinically significant distress or impairment in social, occupational, or other important areas of functioning, but do not meet all criteria for an etiologically related disorder.

[0284] Cognitive dysfunction can take the form of neurocognitive disorders.

[0285] Mild neurocognitive impairment, also known as mild cognitive impairment, is characterized by a slight cognitive decline from a previous level of performance in one or more cognitive domains. Affected individuals remain independent and are able to perform everyday tasks. However, they typically function at a suboptimal level. Compensatory strategies are employed to maintain independence, resulting in increased effort in performing everyday tasks.

[0286] Severe neurocognitive disorders involve significant cognitive decline from previous levels of performance in one or more cognitive domains, which impairs independence in daily living.

[0287] Measuring cognitive dysfunction Cognitive dysfunction can be assessed by questionnaire or neuropsychological assessment.

[0288] The questionnaire assesses the patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a particular psychiatric or neurological disorder may include items related to cognitive function.

[0289] Neuropsychological evaluation is a process that comprehensively evaluates a subject's cognitive, psychological / emotional, and behavioral functioning. The core of a neuropsychological evaluation is the administration of neuropsychological tests to formally assess cognitive function.

[0290] Performance on these tests is compared to norms appropriate for the patient's age, educational achievement, and cultural background. The tests often use a set of performance-based questions, also known as a neuropsychological test battery.

[0291] Abilities tested include language processing, visuospatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive function, processing speed, and sensory-perceptual function.

[0292] Common tests to assess cognitive dysfunction include the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog™, the Screening for Psychiatric Cognitive Impairment (SCIP), and the MATRICS Consensus Cognitive Battery (MCCB).

[0293] The Montreal Cognitive Assessment (MoCA) is a widely used screening test for detecting cognitive impairment. It assesses various cognitive domains: short-term memory; visuospatial ability; executive function; attention, concentration, and working memory; language; and orientation to time and space. The total possible score is 30. A score of 26 or higher is considered normal, a score of 18–25 is considered mild cognitive impairment, a score of 10–17 is considered moderate cognitive impairment, and a score below 10 is considered severe cognitive impairment.

[0294] The Mini-Mental State Examination (MMSE) is an 11-question measure that tests five areas of cognitive function: orientation, memory, attention and calculation, recall, and language. The maximum score is 30. Raw scores may need to be adjusted for academic achievement and age.

[0295] Herein, four cutoff levels are used to classify the severity of cognitive impairment: 24-30 means no cognitive impairment, 19-23 means mild cognitive impairment, 10-18 means moderate cognitive impairment, and 9 or less means severe cognitive impairment.

[0296] When used repeatedly, the MMSE is suitable for measuring changes in cognitive status.

[0297] The Mini-Cog™ is a short cognitive impairment screening questionnaire. It combines a three-word repetition test with a clock-drawing test. The clock-drawing test assesses many cognitive areas that may be affected, including executive function, visuospatial ability, motor programming, and attention. One point is awarded for each of three words correctly recited after performing the clock-drawing test. A correctly drawn clock is worth two points. A score below four indicates cognitive impairment.

[0298] The Screen for Psychiatric Cognitive Impairment (SCIP) is a well-validated screening instrument for assessing cognitive performance in psychiatric patients.

[0299] The SCIP consists of five subscales: the Immediate Verbal Learning Test (VLT-I), Working Memory Test (WMT), Verbal Fluency Test (VFT), Delayed Verbal Learning Test (VLT-D), and Processing Speed ​​Test (PST). Three different test formats are available to facilitate repetition and reduce learning effects. Subscale scores are calculated for each of the five tests, and a total score is calculated by summing the subscale scores. A total score below 70 indicates cognitive dysfunction.

[0300] Cognitive dysfunction can also be assessed using the MCCB (MATRICS Consensus Cognitive Battery) or one or more of its various subtests, including the Trail Making Test, Part A (a test of processing speed); the Brief Assessment of Cognition in Schizophrenia, Symbol Coding subtest (processing speed); the Hopkins Verbal Learning Test-Revised, Immediate Repetition, Limited to 3 Learning Trials (verbal learning); the Wechsler Memory Scale-Third Edition, Spatial Span subtest (working memory (nonverbal)); the Letter-Digit Span Test (working memory (verbal)); the Neuropsychological Assessment Battery, Maze subtest (reasoning and problem solving); the Brief Visuospatial Memory Test-Revised (visual learning); the Category Fluency Test, Animal Name Recall (processing speed); the Mayer-Salovey-Caruso Emotional Intelligence Test, Emotion Management Section (social cognition); and the Continuous Performance Test, Identical Pairs Version (attention / vigilance).

[0301] This test battery is suitable for measuring cognitive change.

[0302] Further tests include the Verbal Recognition Memory (VRM) test, the Rapid Visual Processing (RVP) test, the Spatial Working Memory (SWM) test, and the Digit Symbol Substitution Test (DSST).

[0303] Mechanisms underlying cognitive dysfunction Brain processes can be examined by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0304] 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 areas containing correlated and anticorrelated fluctuations.

[0305] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit synchronized activity in the absence of any explicit cognitive task (i.e., the resting state). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0306] Various resting-state networks have been identified and named primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0307] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0308] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks are known to be impaired in various pathological conditions, including certain forms of cognitive dysfunction, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or one or more additional resting-state networks.

[0309] Resting-state fMRI is particularly advantageous when studying populations affected by cognitive dysfunction because it allows for the examination of functional connectivity while eliminating the need for tasks that may be confounded by underlying cognitive or motor dysfunction.

[0310] Cognitive processes are reflected in the functional connectivity of specific brain regions within and / or between regions located in different networks.

[0311] In particular, certain core networks, sometimes called "higher-order cognitive networks," appear to be essential for most mental activities.

[0312] The frontoparietal control network (FPCN), also known as the frontoparietal network (FPN), central executive network (CEN), or executive network (EN), is typically associated with executive functions, including maintaining and updating important information in working memory, inhibiting impulsive responses, and using flexible problem-solving strategies to guide decisions and goal-directed behavior.

[0313] Another core network is the default mode network (DMN). The DMN contains brain regions that are most active when a person's attention is not focused on a specific task. DMN activity is associated with introspection, episodic memory, memory consolidation, social and self-related cognition, integration of cognitive and emotional processing, and free-flowing, non-task-related mind wanderings.

[0314] The third network is the salience network, also known as the cingulo-opercular network. This network is involved in identifying salient stimuli and events—those that other brain networks should pay attention to. This network plays a central role in regulating mental processes and behavior.

[0315] The fourth network is the dorsal attention network (DAN), which is associated with top-down, goal-directed attention processes.

[0316] The above networks do not function independently; in fact, there are many connections between them. Cooperation between networks is essential for task-specific function.

[0317] Throughout the lifespan, brain networks undergo functional reorganization with concomitant effects on cognition. During healthy aging, age-related changes in higher-order cognitive networks are observed.

[0318] Patients with cognitive dysfunction, compared to healthy age-matched controls, exhibit altered functional connectivity within and / or between resting-state networks, including the default mode network, executive network, salience network, and dorsal attention network.

[0319] Resting-state networks involved in cognition are often affected by psychiatric or neurological disorders, as described herein.

[0320] Resting-state networks involved in cognition are also affected by psychiatric or neurological pathologies that are the consequence of certain medical conditions, as well as unspecified neurocognitive disorders.

[0321] Furthermore, resting-state networks involved in cognition are affected by sleep disorders, such as insomnia, and indeed cognitive dysfunction and sleep dysfunction are correlated.

[0322] Patients with sleep disorders have worse cognitive function, and patients with cognitive dysfunction often also suffer from sleep disorders.

[0323] Treating cognitive dysfunction According to the present invention, cognitive dysfunction occurring in patients suffering from psychiatric or nervous system disorders or medical conditions leading to related psychiatric or nervous system pathologies can be treated.Furthermore, cognitive dysfunction occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0324] Cognitive dysfunction in neurocognitive disorder not otherwise specified may also be treated.

[0325] In patients suffering from cognitive dysfunction associated with another condition, such as those detailed above, treatment of the cognitive dysfunction according to the present invention leads to an improvement in the condition associated with the cognitive dysfunction.

[0326] Treatment according to the present invention relies on the administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0327] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting networks. This disruption leads to the resetting of pathologically abnormal connections as the network reconnects. New, healthy functional connections are established, resulting in lasting benefits.

[0328] Thus, in accordance with the present invention, affecting these networks by the therapies described herein will lead to an improvement in cognitive dysfunction, and, if the patient being treated is suffering from a psychiatric or neurological disorder, also lead to an improvement in the disorder, and, if the patient being treated is suffering from a medical condition that leads to the associated psychiatric or neurological condition, also lead to an improvement in the associated psychiatric or neurological condition, and, if the patient being treated is suffering from a sleep disorder, such as insomnia, also lead to an improvement in the sleep disorder, e.g., insomnia, and, if the patient is suffering from an unspecified neurocognitive disorder, also lead to an improvement in one or more symptoms of the disorder.

[0329] To further support the clinical application of 5-MeO-DMT in patients suffering from cognitive dysfunction, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in cognitive dysfunction that are also typically observed in patients with other disorders.

[0330] These 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 observations made in this study may be meaningful for devising treatments for other conditions associated with cognitive dysfunction, as detailed below.

[0331] 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 present context are those receiving a single 12 mg dose and those receiving an individualized daily dosing regimen (IDR) that allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) per day based on the intensity of the patient-reported psychedelic experience.

[0332] Data collected included treated patients' ratings on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on the items that make up the various rating scales and recognized that specific subscore items, such as those related to cognitive dysfunction, may also be associated with other pathologies in which cognitive dysfunction is based on similarly altered functional connectivity within and / or between the default mode network, executive control network, salience network, and dorsal attention network.

[0333] Multiple patients within the recruited cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0334] More specifically, one aspect that may be treated by administration of 5-MeO-DMT is cognitive dysfunction, particularly difficulty concentrating. 5-MeO-DMT may be administered to a patient to reduce or eliminate the patient's cognitive dysfunction, particularly difficulty concentrating.

[0335] A MADRS item of particular significance for concentration and memory impairment is "Difficulty concentrating." This item reflects difficulty organizing thoughts leading to incapacitating inability to concentrate and is rated on a scale ranging from 0 to 6. If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty organizing thoughts, the score is 2. If there is difficulty concentrating and sustaining thoughts, thereby diminishing the ability to read or interact, a score of 4 is given. If the patient cannot read or interact without great difficulty, the score is 6.

[0336] In the study group receiving the individualized medication regimen, the MADRS "Difficulty concentrating" composite score for all eight patients was 30 at baseline.

[0337] After 2 hours, it had decreased to 11, which corresponds to a 19-point or 63% improvement. After 1 day of treatment, it had decreased to 1, which corresponds to a 29-point or 97% improvement. After 7 days of treatment, it had decreased to 9, which corresponds to a 21-point or 70% improvement.

[0338] In the 12 mg group, the MADRS "Difficulty concentrating" composite score for all four patients was 16 at baseline.

[0339] After 2 hours, it had decreased to 7, which corresponds to a 9-point or 56% improvement. After 1 day of treatment, it had decreased to 2, which corresponds to a 14-point or 88% improvement. After 7 days of treatment, it had decreased to 3, which corresponds to a 13-point or 81% improvement.

[0340] Thus, in accordance with the present invention, treatment of a patient suffering from cognitive dysfunction with 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, reduces or eliminates the cognitive dysfunction.

[0341] More specifically, according to the present invention, treatment of a patient suffering from cognitive dysfunction, which is a deficit or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, for example, when the cognitive dysfunction affects the cognitive domain of complex attention, e.g., one or more subdomains of the cognitive domain of complex attention selected from sustained attention, divided attention, selective attention, and processing speed, particularly sustained attention.

[0342] In patients suffering from cognitive dysfunction associated with a psychiatric or nervous system disorder, treatment of the cognitive dysfunction according to the present invention leads to an improvement in the pathology associated with the cognitive dysfunction.

[0343] Although cognitive dysfunction may be considered a condition worthy of treatment regardless of other conditions, disorders, or symptoms that the individual may suffer from, several psychiatric and neurological disorders are associated with cognitive dysfunction. Notably, the relationship between cognitive dysfunction and psychiatric disorders is bidirectional. Not only can psychiatric disorders adversely affect cognitive function, but cognitive dysfunction may also be a contributing factor to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0344] Resting-state networks that are often involved in cognitive dysfunction are also involved in the above pathologies.

[0345] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption leads to a reset of pathologically abnormal brain connections as the networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0346] anxiety Anxiety may be defined as "the anxious anticipation of future danger or misfortune accompanied by physical symptoms of discomfort or tension."

[0347] Anxiety is characterized by intense, excessive, and persistent worry and fear about situations that are only subjectively perceived as threatening, and is often accompanied by muscle tension, restlessness, fatigue, difficulty regulating breath, abdominal tightness, nausea, and difficulty concentrating.

[0348] In anxiety disorders or other anxiety-related psychiatric or neurological disorders, feelings of anxiety are difficult to control and interfere with daily activities.

[0349] Anxiety is a central feature of anxiety disorders, including separation anxiety disorder, specific phobia, social anxiety disorder (social phobia), panic disorder, generalized anxiety disorder (GAD), agoraphobia, and substance / medication-induced anxiety disorder.

[0350] Anxiety is also associated with several other mental and nervous system disorders. Anxiety is also associated with sleep disorders.

[0351] 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 psychiatric and nervous system disorders.

[0352] The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. It is administered by a clinician. It has 14 items that can be divided into a psychological group (items 1-6 and 14) that specifically measure psychological agitation and distress, and a somatic group (items 7-13) that specifically measure somatic complaints related to anxiety.

[0353] The HAM-A items are shown in the table below. [Table 1]

[0354] Each item is rated by the interviewer on a scale of 0 to 4, where 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.

[0355] A total score is obtained by adding up the 14 items. The range of the total score is 0 to 56. Higher scores indicate greater anxiety.

[0356] A score ≤7 was 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.

[0357] The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire designed to assess anxiety with a focus on physical symptoms. These items are rated on a 4-point Likert scale ranging from 0 (not at all) to 3 (severe: barely tolerable). Total scores range from 0 to 63.

[0358] Subthreshold anxiety, as the term is used herein, 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.

[0359] The underlying mechanisms of anxiety Brain processes can be examined by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0360] 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 areas containing correlated and anticorrelated fluctuations.

[0361] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit synchronized activity in the absence of any explicit cognitive task (i.e., the resting state). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0362] Various resting-state networks have been identified and named primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0363] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0364] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks are known to be impaired in various pathological conditions, 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 one or more additional resting-state networks.

