Treatment of mental disorders

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of a psychiatric or nervous system disorder in mothers of children 18 months of age or younger, wherein the 5-MeO-DMT or the pharmaceutically acceptable salt thereof is administered via an intravenous, intramuscular, or subcutaneous route.

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 nervous system disorder.

[0002] Psychiatric disorders can be treated with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The 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 breastfeeding mothers can have a wide range of adverse effects on the affected mother, her child(ren), and her family. For example, women with 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 further lead to a breakdown in mother-child interaction, as indicated by higher rates of indifferent attitudes and lower rates of visual and verbal communication between mother and child. Evidence also suggests an association between maternal mental or neurological disorders and child development, as indicated by the fact that children of patients with mental or neurological disorders may be at higher risk of cognitive developmental disorders.

[0006] Despite these issues, treatment options are quite limited: very generally, known treatments for psychiatric or neurological disorders are often associated with only limited success, especially in patients with more than mild symptoms of the disease.

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

[0008] Furthermore, research has shown that nursing mothers may be reluctant to begin drug 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 / withdraw from medical treatment.

[0010] Against this background, there is a need for improved treatment of psychiatric or nervous system disorders, especially for a treatment that not only effectively addresses the symptoms of the disorder and provides a rapid clinical response, but also avoids interfering with the patient's daily activities, especially in terms of caring for infant(s).The treatment should also improve maternal function.In addition, there is a need for a treatment of psychiatric or nervous system disorders that does not require substantial interruption of breastfeeding.

[0011] In recent years, there has been great interest in hallucinogens for the treatment of psychiatric disorders, but this has not currently translated into treatments for nursing mothers based on such substances. This is due to the general lack of relevant clinical data that would allow conclusions to be drawn about the clinical usefulness of hallucinogens, and to the particular concern that the administration of hallucinogens may not be appropriate for nursing mothers.

[0012] Hallucinogens, including hallucinogens, are compounds, some of which are natural and some of which are synthetic, that are defined by their ability to induce sensory distortions, such as changes in hearing and vision, as well as mood and cognitive distortions in humans after ingestion. The term hallucinogen encompasses a fairly broad group of psychotropic molecules with different mechanisms of action. It has been suggested that some psychiatric disorders could, in principle, be treated with psychotropic molecules such as hallucinogens.

[0013] However, hallucinogens have not been approved by any regulatory agency, and indeed clinical experience with such molecules remains quite limited.

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

[0015] Against this background, it is an object of the present invention to provide, inter alia, treatments that are more effective (i.e., a) a greater percentage of patients experiencing a clinical response, b) a greater mean clinical response, c) a faster onset of clinical response, and / or d) a more durable clinical response) than previously described treatments.

[0016] It is a further object of the present invention to provide compounds and dosage regimens for improving psychotropic therapy that have a better safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for such therapies that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens for such therapies that are associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. A further object of the present invention is to identify specific disease aspects and subgroups of specific disease aspects that would benefit from such improved psychotropic therapy.

[0017] A further object of the present invention is to improve maternal function in patients suffering from psychiatric or neurological disorders, particularly 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 nervous system disorder, including 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- or medication-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. The condition may be post-traumatic stress disorder (PTSD), pain disorders such as chronic pain, fibromyalgia, and migraine, mental and behavioral disorders resulting from psychoactive substance use such as substance use disorders (SUD), psychiatric 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, post-COVID symptoms, or a psychiatric or nervous system disorder associated with traumatic brain injury.

[0019] In one embodiment, the patient may have a sleep disorder.

[0020] The treatment allows for improved maternal function.

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

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

[0023] The present invention also provides dosage ranges and regimens useful for the above treatments.

[0024] In the present invention, 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular, or subcutaneous administration.

[0025] The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered at a dose or dosage regimen that causes the patient to experience a hallucinogenic peak experience. A dose of about 1 mg to about 10 mg of 5-MeO-DMT, or an equimolar amount of a pharmaceutically acceptable salt, may be administered. DETAILED DESCRIPTION OF THE INVENTION

[0026] definition As used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered can be calculated from the weight of the free base, assuming that an equimolar amount is used.

[0027] As used in the context of the present invention, a "patient" to be treated is generally a mother having a child under the age of 18 months, particularly under the age of 12 months, who has been diagnosed with a psychiatric or nervous system disorder by a qualified professional in accordance with accepted medical practice.

[0028] The diagnosis of mental or nervous system disorders can be, for example, according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5) published by the American Psychiatric Association.As will be clear from the following discussion of specific conditions, in some cases, the criteria can be modified or supplemented to better define the patient or patient group that will be particularly benefited from the treatment of the present invention.In any case, the diagnosis is made by a doctor or psychologist.It is not enough for the human subject to believe that he or she is suffering from the disorder.

[0029] As used in the context of the present invention, unless otherwise specified, the terms "treat" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition or disorder, and shall include the administration of compounds and practice of methods according to the present invention to alleviate the signs and / or symptoms of a disease or to eliminate a disease, condition or disorder.

[0030] The patient may suffer from treatment-resistant disease. Treatment-resistant means that the patient has not shown sufficient improvement after at least two appropriate treatment courses. In particular, the patient has not shown sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy. For example, the patient has not shown sufficient improvement after at least two appropriate drug therapy courses. At least two previous treatment courses have been carried out, particularly in the current episode of the disease (for example, in the current episode of depression, if the patient suffers from a disorder characterized by depressive episodes).

[0031] As used in the context of the present invention, "suicidal ideation" refers to thinking about, considering, or planning suicide. The presence of suicidal ideation in a patient is diagnosed by a physician or psychologist using established protocols and methods for diagnosing suicidality. Generally, it is not enough for a patient to believe that they are suffering from suicidal ideation. In some circumstances, a patient experiencing suicidal ideation is considered to be at imminent risk of committing suicide or to have an "intent to commit suicide."

[0032] As used in the context of the present invention, and unless otherwise specified, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is desired by a researcher, physician, or other clinician, which biological or clinical response in humans shall include alleviation of the signs and / or symptoms of the disease, condition, or disorder being treated.

[0033] "Clinical response" includes, but is not limited to, improvement on rating scales.

[0034] The severity and change in severity of the condition can be assessed by the Clinical Global Impression (CGI) scale, a measure of symptom severity, treatment response, and treatment efficacy.

[0035] The CGI rating scale was developed to provide a brief, independent assessment of a patient's overall functioning before and after treatment in the opinion of the clinician (Busner, J. and Tagrum, S.D., 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

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

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

[0038] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has an equally simple format. After treatment, clinicians compare the patient's overall clinical condition with their pre-treatment condition (the so-called baseline value). Again, a single question is rated on a 7-point scale: "Compared to the patient's condition at the time of entry into the project (before medication began), this patient's condition has improved greatly since treatment began: 1 = very much; 2 = very much; 3 = minimally; 4 = no change from baseline (before treatment began); 5 = minimally; 6 = very much worse; 7 = very much worse since treatment began."

[0039] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is the counterpart to the Clinical Global Impression (CGI). The PGI consists of a single item based on the CGI, adapted for patient use. It can measure disease severity (PGI-S) or disease improvement (PGI-I).

[0040] The severity and change in severity of the condition may further be assessed using a rating scale applicable to the particular psychiatric or nervous system disorder suffered by the patient.

[0041] Individual items, and subcombinations of individual items, of the scales described herein may be used to assess specific aspects of the disease.

[0042] Maternal functioning can be assessed using the Birkin Index of Maternal Functioning (BIMF).

[0043] When clinical response at an early time point (e.g., 2 hours) after drug administration is assessed based on endpoints developed for longer recall periods (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 sleep items recorded at baseline before drug administration) may be applied.

[0044] At earlier time points, the outlined considerations apply because, on the one hand, to assess clinical response, the pre-treatment state of the patient needs to be kept as low as possible in its influence on any scores recorded after treatment, and, on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0045] At later time points (e.g., Day 1 or later), all items on the relevant scale for assessing clinical response can be assessed, if necessary, using an adapted recall period, typically so that any pretreatment 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).

[0046] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") shall mean the introduction of a quantity of active compound or pharmaceutical ingredient, which may be a predetermined amount, into a patient via any route. The active compound may be administered by intravenous, intramuscular or subcutaneous administration.

[0047] As used in the context of the present invention, unless otherwise specified, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined sequence of one or more individual administrations.

[0048] Mental and nervous system disorders The psychiatric and nervous system disorders treated in accordance with the present invention have in common that they are associated with one or more symptoms from the symptom groups discussed below, including sleep disorders, cognitive dysfunction, anxiety, psychomotor slowing, social / emotional withdrawal, and negative thinking.

[0049] 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 nervous system disorder.

[0050] The psychiatric or nervous system disorder treatable with 5-MeO-DMT or a pharmaceutically acceptable salt thereof is, in particular, major depressive disorder, persistent depressive disorder, bipolar disorder, anxiety disorder, post-traumatic stress disorder, body dysmorphic disorder, obsessive-compulsive disorder, eating disorder, or psychoactive substance abuse.

[0051] In a preferred embodiment, the psychiatric disorder is major depressive disorder.

[0052] In another preferred embodiment, the psychiatric disorder is postpartum depression (PPD), which is a complex mix of physical, emotional and behavioral changes that occur in some women after giving birth.PPD is also known as perinatal-onset major depressive disorder.According to the criteria of DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), PPD is diagnosed when symptoms of major depressive disorder (MDD) begin during pregnancy or within 4 weeks of delivery.

[0053] In another preferred embodiment, the psychiatric disorder is bipolar disorder, for example bipolar II disorder. Patients diagnosed with bipolar disorder are particularly those suffering from a current major depressive episode.

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

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

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

[0057] Treatment outcome is assessed using one or more indexes or scales at one or more time points after the course of treatment has ended.

[0058] The assessment can be performed after the acute hallucinatory experience has subsided. A suitable time point for early assessment is generally about 2-3 hours after the last dose. Early assessments can typically be performed, for example, about 2 hours or about 3 hours after the last 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 as early as the day after treatment (i.e., Day 1) to allow the treated patient an opportunity to get at least one night's sleep.

[0060] Thus, evaluation on day 1 or evaluation on day 1 means evaluation on the day after dosing. Evaluation will be performed no later than 12 hours after the last dose, and in any event no later than one night after the last dose and no later than 36 hours after the last dose. Evaluation can be performed after about 24 hours.

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

[0062] For example, when using one of the scales for assessing the severity of psychiatric or nervous system disorders to evaluate clinical response, if the clinical response is evaluated at an early time point (for example, 2 hours) after drug administration based on the endpoint made during a longer recall period (for example, usually 7 days for MADRS), reasonable modification of such endpoint (for example, changing the MADRS recall period to 2 hours, and carrying forward the sleep items recorded at the baseline before drug administration) can be applied.Unless the recall period is specifically indicated, the same applies to any other scale used herein to evaluate the treatment effect on psychiatric or nervous system disorders.

[0063] At earlier time points, the outlined considerations apply because, on the one hand, to assess clinical response, the pre-treatment state of the patient needs to be kept as low as possible in its influence on any scores recorded after treatment, 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 relevant scales for assessing clinical response can usually be assessed, with a recall period adapted as necessary so that any pre-treatment scores do not need to be carried forward.

[0065] Active Agent Psychiatric or neurological disorders are characterized by several aspects that in themselves constitute a significant disease burden and deserve appropriate treatment. Therefore, treatments are needed, particularly by pharmacological intervention, to improve specific aspects of the disease, rather than just improving the overall disease score.

[0066] The inventors believed that carefully selected hallucinogens may lead to improved treatment and even overall improvement in the disease and maternal functioning.

[0067] The inventors further believed that in the case of treating nursing mothers with psychiatric or neurological disorders, carefully selected hallucinogens may allow nursing to continue substantially uninterrupted.

[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, are described, each with several subtypes). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "hallucinogens," highlighting their remarkable ability to induce qualitatively altered states of consciousness (such as euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences) while minimizing other effects (such as sedation, narcosis, or hyperstimulation).

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

[0070] Various serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets, such as monoamine transporters and minor amine-associated receptors.

[0071] Recently published clinical trials using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations containing DMT) for certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may hinder their clinical use.

[0072] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, RE Jr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who experienced a manic episode after ingesting LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication that subsequently resolved, but a typical manic episode of psychotic proportions followed approximately three weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a manic episode after ingesting psilocybin mushrooms (self-reported). Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ayahuasca (a DMT-containing preparation) consumption in a man with bipolar disorder.

[0073] A further case report is described 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 dosing regimen.

[0075] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogen for therapeutic use. 5-MeO-DMT has a distinct pharmacological profile that differs from that of other hallucinogenic compounds.

[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 a higher affinity for the 5-HT1A receptor subtype compared to other classic hallucinogens.

[0077] As further detailed in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brain were measured. i The inhibitory constants (K values) of psilocin, DMT, and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe α-MeO-DMT and β-MeO-DMT binding affinity for the 5-HT2A receptor are 37, 117, and 122 nM, respectively.

[0078] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor and acts as a potent agonist. In the case of psilocin and DMT, the contribution of 5-HT2A binding is increased compared to 5-MeO-DMT, with the latter showing the largest difference in affinity for 5-HT1A compared to 5-HT2A among the three compounds. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than 5-HT2A binding for the other two compounds.

[0079] 5-HT1A receptor agonism has been reported to reduce impulsivity and aggression, while 5-HT2A receptor agonism may short-term increase these same traits. Furthermore, the dopamine system has been implicated in the pathogenesis of mania, with increased dopamine activity leading to mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0080] Compared to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, preferably using the administration schemes described herein, can be administered to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), e.g., bipolar I disorder and bipolar II disorder, psychotic disorders, e.g., schizophrenia, or personality disorders, e.g., schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders, when 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 sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0083] Furthermore, antidepressant-induced hypomania has been reported in patients suffering from 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 peak experiences (i.e., experiences characterized by an emotional perspective shift described as a "loss of self"), often leading to an overwhelming sense of "oneness with the universe" more quickly than other hallucinogens. 5-MeO-DMT also has a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after intravenous injection, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0085] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. We have demonstrated that 5-MeO-DMT binds to recombinant human 5-HT7 receptors as a radioligand.3 Nonspecific binding was estimated using [H]LSD and serotonin, and the Ki was determined to be 2.3 nM.

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

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

[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. It coordinates circadian rhythms in various brain regions. Disruption of this coordination can lead to disease states, particularly those involving sleep disorders. Resting-state functional connectivity analysis in patients with sleep disorders revealed modulation of functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0090] Expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to its function in regulating the sleep / wake cycle, and the inventors believe this may allow treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on the receptor.

[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, along with its "resetting" of network functional connectivity and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0092] The inventors further believe that 5-MeO-DMT's binding to the 5-HT7 receptor and also to the 5-HT1A receptor as two mediators of its effects (including "resetting" functional network connectivity and neuroplasticity effects) may also achieve beneficial effects in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal. This is supported by the clinical results demonstrated 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 by the monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

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

[0096] Analysis of the pharmacokinetic profile of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. The titration described herein does not result in accumulation and thus does not result in high plasma concentrations, for example, at 10 minutes, 2 hours, or 3 hours after administration.

[0097] The inventors further confirmed that 5-MeO-DMT exhibits various properties that make it an attractive treatment for PPD. In contrast to SSRIs, it is a fast-acting drug (in the 5-MeO-DMT-TRD study, 5 / 8 TRD patients achieved remission within 2 hours after administration, 8 / 8 patients achieved remission on day 1, and 7 / 8 patients maintained remission on day 7). Treating PPD patients with 5-MeO-DMT can not only achieve rapid improvement in depressive symptoms, but also in maternal functioning. Furthermore, 5-MeO-DMT is distinct from SSRIs because it is administered in a single treatment session and optionally re-administered at irregular intervals. SSRIs require long-term daily dosing regimens, which are associated with low compliance, and, in the case of brexanolone, require continuous 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 for continuation of breastfeeding 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. When reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

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

[0102] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than expected based on the natural abundance of this isotope.

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

[0104] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

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

[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 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0108] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0109] Prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used in accordance with the present invention. Such prodrugs of 5-MeO-DMT may be metabolically converted to 5-MeO-DMT. Thus, when reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reference can be substituted for a 5-MeO-DMT prodrug or a salt thereof.

[0110] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated 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 There is R 1 , R 2 , R 3 and R 4is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0112] A preferred example of the organic moiety is —CH(R 3 )OC(O)R 4 and -C(O)OR 1 and R 1 , R 3 and R 4 is defined as above.

[0113] Prodrugs (particularly those of 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, specifically ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0115] Methods for preparing the prodrugs discussed 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 the prodrug at 10 mg / kg was max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[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 intravenously, intramuscularly, or subcutaneously. These routes of administration can ensure rapid onset of action. The most preferred route of administration is intravenous administration, i.e., intravenous injection.

[0119] 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration by injection, and examples of excipients and vehicles for such formulations are known in the art.

[0120] Dosage regimen The present invention also provides dosage ranges, specific dosages, as well as administration regimens (administration schemes) and suitable routes of administration.

[0121] The present invention is based, in part, on the inventors' conclusion that the acute manifestation of a peak hallucinatory experience following administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, drives the therapeutic benefit thereof, either causally or as at least a surrogate behavioral marker of an underlying unknown therapeutic mechanism, in patients as defined herein diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder, and including disorders associated with suicidal ideation (particularly one or more of the aspects defined above).

[0122] The result is a superior therapeutic profile, achieving peak experience more quickly, in a greater proportion of patients, and with greater reproducibility within individual patients compared to previously tested hallucinogens, dosing regimens, and routes of administration.

[0123] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., no reduction or disappearance of the hallucinogenic effect after re-administration) as the basis for a dosing regimen with frequent re-administration (e.g., more than once daily or daily), which is designed to increase the incidence of peak experiences and thereby enhance therapeutic benefit. Such repeated administration within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdosing, which may otherwise result in physical side effects (e.g., serotonin syndrome), negative psychological reactions (e.g., flashbacks of the experience at a later time), the induction of mania or hypomania, or a less meaningful hallucinogenic experience with little or no memory of the altered state (so-called "whiteout"). Furthermore, starting with a low dose generally allows patients to become accustomed to the hallucinogenic experience and prepare them for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at that higher dose. Additionally, the prospect of initiating treatment at lower doses will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0124] Frequent re-administration of serotonergic hallucinogens to improve the rate and reproducibility of peak experiences, as well as to enhance therapeutic efficacy, reduce side effects, and improve compliance rates, may not be possible with other hallucinogens due to the slow onset and long duration of hallucinogen effects, and the rapid onset of tolerance (i.e., reduced or absent hallucinogen effects after re-administration), which may last for several days.

[0125] Patients as defined herein who are diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder, and including disorders associated with suicidal ideation, are treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0126] In a preferred embodiment, the 5-MeO-DMT is administered as monotherapy, ie, the patient is not receiving any other treatment for the diagnosed disorder.

[0127] The dosage of 5-MeO-DMT administered to patients diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder and disorders associated with suicidal ideation, ranges from about 1 mg to about 10 mg, or any amount within that range, and is administered in the form of a formulation for administration based on a pharmaceutically acceptable salt of 5-MeO-DMT, e.g., the hydrobromide salt, the weight of which can be calculated from the specified weight of the 5-MeO-DMT free base, assuming an equimolar amount is used. Specific useful amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Note that, when a range such as "about 1 mg to about 10 mg" is given herein, the inventors contemplate all individual values ​​within that range, some of which may be specifically mentioned, but not all (simply for purposes of brevity).

[0128] In a preferred embodiment, the improved method for treating a patient as defined herein diagnosed with a disorder as defined herein (including treatment-resistant forms of the disorder, including a disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises an onset of a clinical response within about 2 hours after administration of 5-MeO-DMT.

[0129] In a preferred embodiment, the improved method for treating a patient as defined herein 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 that occurs within about 2 hours after administration of 5-MeO-DMT and remains active 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.

[0130] 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 a disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0131] In one preferred embodiment, this more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with the interval between each administration within each treatment block being at least about 1 hour and not more than about 24 hours, and with the interval between the end of one treatment block and the start of the next treatment block being at least about 6 days.

[0132] In an even more preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, with the interval between each dose within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0133] In a most preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, with the interval between each dose within each treatment block being about 1 to 4 hours, preferably 1 to 2 hours, and with the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0134] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0135] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0136] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic peak experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0137] For embodiments in which the dosage is increased with each subsequent administration, the dosage for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage for the previous administration. For example, if the dosage for the first administration is 1 mg and the dosage increase is 3 mg, the dosage for the second administration will be 4 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage for the third administration will be 7 mg.

[0138] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration and to a dosage selected from about 7 mg to about 9 mg for the third administration, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0139] In additional preferred embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration, unless the patient has yet to experience a hallucinogenic peak experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific amounts useful for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0140] Similarly, in a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1.5 mg to about 2.5 mg for the first administration, and then increased to a dosage selected from about 3.5 mg to about 4.5 mg for the second administration and to a dosage selected from about 5.5 mg to about 6.5 mg for the third administration, unless the patient has yet to experience a peak hallucinogenic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects. Specific amounts useful for the first, second, and third administrations are, for example, about 2 mg, about 4 mg, and about 6 mg.

[0141] In a more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2.5 mg to about 3.5 mg for the first administration, and then increased to a dosage selected from about 4.5 mg to about 5.5 mg for the second administration and to a dosage selected from about 6.5 mg to about 7.5 mg for the third administration, unless the patient has yet to experience a peak hallucinogenic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects. Specific amounts useful for the first, second, and third administrations are, for example, about 3 mg, about 5 mg, and about 7 mg.

[0142] In a more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4.5 mg to about 5.5 mg for the second administration and to a dosage selected from about 7 mg to about 8 mg for the third administration, unless the patient has yet to experience a peak hallucinogenic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects. Specific amounts useful for the first, second, and third administrations are, for example, about 2.5 mg, about 5 mg, and about 7.5 mg.

[0143] In a more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of a first treatment block, and then increased with each subsequent administration within the first treatment block until it reaches 10 mg or until all administrations within that treatment block are administered, whichever occurs first, or until the patient experiences a peak hallucinatory experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if a patient experiences a peak hallucinatory experience at an 8 mg dose, and therefore the highest dosage in the first treatment block is 8 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 8 mg.

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

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

[0146] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 3 mg to about 5 mg for the second administration of the first treatment block and to a dosage selected from about 5 mg to about 7 mg for the third administration of the first treatment block, unless the patient has yet to experience a peak hallucinogenic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts useful for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 4 mg, and about 6 mg.

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

[0148] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1.5 mg to about 3.5 mg for the first administration of a first treatment block, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block and to a dosage selected from about 6.5 mg to about 8.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a peak hallucinogenic experience within that treatment block or the supervising physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts useful for the first, second, and third administrations in a first treatment block are, for example, about 2.5 mg, about 5 mg, and about 7.5 mg. Preferably, a pharmaceutically acceptable salt of 5-MeO-DMT is used in all of the above dosing regimens, it being understood that the appropriate weight of the salt to be administered can be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0149] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0150] The occurrence of a "peak hallucinatory experience" in a patient can be confirmed by achieving at least 60% of the maximum possible score on each of the four subscales (mysticism, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experiences Questionnaire (MEQ30) (reviewed in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0151] The occurrence of a "peak hallucinatory experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic-Infinite (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (reviewed in Roseman L et al., Front Pharmacol. 2018;8:974).

[0152] In accordance with the present invention, the occurrence of a "peak hallucinatory experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES), also known as the Peak Hallucinatory Experience Questionnaire (PPEQ), which is the average of the patient's responses, rated from 0 to 100, to the following three questions: 1. How intense the experience was, 2. To what extent did it cause loss of control, and 3. How severe (i.e., profound and significant) was the experience?

[0153] Sleep disorders There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. NREM sleep can be divided into four stages (I-IV). These NREM stages correspond to increasing depths of sleep. NREM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. Early in the night, NREM sleep is deeper and occupies a disproportionate amount of time, especially within the first sleep cycle. As the night progresses, NREM sleep becomes shallower, with a greater proportion of each cycle allocated to REM sleep.

[0154] Normal, healthy sleep consists of different stages, as outlined above, which proceed sequentially and in a tightly regulated sequence throughout the night.

[0155] When this tight regulation is disrupted, sleep disorders occur.

[0156] A sleep disorder refers to a condition that affects the quality, timing, or duration of sleep, whether idiopathic or occurring in the context of a medical condition (e.g., a psychiatric or nervous system disorder). Sleep disorders affect a person's ability to function adequately while awake.