[0365] Based on such studies, several brain regions have been linked to anxiety and anxiety disorders. Thus, the pathophysiology of anxiety and anxiety disorders involves abnormal connectivity between the amygdala and frontal regions and between the frontal and striatal regions. Anxiety and anxiety disorders are associated with specific alterations in resting-state networks.

[0366] 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 various anxiety disorders.

[0367] Treating anxiety According to the present invention, anxiety occurring in patients suffering from an anxiety disorder or another anxiety-related psychiatric or nervous system disorder can be treated. Additionally, anxiety occurring in patients suffering from a sleep disorder, such as insomnia, can be treated.

[0368] In patients suffering from anxiety associated with another psychiatric or nervous system disorder, or a sleep disorder, such as insomnia, treatment of anxiety according to the present invention will lead to an improvement in the anxiety-related condition.

[0369] Treatment according to the present invention relies on the administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0370] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting networks. This disruption leads to the resetting of pathologically abnormal connections as the network reconnects. New, healthy functional connections are established, resulting in lasting benefits.

[0371] Thus, in accordance with the present invention, affecting these networks by the therapies described herein leads to an improvement in anxiety, and, if the treated patient suffers from another anxiety-related psychiatric or nervous system disorder, also leads to an improvement in that disorder, and, if the treated patient suffers from a sleep disorder, e.g., insomnia, also leads to an improvement in the sleep disorder, e.g., insomnia.

[0372] To further support the clinical application of 5-MeO-DMT in patients suffering from anxiety, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in anxiety that are also typically observed in patients with other disorders.

[0373] These 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 unique condition, the inventors have determined that certain clinical observations made in this study, as detailed below, have implications for devising treatments for anxiety disorders and other anxiety-related conditions.

[0374] 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 present context are those receiving a single 12 mg dose and those receiving an individualized daily dosing regimen (IDR) that allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) per day based on the intensity of the patient-reported psychedelic experience.

[0375] Data collected included treated patients' ratings on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on the items that make up the various rating scales, acknowledging that specific subscore items, such as those related to anxiety, may also be relevant to other conditions where anxiety is based on similarly altered functional connectivity within and / or between resting-state networks.

[0376] Multiple patients within the recruited cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0377] More specifically, one aspect that may be treated by administration of 5-MeO-DMT is anxiety. 5-MeO-DMT may be administered to a patient to reduce or eliminate their anxiety.

[0378] A particularly relevant BPRS item in this regard is "Anxiety." This item concerns complaints of apprehension, tension, fear, panic, or worry. Possible scores are: 1: No anxiety. 2: Very mild. Some discomfort from worry or worries that are low in frequency for most healthy people occur more frequently than normal. 3: Mild. Frequent anxiety, but quick to redirect attention elsewhere. 4: Moderate. Almost constant worry, unable to attend to other things easily, but not interfering with function, or occasional anxiety with accompanying autonomic symptoms, but not interfering with function. 5: Moderately severe. Frequent but not daily periods of anxiety with accompanying autonomic symptoms, or some areas of function are disrupted by anxiety or worry. 6: Severe. Anxiety with accompanying autonomic symptoms occurs daily but not all day, or many areas of function are disrupted by anxiety or constant worry. 7: Very severe. Anxiety with accompanying autonomic symptoms persists throughout the day or most functional areas are disrupted by anxiety or constant worry.

[0379] In the study group receiving the individualized medication regimen, the BPRS "anxiety" total score for all eight patients was 37 at baseline.

[0380] After 3 hours, it had decreased to 19, which corresponds to an 18-point or 49% improvement. After 1 day of treatment, it had decreased to 16, which corresponds to a 21-point or 57% improvement. After 7 days of treatment, it had decreased to 17, which corresponds to a 20-point or 54% improvement.

[0381] In the 12 mg group, the BPRS "anxiety" total score for all four patients was 25 at baseline.

[0382] After 3 hours, it had decreased to 11, which corresponds to a 14-point or 56% improvement. After 1 day of treatment, it had decreased to 6, which corresponds to a 19-point or 76% improvement. After 7 days of treatment, it had decreased to 6, which corresponds to a 19-point or 76% improvement.

[0383] The inventors conclude that 5-MeO-DMT may be used to treat anxiety in patients, such as those suffering from anxiety disorders and those suffering from psychiatric or nervous system disorders with associated anxiety.

[0384] Thus, in accordance with the present invention, treatment of a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0385] The MADRS item "Inner Tension" describes unexplained discomfort, edginess, inner turmoil, and mental tension that can lead to either panic, fear, or distress. It is rated according to intensity, frequency, duration, and the degree of relief sought.

[0386] If the patient is calm and there is only transient inner tension, a score of 0 is given. If there is occasional nervousness and unexplained discomfort, a score of 2 is given. If there is a persistent sense of inner tension or intermittent panic that the patient cannot conquer without some difficulty, the score is 4. In the case of persistent fear or distress and overwhelming panic, the score is 6.

[0387] In the study involving patients with TRD, in the study group receiving the individualized medication regimen, the overall score for the MADRS item "internal tension" for all eight patients was 26 at baseline. After two hours, it had decreased to 11, corresponding to a 15-point or 58% improvement. After one day of treatment, it had decreased to 6, corresponding to a 20-point or 77% improvement. After seven days of treatment, it had decreased to 12, corresponding to a 14-point or 54% improvement.

[0388] In the 12 mg group, the MADRS "internal tension" total score for all four patients was 13 at baseline. After two hours, it had decreased to 2, corresponding to an 11-point or 85% improvement. After one day of treatment, it had decreased to 3, corresponding to a 10-point or 77% improvement. After seven days of treatment, it had decreased to 5, corresponding to an 8-point or 62% improvement.

[0389] These results further support the inventors' conclusion that treatment according to the present invention reduces or eliminates symptoms of anxiety.

[0390] 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 at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, compared to the respective scores before treatment.

[0391] The clinical response in patients suffering from anxiety symptoms, 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 of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in patients suffering from anxiety symptoms, as 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0392] 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at 1 day, e.g., about 24 hours; at 7 days; at 14 days; and / or at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0393] Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0394] Thus, in accordance with the present invention, treatment of a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0395] Psychomotor retardation The main features observed in patients suffering from psychomotor retardation are decreased energy and activity, as well as decreased motivation.

[0396] Psychomotor retardation involves a slowing of the individual's thinking and a decrease in physical movements. Psychomotor impairment can cause a noticeable slowing of physical and emotional responses.

[0397] Psychomotor retardation may be associated with a psychiatric or nervous system disorder or some other medical condition.

[0398] Mental or nervous system disorders leading to or associated with psychomotor retardation include disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorders (BD) such as bipolar I disorder and bipolar II disorder; postpartum depression (PPD); seasonal affective disorder and persistent depressive disorder; mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; and chronic fatigue syndrome.

[0399] Psychomotor retardation can also occur in patients suffering from sleep disorders, such as insomnia.

[0400] Measurement of psychomotor retardation Psychomotor retardation can be assessed by measuring various aspects, which may include, for example, various types of drawing tasks and tests, such as the Trail Making Test (TMT), the Digit Symbol Substitution Test (DSST), or the Gibson Spiral Maze Test (GSM), and others known in the art.

[0401] For example, in the Trail Making Test (TMT), subjects must connect 25 circles containing either numbers (TMT A) or number-letter combinations (TMT B) in ascending order. In TMT-B, the task requirements are similar, but subjects must alternate between numbers and letters (1, A, 2, B, 3, C, etc.). Thus, this test assesses processing speed (TMT A) or cognitive flexibility (TMT B). The score for each part represents the time required to complete the task.

[0402] Another test of grapheme ability is the Gibson Spiral Maze (GSM), which assesses only psychomotor speed and is not affected by cognitive ability. Participants performing the GSM must successfully navigate a spiral maze from start to finish without touching the borders.

[0403] The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of number-symbol pairs followed by a list of numbers. Subjects must write the corresponding symbol under each number as quickly as possible. The score is the number of symbols correctly reported in 90 seconds. A further example of a motor test is the finger tapping test.

[0404] Thus, certain tests combine measures of both motor and cognitive aspects of psychomotor retardation, while still other tests assess only motor aspects.

[0405] Speech analysis can be a further indicator of psychomotor retardation.

[0406] The main scales available for assessment and measurement include the severity of psychomotor retardation, the Salpêtrière Retardation Rating Scale (SRRS) and the Motor Agitation and Retardation Scale (MARS).

[0407] The Salpêtrière Retardation Rating Scale (SRRS), developed by Widlocher, assesses cognitive and motor aspects with 15 items. The first three measure movement, specifically the quality of gait and slowness of limb, trunk, head, and neck movements. The next three items focus on speech, including fluency, tone of voice, and length of response. Two items are designed to objectively measure cognitive function. These questions are based on interview conversations and measure the patient's ability to approach and develop a topic. Further items are subjective, assessing rumination, fatigue, level of interest, time perception, memory, and concentration. The final item on the scale relates to an overall assessment of the patient's psychomotor retardation. These items are scaled based on the severity of the presenting symptoms, from 0 (absent) to 4 (severe), with a total score ranging from 0 to 60.

[0408] The Motor Agitation Retardation Scale (MARS) assesses only motor aspects. It was designed to assess psychomotor abnormalities in depressive disorders. Psychomotor abnormalities are divided into five major physical categories, including eyes, face, voice, limbs, and trunk, resulting in a total of 19 items. Items in the eye category include gaze direction, blink rate, gaze, and eye movements. Items associated with the face category include facial expression and facial expressivity. Items in the voice category include volume, inarticulateness, tone, and onset time. Items in the limb category include hand, foot, and leg movements, gait, slowness of movement, and hand tension. Items in the trunk category include posture, immobility, and axial movement. The severity of each item ranges from 1 to 4, with 4 being the most severe. Nine of the 19 items relate to motor agitation, and 10 assess motor retardation. Delay items include abnormal gait, trunk / proximal limb immobility, poor posture, slowness of movement (i.e., Limb and Trunk category); lack of facial expression, downcast eyes (i.e., Eye and Face category); and decreased vocal volume, slurred speech, delayed speech onset, monotonous speech (i.e., Voice category). The MARS scale provides a rapid clinical assessment of motor signs.

[0409] Resting-state networks and psychomotor retardation Brain processes can be examined by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0410] 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 areas containing correlated and anticorrelated fluctuations.

[0411] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit synchronized activity in the absence of any explicit cognitive task (i.e., the resting state). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0412] Various resting-state networks have been identified and named primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0413] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0414] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks are known to be impaired in various pathological conditions, including certain forms of psychomotor retardation, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or one or more additional resting-state networks.

[0415] For example, abnormalities in functional connectivity from the somatosensory motor network (SMN) to the visual (VN), dorsal attention (DAN), and default mode networks have been reported, which correlated with both psychomotor retardation and agitation in depressive disorders.

[0416] Resting-state networks involved in psychomotor retardation are often affected by psychiatric or neurological disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorders (BD), including bipolar I and II disorders; postpartum depression (PPD); seasonal affective disorder and persistent depressive disorder; mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, including Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular and Parkinson's disease dementia; Parkinson's disease; and chronic fatigue syndrome.

[0417] Resting-state networks involved in psychomotor retardation are also affected by sleep disorders, such as insomnia, and indeed psychomotor retardation and sleep dysfunction are correlated.

[0418] Treatment of psychomotor retardation and mental or nervous system disorders According to the present invention, psychomotor retardation in patients suffering from psychiatric or nervous system disorders can be treated. Additionally, psychomotor retardation occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0419] In patients suffering from psychomotor retardation associated with another condition, such as those detailed above, treatment of psychomotor retardation according to the present invention leads to an improvement in the condition associated with the psychomotor retardation.

[0420] Treatment according to the present invention relies on the administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0421] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting networks. This disruption leads to the resetting of pathologically abnormal connections as the network reconnects. New, healthy functional connections are established, resulting in lasting benefits.

[0422] Thus, in accordance with the present invention, affecting these resting-state networks by the therapies described herein leads to an improvement in psychomotor retardation, and also to an improvement in a psychiatric or nervous system disorder, if the treated patient suffers from such a disorder, and also to an improvement in a sleep disorder, e.g., insomnia, if the treated patient suffers from such a disorder.

[0423] To further support the clinical application of 5-MeO-DMT in patients suffering from psychomotor retardation, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in psychomotor retardation that are also typically observed in patients with other disorders.

[0424] These 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 observations made in this study may be meaningful for devising treatments for other conditions associated with psychomotor retardation, as detailed below.

[0425] 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 present context are those receiving a single 12 mg dose and those receiving an individualized daily dosing regimen (IDR) that allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) per day based on the intensity of the patient-reported psychedelic experience.

[0426] Data collected included treated patient ratings on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on the items that make up the various rating scales, recognizing that specific subscore items, such as those related to psychomotor retardation, may also be associated with other conditions in which psychomotor retardation is based on similarly altered functional connectivity within and / or between the somatomotor / sensorimotor network, visual network, dorsal attention network, and default mode network.

[0427] Multiple patients within the recruited cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0428] More specifically, one condition that can be treated by administration of 5-MeO-DMT is psychomotor retardation. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's psychomotor retardation.

[0429] A MADRS scale item of particular significance for psychomotor retardation is "fatigue," which describes difficulty initiating movements or slowness in initiating and performing daily activities.

[0430] A score of 0 means little difficulty initiating movement and no fatigue. A score of 2 is given if the patient has difficulty initiating activity. A score of 4 means there is difficulty in starting simple routine activities that are performed with effort. A score of 6 is given in cases of complete fatigue where the patient is unable to do anything without help.

[0431] In the study group receiving the individualized medication regimen, the MADRS "Fatigue" composite score for all eight patients was 27 at baseline.

[0432] After 2 hours, it had decreased to 10, which corresponds to a 17-point or 63% improvement. After 1 day of treatment, it had decreased to 5, which corresponds to a 22-point or 81% improvement. After 7 days of treatment, it had decreased to 3, which corresponds to a 24-point or 89% improvement.

[0433] In the 12 mg group, the MADRS "Fatigue" composite score for all four patients was 16 at baseline. After two hours, it had decreased to 10, corresponding to a 6-point or 38% improvement. After one day of treatment, it had decreased to 0, corresponding to a 16-point or 100% improvement. After seven days of treatment, it had decreased to 3, corresponding to a 13-point or 81% improvement.