[0157] Common forms of sleep disorders include problems falling asleep and maintaining sleep (insomnia), excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or partial awakenings (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0158] Insomnia is a sleep disorder that makes it difficult for people to fall asleep or stay asleep. People with insomnia have difficulty falling asleep, frequent awakenings during the night, difficulty returning to sleep, waking too early in the morning, unrefreshing sleep, and / or at least one daytime problem due to lack of sleep, such as fatigue, sleepiness, mood, concentration problems, or accidents at work or while driving.

[0159] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. Sleep drunkenness involves difficulty transitioning from sleep to wakefulness. Individuals experiencing sleep drunkenness report waking up with confusion, disorientation, and sluggishness, followed by repeated returns to sleep.

[0160] Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances resulting from alterations in an individual's internal circadian rhythm or from imbalances between the circadian rhythm and desired or necessary work or social schedules. This dyssynchronization can be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep duration is typically shortened and disrupted, performance during desired wakefulness is reduced, and intermittent opportunities to return to a normal sleep schedule are unsuccessful.

[0161] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (such as sleepwalking or nightmares) that people experience before falling asleep, during sleep, or during periods of wakefulness between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0162] Sleep-related breathing disorders are characterized by abnormal breathing difficulties during sleep. Breathing is a complex process that depends heavily on the coordinated action of respiratory muscles and the brain (control center). One form of sleep-related breathing disorder is central sleep apnea. Central sleep apnea occurs when the brain stops sending signals that control breathing, for example, due to an underlying disease. Central sleep apnea potentially has serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, which leads to sleep fragmentation due to microarousals or awakenings. The result can be excessive daytime sleepiness.

[0163] In sleep-related movement disorders, repetitive, relatively simple, and usually stereotyped movements interfere with sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0164] Lack of adequate quantity or quality of sleep can cause personality changes, worsen existing mental disorders, and even trigger the onset of mental disorders.Sleep disorders can also interfere with cognitive function and cause memory impairment.Sleep-deprived subjects may experience difficulty in decision-making, irritability, executive function problems, and slow reaction times.Insomnia can also negatively impact life by contributing to the development of obesity, diabetes, and heart disease.

[0165] Treatment for sleep disorders varies depending on the type and underlying cause. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatments may also include medication or psychotherapy.

[0166] Available treatments are not successful in all patients, may be associated with side effects, and / or may require long-term treatment to achieve relevant therapeutic benefits.

[0167] In patients suffering from sleep disorders associated with psychiatric or nervous system disorders, known treatments for the psychiatric or nervous system disorders do not always improve the sleep disorder.

[0168] For example, sleep disorders are often associated with psychiatric disorders such as depression. However, treatment of depression does not necessarily lead to improvement of the associated sleep disorders. Most antidepressants have been shown to affect sleep structure, and while some classes of antidepressants improve sleep, others may cause sleep disorders.

[0169] Although sleep disorders may be considered a condition worthy of treatment regardless of any other conditions, disorders, or symptoms that an individual may have, some mental and nervous system disorders are associated with sleep disorders. In particular, the relationship between sleep and mental or nervous system disorders is often bidirectional. Not only can mental or nervous system disorders adversely affect healthy sleep patterns, but sleep disorders can also be a contributing factor to the onset, progression, and prognosis of mental health or nervous system disorders.

[0170] Treatment according to the present invention reduces or eliminates sleep disorders and preferably also improves associated psychiatric or nervous system disorders.

[0171] Measurement of sleep disturbances Sleep can be assessed by measuring parameters such as sleep time, sleep architecture, sleep latency, and wake frequency and duration throughout the night. Quantitative metrics can be measured using objective methods, including polysomnography, actigraphy, and sleep latency measurements, or using self-reported metrics (questionnaires).

[0172] Polysomnography is a technique that requires patients to be monitored overnight in a specialized clinic, where various functions are measured throughout the night, including eye movements, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body position and movements, snoring, and heart rate.

[0173] Another quantitative measurement is actigraphy, in which an actimetry sensor is worn to measure motor activity, which is continuously recorded and used to assess the sleep-wake cycle. This technology allows patients to continue their normal routine while the necessary data is recorded in a natural sleep environment.

[0174] Sleep latency can be measured by the Multiple Sleep Latency Test (MSLT). This test provides an objective metric for determining how long it takes a person to fall asleep during multiple test naps. A mean sleep latency of approximately 10 minutes is considered normal; a mean sleep latency of less than 8 minutes indicates a sleep disorder (excessive daytime sleepiness). Concomitant analysis of brain activity can aid in further diagnosis of sleep disorders.

[0175] Sleep assessment questionnaires collect assessments of elements of sleep quality, such as perceived depth of sleep, difficulty waking, and restfulness after sleep, as well as assessments of other factors that may affect sleep quality, such as comorbid conditions and medication use. Assessment of qualitative aspects of the sleep experience is important because sleep disorders can often persist despite normal quantitative measures of sleep.

[0176] Questionnaires may not only facilitate rapid and accurate assessment of complex clinical problems but also help track patients' progress.

[0177] Various sleep quality indices are known. The following indices each include examples of questionnaires for assessing sleep generally, and for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias specifically. However, the present invention is not limited to the use of any particular indices or questionnaires.

[0178] Some questionnaires rely on a recall period (recall window) of several days or weeks. This may be appropriate for diagnosing sleep disorders, but it is not always appropriate for evaluating the rapid onset of therapeutic effect, especially the effect after treatment. For some questionnaires, the recall period can be modified so that the score obtained reflects the period after treatment. In order to evaluate the effect of treatment on the sleep of patients suffering from certain conditions, the questionnaires specifically considered herein rely on a recall period that does not start earlier than the time when acute hallucinatory experience subsides after the last administration. To meet this criterion, the recall period that is usually applied is modified as necessary.

[0179] Sleep quality in general can be assessed using, for example, the Sleep-50 questionnaire.

[0180] The SLEEP-50 questionnaire consists of 50 items designed to screen for various sleep disorders in the general population. The scale consists of nine subscales that reflect some of the most common sleep-related disorders and conditions and factors necessary for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic limb movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep conditions on daily functioning. For each item, respondents are asked to indicate on a scale ranging from 1 ("not at all true") to 4 (very true") how closely the statement matches their own experiences over the past month or another appropriate recall window.

[0181] To diagnose a sleep disorder, not only must specific subscales (e.g., insomnia) exceed certain cutoff points, but respondents must also meet cutoffs of at least 3 or 4 ("very true" or "very true," respectively) on subscales assessing the impact of sleep pathology on daily functioning (Spoormaker et al., Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0182] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0183] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other assessment tools include the Insomnia Severity Index, the Espie Sleep Disorders Questionnaire, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0184] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disorders. The PSQI is a self-rated questionnaire containing 19 questions. Respondents are asked to indicate how often they have experienced specific sleep difficulties over the past month or another suitable recall period.

[0185] The 19 self-rated questions assess a wide variety of sleep quality factors, including estimates of sleep duration and sleep latency, as well as estimates of the frequency and severity of specific sleep-related problems. These 19 items are organized into scores for seven components: (1) subjective sleep quality, (2) sleep latency, (3) sleep duration, (4) habitual sleep efficiency, (5) sleep disturbances, (6) use of sleep medications, and (7) daytime dysfunction.

[0186] Each component is assigned a score of 0 to 3. Higher scores indicate more acute sleep disturbances. Details of how the Pittsburgh Sleep Quality Index is scored can be found in the appendix to Buysse et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May;28(2):193-213.

[0187] The scores for the seven components are then summed to produce a single overall score ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. The cutoff value for the overall score is 5, which distinguishes poor sleepers from good sleepers. A overall score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0188] When the PSQI is used to assess treatment outcome, successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 5 or less.

[0189] The Insomnia Severity Inventory (ISI) is a short questionnaire assessing subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning, how significant the respondent perceives their insomnia compared to others, and the overall level of distress caused by sleep problems. Individual responses can be scored from 0 (none) to 4 (very much). Higher total scores correspond to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 means "subthreshold insomnia," 15–21 means "clinical insomnia (moderate severity)," and 22–28 means "clinical insomnia (severe)" (A. Shahid et al. (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.

[0190] Successful treatment is indicated by (i) a reduction in score (eg, greater than 7 points, particularly greater than 8 points), preferably (ii) a reduction below the cutoff for clinically significant insomnia.

[0191] The Espie Sleep Disorders Questionnaire (SDQ) assesses the subjective experience of insomnia. Following assessments of emotional restlessness / agitation, mental overactivity, consequences of insomnia, and lack of sleep readiness, the SDQ specifically addresses beliefs about the causes of sleep problems. Respondents use a 5-point scale to indicate the extent to which a particular statement about insomnia describes their experience. 1 means "not at all true," while 5 means "very true." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., loc. cit.;).

[0192] Successful treatment is indicated by a decrease in score.

[0193] The Patient-Reported Outcomes Information System (PROMIS) Sleep Disorders Instrument is a universal measure for assessing sleep disorders. This instrument is available as a long form and four different short forms (e.g., 4-item, 6-item, and 8-item) and assesses self-reported perceptions of sleep quality, sleep depth, and any perceived difficulty associated with falling asleep and staying asleep over a 7-day period.

[0194] Each item in the measure is rated on a 5-point scale. The raw scores of the items are summed to obtain a total raw score. The total raw score is then converted to a standardized T-score using a conversion table.

[0195] Successful treatment is indicated by a decrease in the T-score.

[0196] Hypersomnia or hypersomnia can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0197] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate how likely they are to fall asleep in eight different situations, representing moments of relative inactivity (such as an afternoon nap or sitting in a car stopped in traffic). Using a scale of 0 to 3 (0 meaning "never doze off" and 3 meaning "likely doze off"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (A. Shahid et al., loc. cit.).

[0198] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease to 10 or less.

[0199] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a specific point in time. The scale consists of only one item, requiring respondents to select one of seven statements that best describes their current perceived level of sleepiness. To assess sleepiness levels, a scale ranging from 1 (= energetic and active; alert; not sleepy) to 7 (= drowsy; likely to fall asleep easily; unable to stay awake) is used.

[0200] Successful treatment is indicated by a decrease in score.

[0201] Parasomnias can be assessed by the Paris Awake Disorders Severity Scale (PADSS).

[0202] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists and rates the frequency of parasomnias and includes outcome measures (Arnulf et al., A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0203] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0204] 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.

[0205] Successful treatment is indicated by a decrease in score.

[0206] A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Scale. The 10-item questionnaire asks respondents to indicate how acutely affected they have been by the disorder over the past week using a Likert-type rating. Questions can be categorized into one of two categories: the disorder's symptoms (nature, intensity, and frequency) and their impact (sleep problems, impairment of daily functioning, and resulting mood changes). Each of the 10 questions requires respondents to rate their experience with RLS on a scale of 0 to 4 (4 representing the most severe and frequent symptoms, 0 representing the least). Total scores can range from 0 to 40. As a brief measure with good psychometric quality, this instrument may be suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes. (A. Shahid et al., loc. cit.)

[0207] Treatment response can be assessed by a reduction in score.

[0208] Resting-state networks and sleep disorders Brain processes can be studied by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0209] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0210] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0211] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0212] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0213] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in various pathologies, which are associated with altered functional connectivity between one or more regions within a specific resting-state network and / or within one or more additional resting-state networks.

[0214] Modulation of the resting network can be found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0215] A key network involved in sleep is the default mode network (DMN). Generally, the DMN is deactivated during tasks and activated during rest. The DMN is involved in multiple cognitive processes, including higher 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 important in the context of sleep disturbances.

[0216] Resting-state network impairments may also be seen in psychiatric or neurological disorders, as discussed further herein.

[0217] Resting-state networks involved in sleep disorders are also influenced by mental or neurological conditions that are the result of certain medical conditions.

[0218] In patients with insomnia, dysfunctional connectivity is observed within the default mode network (DMN) and within the salience network, which is involved in the detection and integration of emotional and sensory stimuli. Research suggests that these networks contain important regions that integrate emotional and bodily states, and that dysfunctional connectivity within these networks and / or between these networks and other brain regions may underlie patients' reduced vigilance, subjective distress, and sleep continuity.

[0219] 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 DMN functional connectivity correlates with self-reported sleepiness severity.

[0220] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm disturbances contribute to altered resting-state function of the cerebellum, which is involved in sleep regulation, as well as cognitive functions such as responsiveness and alertness. Furthermore, functional connectivity of the DMN is fundamentally different between early and late circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disturbances may result in alterations in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various diseases associated with circadian rhythm disturbances.

[0221] Although it is technically difficult to perform functional brain imaging during a parasomnia event, precuneus differences have been observed in disturbances of arousal that represent non-REM parasomnia.

[0222] The precuneus is involved in analyzing and integrating visual, auditory, and sensory information, as well as monitoring movements. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnias, the default mode network is affected.

[0223] Resting-state fMRI studies in patients suffering from sleep-related breathing disorders such as central sleep apnea show significant global and regional connectivity deficits, particularly in the default mode network (DMN) and regions involved in the arousal and sensorimotor systems.

[0224] 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.

[0225] In many cases, abnormal functional connectivity of resting-state networks involved in sleep disorders is also involved in the above-listed conditions, and therefore, in accordance with the present invention, affecting these networks with therapies according to the present invention results in amelioration of the sleep disorder and, if the patient being treated has a psychiatric or nervous system disorder, also results in amelioration of that disorder.

[0226] Treatment of sleep disorders and mental and nervous system disorders According to the present invention, sleep disorders can be treated in patients suffering from idiopathic sleep disorders as well as psychiatric or nervous system disorders. In the case of patients suffering from sleep disorders associated with psychiatric or nervous system disorders, treatment of the sleep disorder according to the present invention leads to improvement of the condition related to the sleep disorder.

[0227] The resting state networks involved in sleep disorders are often also involved in the conditions listed above.

[0228] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption resets pathological, incomplete brain connections as the network reconnects. New, healthy functional connections are established, with lasting effects.

[0229] The long-lasting effects can be explained by 5-MeO-DMT's neuroplasticity-promoting properties. 5-MeO-DMT promotes structural and functional plasticity, particularly at synapses, the sites where neurons connect and communicate with each other. 5-MeO-DMT regulates the morphogenesis and maturation of dendritic spines, which initiates the formation of new synaptic connections. These new connections can be strengthened, weakened, or even eliminated, depending on activity.

[0230] The resulting new synapses then influence the pattern of neuronal activity, and we conclude that such reciprocal structural and functional modifications contribute to the proper establishment of networks and the persistence of effects following 5-MeO-DMT administration.

[0231] From a biochemical point of view, 5-MeO-DMT interacts specifically with the 5-HT receptor.

[0232] 5-HT receptors, receptors for the neurotransmitters 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 through these receptors.

[0233] The brain expresses seven types of 5-HT receptors that can be further separated into several subtypes. The various types and subtypes exhibit distinct spatial distributions.

[0234] 5-MeO-DMT interacts with several 5-HT receptors, which are involved in mediating the effects of 5-MeO-DMT on resting-state networks and neuroplasticity.

[0235] 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.

[0236] 5-HT7 receptors are involved in neurogenesis, synaptogenesis, and dendritic spine formation, and are particularly associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0237] 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.

[0238] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination can lead to disease states, particularly those involving sleep disorders. Resting-state functional connectivity analysis in patients with sleep disorders revealed modulation of functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0239] Expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to its function in regulating the sleep / wake cycle, and the inventors believe this may allow treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on the receptor.

[0240] 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, along with its "resetting" of network functional connectivity and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0241] The inventors further believe that 5-MeO-DMT's binding to the 5-HT7 receptor and also to the 5-HT1A receptor as two mediators of its effects (including "resetting" functional network connectivity and neuroplasticity effects) may also achieve beneficial effects in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal. This is supported by the clinical results demonstrated in the studies referred to herein.

[0242] Treatment according to the invention will improve the sleep disorder and, if the treated patient suffers from a psychiatric or nervous system disorder, will also improve that disorder.

[0243] Clinical data from studies of patients suffering from treatment-resistant depression (TRD) or postpartum depression (PPD) confirm that administration of 5-MeO-DMT can successfully treat sleep disorders.

[0244] The TRD study, described in more detail in the Examples section below, assessed, among other things, the MADRS item "Decreased Sleep," which reflects insomnia.

[0245] The MADRS item "Decreased Sleep" describes the experience of decreased sleep duration or depth compared to the subject's normal pattern when well. A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects slight difficulty falling asleep or slightly short, light, or intermittent sleep. A score of 4 means reduced or interrupted sleep for at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0246] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Decreased Sleep" across all eight patients was 25 at baseline. By day 1 after treatment (the earliest time point to assess the treatment's impact on sleep), the score had decreased to 12, representing a 13-point or 52% improvement. By day 7 after treatment, the score had decreased to 9, representing a 16-point or 64% improvement.

[0247] In the 12 mg group, the aggregate score for the MADRS item "Decreased Sleep" across all four patients was 12 at baseline. One day after treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. Seven days after treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0248] Thus, there is a significant improvement in the "Sleep Decreased" score, a scale item particularly relevant to sleep disorders. The inventors conclude that 5-MeO-DMT can be used to treat sleep disorders, particularly in patients suffering from psychiatric or nervous system disorders.

[0249] Cognitive dysfunction Cognition includes the skills required for thinking, memory, attention and problem solving.The loss or decline of these skills leads to cognitive dysfunction, and the term cognitive dysfunction is used herein to refer to the deficit or impairment of any domain of cognition.Cognitive dysfunction may be one of the symptoms of the patient's underlying pathology.

[0250] DSM-5 defines six major domains of cognitive function: complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0251] Cognitive dysfunction can affect one or more of these domains; indeed, cognitive abilities are highly interrelated and it is not unusual for more than one domain to be affected.

[0252] For example, the domain of complex attention includes the subdomains of sustained attention (commonly called "concentration" or "focus"), divided attention, selective attention, and processing speed.

[0253] Thus, complex attention clearly encompasses aspects important for executive function and various cognitive tasks such as learning and memory. Cognitive control or executive function is essentially attentional, and perception and decision-making are heavily influenced by attentional abilities.

[0254] As a result, attention is not only tested in isolation, but also by cognitive control tasks / executive functions, for example. When attention is impaired, other types of cognitive abilities are likely impaired as well. Before one can comprehend language, perceive visual-spatial relationships, remember information, or solve problems, one must pay attention to a stimulus.

[0255] Cognitive dysfunction, a term used herein to refer to an acquired condition and therefore represents a decline from a previously achieved level of functioning, and can be associated with a variety of processes.

[0256] In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained with aging and may even improve over time. However, even in the absence of any pathological condition, aging leads to declines in abilities such as abstract thinking, reasoning, and decision-making. These declines are associated with fundamental age-related deficits in processing speed, attention, memory, and executive function, indicative of cognitive aging.

[0257] Apart from normal aging, cognitive dysfunction may be associated with a psychiatric or neurological disorder or some other medical condition.

[0258] The psychiatric or nervous system disorders discussed herein result in or are associated with cognitive dysfunction.

[0259] 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 the full criteria for any etiologically related disorder.

[0260] Cognitive dysfunction can take the form of neurocognitive disorders.

[0261] Mild neurocognitive impairment, also known as mild cognitive impairment, is characterized by a mild decline in cognitive function from a previous level of performance in one or more cognitive domains. Affected patients still maintain independence and are able to perform daytime tasks. However, patients typically function at a suboptimal level. The implementation of compensatory strategies to maintain independence makes daily tasks more difficult.

[0262] Major neurocognitive disorders involve a significant decline in cognitive function from a previous level of performance in one or more cognitive domains. Cognitive impairment interferes with independence in daily life.

[0263] Measuring cognitive dysfunction Cognitive impairment can be assessed by questionnaire or by neuropsychological assessment.

[0264] The questionnaire assesses the mental state of the patient based on observations made by the patient, caregiver, or clinician who administers the questionnaire. Questionnaires used to assess whether a patient suffers from a specific psychiatric or nervous system disorder may include items related to cognitive function.

[0265] A neuropsychological evaluation is a process in which a person's cognitive, psychological / emotional, and behavioral functioning is comprehensively evaluated. A central part of a neuropsychological evaluation is the administration of neuropsychological tests for the formal evaluation of cognitive function.

[0266] Performance on these tests is compared to norms appropriate for the patient's age, educational achievement, and cultural background. Testing often uses a series of performance-based questions, also known as a neuropsychological test battery.

[0267] Abilities tested include language processing, visual-spatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive function, processing speed, and sensory-perceptual function.

[0268] Common tests to assess cognitive dysfunction are the Montreal Cognitive Assessment (MoCA), the Short Mental Status Examination (MMSE), the Mini-Cog™, the Screening for Psychiatric Cognitive Impairment (SCIP), and the MATRICS Consensus Cognitive Assessment Battery (MCCB).

[0269] The Montreal Cognitive Assessment (MoCA) is a widely used screening test for detecting cognitive impairment. The MoCA assesses different cognitive domains, including short-term memory; visuospatial ability; executive function; attention, concentration, and working memory; language; and orientation to time and space. The total possible score is 30. A score of 26 or higher is considered normal, a score of 18–25 is considered mild cognitive impairment, a score of 10–17 is considered moderate cognitive impairment, and a score below 10 is considered severe cognitive impairment.

[0270] The Mini-Mental Status Examination (MMSE) is an 11-question measure that examines five domains of cognitive function: orientation, memory, attention and calculation, recall, and language. The maximum score is 30. Raw scores may also need to be adjusted for highest level of education and age.

[0271] Herein, four cut-off levels are used to classify the severity of cognitive impairment: 24-30 means no cognitive impairment, 19-23 means mild cognitive impairment, 10-18 means moderate cognitive impairment, and 9 or less means severe cognitive impairment.

[0272] When used repeatedly, the MMSE is suitable for measuring changes in cognitive status.

[0273] The Mini-Cog™ is a short cognitive impairment screening questionnaire. The Mini-Cog™ combines a three-word recall and a clock drawing test. The clock drawing test assesses many cognitive domains that may be affected, including executive function, visuospatial ability, motor programming, and attention. One point is awarded for each of three words correctly recalled after performing the clock drawing test. A correctly drawn clock is awarded two points. A score below four indicates cognitive impairment.

[0274] The Screening for Cognitive Impairment in Psychiatry (SCIP) is a highly regarded screening tool for assessing cognitive abilities in psychiatric patients.

[0275] The SCIP consists of five subscales: the Verbal Learning Test-Immediate (VLT-I), Working Memory Test (WMT), Verbal Fluency Test (VFT), Verbal Learning Test-Delayed (VLT-D), and Processing Speed ​​Test (PST). There are three different test formats to facilitate repetition and thus reduce learning effects. Subscale scores are calculated for each of the five tests, and a total score is calculated from the sum of the subscale scores. A total score of less than 70 indicates cognitive dysfunction.

[0276] Cognitive dysfunction can also be assessed by the MCCB (MATRICS Consensus Cognitive Battery) or by one or more of its various subtests: Trail Making Test, Part A (a test of processing speed); Brief Cognitive Assessment for Schizophrenia, Symbol Coding subtest (processing speed); Hopkins Verbal Learning Test-Revised, Immediate Recall, 3 learning trials only (verbal learning); Wechsler Memory Scale-3, Spatial Span subtest (Working Memory (Nonverbal)); Letter Span Test (Working Memory (Verbal)); Neuropsychological Assessment Battery, Maze subtest (Reasoning and Problem Solving); Brief Visuospatial Memory Test-Revised (visual learning); Category Fluency Test, Animal Naming (processing speed); Mayer-Salovey-Caruso Emotional Intelligence Test, Emotion Management Domain (social cognition); and Continuous Performance Test, Identical Pairs Version (attention / arousal).

[0277] The test battery is suitable for measuring cognitive change.

[0278] 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).

[0279] Mechanisms of cognitive dysfunction Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0280] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0281] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0282] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0283] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0284] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in various pathologies. Such disease states, including certain forms of cognitive dysfunction, 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.

[0285] Resting-state fMRI is particularly advantageous when studying populations affected by cognitive dysfunction, as it allows for the examination of functional connectivity while eliminating task demands that may be confounded by underlying cognitive or motor impairments.

[0286] Cognitive processes are reflected by the functional connectivity of specific brain regions within and / or between regions located in different networks.

[0287] In particular, certain core networks, also known as "higher-order cognitive networks," are thought to be essential for most mental activities.

[0288] The frontoparietal control network (FPCN), also known as the frontoparietal network (FPN), central executive network (CEN), or executive network (EN), is typically associated with executive functions, including holding and updating relevant information in working memory, inhibiting impulsive responses, and using flexible problem-solving strategies to guide decisions and goal-directed behavior.