[0434] Thus, the score for "fatigue," a scale item of particular relevance for psychomotor retardation, is significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat psychomotor retardation in patients, particularly in patients who also suffer from a psychiatric or nervous system disorder, or a sleep disorder, such as insomnia.

[0435] Thus, in accordance with the present invention, treatment of a patient suffering from psychomotor retardation with 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, reduces or eliminates the psychomotor retardation.

[0436] Social / emotional withdrawal or isolation Symptoms such as anhedonia, emotional withdrawal, and flat affect are lumped together herein as social / emotional withdrawal or detachment. Decreased social engagement is a further aspect associated with social / emotional withdrawal or detachment.

[0437] Anhedonia is the inability to experience pleasure. A patient does not suffer from anhedonia unless there is a subjectively diminished ability to experience pleasure in usual activities. Anhedonia can be mild, where pleasure from activities that normally give pleasure is slightly diminished; moderate, where pleasure from activities that normally give pleasure is markedly diminished or some pleasure from isolated activities is preserved; or severe, where there is a complete lack of ability to experience pleasure.

[0438] Anhedonia includes components of completion (or liking) and anticipation (or wanting). Completion pleasure refers to the "in-the-moment" pleasure experienced by subjects directly involved in a pleasurable activity, while anticipatory pleasure refers to the experience of pleasure related to a future activity.

[0439] Affective flattening is characterized by a subjective sensation of a decreased intensity or range of moods or emotions. A subject does not exhibit affective flattening if they do not experience a decrease in the intensity or range of moods or emotions. Mild is a slight narrowing of the range of emotions or a transient decrease in the range or intensity of emotions; moderate is a significant narrowing of the range or intensity of emotions, with some emotions remaining, e.g., an inability to cry; and severe is a significant and pervasive narrowing of the range of emotions or an inability to experience normal emotions.

[0440] Emotional withdrawal or detachment is an inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes an item on emotional withdrawal, characterized as a deficit in a subject's ability to emotionally engage in an interview situation. According to this BPRS item description, emotional withdrawal is not present if there is a lack of emotional engagement, as indicated by an occasional lack of interactive commentary, occasional appearance of distraction, or awkward smiling, but most of the time naturally conversing with the interviewer. A mild form of emotional withdrawal is present if there is a lack of emotional engagement, as indicated by a lack of interactive commentary, appearance of distraction, or a notable lack of warmth, but by responsiveness to the interviewer when spoken to. A moderate form is present if emotional contact is absent most of the time during the interview because the subject does not elaborate on their answers, does not make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by mental material. Furthermore, if emotional contact is absent most of the time during the interview, it is considered moderately severe. A severe form exists when the subject actively avoids emotional participation, or when the subject is frequently unresponsive or responds with "yes / no" answers, or responds with very little affect. A very severe form exists when the subject consistently avoids emotional participation, is unresponsive, or responds with "yes / no" answers, or may leave the interview midway, or simply does not respond at all.

[0441] Reduced social engagement characterizes subjective complaints of reduced social and interpersonal involvement or interaction. Absence of complaints of reduced social and interpersonal involvement or interaction indicates no reduced social engagement. Mild is slight reduction in social engagement without social or interpersonal dysfunction; moderate is marked reduction in social engagement with functional sequelae, such as avoidance of some social engagement or conversation; and severe is marked reduction in social interaction or avoidance of almost all forms of social contact, such as refusing to answer the phone or meet with friends or family.

[0442] The social / emotional withdrawal or detachment may be associated with a psychiatric or neurological disorder or some other medical condition.

[0443] Mental or nervous system disorders leading to or associated with social / emotional withdrawal or estrangement include mental or nervous system disorders such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorders (BD) such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); and post-traumatic stress disorder (PTSD). pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0444] Social / emotional withdrawal or isolation can also occur in patients suffering from sleep disorders, such as insomnia.

[0445] Social / emotional withdrawal or detachment can also occur in patients suffering from medical conditions that lead to associated psychiatric or neurological pathologies, including traumatic brain injury (TBI).

[0446] Measuring social / emotional withdrawal or distancing Social / emotional withdrawal or detachment (often referred to herein as social / emotional withdrawal), or individual aspects thereof, such as anhedonia, emotional withdrawal, and flat affect, can be assessed by a variety of methods, such as questionnaires or scales.

[0447] Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient suffers from a specific psychiatric or neurological disorder may include items related to social / emotional withdrawal or detachment.

[0448] The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale measuring anhedonia (i.e., the inability to experience pleasure). These items cover the domains of social interactions, food and beverages, sensory experiences, and interests / recreation. A score of 2 or less constitutes a "normal" score, and an "abnormal" score is defined as 3 or greater. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Each "disagree" response is scored as 1, and each "agree" response is scored as 0. Thus, the final score ranges from 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. The SHAPS has been used to measure anhedonia in depression but is also frequently used to assess anhedonia in other patient populations.

[0449] In principle, SHAPS measures hedonic tone over the past few days using 14 hypothetical items, but because these items are hypothetical, shorter recall periods may be applied appropriately for earlier assessment time points.

[0450] Alternatively or additionally, anhedonia can be assessed using the Dimensional Anhedonia Rating Scale (DARS), which measures interest, motivation, effort, and pleasure of completion in four domains: hobbies, food / drinks, social activities, and sensory experiences. It contains 17 items assessing current anhedonia. The DARS is rated on a 5-point Likert scale ranging from 0 (not at all true) to 4 (very true), with higher scores indicating lower anhedonia. All items are summed to obtain a total score ranging from 0 to 68. For each of the four hedonic domains—hobbies (4 items, total score 0–16), food / drinks (4 items, total score 0–16), social activities (4 items, total score 0–16), and sensory experiences (5 items, total score 0–20)—patients are asked to provide two or three examples of activities they particularly enjoy.

[0451] The DSM-5 Personality Inventory (PID-5) Adult Version is a 220-item self-rating personality trait scale for adults aged 18 years and older. It assesses 25 personality trait facets, including anhedonia, anxiousness, attention-seeking, callousness, dishonesty, depressive tendency, distractibility, eccentricity, emotional lability, grandiosity, hostility, impulsivity, avoidance of intimacy, lack of commitment, manipulativeness, perceptual dysregulation, perseverance, limited emotionality, rigid perfectionism, risk-taking, separation anxiety, submissiveness, suspiciousness, unconventional beliefs and experiences, and social withdrawal, with each trait facet consisting of 4 to 14 items.

[0452] The Anhedonia trait facet includes items 1, 23, 26, 30R, 124, 155R, 157, and 189 (reverse-scored items are marked with the letter "R"), the Withdrawal trait facet includes items 10, 20, 75, 82, 136, 146, 147, 161, 182, and 186, and the Intimacy Avoidance trait facet includes items 89, 97R, 108, 120, 145, and 203. Combining these three trait facets yields a broader trait domain called estrangement.

[0453] The scale is completed by the subject prior to a clinician visit, and each item asks the subject to rate how well the item describes them overall.

[0454] Each item in this scale is rated on a 4-point scale. Item response categories are: 0 = not true at all or rarely true; 1 = not true sometimes or slightly; 2 = true sometimes or slightly; 3 = true very often or often. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, these items are reverse scored before calculating the scale score.

[0455] Scores for items within each trait facet should be summed and entered in the appropriate raw facet score box. Additionally, clinicians are asked to calculate and use a mean score for each facet and domain. The mean score reduces the overall score and each domain score to a 4-point scale, allowing clinicians to consider the subject's personality dysfunction relative to observed norms. The mean facet score is calculated by dividing the raw facet score by the number of items within the facet (e.g., if all items within the "anhedonia" facet were rated "sometimes or somewhat true," the mean facet score would be 16 / 8 = 2, indicating moderate anhedonia). The mean domain score is calculated by summing and then averaging the three facet scores that primarily contribute to a particular domain. For example, if the mean facet scores for anhedonia, intimacy avoidance, and withdrawal (a scale primarily indexing estrangement) are all 2, the sum of these scores would be 6, and the mean domain score would be 6 / 3 = 2. Higher mean scores indicate greater dysfunction in a particular personality trait facet or domain.

[0456] High scores on facets or domains may indicate significant problem areas for the subject receiving care that may require further evaluation, treatment, and follow-up.

[0457] Resting networks and social / emotional withdrawal or isolation Brain processes can be examined by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0458] 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 areas containing correlated and anticorrelated fluctuations.

[0459] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit synchronized activity in the absence of any explicit cognitive task (i.e., the resting state). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0460] Various resting-state networks have been identified, named primarily on the basis of spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0461] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0462] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks are known to be impaired in various pathological conditions, including certain forms of social / emotional withdrawal or estrangement, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or one or more additional resting-state networks.

[0463] Alterations in RSNs are also involved in anhedonia, an important aspect of social / emotional withdrawal or detachment. More specifically, anhedonia is associated with hyperconnectivity in the visual network, as well as expansion of the visual network, dorsal attention network (DAN), and default mode network (DMN). Anhedonia is also associated with decreased inter-network connectivity among the DMN, salience, DAN, somatomotor, and visual networks.

[0464] Furthermore, emotional detachment in adult psychopathy has been associated with structural abnormalities in the dorsal DMN. The dorsal DMN is of particular interest in the development of psychopathy due to its associated functions. Specifically, the dorsal DMN and the regions it connects with (the medial prefrontal cortex and posterior cingulate cortex (PCC)) are responsible for emotional, social, and moral processing. In adult psychopathy, microstructural abnormalities within the dorsal DMN are associated with the affective and interpersonal differences that define the disorder.

[0465] Thus, patients suffering from social / emotional withdrawal or estrangement exhibit altered functional connectivity within and / or between RSNs compared to healthy age-matched controls. Alterations are observed within and / or between DMN, salience, DAN, somatomotor, and visual networks.

[0466] RSNs, often involved in social / emotional withdrawal or detachment, are associated with psychiatric or neurological disorders such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, e.g., Chronic pain and fibromyalgia; mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0467] Resting-state networks involved in social / emotional withdrawal or distancing are also affected by mental or neurological pathologies that are the consequence of certain medical conditions, such as traumatic brain injury (TBI).

[0468] Resting-state networks involved in social / emotional withdrawal or detachment are also affected by sleep disorders, such as insomnia, and indeed, social / emotional withdrawal or detachment and sleep dysfunction are correlated.

[0469] Treatment of social / emotional withdrawal or isolation and mental or nervous system disorders According to the present invention, social / emotional withdrawal or isolation that occurs in patients suffering from psychiatric or nervous system disorders can be treated. Additionally, social / emotional withdrawal or isolation that occurs in patients suffering from sleep disorders, such as insomnia, can be treated.

[0470] In patients suffering from social / emotional withdrawal or isolation associated with another condition, such as those detailed above, treatment of the social / emotional withdrawal or isolation according to the present invention leads to an improvement in the condition associated with the social / emotional withdrawal or isolation.

[0471] Treatment according to the present invention relies on the administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0472] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting networks. This disruption leads to the resetting of pathologically abnormal connections as the network reconnects. New, healthy functional connections are established, resulting in lasting benefits.

[0473] Thus, in accordance with the present invention, affecting these networks by the therapies described herein leads to an improvement in social / emotional withdrawal or detachment, and also to an improvement in a psychiatric or neurological disorder if the treated patient suffers from that disorder, and also to an improvement in a sleep disorder, e.g., insomnia, if the treated patient suffers from that disorder.

[0474] To further support the clinical application of 5-MeO-DMT in patients suffering from social / emotional withdrawal or detachment, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in social / emotional withdrawal or detachment that are also typically observed in patients with other disorders.

[0475] These 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 observations made in this study, as detailed below, may be meaningful for devising treatments for other conditions associated with social / emotional withdrawal or estrangement.

[0476] 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 present context are those receiving a single 12 mg dose and those receiving an individualized daily dosing regimen (IDR) that allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) per day based on the intensity of the patient-reported psychedelic experience.

[0477] Data collected included treated patient ratings on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on the items that comprise the various rating scales, acknowledging that specific subscore items, such as those related to social / emotional withdrawal or detachment, may also be associated with other conditions in which social / emotional withdrawal or detachment is based on similarly altered functional connectivity within and / or between the default mode network, salience, dorsal attention, somatomotor, and visual networks.

[0478] Multiple patients within the recruited cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0479] More specifically, one aspect that can be treated by administering 5-MeO-DMT is social / emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and / or flat affect. A further therapeutic aspect is reduced social engagement. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's social / emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and / or flat affect. Furthermore, reduced social engagement is improved, i.e., reduced or eliminated.

[0480] The MADRS scale item "inability to feel," which is particularly relevant for social / emotional withdrawal or detachment, describes the subjective experience of decreased interest in one's surroundings or activities that usually bring pleasure. A reduced ability to respond emotionally to situations or people.

[0481] A score of 0 indicates normal interest in surroundings and others, a score of 2 indicates a diminished ability to enjoy normal interests. A score of 4 is given in cases of loss of interest in surroundings and loss of feelings toward friends and acquaintances. A score of 6 reflects an emotional numbness, an inability to feel anger, sadness, or joy, and a total inability or even distress to sympathize with close relatives and friends.

[0482] In the study group receiving the individualized medication regimen, the MADRS "Apathy" composite score for all eight patients was 36 at baseline. After two hours, it had decreased to 12, corresponding to a 24-point or 67% improvement. After one day of treatment, it had decreased to 2, corresponding to a 34-point or 94% improvement. After seven days of treatment, it had decreased to 6, corresponding to a 30-point or 83% improvement.

[0483] In the 12 mg group, the MADRS "Apathy" composite score for all four patients was 16 at baseline. After two hours, it had decreased to 9, corresponding to a 7-point or 44% improvement. After one day of treatment, it had decreased to 1, corresponding to a 15-point or 94% improvement. After seven days of treatment, it had decreased to 1, corresponding to a 15-point or 94% improvement.

[0484] BPRS scale items of particular relevance for social / emotional withdrawal or detachment are "emotional withdrawal" and "affective blunting."

[0485] The BPRS item "Emotional Withdrawal" relates to deficits in the patient's ability to be emotionally involved in the interview situation. Possible scores are: 1: No emotional withdrawal. 2: Very mild. Lack of emotional engagement, indicated by occasional absence of interactive comments, occasional appearance of distraction, awkward smiling, but mostly natural conversation with the interviewer. 3: Mild. Lack of emotional engagement, as indicated by not making interactive comments, appearing distracted, or a noticeable lack of warmth, but responsive to the interviewer when spoken to. 4: Moderate. Emotional contact is absent for much of the interview because the subject does not elaborate on answers, does not make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by mental material. 5: Moderately severe. Same as 4, but emotional contact is absent for most of the interview. 6: Severe. Actively avoids emotional involvement. Frequent non-responsiveness or yes / no responses (not simply paranoia). Responds with minimal emotional involvement. 7: Very severe. Always avoids emotional involvement. Unresponsive or yes / no responses (not simply paranoid). May leave the interview midway or simply not respond at all.