[0289] Another core network is the default mode network (DMN). The DMN contains areas in the brain that are most active when a person's attention is not focused on any specific task. DMN activity is associated with introspection, episodic memory, memory consolidation, social and self-related cognition, the integration of cognitive and emotional processing, and task-unrelated mind-wandering.

[0290] The third network is the salience network, also known as the cingulate-opercular network. This network is involved in identifying salient stimuli and events—those that other brain networks need to pay attention to. This network plays a central role in governing mental processes and behavior.

[0291] The fourth network is the dorsal attention network (DAN), which is associated with top-down, goal-directed attention processes.

[0292] The above networks do not operate independently. In fact, there are many connections between them. The cooperation between the networks is essential for their application-specific functionality.

[0293] Throughout the lifespan, brain networks undergo functional reorganization that simultaneously influences cognition. In healthy aging, age-related changes are observed in higher-level cognitive networks.

[0294] Patients suffering from cognitive dysfunction exhibit functional alterations within and / or between resting-state networks when compared to healthy, age-matched controls. Alterations are observed within and / or between the default mode network, executive network, salience network, and dorsal attention network.

[0295] Resting-state networks involved in cognition are often affected by psychiatric or neurological disorders, as discussed herein.

[0296] Resting-state networks involved in cognition are also affected by psychiatric or neurological conditions that are the result of certain medical conditions and in neurocognitive disorders not otherwise specified.

[0297] Furthermore, resting-state networks involved in cognition are affected by sleep disorders, such as insomnia, and indeed cognitive dysfunction and sleep disorders are correlated.

[0298] Cognitive function is impaired in patients with sleep disorders, and patients with cognitive dysfunction often also have sleep disorders.

[0299] Treating cognitive dysfunction According to the present invention, cognitive dysfunction occurring in patients suffering from psychiatric or nervous system disorders or from medical conditions that lead to related psychiatric or nervous system conditions can be treated.Furthermore, cognitive dysfunction occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0300] Cognitive dysfunction in neurocognitive disorder not otherwise specified can also be treated.

[0301] In patients suffering from cognitive dysfunction associated with another condition detailed above, treatment of the cognitive dysfunction according to the present invention leads to an improvement in the condition associated with the cognitive dysfunction.

[0302] Treatment according to the present invention is carried out by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0303] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to a resetting of pathological maladaptive connections as the networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0304] Therefore, according to the present invention, by affecting these networks by the therapies described herein, cognitive dysfunction is improved, and if the treated patient suffers from a psychiatric or nervous system disorder, the disorder is also improved.If the treated patient suffers from a medical condition that leads to a related psychiatric or nervous system condition, the related psychiatric or nervous system condition is also improved.If the treated patient suffers from a sleep disorder, such as insomnia, the sleep disorder, such as insomnia, is also improved.If the patient suffers from an unspecified neurocognitive disorder, one or more other symptoms of the disorder are also improved.

[0305] To further support the clinical application of 5-MeO-DMT in patients suffering from cognitive dysfunction, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric disorders and noted specific improvements in cognitive dysfunction that are also commonly observed in patients with other disorders.

[0306] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific medical condition, the inventors have determined that certain clinical findings from the study are relevant to the design of drugs for the treatment of other medical conditions associated with cognitive dysfunction, as described in more detail below.

[0307] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest are those receiving a single 12 mg dose and those receiving an intra-day individualized dosing regimen (IDR) that allows for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0308] The collected data included assessments of treated patients 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 improvements in overall MADRS scores, the inventors focused on items included in various scales, noting that specific subscore items (e.g., items related to cognitive dysfunction) are associated with other conditions in which cognitive dysfunction is based on altered functional connectivity within and / or between the default mode network, executive control network, salience network, and dorsal attention network.

[0309] 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.

[0310] More specifically, an aspect that can be treated by administration of 5-MeO-DMT is cognitive dysfunction, particularly difficulty concentrating. 5-MeO-DMT can be administered to a patient to reduce or eliminate cognitive dysfunction, particularly difficulty concentrating, in the patient.

[0311] The MADRS item that is particularly relevant to poor concentration and memory is "Difficulty concentrating." This item reflects difficulty organizing thoughts, leading to an incapacitating lack of concentration, and is scored 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, leading to a decreased ability to read or sustain a conversation, a score of 4 is assigned. If the patient is unable to read or converse without great difficulty, the score is 6.

[0312] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Difficulty concentrating" across all eight patients was 30 at baseline.

[0313] After 2 hours, the score decreased to 11, which corresponds to a 19-point or 63% improvement. On day 1 after treatment, the score decreased to 1, which corresponds to a 29-point or 97% improvement. On day 7 after treatment, the score decreased to 9, which corresponds to a 21-point or 70% improvement.

[0314] In the 12 mg group, the combined score for the MADRS item "Difficulty concentrating" across all four patients was 16 at baseline.

[0315] After 2 hours, the score decreased to 7, which corresponds to a 9-point or 56% improvement. On day 1 after treatment, the score decreased to 2, which corresponds to a 14-point or 88% improvement. On day 7 after treatment, the score decreased to 3, which corresponds to a 13-point or 81% improvement.

[0316] Thus, in accordance with the present invention, treating a patient suffering from cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction.

[0317] More specifically, according to the present invention, treating a patient suffering from cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, wherein the cognitive dysfunction is a deficiency or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition. For example, the cognitive dysfunction is reduced or eliminated when it affects the cognitive domain 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.

[0318] In patients suffering from cognitive dysfunction associated with a psychiatric or nervous system disorder, treating the cognitive dysfunction according to the present invention results in an improvement in cognition associated with the cognitive dysfunction.

[0319] Although cognitive dysfunction can be considered a condition worthy of treatment regardless of any other conditions, disorders, or symptoms that an individual may suffer from, some psychiatric disorders and nervous system disorders are associated with cognitive dysfunction. In particular, the relationship between cognitive dysfunction and psychiatric disorders is bidirectional. Not only can psychiatric disorders adversely affect cognitive function, but cognitive dysfunction can also contribute to the onset, progression, and prognosis of psychiatric or nervous system disorders.

[0320] Resting-state networks often involved in cognitive dysfunction are also involved in the above conditions.

[0321] 5-MeO-DMT has the ability to disrupt established functional connectivity patterns in resting-state networks. This disruption resets pathological, incomplete brain connections as the network rewires. New, healthy functional connections are established with lasting effects.

[0322] anxiety Anxiety may also be defined as "an anxious anticipation of future danger or misfortune accompanied by physical symptoms of discomfort or tension."

[0323] Anxiety is characterized simply by intense, excessive, persistent worry and fear about situations that are subjectively perceived as threatening, and is often accompanied by muscle tension, restlessness, fatigue, difficulty breathing, abdominal tightness, nausea, and problems concentrating.

[0324] In anxiety disorders, or other anxiety-related psychiatric or neurological disorders, feelings of anxiety are difficult to control and interfere with daily activities.

[0325] 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.

[0326] Anxiety is also associated with several other psychiatric and nervous system disorders. Anxiety is also associated with sleep disorders.

[0327] Anxiety assessment Several rating scales for assessing anxiety are known in the art, and anxiety symptoms are further assessed as part of various rating scales used to assess psychiatric and nervous system disorders.

[0328] The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. This scale is administered by a clinician. It has 14 items that can be divided into a group of psychological items (items 1-6 and 14) that specifically assess mental agitation and psychological distress, and a group of physical items (items 7-13) that specifically assess somatic complaints related to anxiety.

[0329] The HAM-A items are shown in the table below. [Table 1] Each item is rated by the interviewer on a scale of 0 to 4: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.

[0330] A total score is obtained by summing the 14 items. The total score ranges from 0 to 56. Higher scores indicate greater anxiety.

[0331] A score of ≦7 is considered to represent no or minimal anxiety; mild anxiety a score of 8-14; moderate anxiety a score of 15-23; and severe anxiety a score of ≧24.

[0332] The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire developed to assess anxiety, focusing on physical symptoms. These items are rated on a 4-point Likert scale ranging from 0 (not at all) to 3 (severe: barely tolerable). Total scores range from 0 to 63.

[0333] The term subthreshold anxiety as 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.

[0334] Mechanisms of anxiety Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0335] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0336] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0337] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0338] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0339] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in various pathologies, including certain forms of anxiety, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0340] Based on such studies, multiple brain regions have been linked to anxiety and anxiety disorders.Therefore, the pathophysiology of anxiety and anxiety disorders involves abnormal connectivity between the amygdala-frontal region and the frontal-striatal region.Anxiety and anxiety disorders are associated with specific changes in resting-state networks.

[0341] Anxiety and anxiety disorders exhibit abnormalities within and / or between the default mode network, salience network, and sensorimotor network. The resting balance within and / or between each of these networks differs in anxiety disorders.

[0342] Treating anxiety According to the present invention, anxiety occurring in patients suffering from an anxiety disorder or other 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.

[0343] In patients suffering from anxiety associated with another psychiatric or nervous system disorder or sleep disorder, eg, insomnia, treatment of anxiety according to the present invention improves the anxiety-related condition.

[0344] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0345] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the resetting of pathological maladaptive connections as the networks reconnect. New, healthy functional connections are established, resulting in lasting benefits.

[0346] Thus, in accordance with the present invention, by affecting these networks with the treatments described herein, anxiety will be improved. If the treated patient suffers from another psychiatric or nervous system disorder related to anxiety, that disorder will also be improved, and if the treated patient suffers from a sleep disorder, e.g., insomnia, that sleep disorder, e.g., insomnia, will also be improved.

[0347] To further support the clinical application of 5-MeO-DMT in patients with anxiety, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in anxiety that are also commonly observed in patients with other disorders.

[0348] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific condition, the inventors have determined that certain clinical findings from the trial are relevant to devising treatments for anxiety disorders and other anxiety-related conditions, as discussed in more detail below.

[0349] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest are those receiving a single 12 mg dose and those receiving an intra-day individualized dosing regimen (IDR) that allows for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0350] The collected data included assessments of treated patients against several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvements in overall MADRS scores, the inventors focused on items included in various scales, noting that specific subscore items (such as items related to anxiety) are related to other conditions, in which anxiety is similarly based on changes in functional connectivity within and / or between resting-state networks.

[0351] 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.

[0352] Furthermore, a particular condition that can be treated by administration of 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to a patient to reduce or eliminate anxiety in the patient.

[0353] A particularly relevant BPRS item in this regard is "Anxiety." This item concerns reported apprehension, tension, fear, panic, or worry. Possible scores are as follows:

[0354] 1- No anxiety.

[0355] 2 - Very mild. Reports discomfort due to worry that occurs more frequently than most healthy people or occasional worry.

[0356] 3 - Mild. Frequent anxiety, but able to quickly redirect attention elsewhere.

[0357] 4 - Moderate. Worried most of the time and unable to easily focus on other things, but does not impair functioning, or occasional autonomic anxiety, but does not impair functioning.

[0358] 5 - Moderately severe. There are frequent but not daily periods of autonomic anxiety, or some areas of functioning are impaired by anxiety or worry.

[0359] 6 - Severe. Autonomic anxiety occurs daily but not all day long, or many areas of functioning are impaired by anxiety or constant worry.

[0360] 7 - Most severe. Anxiety with autonomic symptoms persists throughout the day or most areas of functioning are impaired by anxiety or constant worry.

[0361] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "anxiety" across all eight patients was 37 at baseline.

[0362] After 3 hours, the score decreased to 19, which corresponds to an 18-point or 49% improvement. On day 1 after treatment, the score decreased to 16, which corresponds to a 21-point or 57% improvement. On day 7 after treatment, the score decreased to 17, which corresponds to a 20-point or 54% improvement.

[0363] In the 12 mg group, the baseline score for the BPRS "anxiety" item was 25 when aggregated across all four patients.

[0364] After 3 hours, the score decreased to 11, which corresponds to a 14-point or 56% improvement. On day 1 after treatment, the score decreased to 6, which corresponds to a 19-point or 76% improvement. On day 7 after treatment, the score decreased to 6, which corresponds to a 19-point or 76% improvement.

[0365] 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.

[0366] As a result, in accordance with the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.

[0367] The MADRS item "inner tension" describes a vague feeling of discomfort, irritability, inner confusion, or mental tension (leading to either panic, fear, or anguish), which is rated according to intensity, frequency, duration, and the degree of relief sought.

[0368] If the patient is calm and experiences only fleeting inner tension, a score of 0 is assigned. If there is occasional agitation and unexplained discomfort, a score of 2 is assigned. If there is continuous inner tension or intermittent panic that the patient manages to overcome with some difficulty, a score of 4 is assigned. If there is constant fear or anguish and overwhelming panic, a score of 6 is assigned.

[0369] In the study identified above that included patients with TRD, in the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "internal tension" across all eight patients was 26 at baseline. After two hours, the score decreased to 11, corresponding to a 15-point or 58% improvement. One day after treatment, the score decreased to 6, corresponding to a 20-point or 77% improvement. Seven days after treatment, the score decreased to 12, corresponding to a 14-point or 54% improvement.

[0370] In the 12 mg group, the aggregate score for the MADRS item "internal tension" across all four patients was 13 at baseline. After two hours, the score decreased to 2, corresponding to an 11-point or 85% improvement. On post-treatment day 1, the score decreased to 3, corresponding to a 10-point or 77% improvement. On post-treatment day 7, the score decreased to 5, corresponding to an 8-point or 62% improvement.

[0371] These results further support the inventors' conclusion that treatment according to the present invention reduces or eliminates symptoms of anxiety.

[0372] Treatment according to the present invention results in a clinical response in patients suffering from symptoms of anxiety reflected by at least a 50% decrease in the HAM-A score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day (e.g., about 24 hours), at 7 days, at 14 days, and at 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, compared to the respective scores before treatment.

[0373] The clinical response reflected by at least a 50% reduction in the HAM-A score in a patient suffering from anxiety compared to the respective score before treatment occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response reflected by at least a 50% reduction in the HAM-A score in a patient suffering from anxiety preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0374] Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms is reflected by a HAM-A score of 7 or less about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0375] Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, occurs within about 2 hours of the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Amelioration of anxiety symptoms in a patient suffering from anxiety symptoms, as reflected by a HAM-A score of 7 or less, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0376] As a result, in accordance with the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.

[0377] psychomotor inhibition The main aspects observed in patients with psychomotor depression are decreased energy and activity and decreased motivation.

[0378] Psychomotor retardation involves slowed thinking and reduced movement in an individual. Psychomotor impairment can cause noticeable slowing of physical and emotional responses.

[0379] Psychomotor retardation may be associated with a psychiatric or nervous system disorder or some other medical condition.

[0380] Psychiatric or nervous system disorders that cause or are associated with psychomotor slowing include 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, mental and behavioral disorders resulting from psychoactive substance use (e.g., substance use disorders (SUDs)), psychotic disorders (e.g., schizophrenia), dementia (e.g., Alzheimer's disease (AD)), dementia with Lewy bodies (DLB), vascular dementia and Parkinson's disease dementia, Parkinson's disease, and chronic fatigue syndrome.

[0381] Psychomotor depression can also occur in patients suffering from sleep disorders, such as insomnia.

[0382] Measurement of psychomotor inhibition Psychomotor inhibition 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), as well as other tests known in the art.

[0383] In the Trail Making Test (TMT), for example, subjects must connect 25 circles containing either numbers (TMT A) or number-letter combinations (TMT B) in ascending order. The task requirements are similar for TMT-B, except that 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 taken to complete the task.

[0384] Another test that involves grapheme skills is the Gibson Spiral Maze (GSM), which assesses only psychomotor speed and is not affected by cognitive ability. To achieve the GSM, subjects must accurately trace a spiral maze from start to finish without touching the borders.

[0385] The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of number-symbol pairs and symbol lists. Subjects must write the corresponding symbol under each number as quickly as possible. The score consists of the number of symbols correctly reported in 90 seconds. A further example of a motor test is the finger tapping test.

[0386] Thus, certain tests combine measures of both the motor and cognitive aspects of psychomotor inhibition, while still other tests assess only the motor aspect.

[0387] Analysis of speech may be a further indicator of psychomotor retardation.

[0388] The main scales available for assessment and measurement include the severity of psychomotor depression, the Salpetriere Retardation Rating Scale (SRRS), and the Motor Agitation and Retardation Scale (MARS).

[0389] The Salpetriere Retardation Rating Scale (SRRS), developed by Widlocher, assesses cognitive and motor aspects with 15 items. The first three items measure the quality of movement, specifically the stride and slowness of limb, trunk, head, and neck movements. The next three items focus on speech, including speech flow, tone of voice, and response duration. 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 and assess rumination, fatigue, interest level, sense of time, memory, and concentration. The final item on this scale relates to an overall assessment of the patient's psychomotor retardation. These items are rated based on the severity of the presenting symptoms, ranging from 0 (no symptoms) to 4 (severe symptoms), with a total score ranging from 0 to 60.

[0390] The Motor Agitation and Retardation Scale (MARS) assesses only motor aspects. It was designed to assess psychomotor impairments in depressive disorders. Psychomotor impairments are divided into five major physical categories, including eyes, face, voice, limbs, and trunk, and the scale contains 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. The voice category includes items such as voice volume, intelligibility, tone, and onset time. Items in the limb category include hand, foot, and leg movements, stride, 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 inhibition. Inhibitory items include abnormal gait, trunk / proximal limb immobility, postural collapse, slowness of movement (i.e., Limbs and Trunk category), lack of facial expressiveness, downcast gaze (i.e., Eyes and Face category), and reduced vocal volume, slurred speech, delayed speech initiation, monotonous speech (i.e., Voice category). The MARS scale provides a rapid clinical assessment of motor signs.

[0391] Resting-state networks and psychomotor inhibition Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0392] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0393] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0394] Distinct resting-state networks have been identified and named, primarily based on spatial similarities between the resting-state networks and activation patterns seen in task-fMRI experiments.

[0395] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0396] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in various pathologies, including certain forms of psychomotor depression, associated with altered functional connectivity between one or more regions within a specific resting-state network and / or one or more additional resting-state networks.

[0397] For example, abnormalities in functional connectivity have been reported from the somatosensory-motor network (SMN) to the visual (VN), dorsal attention (DAN), and default mode networks, which correlated with both psychomotor inhibition and psychomotor agitation in depressive disorders.

[0398] In many cases, resting-state networks involved in psychomotor inhibition are affected in psychiatric or neurological 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, mental and behavioral disorders resulting from psychoactive substance use (e.g., substance use disorders (SUD)), psychotic disorders (e.g., schizophrenia), dementia (e.g., Alzheimer's disease (AD)), dementia with Lewy bodies (DLB), vascular and Parkinson's disease dementia, Parkinson's disease, and chronic fatigue syndrome.

[0399] Resting-state networks involved in psychomotor inhibition are also affected by sleep disturbances (e.g., insomnia), and indeed, psychomotor inhibition and sleep disturbances are correlated.

[0400] Treatment of psychomotor depression 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 (e.g., insomnia) can be treated.

[0401] In patients suffering from psychomotor depression associated with another condition detailed above, treatment of psychomotor depression according to the present invention will result in improvement of the condition associated with psychomotor depression.

[0402] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0403] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the resetting of pathological maladaptive connections as the networks reconnect. New, healthy functional connections are established with lasting effects.

[0404] Thus, in accordance with the present invention, influencing these resting state networks by the treatment methods described in the present invention results in an improvement in psychomotor inhibition, and in the case where the treated patient has a psychiatric or nervous system disorder, also results in an improvement in the disorder, and in the case where the treated patient has a sleep disorder, e.g., insomnia, also results in an improvement in the sleep disorder, e.g., insomnia.

[0405] To further support the clinical application of 5-MeO-DMT in patients suffering from psychomotor depression, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in psychomotor depression that are also commonly observed in patients with other disorders.

[0406] 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 are relevant to the design of treatments for other conditions associated with psychomotor slowing, as discussed in detail below.

[0407] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, as determined by the intensity of the patient-reported hallucinatory experience.

[0408] Data collected included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS). While the focus of this study was to demonstrate treatment efficacy through improvements in overall MADRS scores, we focused on items across the various scales and noted that specific subscore items (e.g., items related to psychomotor inhibition) are associated with other conditions, in which psychomotor inhibition is based on alterations in functional connectivity within and / or between the somatomotor / sensorimotor network, visual network, dorsal attention network, and default mode network.

[0409] 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.

[0410] More specifically, a condition that can be treated by administration of 5-MeO-DMT is psychomotor depression. 5-MeO-DMT can be administered to a patient to reduce or eliminate psychomotor depression in the patient.

[0411] The MADRS scale item that is particularly relevant to psychomotor inhibition is "inhibition," which describes difficulty getting started or slowness in initiating and performing daily activities.

[0412] A score of 0 means that there is almost no difficulty in starting anything and there is no inactivity. A score of 2 is assigned if the patient has difficulty initiating activities. A score of 4 means that simple activities that are usually performed are difficult to start and require effort to perform. A score of 6 is assigned in case of complete inhibition, i.e. the patient is unable to do anything without assistance.

[0413] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inhibition" across all eight patients was 27 at baseline.

[0414] After 2 hours, it had decreased to 10, which corresponds to a 17-point or 63% improvement. One day after treatment, it had decreased to 5, which corresponds to a 22-point or 81% improvement. Seven days after treatment, it had decreased to 3, which corresponds to a 24-point or 89% improvement.

[0415] In the 12 mg group, the aggregate score for the "inhibition" item on the MADRS across all four patients was 16 at baseline. After two hours, it decreased to 10, which corresponds to a 6-point or 38% improvement. On day 1 after treatment, it decreased to 0, which corresponds to a 16-point or 100% improvement. On day 7 after treatment, it decreased to 3, which corresponds to a 13-point or 81% improvement.

[0416] Thus, scores for "inhibition," a scale item particularly related to psychomotor retardation, are significantly improved. The inventors conclude that 5-MeO-DMT may be used to treat psychomotor retardation in patients, particularly those who also suffer from psychiatric or nervous system disorders or sleep disorders, such as insomnia.

[0417] Thus, in accordance with the present invention, treating a patient suffering from psychomotor depression with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the psychomotor depression.

[0418] Social / emotional withdrawal or detachment Symptoms such as anhedonia, emotional withdrawal, and flat affect are collectively referred to herein as social / emotional withdrawal or detachment. Decreased social engagement is a further aspect associated with social / emotional withdrawal or detachment.

[0419] Anhedonia is the inability to experience pleasure. A patient does not suffer from anhedonia if there is no subjective decrease in the ability to experience pleasure from usual activities. Anhedonia is mild, when pleasure from usual pleasurable activities is slightly reduced; moderate, when pleasure from usual pleasurable activities is significantly reduced, with some pleasure from isolated activities maintained; or severe, when there is a complete inability to experience pleasure.

[0420] Anhedonia consists of a consummatory (or liking) component and an anticipatory (or wanting) component. Consummatory pleasure refers to the "in-the-moment" pleasure experienced by a subject directly engaged in a pleasurable activity, while anticipatory pleasure refers to the experience of pleasure associated with a future activity.

[0421] Flat affect is characterized by a subjective sense of a decrease in the intensity or range of emotions and emotions. If there is no subjective sense of a decrease in the intensity or range of emotions, a subject does not exhibit flat affect. Flat affect is mild when the range of emotions is slightly constricted or the range or intensity of emotions is temporarily reduced; moderate when the range or intensity of emotions is significantly constricted, with some emotions remaining, e.g., an inability to cry; and severe when the range of emotions is significantly and completely constricted, or the subject is unable to experience normal emotions.

[0422] Emotional withdrawal or detachment is the inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes an item on emotional withdrawal, which is characterized as a lack of emotional engagement by a subject in an interview situation. According to this BPRS item description, emotional withdrawal is absent if a lack of emotional engagement is not indicated by an occasional inability to return feedback, appearing distracted, or smiling awkwardly, but by spontaneously engaging with the interviewer most of the time. A mild form of emotional withdrawal is indicated if a lack of emotional engagement is indicated by a noticeable inability to return feedback, appearing distracted, or lacking warmth, but responds to the interviewer when prompted. A moderate form of emotional withdrawal is absent for most of the interview because the subject does not respond in detail, is unable to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychopathic traits. Furthermore, if emotional contact is absent for most of the interview, it is moderately severe. If the subject actively avoids emotional engagement, or if the subject is frequently unresponsive, responds with yes / no, or responds with minimal emotion, it is a severe form. If the subject consistently avoids emotional engagement, is unresponsive, responds with yes / no, walks away during the interview, or does not respond at all, it is very severe.