[0486] The total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, it was reduced to 8, which corresponds to a 5-point or 38% improvement. After 1 day of treatment, it was reduced to 8, which corresponds to a 5-point or 38% improvement. After 7 days of treatment, it was reduced to 8, which corresponds to a 5-point or 38% improvement.

[0487] In the 12 mg group, the BPRS "emotional withdrawal" total score was 13 at baseline. After 3 hours, it had decreased to 11, corresponding to a 2-point or 15% improvement. After 1 day of treatment, it had decreased to 8, corresponding to a 5-point or 38% improvement. After 7 days of treatment, it had decreased to 6, corresponding to a 7-point or 54% improvement.

[0488] The BPRS item "affective blunting" relates to a limited range of emotional expression in face, voice, and gesture, as well as a pronounced indifference or flatness even when discussing distressing topics. Possible scores are: 1: No emotional blunting. 2: Very mild. Emotional range is slightly suppressed or subdued, but facial expressions and tone of voice are within the normal range and appropriate. 3: Mild. Overall emotional range is muted, suppressed, or subdued, with few spontaneous and appropriate emotional responses. Slight monotony in tone of voice. 4: Moderate. Emotional range is significantly diminished, and the patient rarely displays emotion, smiles, or responds to distressing topics. The tone of voice is monotonous or spontaneous motor activity is significantly reduced. After displaying emotion or gestures, the patient usually returns to a neutral affect. 5: Moderately severe. Emotional range is very diminished, the patient only rarely shows emotion, smiles, or responds to distressing topics, gestures are few, facial expression rarely changes, and the tone of voice is often monotonous. 6: Severe. Little emotional range or expression. Speech and gestures are almost always mechanical. Facial expression is unchanging. Voice tone is almost always monotonous. 7: Extremely severe. Stiff movements with virtually no range or expression of emotion. Vocal tone is always monotonous.

[0489] The total score for the BPRS item "blunted affect" was 15 at baseline. After 3 hours, it had decreased to 11, corresponding to a 4-point or 27% improvement. After 1 day of treatment, it had decreased to 8, corresponding to a 7-point or 47% improvement. After 7 days of treatment, it had decreased to 8, corresponding to a 7-point or 47% improvement.

[0490] In the 12 mg group, the BPRS "blunted affect" total score was 11 at baseline. After 3 hours, it had decreased to 8, corresponding to a 3-point or 27% improvement. After 1 day of treatment, it had decreased to 6, corresponding to a 5-point or 45% improvement. After 7 days of treatment, it had decreased to 5, corresponding to a 6-point or 55% improvement.

[0491] Thus, scores on scale items particularly relevant to social / emotional withdrawal or detachment, namely "Apathetic Disappearance" (MADRS), "Emotional Withdrawal" (BPRS), and "Bulled Affect" (BPRS), improved significantly. The inventors conclude that 5-MeO-DMT can be used to treat social / emotional withdrawal or detachment in patients, particularly in patients who also suffer from a psychiatric or nervous system disorder, or a sleep disorder, such as insomnia.

[0492] Thus, in accordance with the present invention, treatment of a patient suffering from social / emotional withdrawal or isolation with 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, reduces or eliminates the social / emotional withdrawal or isolation.

[0493] Negative thinking Symptoms such as pessimism, feelings of worthlessness, powerlessness and hopelessness, as well as pathological, excessive or inappropriate guilt, are lumped together in this book as negative thinking.

[0494] Feelings of helplessness and hopelessness (also simply referred to as helplessness and hopelessness) are characterized by subjective impressions of pessimism or gloom about the future, lack of ability to cope, or a sense of loss of control. If the patient does not have such feelings, there are no feelings of helplessness and hopelessness. Helplessness and hopelessness are mild when there is occasional and mild feeling of not being able to cope as usual or pessimism; moderate when the patient often feels unable to cope or has occasional significant feelings of helplessness or hopelessness; and severe when the pessimism, helplessness, or hopelessness is pronounced and persistent.

[0495] Feelings of worthlessness (also simply called worthlessness) characterize subjective impressions or thoughts of self-worth or diminished self-worth. If the patient does not have such feelings, there is no feeling of worthlessness. They can be mild (i.e., slightly diminished self-worth), moderate (i.e., some feelings of worthlessness and diminished self-worth), or severe (i.e., marked, profound, or persistent feelings of worthlessness, e.g., feeling that others would be better off without them and being unable to appreciate their positive traits).

[0496] Feelings of guilt (also simply called guilt) are characterized by subjective impressions of self-blame, a sense of failure, or regret for real or imagined past wrongdoings. Guilt is absent if the patient has no such feelings. It can be mild, as in slightly decreased self-esteem or increased self-criticism; moderate, as in significant and what can be considered excessive rumination about failure, self-criticism, lack of ability to cope, or rumination about past failures and their impact on others; or severe, as in marked, profound, or persistent guilt, e.g., feeling that punishment was deserved or not clearly recognized as excessive.

[0497] Negative thoughts may be associated with a psychiatric or nervous system disorder or some other medical condition.

[0498] Mental or nervous system disorders leading to or associated with negative thinking include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); 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; mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease (AD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0499] Negative thoughts can also occur in patients suffering from sleep disorders, such as insomnia.

[0500] Negative thinking can also occur in patients suffering from medical conditions that lead to associated mental or neurological pathologies, including traumatic brain injury (TBI).

[0501] Measuring negative thinking Negative thoughts or individual aspects thereof, such as feelings of worthlessness, helplessness and hopelessness, and guilt, can be assessed by a variety of methods, such as questionnaires or scales.

[0502] The questionnaire assesses the patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient is suffering from a particular psychiatric or neurological disorder may include items related to negative thinking.

[0503] Measures that assess related aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule-Expanded Form (PANAS-X), or the State Hope Scale (SHS).

[0504] The State Shame Guilt Scale (SSGS) is a self-rating scale of momentary (state) shame and guilt experiences. It includes two subscales: the Shame and Guilt subscales. The Shame subscale includes items 1, 3, 5, 7, and 9. The Guilt subscale includes items 2, 4, 6, 8, and 10. All items are scored positively and rated on a 5-point Likert scale. It includes several statements that may or may not describe how the patient is currently feeling. Higher scores indicate greater shame or guilt.

[0505] The Positive and Negative Affect Inventory-Extended (PANAS-X) is a 60-item expansion of the PANAS. The PANAS-X measures 11 specific emotions: fear, sadness, guilt, hostility, shyness, fatigue, surprise, cheerfulness, self-esteem, concern, and calmness. Thus, the PANAS-X measures mood at two distinct levels. The basic negative affect scales are fear, hostility, guilt, and sadness, while the guilt scale includes six items: guilty, ashamed, blameworthy, angry at self, disgusted with self, and dissatisfied with self. Each response should be rated as 1 = rarely or completely true; 2 = not very true; 3 = fairly true; 4 = very true; or 5 = very true. However, researchers under more severe time constraints may choose to select and evaluate only those scales that are most relevant to their research.

[0506] Increasing guilt intensity is reflected by increasing scores on the guilt scale.

[0507] The PANAS-X is simple and easy to administer. Most subjects complete the entire 60-item inventory in 10 minutes or less. The scale consists of multiple words and phrases that describe a range of feelings and emotions. Although patients are required to indicate the extent to which they have felt a particular way over the past few weeks, trait scores on the PANAS-X scale have been found to be stable over time, including "at this time," "today," and "past few days," suggesting that shorter, more appropriate recall periods may be applied.

[0508] The State Hope Scale (SHS) has three agency items and three pathways items to which respondents describe their current state of being. The agency subscale score is obtained by summing items 2, 4, and 6, which relate to one's perceived ability to use pathways to achieve desired goals. The pathways subscale score is obtained by summing items 1, 3, and 5, which relate to thoughts used to identify possible ways to achieve goals. The State Hope Scale total score is obtained by summing the three agency items and the three pathways items. Scores can range from a minimum of 6 to a maximum of 48, with higher hope reflected by higher scores on this scale.

[0509] Negative thoughts or aspects thereof may also be reflected in other scales such as the HAM-D, MADRS, BPRS or BDRS, the relevant items of which may be generally applicable for assessing negative thoughts and aspects thereof.

[0510] Resting-state network and negative thoughts Brain processes can be examined by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0511] 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 areas containing correlated and anticorrelated fluctuations.

[0512] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit synchronized activity in the absence of any explicit cognitive task (i.e., the resting state). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0513] Various resting-state networks have been identified, named primarily on the basis of spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0514] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional organization. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0515] RSNs have been shown to be involved in various aspects of complex brain function, and these connectivity networks are known to be impaired in various pathological conditions, including certain forms of negative thinking, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or one or more additional resting-state networks.

[0516] Major depressive disorder (MDD) is a disorder broadly characterized by high levels of negative affect and lower levels of positive affect. More specifically, low levels of positive affect, such as hope, translate into high levels of hopelessness and high levels of negative affect, such as guilt. MDD has been the focus of research in the field of rs-fMRI, which has shown that MDD is a disorder characterized by widespread network dysfunction. This dysfunction has been found primarily in networks and areas related to emotion regulation. These include the default mode network (DMN), salience network, affect network, and prefrontal cortex. Thus, various aspects of negative thinking may be associated with abnormal resting-state networks.

[0517] Resting-state network connectivity dysfunction has also been reported in patients with repetitive negative thinking (RNT), including altered connectivity between the left executive control network and the anterior salience network with the ventral default mode network.

[0518] Thus, patients suffering from negative thinking, compared with healthy age-matched controls, exhibit altered functional connectivity within and / or between resting-state networks, with alterations observed within and / or between at least the default mode network, executive control network, salience network, emotion network, and prefrontal cortex.

[0519] RSNs involved in negative thinking are often affected by psychiatric or nervous system disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, e.g., chronic pain; mental and behavioral disorders resulting from the use of psychoactive substances, e.g., substance use disorders (SUDs); psychotic disorders, e.g., schizophrenia; dementia, e.g., Alzheimer's disease (AD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, e.g., schizotypal personality disorder and borderline personality disorder (BPD).

[0520] Resting-state networks involved in negative thinking are also affected by mental or neurological pathologies that are the consequence of certain medical conditions, such as traumatic brain injury (TBI).

[0521] The resting-state network involved in negative thinking is also affected by sleep disorders, such as insomnia, and in fact, negative thinking is correlated with sleep dysfunction.

[0522] Treatment of negative thinking and mental or nervous system disorders According to the present invention, negative thoughts occurring in patients suffering from psychiatric or nervous system disorders can be treated. Additionally, negative thoughts occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0523] In patients suffering from negative thinking associated with another condition, such as those detailed above, treatment of negative thinking according to the present invention will lead to an improvement in the condition associated with the negative thinking.

[0524] Treatment according to the present invention relies on the administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0525] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting networks. This disruption leads to the resetting of pathologically abnormal connections as the network reconnects. New, healthy functional connections are established, resulting in lasting benefits.

[0526] Thus, in accordance with the present invention, affecting these networks by the therapies described herein leads to an improvement in negative thinking, and, if the treated patient suffers from a psychiatric or nervous system disorder, also leads to an improvement in that disorder, and, if the treated patient suffers from a sleep disorder, e.g., insomnia, also leads to an improvement in the sleep disorder, e.g., insomnia.

[0527] To further support the clinical application of 5-MeO-DMT in patients suffering from negative thinking, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in negative thinking that are also typically observed in patients with other disorders.

[0528] These 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 observations made in this study may be meaningful for devising treatments for other conditions associated with negative thinking, as detailed below.

[0529] 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 present context are those receiving a single 12 mg dose and those receiving an individualized daily dosing regimen (IDR) that allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) per day based on the intensity of the patient-reported psychedelic experience.

[0530] Data collected included treated patients' ratings on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, the inventors focused on the items that comprise the various rating scales, recognizing that specific subscore items, such as those related to negative thinking, may also be associated with other pathologies in which negative thinking is based on similarly altered functional connectivity within and / or between the default mode network, executive control network, salience network, emotion network, and prefrontal cortex.

[0531] Multiple patients within the recruited cohort showed significant improvement, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0532] More specifically, one aspect that may be treated by administration of 5-MeO-DMT is negative thoughts, particularly feelings of worthlessness, helplessness and hopelessness, and / or guilt. 5-MeO-DMT may be administered to a patient to reduce or eliminate the patient's negative thoughts, particularly feelings of worthlessness, helplessness and hopelessness, and / or guilt.

[0533] A particularly meaningful MADRS scale item for negative thinking is "pessimistic thinking," which represents thoughts of guilt, inferiority, self-blame, sinfulness, regret, and catastrophizing.

[0534] If there are no pessimistic thoughts, a score of 0 is given. If thoughts of failure, self-blame, or self-deprecation fluctuate, the score is 2. A score of 6 is given in the case of persistent self-criticism, or clear but still rational thoughts of guilt or fault, and the patient becomes increasingly pessimistic about the future. In the case of delusions of ruin, remorse, or irreparable fault, and irrational and unwavering self-criticism, a score of 6 is given.

[0535] In the study group receiving the individualized medication regimen, the MADRS item "Pessimistic Thinking" composite score for all eight patients was 28 at baseline.

[0536] After 2 hours, it had decreased to 7, which corresponds to a 21-point or 75% improvement. After 1 day of treatment, it had decreased to 4, which corresponds to a 24-point or 86% improvement. After 7 days of treatment, it had decreased to 3, which corresponds to a 25-point or 89% improvement.

[0537] In the 12 mg group, the MADRS "Pessimistic Thinking" composite score for all four patients was 16 at baseline. After two hours, it had decreased to 8, corresponding to an 8-point or 50% improvement. After one day of treatment, it had decreased to 7, corresponding to a 9-point or 56% improvement.

[0538] By the seventh day after treatment, this had decreased to 8, which corresponds to an 8-point or 50% improvement.