[0423] Reduced social engagement is characterized by subjective reports of decreased social and interpersonal involvement or interaction. If there is no report of decreased social and interpersonal involvement or interaction, social engagement is not decreased. Mild is when social engagement is slightly reduced and there is no impairment in social or interpersonal functioning; moderate is when social engagement is clearly reduced and there is some functional sequelae, e.g., avoidance of some social engagement or conversation; and severe is when social interaction is significantly reduced or almost all forms of social contact are avoided, e.g., refusing to answer the phone or meet with friends or family.

[0424] Social / emotional withdrawal or detachment may be associated with psychiatric or neurological disorders, or with several other medical conditions.

[0425] Mental or nervous system disorders that lead to or are associated with social / emotional withdrawal or detachment include 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 disorder and related disorders (e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD)), post-traumatic stress disorder (PTSD), These include pain disorders (e.g., chronic pain and fibromyalgia), mental and behavioral disorders resulting from psychoactive substance use (e.g., substance use disorders (SUDs)), psychotic disorders (e.g., schizophrenia), dementia (e.g., 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 (e.g., schizotypal personality disorder and borderline personality disorder (BPD)).

[0426] Social / emotional withdrawal or detachment can also manifest in patients suffering from sleep disorders, such as insomnia.

[0427] Social / emotional withdrawal or detachment can also occur in patients suffering from medical health conditions that lead to associated mental or neurological conditions, including traumatic brain injury (TBI).

[0428] Measuring social / emotional withdrawal or detachment Social / emotional withdrawal or detachment (often referred to herein as social / emotional withdrawal), or its individual aspects, e.g., anhedonia, emotional withdrawal, and flat affect, can be assessed by different instruments, e.g., questionnaires or scales.

[0429] 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 has a specific mental or neurological disorder may include items related to social / emotional withdrawal or detachment.

[0430] The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale measuring anhedonia, or the inability to experience pleasure. Items encompass the domains of social interactions, food and drink, sensory experiences, and interests / pastime. A score of 2 or less defines a "normal" score, while an "abnormal" score is defined as 3 or greater. Each item has four response options: strongly disagree, disagree, agree, and strongly agree. Each "disagree" response is worth 1 point, and each "agree" response is worth 0 points. Thus, final scores range from 0 to 14. The SHAPS has adequate construct validity and adequate test-retest reliability. High internal consistency has also been reported. The SHAPS has been used to measure anhedonia in depression, but it is also frequently used to assess anhedonia in other patient populations.

[0431] In principle, SHAPS measures hedonic tone over the past few days using 14 hypothetical formulated items, although due to the hypothetical nature of the items, shorter recall periods may be applied appropriately for earlier assessments.

[0432] Alternatively or additionally, the Dimensional Anhedonia Rating Scale (DARS), which measures interest, motivation, effort, and pleasure of completion across four hedonic domains: hobbies, food / drink, social activities, and sensory experiences, can be used to assess anhedonia. It consists of 17 items assessing current anhedonia status. The DARS is rated on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much), with higher scores indicating less anhedonia. When all items are summed, the total score ranges from 0 to 68. Participants are asked to provide two or three examples of their favorite activities for each of the four hedonic domains: hobbies (4 items, total score 0–16), food / drink (4 items, total score 0–16), social activities (4 items, total score 0–16), and sensory experiences (5 items, total score 0–20).

[0433] The Personality Inventory for DSM-5 (PID-5)-Adult is a 220-item self-rated personality trait scale for adults aged 18 years and older. The test assesses 25 personality trait facets, including anhedonia, anxiety, attention-seeking, callousness, fakeness, depression, distractibility, eccentricity, emotional lability, grandiosity, hostility, impulsivity, intimacy avoidance, irresponsibility, manipulativeness, perceived loss of control, obsessive attachment, limited emotionality, rigid perfectionism, risk-taking, separation anxiety, submissiveness, suspiciousness, unusual beliefs and experiences, and social withdrawal, with each trait facet consisting of 4 to 14 items.

[0434] The trait facet Anhedonia includes items 1, 23, 26, 30R, 124, 155R, 157, and 189 (reverse-scored items are marked with the letter "R"), the trait facet Withdrawal includes items 10, 20, 75, 82, 136, 146, 147, 161, 182, and 186, and the trait facet Intimacy Avoidance includes items 89, 97R, 108, 120, 145, and 203. Combining these three trait facets yields a broader trait domain termed "Detachment."

[0435] This measure is completed by individuals before seeing a clinician. For each item, individuals are asked to rate how well the item generally describes them.

[0436] Each metric item is rated on a 4-point scale. Item response categories are: 0 = not true at all or not true most of the time; 1 = not true sometimes or not true very often; 2 = true sometimes or very often; and 3 = true very much or true most of the time. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, the items are reverse coded before calculating the scale score.

[0437] Scores for items within each trait facet should be summed and entered into the appropriate raw facet score box. Additionally, clinicians are asked to calculate and use a mean score for each facet and domain. Mean scores reduce the overall score and each domain score to a four-point scale, allowing clinicians to consider an individual's personality dysfunction relative to observed norms. The mean facet score is calculated by dividing the raw facet score by the number of items in the facet (e.g., if all items within the "anhedonia" facet are 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 averaging the three facet scores that primarily contribute to a specific domain. For example, if the mean facet scores for anhedonia, intimacy avoidance, and withdrawal (a measure primarily measuring detachment) are all 2, these scores would sum to 6, resulting in a mean domain score of 6 / 3 = 2. Higher mean scores indicate greater dysfunction of specific personality trait facets or domains.

[0438] High scores on any aspect or domain may indicate an area of ​​importance and problem for the individual receiving care, which may require further assessment, treatment, and follow-up.

[0439] Resting-state networks and social / emotional withdrawal or detachment Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0440] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0441] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0442] Various resting-state networks have been identified and named primarily based on spatial similarities between resting-state networks and activity patterns seen in task-fMRI experiments.

[0443] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0444] RSNs have been shown to be responsible for various aspects of complex brain function, and these connective networks have been found to be impaired in various pathologies, including certain forms of social / emotional withdrawal or detachment, which are associated with modulation of functional connectivity between one or more regions within a specific resting-state network and / or one or more additional resting-state networks.

[0445] Anhedonia, an important aspect of social / emotional withdrawal or detachment, is associated with modulation of RSNs. More specifically, anhedonia is associated with hyperconnectivity of the visual network and expansion of the visual network, dorsal attention network (DAN), and default mode network (DMN). Anhedonia is also associated with decreased inter-network connectivity between the DMN network, salience network, DAN network, somatomotor network, and visual network.

[0446] Furthermore, emotional detachment in adult psychopathy is 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)) underpin emotional, social, and moral processing. In adult psychopathy, microstructural abnormalities within the dorsal DMN are linked to the emotional and interpersonal differences that define the disorder.

[0447] Thus, patients suffering from social / emotional withdrawal or detachment have altered functional connectivity within and / or between RSNs compared to age-matched healthy controls. Alterations are observed within and / or between the DMN, salience, DAN, somatomotor, and visual networks.

[0448] In many cases, RSNs 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) (e.g., 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 disorder and related disorders (e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD)), posttraumatic stress disorder (PTSD), and pain. Pain disorders (e.g., chronic pain and fibromyalgia), mental and behavioral disorders resulting from psychoactive substance use (e.g., substance use disorders (SUDs)), psychotic disorders (e.g., schizophrenia), dementia (e.g., 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), personality disorders (e.g., schizotypal personality disorder and borderline personality disorder (BPD)).

[0449] Resting-state networks involved in social / emotional withdrawal or detachment are also affected by mental or nervous system conditions that are the result of certain medical health conditions, such as traumatic brain injury (TBI).

[0450] The 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 disorders are correlated.

[0451] Treatment of social / emotional withdrawal or detachment and mental or nervous system disorders According to the present invention, social / emotional withdrawal or detachment occurring in patients suffering from psychiatric or nervous system disorders can be treated, and further, social / emotional withdrawal or detachment occurring in patients suffering from sleep disorders, such as insomnia, can be treated.

[0452] As detailed above, in patients suffering from social / emotional withdrawal or detachment in association with other conditions, treatment of the social / emotional withdrawal or detachment in accordance with the present invention leads to an improvement in the condition associated with the social / emotional withdrawal or detachment.

[0453] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0454] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the resetting of pathological maladaptive connections as the networks reconnect. New, healthy functional connections are established, with lasting effects.

[0455] Thus, in accordance with the present invention, affecting these networks by the therapies described herein will result in an improvement in social / emotional withdrawal or detachment, an improvement in a psychiatric or nervous system disorder if the treated patient suffers from that disorder, and an improvement in a sleep disorder, e.g., insomnia, if the treated patient suffers from that disorder.

[0456] 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 illness, noting specific improvements in social / emotional withdrawal or detachment that are also commonly observed in patients with other disorders.

[0457] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific condition, as detailed below, the inventors have determined that certain clinical findings from the trial are relevant to the design of drugs for the treatment of other conditions related to social / emotional withdrawal or detachment.

[0458] In clinical trials, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest are those receiving a single 12 mg dose and those receiving an individualized daily dose regimen (IDR), which allows for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0459] The collected data included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychotic Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvements in overall MADRS scores, we focused on items across various scales and noted that specific subscore items (such as those related to social / emotional withdrawal or detachment) are associated with other conditions, in which social / emotional withdrawal or detachment is based on altered functional connectivity within and / or between the default mode network, salience network, dorsal attention network, somatomotor network, and visual network.

[0460] 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.

[0461] More specifically, the condition that can be treated by administering 5-MeO-DMT is social / emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and / or flattened affect. A further condition that can be treated 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 flattened affect. Furthermore, the reduced social engagement is improved, i.e., reduced or eliminated.

[0462] The MADRS scale item "Inability to have emotions" is particularly relevant to social / emotional withdrawal or detachment, which typically describes the subjective experience of decreased interest in one's surroundings or in activities that give pleasure. There is a diminished ability to respond to situations or people with appropriate emotions.

[0463] A score of 0 indicates normal interest in surroundings and other people, while a score of 2 indicates a diminished ability to enjoy things that normally interest one. A score of 4 is assigned when there is a loss of interest in surroundings and a loss of emotion toward friends and acquaintances. A score of 6 reflects the experience of being emotionally numb and an inability to feel anger, deep sadness, or joy, and a complete or painful inability to sympathize with close relatives and friends.

[0464] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inability to Have Emotions" across all eight patients was 36 at baseline. After two hours, it decreased to 12, which corresponds to a 24-point or 67% improvement. One day after treatment, it decreased to 2, which corresponds to a 34-point or 94% improvement. Seven days after treatment, the score decreased to 6, which corresponds to a 30-point or 83% improvement.

[0465] In the 12 mg group, the aggregate score for the MADRS item "Inability to Have Emotions" across all four patients was 16 at baseline. After two hours, it decreased to 9, which corresponds to a 7-point or 44% improvement. On day 1 after treatment, it decreased to 1, which corresponds to a 15-point or 94% improvement. On day 7 after treatment, the score decreased to 1, which corresponds to a 15-point or 94% improvement.

[0466] BPRS scale items that are particularly relevant to social / emotional withdrawal or detachment are "emotional withdrawal" and "affective blunting."

[0467] The BPRS item "Emotional Withdrawal" relates to a deficit in the patient's ability to engage emotionally in interview situations. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. Lack of affective engagement is indicated by an occasional failure to return feedback, appearing distracted at times, or smiling awkwardly, but the individual spontaneously engages with the interviewer most of the time. 3- Mild. Lack of emotional engagement is indicated by a noticeable inability to return feedback, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4- Moderate. Emotional contact is absent for much of the interview because the subject does not elaborate on responses, fails to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychotic content. 5 - Moderately severe. Same as 4, but emotional contact is absent for most of the interview. 6- Severe. Actively avoids emotional involvement. Often does not respond or gives yes / no responses (not solely due to paranoia). Responds with very little emotion. 7- Most severe. Consistently avoids emotional involvement. Does not respond or gives yes / no responses (not solely due to paranoia). May walk out during the interview or not respond at all.

[0468] The aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score decreased to 8, which corresponds to a 5-point or 38% improvement. On day 1 after treatment, it decreased to 8, which corresponds to a 5-point or 38% improvement. On day 7 after treatment, the score decreased to 8, which corresponds to a 5-point or 38% improvement.

[0469] In the 12 mg group, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score decreased to 11, corresponding to a 2-point or 15% improvement. On post-treatment day 1, the score decreased to 8, corresponding to a 5-point or 38% improvement. On post-treatment day 7, the score decreased to 6, corresponding to a 7-point or 54% improvement.