[0539] A BPRS item of particular relevance to negative thinking is "Guilt." This item relates to excessive worry or regret about past actions. Possible scores are: 1: No guilt. 2: Very mild. You feel bad about disappointing someone or failing at something, but you don't dwell on it. You can easily shift your mind to other things. 3: Mild. Somewhat preoccupied with disappointing someone or failing at something. Tends to express guilt to others. 4: Moderate. Excessive preoccupation with guilt, having made mistakes, or having done or not done something that has hurt others, but easily able to shift attention elsewhere. 5: Moderately severe. Guilt, preoccupation with disappointing someone or failing at something, and difficulty focusing on other things without great effort. No delusions. 6: Severe. Delusions of guilt or irrational self-blame totally out of proportion to the situation. Moderately obsessive. 7: Extremely severe. Delusions of guilt or irrational self-blame grossly out of proportion to the circumstances. Subject is highly preoccupied with feelings of guilt and likely to disclose or act on these delusions.

[0540] In the study group receiving the individualized medication regimen, the total score for the BPRS item "guilt" for all eight patients was 34 at baseline.

[0541] After 3 hours, it had decreased to 14, which corresponds to a 20-point or 59% improvement. After 1 day of treatment, it had decreased to 11, which corresponds to a 23-point or 68% improvement. After 7 days of treatment, it had decreased to 10, which corresponds to a 24-point or 71% improvement.

[0542] In the 12 mg group, the BPRS item "guilt" total score for all four patients was 18 at baseline.

[0543] After 3 hours, it had decreased to 9, which corresponds to a 9-point or 50% improvement. After 1 day of treatment, it had decreased to 5, which corresponds to a 13-point or 72% improvement. After 7 days of treatment, it had decreased to 5, which corresponds to a 13-point or 72% improvement.

[0544] Thus, scores on the MADRS scale item "Pessimistic Thinking," which is particularly relevant to negative thinking, improved significantly, as did scores on the BPRS item "Guilt." The inventors conclude that 5-MeO-DMT may be used to treat negative thinking in patients, particularly in patients who also suffer from a psychiatric or nervous system disorder, or a sleep disorder, such as insomnia.

[0545] Thus, in accordance with the present invention, treatment of a patient suffering from negative thoughts with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the negative thoughts.

[0546] Maternal function In addition to the above, the inventors believe that psychiatric or neurological disorders as defined herein, particularly disorders involving one or more symptoms selected from sleep disorders, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking, impair maternal functioning. Indeed, each of the symptoms described has the potential to impair maternal functioning in its own right (and is therefore independently treatable).

[0547] The first year after birth is particularly crucial for both mother and baby, as in most cases the mother is the primary caregiver and therefore shoulders the majority of the work associated with infant care tasks.

[0548] Maternal functioning includes the mother's aptitude for interacting with her infant(s) and aspects of her self-care.

[0549] Maternal functioning, including the emotional aspects of motherhood, is also important for child development. Indeed, the quality of mother-infant interactions during the first year after birth influences infant development. High levels of maternal functioning are likely to correlate with positive infant development outcomes. Similarly, functional abnormalities during the postpartum period may interfere with optimal infant development.

[0550] The Barkin Index of Maternal Functioning (BIMF) was designed to measure functioning during the first year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is scored from 0 to 6, resulting in a maximum total score of 120. Higher scores indicate better maternal functioning.

[0551] The BIMF identifies the main domains of functioning for mothers during the postpartum period as self-care, infant care, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0552] A BIMF score of 95 or less is considered herein to represent slight impairment of maternal function, a score of 80 or less is considered herein to represent impairment of maternal function, and a score of 65 or less is considered herein to represent severe impairment of maternal function. The present invention particularly allows for improvement of maternal function in patients who had a score of 80 or less before treatment, and even in patients who had a score of 65 or less.

[0553] As already mentioned above, the present invention makes it possible to treat patients suffering from psychiatric or nervous system disorders, which treatment not only leads to a reduction in the score assessing the severity of depression, but also improves maternal functioning, as will be described in more detail below.

[0554] To further support the clinical application of 5-MeO-DMT in patients suffering from psychiatric or neurological disorders, the present inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed improvements in certain aspects of the disease that are also typically observed in patients with psychiatric or neurological disorders. In particular, the present inventors observed improvements in various symptoms and symptom combinations that the present inventors determined to be related to maternal function.

[0555] These data come 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), results that have been confirmed by a recent study in patients with postpartum depression (see the Examples section below).

[0556] In this TRD 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 present context are those receiving a single 12 mg dose and those receiving an individualized daily dosing regimen (IDR) that allowed multiple escalating doses (6 mg, 12 mg, and 18 mg) per day based on the intensity of the patient-reported psychedelic experience.

[0557] Data collected included treated patients' ratings on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on the items that make up the various rating scales and recognized that some subscore items may be particularly meaningful for patients with psychiatric or neurological disorders and related to maternal functioning.

[0558] Multiple patients in the recruited cohort showed significant improvement in one or more of these subscores, supporting our findings that 5-MeO-DMT is a suitable compound for treating patients with psychiatric or neurological disorders and for improving maternal function in these patients.

[0559] The specific subscore items for each scale are identified in further detail below. We conclude that effectiveness in treating one or more of these symptoms results in significant improvements in overall outcome in patients with psychiatric or nervous system disorders treated with 5-MeO-DMT.

[0560] Thus, treatment according to the present invention reduces or eliminates (or ameliorates or eliminates) aspects of the disease.

[0561] When the aspect is rated on the MADRS scale, there is an improvement (decrease) of at least 1 point, or the patient is in complete remission (elimination) after treatment, i.e., the respective aspect is scored as 0.

[0562] When the aspect is rated on the BPRS scale, there is an improvement (decrease) of at least 1 point, or the patient is in complete remission (elimination) after treatment, i.e., each aspect is rated as 1.

[0563] Clinical response may also 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 of at least 1. Preferably, the CGI-S is decreased by at least 2 and / or to a score of 0. A decrease in the CGI-S of at least 3 and / or to a score of 0 is particularly preferred.

[0564] The inventors further believe that the improvements observed in specific MADRS items translate into improvements in aspects of maternal functioning.

[0565] MADRS items of particular significance are described in more detail below.

[0566] The MADRS item "Inner Tension" describes unexplained discomfort, edginess, inner turmoil, and mental tension that can lead to either panic, fear, or distress. It is rated according to intensity, frequency, duration, and the degree of relief sought.

[0567] If the patient is calm and there is only transient inner tension, a score of 0 is given. If there is occasional nervousness and unexplained discomfort, a score of 2 is given. If there is a persistent sense of inner tension or intermittent panic that the patient cannot conquer without some difficulty, the score is 4. In the case of persistent fear or distress and overwhelming panic, the score is 6.

[0568] The inventors have determined that an increased score on the MADRS item "internal strain" adversely affects both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). An increased score on the MADRS item "internal strain" impairs mother-infant interaction and maternal psychological well-being as assessed by the BIMF.

[0569] Conversely, improvements on this MADRS item would translate to improvements in maternal functioning, particularly in the BIMF function domain, mother-infant interaction, and / or maternal psychological well-being.

[0570] In the study involving patients with TRD, in the study group receiving the individualized medication regimen, the overall score for the MADRS item "internal tension" for all eight patients was 26 at baseline. After two hours, it had decreased to 11, corresponding to a 15-point or 58% improvement. After one day of treatment, it had decreased to 6, corresponding to a 20-point or 77% improvement. After seven days of treatment, it had decreased to 12, corresponding to a 14-point or 54% improvement.

[0571] In the 12 mg group, the MADRS "internal tension" total score for all four patients was 13 at baseline. After two hours, it had decreased to 2, corresponding to an 11-point or 85% improvement. After one day of treatment, it had decreased to 3, corresponding to a 10-point or 77% improvement. After seven days of treatment, it had decreased to 5, corresponding to an 8-point or 62% improvement.

[0572] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or nervous system disorders to achieve a reduction or elimination of inner tension.

[0573] The improvement in inner tension is reflected by an improvement in the inner tension score on the MADRS item at least about 2 hours after the final 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.

[0574] Improvement in inner tension, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0575] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0576] Improvement in inner tension, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0577] The improvement in inner tension, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0578] The inventors further conclude that the reduction or elimination of internal tension achieved by treating patients with psychiatric or nervous system disorders not only leads to a decrease in the MADRS total score, but also to improved maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in the BIMF score is also observed on days 1, 7, 14, and / or 28 after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0579] Since inner strain also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "inner strain" item of the MADRS further contributes to an overall improvement in maternal functioning.

[0580] The MADRS item "Fatigue" describes difficulty in starting to move or slowness in initiating and performing daily activities.

[0581] A score of 0 means little difficulty initiating movement and no fatigue. A score of 2 is given if the patient has difficulty initiating activity. A score of 4 means there is difficulty in starting simple routine activities that are performed with effort. A score of 6 is given in cases of complete fatigue where the patient is unable to do anything without help.

[0582] The inventors have determined that an increased score on the MADRS item "fatigue" adversely affects both aspects of maternal functioning (the mother's ability to interact with her infant(s) and her self-care). An increased score on the MADRS item "fatigue" impairs infant care, self-care, psychological well-being, management, and adaptation.

[0583] Conversely, improvement on this MADRS item would translate to improvements in maternal functioning, particularly in the BIMF functioning domains of infant care, self-care, psychological well-being, management, and / or adaptation.

[0584] In the study group receiving the individualized dosing regimen, the overall score for the MADRS item "Fatigue" for all eight patients was 27 at baseline. After two hours, it had decreased to 10, corresponding to a 17-point or 63% improvement. After one day of treatment, it had decreased to 5, corresponding to a 22-point or 81% improvement. After seven days of treatment, it had decreased to 3, corresponding to a 24-point or 89% improvement.

[0585] In the 12 mg group, the MADRS "Fatigue" composite score for all four patients was 16 at baseline. After two hours, it had decreased to 10, corresponding to a 6-point or 38% improvement. After one day of treatment, it had decreased to 0, corresponding to a 16-point or 100% improvement. After seven days of treatment, it had decreased to 3, corresponding to a 13-point or 81% improvement.

[0586] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or nervous system disorders to achieve a reduction or elimination of fatigue.

[0587] The improvement in fatigue is reflected by an improvement in the fatigue score on the MADRS item at least about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0588] Improvement in fatigue, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0589] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0590] Improvement in fatigue, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0591] The improvement in fatigue, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0592] The inventors further conclude that the reduction or elimination of fatigue achieved by treating patients with psychiatric or nervous system disorders not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on days 1, e.g., about 24 hours; 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Because fatigue also impacts other aspects of psychiatric or nervous system disorders, the inventors conclude that the improvement observed in the "Fatigue" item of the MADRS further contributes to an overall improvement in maternal functioning.

[0593] The MADRS item "Affective Loss" describes the subjective experience of decreased interest in one's surroundings or activities that normally bring pleasure. A decreased ability to respond emotionally to situations or people.

[0594] A score of 0 indicates normal interest in surroundings and others, a score of 2 is a diminished ability to enjoy normal interests. A score of 4 is given in case of loss of interest in surroundings and loss of feelings towards friends and acquaintances. A score of 6 reflects an emotional numbness, an inability to feel anger, sadness, or joy, and a total inability or even distress to sympathize with close relatives and friends.

[0595] The inventors have determined that an increased score on the MADRS item "emotional loss" adversely affects both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). An increased score on the MADRS item "emotional loss" impairs maternal-infant interaction and psychological well-being.

[0596] Conversely, improvements on this MADRS item would translate to improvements in maternal functioning, particularly in the BIMF function domain, mother-infant interaction, and / or psychological well-being.

[0597] In the study group receiving the individualized medication regimen, the MADRS "Apathy" composite score for all eight patients was 36 at baseline. After two hours, it had decreased to 12, corresponding to a 24-point or 67% improvement. After one day of treatment, it had decreased to 2, corresponding to a 34-point or 94% improvement. After seven days of treatment, it had decreased to 6, corresponding to a 30-point or 83% improvement.

[0598] In the 12 mg group, the MADRS "Apathy" composite score for all four patients was 16 at baseline. After two hours, it had decreased to 9, corresponding to a 7-point or 44% improvement. After one day of treatment, it had decreased to 1, corresponding to a 15-point or 94% improvement. After seven days of treatment, it had decreased to 1, corresponding to a 15-point or 94% improvement.

[0599] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of emotional loss.

[0600] The improvement in exasperation is reflected by an improvement in the exasperation score on the MADRS item at least about 2 hours after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after; on day 7; on day 14; and / or on day 28 after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0601] Improvement in exasperation, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0602] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0603] Improvement in apathy, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0604] The improvement in exacerbation, as reflected by a reduction in the CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0605] The inventors further conclude that the reduction or elimination of emotional extinction by treating patients with psychiatric or neurological disorders not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within approximately 2 hours, and an increase in the BIMF score is also observed on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 13 Because emotional extinction also impacts other aspects of psychiatric or neurological disorders, the inventors conclude that the improvement observed in the "emotional extinction" item of the MADRS further contributes to an overall improvement in maternal functioning.

[0606] The MADRS item "Difficulty concentrating" describes difficulty organizing thoughts that leads to an incapacitating lack of concentration.

[0607] If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty organizing thoughts, the score is 2. If there is difficulty concentrating and sustaining thoughts, thereby diminishing the ability to read or interact, a score of 4 is given. If the patient cannot read or interact without great difficulty, the score is 6.

[0608] The inventors have determined that an increased score on the MADRS item "Difficulty concentrating" adversely affects both aspects of maternal functioning (the mother's ability to interact with her infant(s) and her self-care). An increased score on the MADRS item "Difficulty concentrating" impairs infant care and management.

[0609] Conversely, improvement on this MADRS item would translate to improved maternal functioning, particularly infant care and / or management in the BIMF functioning domain.

[0610] In the study group receiving the individualized medication regimen, the overall score for the MADRS item "Difficulty concentrating" for all eight patients was 30 at baseline. After two hours, it had decreased to 11, corresponding to a 19-point or 63% improvement. After one day of treatment, it had decreased to 1, corresponding to a 29-point or 97% improvement. After seven days of treatment, it had decreased to 9, corresponding to a 21-point or 70% improvement.

[0611] In the 12 mg group, the MADRS "Difficulty concentrating" composite score for all four patients was 16 at baseline. After two hours, it had decreased to 7, corresponding to a 9-point or 56% improvement. After one day of treatment, it had decreased to 2, corresponding to a 14-point or 88% improvement. After seven days of treatment, it had decreased to 3, corresponding to a 13-point or 81% improvement.

[0612] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or nervous system disorders to achieve a reduction or elimination of concentration difficulties.

[0613] The improvement in difficulty concentrating is reflected by an improvement in the difficulty concentrating score on the MADRS item at least about 2 hours after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after; on day 7; on day 14; and / or on day 28.

[0614] Improvement in concentration difficulties, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0615] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0616] Improvement in concentration difficulties, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0617] The improvement in concentration difficulties, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0618] The inventors further conclude that reducing or eliminating concentration difficulties by treating patients with psychiatric or nervous system disorders not only leads to a decrease in the MADRS total score, but also to improved maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within approximately 2 hours, and the increase in the BIMF score is also observed on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0619] Because difficulty concentrating also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "difficulty concentrating" item of the MADRS further contributes to an overall improvement in maternal functioning.

[0620] The MADRS item "negative thinking" represents thoughts of guilt, inferiority, self-blame, sinfulness, regret, and catastrophizing.

[0621] If there are no pessimistic thoughts, a score of 0 is given. If thoughts of failure, self-blame, or self-deprecation fluctuate, the score is 2. A score of 6 is given in the case of persistent self-criticism, or clear but still rational thoughts of guilt or fault, and the patient becomes increasingly pessimistic about the future. In the case of delusions of ruin, remorse, or irreparable fault, and irrational and unwavering self-criticism, a score of 6 is given.

[0622] The inventors have determined that an increased score on the MADRS item "pessimistic thinking" adversely affects both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). An increased score on the MADRS item "pessimistic thinking" impairs psychological well-being, social support, and control.

[0623] Conversely, improvement on this MADRS item would translate to improved psychological well-being, social support, and / or control in maternal functioning, particularly the BIMF functioning domain.

[0624] In the study group receiving the individualized medication regimen, the overall score for the MADRS item "Pessimistic Thinking" for all eight patients was 28 at baseline. After two hours, it had decreased to 7, corresponding to a 21-point or 75% improvement. After one day of treatment, it had decreased to 4, corresponding to a 24-point or 86% improvement. After seven days of treatment, it had decreased to 3, corresponding to a 25-point or 89% improvement.

[0625] In the 12 mg group, the MADRS "Pessimistic Thinking" total score for all four patients was 16 at baseline. After two hours, it had decreased to 8, corresponding to an 8-point or 50% improvement. After one day of treatment, it had decreased to 7, corresponding to a 9-point or 56% improvement. After seven days of treatment, it had decreased to 8, corresponding to an 8-point or 50% improvement.

[0626] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of negative thinking.

[0627] The improvement in negative thinking is reflected by an improvement in the negative thinking score on the MADRS item at least about 2 hours after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after; on day 7; on day 14; and / or on day 28 after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0628] Improvement in negative thinking, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0629] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0630] Improvement in negative thinking, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0631] The improvement in negative thinking, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0632] The inventors further conclude that reducing or eliminating negative thinking by treating patients with psychiatric or nervous system disorders not only leads to a decrease in the MADRS total score, but also to improved maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in the BIMF score is also observed on days 1, 7, 14, and / or 28 after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0633] Because pessimistic thinking also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "pessimistic thinking" item of the MADRS further contributes to an overall improvement in maternal functioning.

[0634] The MADRS item "Decreased Sleep" describes the experience of sleep that is reduced in duration or depth compared to the subject's own normal pattern when well.

[0635] If the subject's sleep is normal, a score of 0 is given. A score of 2 reflects slight difficulty falling asleep or slightly reduced, light, or intermittent sleep. A score of 4 means sleep is reduced or interrupted by at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0636] The inventors have determined that an increased score on the MADRS item "reduced sleep" adversely affects both aspects of maternal functioning (the mother's ability to interact with her infant(s) and the mother's self-care). An increased score on the MADRS item "reduced sleep" impairs self-care, psychological well-being and control.

[0637] Conversely, improvement on this MADRS item would translate to improved self-care, psychological well-being, and / or management in maternal functioning, particularly the BIMF functioning domain.

[0638] In the study group receiving the individualized medication regimen, the overall score for the MADRS item "Decreased Sleep" for all eight patients was 25 at baseline. By post-treatment day 1, the earliest time point for assessing the effect of treatment on sleep, it had decreased to 12, representing a 13-point or 52% improvement. By post-treatment day 7, it had decreased to 9, representing a 16-point or 64% improvement.

[0639] In the 12 mg group, the MADRS "Decreased Sleep" composite score for all four patients was 12 at baseline. It decreased to 10 on post-treatment day 1, corresponding to a 2-point or 17% improvement. It decreased to 6 on post-treatment day 7, corresponding to a 6-point or 50% improvement.

[0640] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or nervous system disorders to achieve a reduction or elimination of sleep loss.

[0641] The reduction or elimination of sleep deprivation is reflected by an improvement in the sleep deprivation score on the MADRS item at least 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.

[0642] Improvement in sleep reduction, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 24 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0643] Improvement in sleep reduction, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 24 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0644] The improvement in sleep reduction, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0645] The inventors further conclude that reducing or eliminating sleep loss by treating patients with psychiatric or nervous system disorders not only leads to a decrease in the MADRS total score, but also to improved maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 24 hours, and the increase in the BIMF score is also observed on days 1, e.g., about 24 hours; 7, 14, and / or 28 after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0646] Because sleep reduction also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "sleep reduction" item of the MADRS further contributes to an overall improvement in maternal functioning.

[0647] A further aspect of psychiatric or neurological disorders that may be treated by administration of 5-MeO-DMT is suicidal ideation. Administering 5-MeO-DMT to a patient with a psychiatric or neurological disorder can reduce or eliminate suicidal ideation in the patient.

[0648] In the clinical trials described above involving the administration of 5-MeO-DMT, the MADRS item "suicidal thoughts" was assessed, among other things.

[0649] "Suicidal thoughts" refers to feeling that life is not worth living and being willing to die a natural death, having suicidal thoughts, and / or making preparations to commit suicide. A suicide attempt should not, in itself, affect the rating of this MADRS item.

[0650] A score of 0 means the patient is enjoying life. A score of 2 is given if the patient with a psychiatric or neurological disorder is fed up with life and / or has only transient suicidal thoughts. A score of 4 means the patient would rather be dead, suicidal thoughts are common, and suicide is considered as a possible solution, but the patient does not have a specific plan or intent. A score of 6 is given if the patient has a clear plan for suicide and / or is actively preparing.

[0651] This MADRS scale item is particularly relevant for suicidal ideation.

[0652] The inventors have determined that an increased score on the MADRS item "suicidal thoughts" adversely affects both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). An increased score on the MADRS item "suicidal thoughts" impairs self-care, psychological well-being and control.

[0653] Conversely, improvement on this MADRS item would translate to improved self-care, psychological well-being, and / or management in maternal functioning, particularly the BIMF functioning domain.

[0654] In the study group receiving the individualized medication regimen, the MADRS "Suicidal Thoughts" composite score for all eight patients was 11 at baseline. After two hours, it had decreased to 3, corresponding to an 8-point or 73% improvement. After one day of treatment, it had decreased to 1, corresponding to a 10-point or 91% improvement. After seven days of treatment, it had decreased to 3, corresponding to an 8-point or 73% improvement.

[0655] In the 12 mg group, the MADRS "suicidal thoughts" composite score for all four patients was 8 at baseline. After two hours, it had decreased to 3, corresponding to a 5-point or 63% improvement. After one day of treatment, it had decreased to 5, corresponding to a 3-point or 38% improvement. After seven days of treatment, it had decreased to 7, corresponding to a 1-point or 13% improvement.

[0656] Thus, scores on "suicidal thoughts," a particularly meaningful scale item for suicidal ideation, are significantly improved, at least in patients on individualized dosing regimens. We conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients with psychiatric or neurological disorders.

[0657] Thus, in accordance with the present invention, treating a patient with a psychiatric or nervous system disorder who suffers from suicidal ideation reduces or eliminates the suicidal ideation.

[0658] The reduction or elimination of suicidal ideation is reflected by an improvement in the score for the Suicidal Thoughts on the MADRS item at least about 2 hours after the final 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.

[0659] If the patient is experiencing suicidal ideation, improvement in suicidal ideation is reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score at about 2 hours; 1 day, e.g., about 24 hours; 7 days; 14 days; and / or 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0660] Improvement in suicidal ideation, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0661] Alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, for example, about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0662] Improvement in suicidal ideation, as assessed by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0663] The improvement in suicidal ideation, as assessed by a reduction in CGI-S score or 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0664] The inventors further conclude that reducing or eliminating suicidal thoughts by treating patients with psychiatric or nervous system disorders not only leads to a decrease in the MADRS total score, but also to improved maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in the BIMF score is also observed on days 1, 7, 14, and / or 28 after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0665] Because suicidal thoughts also impact other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "suicidal thoughts" item of the MADRS further contributes to an overall improvement in maternal functioning.

[0666] The BPRS item "Emotional Withdrawal" relates to deficits in the patient's ability to be emotionally involved in the interview situation. Possible scores are: 1: No emotional withdrawal. 2: Very mild. Lack of emotional engagement, indicated by occasional absence of interactive comments, occasional appearance of distraction, awkward smiling, but mostly natural conversation with the interviewer. 3: Mild. Lack of emotional engagement, as indicated by not making interactive comments, appearing distracted, or a noticeable lack of warmth, but responsive to the interviewer when spoken to. 4: Moderate. Emotional contact is absent for much of the interview because the subject does not elaborate on answers, does not make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by mental material. 5: Moderately severe. Same as 4, but emotional contact is absent for most of the interview. 6: Severe. Actively avoids emotional involvement. Frequent non-responsiveness or yes / no responses (not simply paranoia). Responds with minimal emotional involvement. 7: Very severe. Always avoids emotional involvement. Unresponsive or yes / no responses (not simply paranoid). May leave the interview midway or simply not respond at all.

[0667] The inventors have determined that increased scores on the BPRS item "emotional withdrawal" negatively impact both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). Increased scores on the BPRS item "emotional withdrawal" impair psychological well-being, mother-infant interaction, and social support.

[0668] Conversely, improvement on this BPRS item would translate to improvements in maternal functioning, particularly psychological well-being, mother-child interaction, and / or social support in the BIMF functioning domain.

[0669] In the study group receiving the individualized medication regimen, the overall score for the BPRS item "Emotional Withdrawal" was 13 at baseline. After 3 hours, it had decreased to 8, which corresponds to a 5-point or 38% improvement. After 1 day of treatment, it had decreased to 8, which corresponds to a 5-point or 38% improvement. After 7 days of treatment, it had decreased to 8, which corresponds to a 5-point or 38% improvement.

[0670] In the 12 mg group, the BPRS "emotional withdrawal" total score was 13 at baseline. After 3 hours, it had decreased to 11, corresponding to a 2-point or 15% improvement. After 1 day of treatment, it had decreased to 8, corresponding to a 5-point or 38% improvement. After 7 days of treatment, it had decreased to 6, corresponding to a 7-point or 54% improvement.

[0671] We conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of emotional withdrawal.

[0672] The reduction or elimination of emotional withdrawal is reflected by an improvement in the BPRS item emotional withdrawal score at least about 2 hours after the final 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0673] Improvement in emotional withdrawal, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0674] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0675] Improvement in emotional withdrawal, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0676] The improvement in emotional withdrawal, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0677] The inventors further conclude that reducing or eliminating emotional withdrawal by treating patients with psychiatric or nervous system disorders not only leads to a decrease in BPRS total score, but also to improved maternal functioning, as reflected by an increase in BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in BIMF score is also observed on days 1, 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0678] Because emotional withdrawal also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "emotional withdrawal" item of the BPRS further contributes to an overall improvement in maternal functioning.

[0679] The BPRS item "affective blunting" relates to a limited range of emotional expression in face, voice, and gesture, as well as a pronounced indifference or flatness even when discussing distressing topics. Possible scores are: 1: No emotional blunting. 2: Very mild. Emotional range is slightly suppressed or subdued, but facial expressions and tone of voice are within the normal range and appropriate. 3: Mild. Overall emotional range is muted, suppressed, or subdued, with few spontaneous and appropriate emotional responses. Slight monotony in tone of voice. 4: Moderate. Emotional range is significantly diminished, and the patient rarely displays emotion, smiles, or responds to distressing topics. The tone of voice is monotonous or spontaneous motor activity is significantly reduced. After displaying emotion or gestures, the patient usually returns to a neutral affect. 5: Moderately severe. Emotional range is very diminished, the patient only rarely shows emotion, smiles, or responds to distressing topics, gestures are few, facial expression rarely changes, and the tone of voice is often monotonous. 6: Severe. Little emotional range or expression. Speech and gestures are almost always mechanical. Facial expression is unchanging. Voice tone is almost always monotonous. 7: Extremely severe. Stiff movements with virtually no range or expression of emotion. Vocal tone is always monotonous.

[0680] The inventors have determined that an increased score on the BPRS item "flattened affect" negatively impacts both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and her self-care). An increased score on the BPRS item "flattened affect" impairs psychological well-being and mother-infant interaction.

[0681] Conversely, improvement on this BPRS item would translate to improved maternal functioning, particularly psychological well-being and / or mother-infant interaction in the BIMF functioning domain.

[0682] The total score for the BPRS item "blunted affect" was 15 at baseline. After 3 hours, it had decreased to 11, corresponding to a 4-point or 27% improvement. After 1 day of treatment, it had decreased to 8, corresponding to a 7-point or 47% improvement. After 7 days of treatment, it had decreased to 8, corresponding to a 7-point or 47% improvement.

[0683] In the 12 mg group, the BPRS "blunted affect" total score was 11 at baseline. After 3 hours, it had decreased to 8, corresponding to a 3-point or 27% improvement. After 1 day of treatment, it had decreased to 6, corresponding to a 5-point or 45% improvement. After 7 days of treatment, it had decreased to 5, corresponding to a 6-point or 55% improvement.

[0684] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of affective blunting.

[0685] The reduction or elimination of blunted affect is reflected by an improvement in the blunted affect score on the BPRS item at least about 2 hours after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after; on day 7; on day 14; and / or on day 28.

[0686] Improvement in affective blunting, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0687] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0688] Improvement in affective blunting, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0689] The improvement in affective blunting, as reflected by a reduction in the CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0690] The inventors further conclude that reduction or elimination of blunted affect by treating patients with psychiatric or nervous system disorders not only leads to a decrease in BPRS total score, but also to improved maternal functioning, as reflected by an increase in BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in BIMF score is also 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.

[0691] Because blunted affect also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "blunted affect" item of the BPRS further contributes to an overall improvement in maternal functioning.

[0692] The BPRS item "Guilt" concerns excessive worry or regret about past actions. Possible scores are: 1: No guilt. 2: Very mild. You feel bad about disappointing someone or failing at something, but you don't dwell on it. You can easily shift your mind to other things. 3: Mild. Somewhat preoccupied with disappointing someone or failing at something. Tends to express guilt to others. 4: Moderate. Excessive preoccupation with guilt, having made mistakes, or having done or not done something that has hurt others, but easily able to shift attention elsewhere. 5: Moderately severe. Guilt, preoccupation with disappointing someone or failing at something, and difficulty focusing on other things without great effort. No delusions. 6: Severe. Delusions of guilt or irrational self-blame totally out of proportion to the situation. Moderately obsessive. 7: Extremely severe. Delusions of guilt or irrational self-blame grossly out of proportion to the circumstances. Subject is highly preoccupied with feelings of guilt and likely to disclose or act on these delusions.

[0693] The inventors have determined that an increased score on the BPRS item "guilt" negatively impacts both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). An increased score on the BPRS item "guilt" impairs self-care, maternal-infant interaction, psychological well-being, and control.

[0694] Conversely, improvement on this BPRS item would translate to improvements in maternal functioning, particularly in the BIMF function domains of self-care, mother-infant interaction, psychological well-being, and / or management.

[0695] In the study group receiving the individualized medication regimen, the total score for the BPRS item "Guilt" for all eight patients was 34 at baseline. After three hours, it had decreased to 14, corresponding to a 20-point or 59% improvement. After one day of treatment, it had decreased to 11, corresponding to a 23-point or 68% improvement. After seven days of treatment, it had decreased to 10, corresponding to a 24-point or 71% improvement.

[0696] In the 12 mg group, the BPRS "Guilt" total score for all four patients was 18 at baseline. After 3 hours, it had decreased to 9, corresponding to a 9-point or 50% improvement. After 1 day of treatment, it had decreased to 5, corresponding to a 13-point or 72% improvement. After 7 days of treatment, it had decreased to 5, corresponding to a 13-point or 72% improvement.

[0697] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of guilt.

[0698] The reduction or elimination of guilt is reflected by an improvement in the guilt score on the BPRS item at least about 2 hours after the final 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.

[0699] Improvement in guilt, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0700] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0701] Improvement in guilt, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0702] The improvement in guilt, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0703] The inventors further conclude that the reduction or elimination of guilt by treating patients with psychiatric or neurological disorders not only leads to a decrease in BPRS total score, but also to improved maternal functioning, as reflected by an increase in BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in BIMF score is also observed on days 1, 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.

[0704] Because guilt also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "guilt" item of the BPRS further contributes to an overall improvement in maternal functioning.

[0705] The BPRS item "Anxiety" concerns complaints of apprehension, tension, fear, panic, or worry. Possible scores are: 1: No anxiety. 2: Very mild. Some discomfort from worry or worries that are low in frequency for most healthy people occur more frequently than normal. 3: Mild. Frequent anxiety, but quick to redirect attention elsewhere. 4: Moderate. Almost constant worry, unable to attend to other things easily, but not interfering with function, or occasional anxiety with accompanying autonomic symptoms, but not interfering with function. 5: Moderately severe. Frequent but not daily periods of anxiety with accompanying autonomic symptoms, or some areas of function are disrupted by anxiety or worry. 6: Severe. Anxiety with accompanying autonomic symptoms occurs daily but not all day, or many areas of function are disrupted by anxiety or constant worry. 7: Very severe. Anxiety with accompanying autonomic symptoms persists throughout the day or most functional areas are disrupted by anxiety or constant worry.

[0706] The inventors have determined that increased scores on the BPRS item "Anxiety" negatively impact both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). Increased scores on the BPRS item "Anxiety" impair psychological well-being, social support, and control.

[0707] Conversely, improvement on this BPRS item would translate to improved psychological well-being, social support, and / or control in maternal functioning, particularly the BIMF functioning domain.

[0708] In the study group receiving the individualized medication regimen, the BPRS "Anxiety" total score for all eight patients was 37 at baseline. After three hours, it had decreased to 19, corresponding to an 18-point or 49% improvement. After one day of treatment, it had decreased to 16, corresponding to a 21-point or 57% improvement. After seven days of treatment, it had decreased to 17, corresponding to a 20-point or 54% improvement.

[0709] In the 12 mg group, the BPRS "Anxiety" total score for all four patients was 25 at baseline. After 3 hours, it had decreased to 11, corresponding to a 14-point or 56% improvement. After 1 day of treatment, it had decreased to 6, corresponding to a 19-point or 76% improvement. After 7 days of treatment, it had decreased to 6, corresponding to a 19-point or 76% improvement.

[0710] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of anxiety.

[0711] The reduction or elimination of anxiety is reflected by an improvement in the anxiety score on the BPRS item at least about 2 hours after the final 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.

[0712] Improvement in anxiety, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0713] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0714] Improvement in anxiety, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0715] The improvement in anxiety, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0716] The inventors further conclude that the reduction or elimination of anxiety by treating patients with psychiatric or nervous system disorders not only leads to a decrease in BPRS total score, but also to improved maternal functioning, as reflected by an increase in BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in BIMF score is also observed on days 1, 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] Because anxiety also affects other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "anxiety" item of the BPRS further contributes to an overall improvement in maternal functioning.

[0718] The BPRS item "Tension" relates to observable physical and motor symptoms of tension, "nervousness," and agitation. Possible scores are: 1: No tension. 2: Very mild. More fidgety than usual, but within normal limits. There are a few fleeting signs of nervousness, such as picking at fingernails, rocking feet, scratching the scalp a few times, or tapping with the fingers. 3: Mild. Same as "2", but signs of tension are more frequent or exaggerated. 4: Moderate. Symptoms of motor tension are numerous and frequent, with one or more symptoms occasionally occurring simultaneously. For example, shaking the legs while rubbing the hands. Symptoms of tension are sometimes absent. 5: Moderately severe. Symptoms of motor tension are numerous and frequent, and one or more symptoms often occur simultaneously. Symptoms of tension are still rarely absent. 6: Severe. Same as 5, but with constant signs of tension. 7: Very severe. Multiple, constant motor symptoms of tension, such as constant pacing and rubbing of the hands.

[0719] The inventors have determined that an increased score on the BPRS item "strain" negatively impacts both aspects of maternal functioning (the mother's competence in interacting with her infant(s) and the mother's self-care). An increased score on the BPRS item "strain" impairs maternal-infant interaction and psychological well-being.

[0720] Conversely, improvement on this BPRS item would translate to improvements in maternal functioning, particularly in the BIMF function domain, mother-child interaction, and / or psychological well-being.

[0721] In the study group receiving the individualized medication regimen, the BPRS "Tension" composite score for all eight patients was 16 at baseline. After three hours, it had decreased to 11, corresponding to a 5-point or 31% improvement. After one day of treatment, it had decreased to 11, corresponding to a 5-point or 31% improvement. After seven days of treatment, it had decreased to 10, corresponding to a 6-point or 38% improvement.

[0722] In the 12 mg group, the BPRS "Tension" total score for all four patients was 14 at baseline. After 3 hours, it had decreased to 9, corresponding to a 5-point or 36% improvement. After 1 day of treatment, it had decreased to 6, corresponding to an 8-point or 57% improvement. After 7 days of treatment, it had decreased to 6, corresponding to an 8-point or 57% improvement.

[0723] The inventors conclude that 5-MeO-DMT may be used to treat patients with psychiatric or nervous system disorders to achieve a reduction or elimination of tension.

[0724] The reduction or elimination of tension is reflected by an improvement in the BPRS item tension score at least about 2 hours after the final 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.

[0725] Improvement in tone, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0726] Alternatively, or additionally, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0727] Improvement in tone, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0728] The improvement in tone, as reflected by a reduction in CGI-S score or a CGI-I or PGI-I score of at least "much improved," preferably persists for at least 6 days; particularly at least 14 days; and more preferably at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0729] The inventors further conclude that the reduction or elimination of tension by treating patients with psychiatric or nervous system disorders not only leads to a decrease in BPRS total score, but also to improved maternal functioning, as reflected by an increase in BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and the increase in BIMF score is also observed on days 1, 7, 14, and / or 28 after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0730] Because strain also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the "strain" item of the BPRS further contributes to an overall improvement in maternal functioning.

[0731] Improvement in one or more aspects of the psychiatric or neurological disorder also leads to an overall improvement. Preferably, treatment leads to remission.

[0732] Remission of depressive symptoms may be reflected by a MADRS score of 10 or less, occurring within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, or occurring on day 1, e.g., about 24 hours; day 7; day 14, and / or day 28.

[0733] Further alternatively, or in addition, remission of depressive symptoms may be reflected by a HAM-D score of 7 or less, occurring within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, or occurring on day 1, e.g., about 24 hours; day 7; day 14, and / or day 28.

[0734] In light of the above, treatment of patients with psychiatric or nervous system disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof not only leads to a reduction in MADRS scores, including in particular the subscores detailed above, but also to improvements in domains of the BIMF scale. The reduction in MADRS scores and improvement in maternal functioning are supported by clinical data, as described in the Examples section below.

[0735] Improvement in maternal functioning includes improvement in the self-care domain of functioning. For example, improvement in fatigue and / or decreased sleep in the MADRS items leads to an increase in the BIMF scale score reflecting self-care. The improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0736] Improvement in maternal functioning includes improvement in the functional domain of infant care. For example, improvement in fatigue and / or difficulty concentrating on the MADRS items leads to an increase in the BIMF scale score reflecting infant care. The improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 15%, more preferably at least 25%.

[0737] Improvement in maternal functioning includes improvement in the functional domain of maternal-infant interaction. For example, improvement in the MADRS items of emotional apathy and inner tension leads to an increase in the BIMF scale score reflecting maternal-infant interaction. The improvement in the cumulative score of the BIMF scale items reflecting maternal-infant interaction is preferably at least 5%, more preferably at least 15%.

[0738] Improvement in maternal functioning includes improvements in the functional domain of psychological well-being. For example, improvements in the MADRS items of fatigue, pessimistic thinking, emotional loss, internal tension, and / or decreased sleep lead to an increase in the BIMF scale score reflecting psychological well-being. The improvement in the cumulative score of the BIMF scale items reflecting psychological well-being is preferably at least 25%, more preferably at least 35%.

[0739] The improvement of maternal function includes the improvement of the functional domain of social support.For example, the improvement of pessimistic thinking in MADRS item leads to the increase of BIMF scale score that reflects social support.The cumulative score improvement of BIMF scale item that reflects social support is preferably at least 10%, more preferably at least 20%.

[0740] Improvement in maternal functioning includes improvement in the functional domain of management. For example, improvement in the MADRS items fatigue, pessimistic thinking, and / or difficulty concentrating leads to an increase in the BIMF scale score reflecting management. The improvement in the cumulative score of the BIMF scale items reflecting management is preferably at least 20%, more preferably at least 30%.

[0741] Improvement in maternal function includes improvement in the functional domain of adaptation.For example, improvement in fatigue of MADRS item leads to increase in BIMF scale score reflecting adaptation.The cumulative score improvement of BIMF scale item reflecting adaptation is preferably at least 5%, more preferably at least 15%.

[0742] Improved maternal functioning is associated with one or more, and particularly two or more, functional domains from the Barkin Indicator of Maternal Functioning (BIMF) selected from self-care, infant care, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0743] The BIMF total score improves by 10% or more, preferably 20% or more.

[0744] Breastfeeding As noted above, for many medications, a nursing patient may be faced with the decision to discontinue nursing or discontinue / withhold therapy.

[0745] When a decision is made to discontinue breastfeeding in order to receive treatment, this decision negatively impacts maternal functioning, particularly impairing the functional domains of mother-infant interaction and psychological well-being.

[0746] The present invention also addresses the need to treat psychiatric or neurological disorders in nursing mothers without substantially interrupting breastfeeding.

[0747] According to the present invention, breastfeeding may be resumed shortly after treatment.

[0748] The present inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT to determine at what point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt, breastfeeding could be initiated without exposing the nursing infant to associated risks.

[0749] Absorption and distribution of inhaled 5-MeO-DMT is rapid, with peak concentrations and pharmacological effects observed during and shortly after administration.

[0750] Plasma protein binding is low (13-23%).

[0751] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid decline in plasma concentrations. Already 10 minutes after administration, concentrations fall to less than 10% of Cmax, 2 hours later to less than 1% of Cmax, and 3 hours later, 5-MeO-DMT is no longer detectable in plasma. This applies across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation is observed with repeated dosing within the 1-4 hour time frame. Uptitration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0752] To assess the potential significance of metabolites of 5-MeO-DMT that may occur in humans, such metabolites were identified. In an in vitro metabolite identification study in human hepatocytes, 5-MeO-DMT free base was incubated at 10 μM for up to 120 minutes. The identified compounds and their relative proportions are shown in Table 1 below. [Table 2]

[0753] Subsequent assays repeatedly failed to detect the presence of 5-methoxytryptophol but reproducibly demonstrated the presence of 5-MIAA as a major metabolite, making it unlikely that 5-methoxytryptophol plays a significant role in vivo.

[0754] The metabolites listed in the table above are formed via three different pathways.

[0755] The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed via oxidative deamination, which involves enzymatic removal and oxidation of the N-methyl group, resulting in the formation of acetaldehyde. [ka]

[0756] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0757] Secondary amines, primary amines, and aldehydes were not identified, indicating that they were not present in significant concentrations at any time point.

[0758] The aldehyde intermediate metabolite undergoes two separate biotransformations in human hepatocytes: it is either oxidized to 5-methoxyindoleacetic acid or reduced to 5-methoxyindole-3-ethanol. [ka]

[0759] Both resulting metabolites are endogenous substances and are formed in the human body, for example, during the synthesis and metabolism of melatonin and serotonin (see, e.g., Biochemistry of the Pineal. Chapter 3. in Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3. in Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).

[0760] Because the primary metabolic pathway for 5-MeO-DMT rapidly leads to metabolites that are also part of the endogenous metabolic pathway, the inventors determined that oxidative deamination of 5-MeO-DMT does not yield metabolites that require the imposition of restrictions on lactation.

[0761] Furthermore, as described in detail in the Examples section, incubation of 5-methoxytryptophol with human hepatocytes shows a high turnover rate, with the compound being completely eliminated within 24 hours. At a test concentration of 1 μM, the in vitro intrinsic clearance of 5-methoxytryptophol was 16.2 μl / min / million cells (half-life of 142 minutes).

[0762] Thus, the plasma concentration of 5-methoxytryptophol, if any is formed at all, declines rapidly to reach endogenous levels.

[0763] 5-MIAA is a weak acid and will exist in plasma in an ionized form, reducing the likelihood of the compound passing into milk.

[0764] Incubation of 5-MIAA with human hepatocytes showed a low turnover rate, with 75-82% of 5-MIAA remaining after 72 hours. 5-MIAA is believed to be the final metabolic product of 5-MeO-DMT.

[0765] 5-MIAA exhibits relatively low plasma binding of approximately 50% (mean unbound fraction (Fu); see Examples section). It remains in the circulation subject to renal clearance. Given a typical glomerular filtration rate of 90-120 ml / min, this means that 5-MIAA is completely removed from the circulation due to urinary excretion in approximately 1-2 hours (depending on the patient's size and taking into account the increase in blood volume that occurs during pregnancy).

[0766] As a result, the plasma concentration of 5-MIAA also declines rapidly.

[0767] Combined with the rapid clearance of 5-MeO-DMT (<1 hour), this supports the view that the administered therapy and all associated metabolites are cleared from the circulation in approximately 2 hours.

[0768] A further metabolite identified, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The formed metabolite then undergoes glucuronidation catalyzed by UGT. [ka]

[0769] As part of the pharmacokinetic studies, it was determined that bufotenin was barely detectable in human serum, in any case 15 minutes after administration of 5-MeO-DMT.

[0770] Bufotening glucuronide cannot bind to the receptor and exerts no effect. Furthermore, its concentration was too low to be detected in the hepatocyte assay. Bufotening glucuronide is further converted to 5-hydroxyindoleacetic acid. [ka]

[0771] 5-Hydroxyindoleacetic acid is an endogenous substance, occurring, for example, in the metabolism of melatonin and serotonin (see above).

[0772] Because the O-demethylation pathway of 5-MeO-DMT leads to the primary metabolite bufotenin, which is rapidly cleared from plasma, and further metabolism leads to compounds that are present only in very low concentrations and ultimately to metabolites that are also part of endogenous metabolic pathways, the inventors have determined that O-demethylation of 5-MeO-DMT does not yield metabolites that require the imposition of restrictions on breastfeeding.

[0773] The third metabolic pathway involves N-oxidation. [ka]

[0774] In silico modeling of the metabolite formed, 5-MeO-DMT-N-oxide, was deemed non-genotoxic, consistent with the negative results of in vitro genotoxicity evaluation of the parent molecule. As confirmed by observations in rats (Sitaram, BR, Lockett, L., Blackman, GL, McLeod, WR, 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine, and their N-oxides in the rat. Biochemical Pharmacology 36:2235-2231), this compound is water-soluble and rapidly excreted. Because the 5-MeO-DMT metabolic pathway, including N-oxidation, plays only a minor role and produces a low proportion of rapidly excreted metabolites with no apparent toxicity, we determined that N-oxidation of 5-MeO-DMT does not produce metabolites that require the imposition of lactation restrictions.

[0775] Based on the above, the inventors have determined that breastfeeding may be resumed shortly after treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0776] Therefore, if the patient is a nursing mother, she is advised to discontinue nursing until 48 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. In particular, she is advised to discontinue nursing until 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0777] Preferably, breastfeeding should be discontinued for no more than 6 hours, more preferably no more than 3 hours, and most preferably no more than 2 hours after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0778] The shortness of this interruption and the corresponding possibility of resuming breastfeeding soon after treatment contribute to the success of the treatment, especially to maternal function and well-being and the development of the infant(s).

[0779] Treatment of mental or neurological conditions Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0780] A depressive episode is a period of depressed mood and / or loss of pleasure in most activities.

[0781] For example, according to DSM-V, a major depressive episode is characterized by the presence of five or more symptoms 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 pleasure.

[0782] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0783] Disorders characterized by depressive episodes involve one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0784] Severity and success of treatment can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0785] In patients suffering from disorders characterized by depressive episodes, altered functional connectivity is observed within and / or between several brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; and abnormalities in concentration and physiological arousal.

[0786] Treating a patient suffering from a disorder characterized by depressive episodes (including treatment-resistant forms of such a disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof leads to improvement in the disorder characterized by depressive episodes.

[0787] Improvement in the disorder characterized by a depressive episode, as reflected by a reduction in CGI-S score, 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0788] The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in CGI-S score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by depressive episodes, 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0789] Improvement in the disorder characterized by a depressive episode, as reflected by a reduction in the MADRS 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.

[0790] The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in the MADRS score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by depressive episodes, as reflected by a reduction in the MADRS score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0791] Improvement in the disorder characterized by a depressive episode, as reflected by a reduction in the HAM-D 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.

[0792] The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in the HAM-D score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by depressive episodes, as reflected by a reduction in the HAM-D score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0793] Improvement in maternal functioning in patients suffering from a disorder characterized by depressive episodes is reflected by an improvement in the BIMF total score on at least days 7; 14; and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0794] The improvement in maternal functioning in patients suffering from a disorder characterized by depressive episodes, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal functioning, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days; more preferably, for at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0795] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest, which affect how a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0796] Patients may suffer from moderate or severe MDD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. It is further contemplated that patients may suffer from severe major depressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 25 or greater.

[0797] Patients with MDD may also suffer from treatment-resistant forms of the disorder (TRD).

[0798] MDD is accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0799] Severity and success of treatment can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0800] In patients with MDD, dysfunctional connectivity and regulation within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network, is observed. Functional connectivity is significantly different from that observed in healthy controls.

[0801] Treating patients suffering from MDD (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof leads to improvement in the MDD.

[0802] Improvement in MDD, as reflected by a reduction in CGI-S score, 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0803] The improvement in the patient's MDD, as reflected by a reduction in CGI-S score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the MDD, 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0804] Improvement in MDD, as reflected by a reduction in MADRS 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.

[0805] The improvement in MDD in the patient, as reflected by a reduction in the MADRS score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD, as reflected by a reduction in the MADRS score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0806] Improvement in MDD, as reflected by a reduction in HAM-D 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.

[0807] The improvement in MDD in the patient, as reflected by a reduction in the HAM-D score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD, as reflected by a reduction in the HAM-D score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0808] Improvement in maternal function in patients with MDD is reflected by an improvement in the BIMF total score on at least days 7; 14; and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0809] Improvement in maternal function in patients with MDD, as reflected by an improvement in the BIMF total score, occurs within about 6 days of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days; more preferably, for at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0810] persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. It is diagnosed when depression is present for the majority of days for at least two years, with symptom-free periods of less than two months.

[0811] In a depressed state, two or more of the following must be present: 1. feelings of hopelessness; 2. low energy or fatigue; 3. low self-esteem; 4. decreased (insomnia) or increased (hypersomnia) sleep; 5. loss of appetite or overeating; 6. difficulty making decisions or poor concentration.

[0812] Patients with persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0813] Persistent depressive disorder is accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0814] Severity and success of treatment can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0815] In patients with persistent depressive disorder, altered functional connectivity is observed within and / or between several brain regions involved in processing, regulation, emotional memory; cognitive processes related to rumination; and abnormalities in concentration and physiological arousal. Connectivity dysfunction is observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0816] Treating a patient suffering from persistent depressive disorder (including treatment-resistant forms of such disorder) with 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, leads to improvement in the persistent depressive disorder.

[0817] Improvement in persistent depressive disorder, as reflected by a reduction in CGI-S score, 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0818] The improvement in the patient's persistent depressive disorder, as reflected by a reduction in CGI-S score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the persistent depressive 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0819] Improvement in persistent depressive disorder, as reflected by a reduction in MADRS 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.

[0820] The improvement in the patient's persistent depressive disorder, as reflected by a reduction in the MADRS score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the persistent depressive disorder, as reflected by a reduction in the MADRS score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0821] Improvement in persistent depressive disorder, as reflected by a reduction in HAM-D 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.

[0822] The improvement in the patient's persistent depressive disorder, as reflected by a reduction in the HAM-D score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the persistent depressive disorder, as reflected by a reduction in the HAM-D score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0823] Improvement in maternal functioning in patients with persistent depressive disorder is reflected by an improvement in the BIMF total score on at least days 7; 14; and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0824] Improvement in maternal functioning in patients with persistent depressive disorder, as reflected by an improvement in the BIMF total score, occurs within about 6 days of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal functioning, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days; more preferably, for at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0825] Seasonal affective disorder Seasonal affective disorder is a mood disorder with a seasonal pattern; symptoms often begin in the fall and subside in the spring. Many sufferers experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0826] Patients with seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0827] Seasonal affective disorder is associated with one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0828] Severity and success of treatment can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0829] In patients with seasonal affective disorder, altered functional connectivity has been observed within and / or among several brain regions involved in processing, regulation, emotional memory; cognitive processes related to rumination; and abnormalities in focus and physiological arousal. Connectivity dysfunction has been observed within and / or among the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0830] Treating a patient suffering from seasonal affective disorder (including treatment-resistant forms of the disorder) with 5-MeO-DMT or a pharmaceutically acceptable salt thereof leads to improvement in the seasonal affective disorder.

[0831] Improvement in seasonal affective disorder, as reflected by a reduction in CGI-S score, 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0832] The improvement in seasonal affective disorder in the patient, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in seasonal affective 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 final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0833] Improvement in seasonal affective disorder, as reflected by a reduction in MADRS 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.

[0834] The improvement in seasonal affective disorder in the patient, as reflected by a reduction in the MADRS score, occurs within about 2 hours of the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in seasonal affective disorder, as reflected by a reduction in the MADRS score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0835] Improvement in seasonal affective disorder, as reflected by a reduction in the HAM-D 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.

[0836] The improvement in seasonal affective disorder in the patient, as reflected by a reduction in the HAM-D score, occurs within about 2 hours after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in seasonal affective disorder, as reflected by a reduction in the HAM-D score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0837] Improvement in maternal function in patients with seasonal affective disorder is reflected by an improvement in the BIMF total score on at least days 7; 14; and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0838] The improvement in maternal function in patients with seasonal affective disorder, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days; more preferably, for at least 28 days after the final administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0839] Bipolar disorder Bipolar disorder (BD) is a psychiatric illness characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (manic or hypomanic episodes). BD is a chronic, relapsing disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic ...

Claims

1. A pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for treating mental or nervous system disorders in breastfeeding mothers.

2. The pharmaceutical composition according to claim 1, wherein the mental or nervous system disorder is accompanied by one or more symptoms selected from sleep disorders, cognitive impairment, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

3. The pharmaceutical composition according to claim 1, wherein the patient suffers from the treatment-resistant type of the aforementioned disorder.

4. The pharmaceutical composition according to claim 3, wherein the improvement of the impairment, reflected in a decrease in the CGI-S score, is observed about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example, about 24 hours after; on day 7; on day 14; and / or on day 28.

5. The pharmaceutical composition according to claim 3, wherein the improvement of the impairment, reflected in a decrease in the CGI-S score, occurs within approximately two hours of the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 3, wherein the improvement of the impairment, reflected in a decrease in the CGI-S score, persists for at least 6 days after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; particularly for at least 14 days; more preferably for at least 28 days.

7. The pharmaceutical composition according to claim 1, wherein the patient further suffers from mild, insufficient, or severe maternal dysfunction.

8. The pharmaceutical composition according to claim 7, wherein the patient has a Birkin Maternal Function Index (BIMF) score of 95 or less, for example, 80 or less, and particularly 65 or less.

9. The pharmaceutical composition according to claim 1, wherein the treatment improves maternal function.

10. The pharmaceutical composition according to claim 1, wherein the improvement relates to one or more, particularly two or more, functional domains of the Birkin Maternal Function Index (BIMF), selected from self-care, infant care, mother-child interaction, maternal psychological well-being, social support, management, and adaptation.

11. The pharmaceutical composition according to claim 8, wherein the BIMF score is improved by 10% or more, preferably by 20% or more.

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

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

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

15. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent doses, each subsequent dose being greater than the previous dose, unless the patient experiences a peak psychedelic experience.

16. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT is administered in a dose of about 2 mg to about 8 mg in a first dose, then increased to a dose of about 8 mg to about 14 mg in a second dose, unless the patient has already experienced a peak psychedelic experience, then increased to a dose of about 14 mg to about 20 mg in a third dose, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

17. The pharmaceutical composition according to claim 16, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, the third dose of 5-MeO-DMT is about 18 mg, or equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.

18. The pharmaceutical composition according to claim 15, wherein the interval between two administrations is 1 hour or more and 24 hours or less, for example, about 1 to 4 hours, preferably about 1 to 2 hours.

19. The pharmaceutical composition according to claim 12, wherein the occurrence of a peak psychedelic experience is determined by achieving at least 60% of the maximum possible score for each of the four subscales (mysticism, positive mood, transcendence of space and time, and inexpressibility) of the 30-item revised Mystical Experiences Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score for the Oceanic Feeling (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least a total Peak Experience Scale (PES) score of 75.

20. The pharmaceutical composition according to claim 19, wherein the occurrence of a peak psychedelic experience is determined by achieving a total Peak Experience Scale (PES) score of at least 75.

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

22. The pharmaceutical composition according to claim 21, wherein 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas; and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, for example, about 12.5 mg / l.

23. The pharmaceutical composition according to claim 22, wherein the aerosol is produced by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, which is configured on a solid support, to thermal energy, and b) passing air over the thin layer to produce aerosol particles.

24. The pharmaceutical composition according to claim 21, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt administered to the patient is inhaled in a single breath.

25. The pharmaceutical composition according to claim 21, wherein the 5-MeO-DMT is used in the form of a free base.

26. The aforementioned disorders include: disorders characterized by depressive episodes, such as major depressive disorder (MDD), 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 disorders; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); and post-traumatic stress disorder (PTSD). The pharmaceutical composition according to claim 1, which is a psychiatric or neurological disorder related to HIV, COVID-19 sequelae, or traumatic brain injury, e.g., pain disorders, such as chronic pain, fibromyalgia, and migraines; mental and behavioral disorders resulting from the use of psychoactive substances, such as substance use disorders (SUDs); psychotic disorders, such as schizophrenia; 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 HIV-related, COVID-19 sequelae-related, or traumatic brain injury-related mental or neurological disorders.

27. The pharmaceutical composition according to claim 1, wherein the patient suffers from a sleep disorder.

28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the patient is a lactating mother who is advised to discontinue breastfeeding until 48 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition according to any one of claims 1 to 27, wherein the patient is a lactating mother who is advised to discontinue breastfeeding until 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition according to any one of claims 1 to 27, wherein the patient is a lactating mother who is advised to discontinue breastfeeding until 6 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition according to any one of claims 1 to 27, wherein the patient is a lactating mother who is advised to discontinue breastfeeding until three hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

32. The pharmaceutical composition according to any one of claims 1 to 27, wherein the patient is a lactating mother who is advised to discontinue breastfeeding until two hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.