[0470] The BPRS item "blunted affect" relates to a restricted range of emotional expression in face, voice, and body language, as well as a marked indifference or flatness, even when discussing distressing topics. Possible scores are: 1- No emotional blunting. 2- Very mild. Emotional range is somewhat subdued or reserved, but facial expressions and tone of voice are within the normal range and appropriate. 3- Mild. Overall range of emotions is reduced, inhibited, or reserved, and spontaneous and appropriate emotional responses are rare. Voice tone is slightly monotonous. 4- Moderate. The range of affect is significantly reduced; the patient does not show emotion or smile, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Expressions or gestures of emotion are usually followed by a return to a flat affect. 5- Moderately severe. The range of affect is extremely reduced, the patient does not show emotion or smile, or responds minimally to distressing topics, gestures very little, and facial expression rarely changes. The tone of voice is monotonous most of the time. 6- Severe. Little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression is constant. Tone of voice is monotonous most of the time. 7- Most severe. Virtually no emotional range or expression, stiff movements. Monotonous tone of voice throughout.

[0471] The aggregate score for the BPRS item "blunted affect" was 15 at baseline. After 3 hours, the score decreased to 11, which corresponds to a 4-point or 27% improvement. On day 1 after treatment, it decreased to 8, which corresponds to a 7-point or 47% improvement. On day 7 after treatment, the score decreased to 8, which corresponds to a 7-point or 47% improvement.

[0472] In the 12 mg group, the total score for the BPRS item "blunted affect" was 11 at baseline. After 3 hours, the score had decreased to 8, corresponding to a 3-point or 27% improvement. On the first day after treatment, it had decreased to 6, corresponding to a 5-point or 45% improvement. On the seventh day after treatment, the score had decreased to 5, corresponding to a 6-point or 55% improvement.

[0473] Thus, scores on scales specifically related to social / emotional withdrawal or detachment, i.e., "unable to have emotions" (MADRS), "emotional withdrawal" (BPRS), and "blunted affect" (BPRS), are significantly improved. The inventors conclude that 5-MeO-DMT can be used to treat social / emotional withdrawal or detachment in patients, particularly those suffering from psychiatric or nervous system disorders, or sleep disorders, such as insomnia.

[0474] Thus, in accordance with the present invention, treating a patient suffering from social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment.

[0475] Negative thinking Symptoms such as pessimism, feelings of worthlessness, powerlessness and hopelessness, as well as pathological, excessive or inappropriate guilt, are grouped together herein as negative thoughts.

[0476] Helplessness and hopelessness (also simply referred to as helplessness and despair) are characterized by subjective pessimism or worry about the future, a sense of inability to cope, or a lack of control. If the patient does not have such feelings, helplessness and despair are not present. Helplessness and despair are mild when there is an occasional mild feeling of not being able to cope as usual or pessimism; moderate when the patient often feels unable to cope or has significant feelings of helplessness or despair with occasional relief; and severe when the pessimism, helplessness, or despair are markedly and persistently present.

[0477] Feelings of worthlessness (also simply called worthlessness) are characterized by awareness or thoughts of decreased self-worth or self-esteem. If the patient does not have such feelings, there is no worthlessness. They may be mild, i.e., a slightly reduced sense of self-worth; moderate, i.e., some thoughts of worthlessness and decreased self-esteem; or severe, i.e., a pronounced, pervasive, or persistent feeling of worthlessness, e.g., feeling that others would be better off without you, being unable to recognize your positive qualities.

[0478] Guilt (also simply called guilt) is characterized by a sense of self-blame, failure, or remorse for real or imagined past wrongdoings. If the patient has no such feelings, there is no guilt. Mild is characterized by a slight decrease in self-affirmation or a slight increase in self-criticism; moderate is characterized by significant thoughts of failure, self-criticism, inability to cope, or rumination about past failures and the impact on others, perceived as excessive; and severe is characterized by marked, pervasive, or persistent guilt, e.g., a sense of deserving punishment, or a lack of clear perception that it is excessive.

[0479] Negative thoughts may be associated with a psychiatric or neurological disorder or some other medical condition.

[0480] Mental or nervous system disorders that lead to or are associated with negative thinking include 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 disorder 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 psychoactive substance use (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), and personality disorders (e.g., schizotypal personality disorder and borderline personality disorder (BPD)).

[0481] Negative thinking can also occur in patients suffering from sleep disorders, such as insomnia.

[0482] Negative thinking can also occur in patients with medical health conditions that lead to related mental or neurological conditions, including traumatic brain injury (TBI).

[0483] Measuring negative thinking Negative thoughts or individual aspects thereof, such as worthlessness, powerlessness and hopelessness, and guilt, can be assessed by different instruments, such as questionnaires or scales.

[0484] 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 has a particular mental or nervous system disorder may include items related to negative thinking.

[0485] Scales assessing relevant 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).

[0486] The State Shame and Guilt Scale (SSGS) is a self-assessment scale of momentary (state) feelings of shame and guilt. It contains 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 stronger feelings of shame or guilt.

[0487] The Positive and Negative Affect Schedule-Expanded Form (PANAS-X) is a 60-item expanded version of the PANAS. The PANAS-X measures 11 specific emotions: fear, sadness, guilt, hostility, shyness, fatigue, surprise, enjoyment, confidence, concentration, and calmness. Thus, the PANAS-X provides a measure of mood at two distinct levels. The basic negative affect scales are fear, hostility, guilt, and sadness, and the guilt scale includes six items: guilt, shame, blameworthiness, anger at self, self-hatred, and dissatisfaction with self. Each response is scored as 1 = very little or not at all, 2 = slightly, 3 = moderate, 4 = quite a bit, or 5 = extremely. However, researchers facing more severe time constraints may choose to select and assess only the scales most relevant to their study.

[0488] Stronger feelings of guilt are reflected by higher scores on the guilt scale.

[0489] The PANAS-X is simple and easy to administer. Most subjects complete the entire 60-item schedule in 10 minutes or less. The scale consists of many words and phrases that describe various sensations and emotions. Although patients are required to indicate the extent to which they have felt this way over the past few weeks, trait scores on the PANAS-X scale have been found to be stable over time, including between "at this time," "today," and "the past few days," indicating that an adequately short recall period can be applied.

[0490] The State Hope Scale (SHS) has three intention and three planning items, on which respondents describe how they feel "right now." The intention subscale score is obtained by summing items 2, 4, and 6, which relate to the perceived ability to use plans to achieve desired goals, and the planning subscale score is obtained by adding items 1, 3, and 5, which relate to the thoughts used to identify possible ways to achieve goals. The total score for the State Hope Scale is obtained by summing the three intention and three planning items. Scores can range from a minimum of 6 to a maximum of 48, with higher hope reflected by a higher score on this scale.

[0491] Negative thinking or aspects thereof are also reflected in other scales, such as the HAM-D, MADRS, BPRS, or BDRS, whose relevant items may be generally applicable to assessing negative thinking or aspects thereof.

[0492] Resting-state network and negative thoughts Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is linked to blood flow, and the temporal correlation of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0493] Functional brain images are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signals are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0494] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are sets of spatially distinct brain regions that exhibit coordinated activity in the absence of an explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal fluctuations are called resting-state networks (RSNs).

[0495] Various resting-state networks have been identified and named primarily based on spatial similarities between resting-state networks and activity patterns seen in task-fMRI experiments.

[0496] Resting-state fMRI can therefore be used to assess the intrinsic functional organization of the brain, with resting-state networks characterized by aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0497] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been found to be impaired in various pathologies, 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 within one or more additional resting-state networks.

[0498] Major depressive disorder (MDD) is a disorder broadly characterized by high levels of negative affect and low levels of positive affect. More specifically, low levels of positive affect, e.g., hope, correspond to high levels of despair and high levels of negative affect, e.g., guilt. MDD has been the focus of research in the field of rs-fMRI, which indicates that MDD is a disorder characterized by large-scale network dysfunction. This dysfunction has been observed primarily in networks and regions related to emotion regulation. These include the default mode network (DMN), salience network, affect network, and prefrontal cortex. Therefore, different aspects of negative thinking may be associated with abnormal resting-state networks.

[0499] Functional connectivity abnormalities in resting-state networks have also been reported in patients with repetitive negative thinking (RNT), including altered connectivity between the left executive control network and the anterior salience network and ventral default mode network.

[0500] Thus, patients with negative thinking exhibit altered functional connectivity within and / or between resting-state networks when compared to age-matched healthy controls, with alterations observed within and / or between at least the default mode network, executive control network, salience network, affective network, and prefrontal cortex.

[0501] RSNs related to 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) (e.g., 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 disorder 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 psychoactive substance use (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), and personality disorders (e.g., schizotypal personality disorder and borderline personality disorder (BPD)).

[0502] Resting-state networks involved in negative thinking are also affected by mental or nervous system conditions that are the result of certain medical conditions, such as traumatic brain injury (TBI).

[0503] The resting-state network involved in negative thinking is also affected by sleep disorders, such as insomnia, and in fact, negative thinking and sleep disorders are correlated.

[0504] Treatment of negative thinking and mental or nervous system disorders According to the present invention, negative thoughts occurring in patients with mental disorders or nervous system disorders can be treated, and further, negative thoughts occurring in patients with sleep disorders, such as insomnia, can be treated.

[0505] In patients with negative thoughts associated with another condition detailed above, treatment of the negative thoughts in accordance with the present invention will result in an improvement in the condition associated with the negative thoughts.

[0506] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0507] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the resetting of pathological maladaptive connections as the networks reconnect. New, healthy functional connections are established with lasting effects.

[0508] Thus, in accordance with the present invention, influencing these networks by the treatment methods described in the present invention results in an improvement in negative thinking, and in the case where the patient being treated has a psychiatric or nervous system disorder, also results in an improvement in the disorder, and in the case where the patient being treated has a sleep disorder, e.g., insomnia, also results in an improvement in the sleep disorder, e.g., insomnia.

[0509] To further support the clinical application of 5-MeO-DMT in patients with negative thinking, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in negative thinking that are also commonly observed in patients with other disorders.

[0510] 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, as discussed in more detail below, the inventors have determined that certain clinical observations made in this study may be relevant for devising treatments for other conditions associated with negative thinking.

[0511] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were those receiving a single 12 mg dose and those receiving an individualized daily dose regimen (IDR) that allowed for multiple escalating doses (6 mg, 12 mg, and 18 mg) throughout the day, driven by the intensity of the patient-reported hallucinatory experience.

[0512] Data collected included assessments of treated patients 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 improvements in overall MADRS scores, we focused on items across the various scales and noted that specific subscore items (e.g., items related to negative thinking) were associated with other conditions, in which negative thinking is based on alterations in functional connectivity within and / or between the default mode network, executive control network, salience network, affective network, and prefrontal cortex.

[0513] 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.

[0514] More specifically, aspects that can be treated by administration of 5-MeO-DMT are negative thoughts, particularly feelings of worthlessness, helplessness and hopelessness, and / or guilt. 5-MeO-DMT can be administered to a patient to reduce or eliminate negative thoughts, particularly feelings of worthlessness, helplessness and hopelessness, and / or guilt in the patient.

[0515] The item on the MADRS scale that is particularly relevant to negative thinking is "pessimistic thinking," which refers to thoughts of guilt, inferiority, self-blame, guilt, regret, and doom and gloom.

[0516] A score of 0 is assigned if there are no pessimistic thoughts. A score of 2 is assigned if there are fluctuating thoughts of failure, self-blame, or self-deprecation. A score of 3 is assigned if there are persistent self-blame or obvious but reasonable thoughts of guilt or guilt, and the patient is increasingly pessimistic about the future. A score of 6 is assigned if there are delusions of doom, remorse, or irredeemable guilt, and irrational, unwavering self-blame.

[0517] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "pessimistic thinking" across all eight patients was 28 at baseline.

[0518] After 2 hours, it had decreased to 7, which corresponds to a 21-point or 75% improvement. On the first day after treatment, it had decreased to 4, which corresponds to a 24-point or 86% improvement. On the seventh day after treatment, it had decreased to 3, which corresponds to a 25-point or 89% improvement.

[0519] In the 12 mg group, the aggregate score for the MADRS item "pessimistic thinking" across all four patients was 16 at baseline. After two hours, it had decreased to 8, which corresponds to an 8-point or 50% improvement. One day after treatment, it had decreased to 7, which corresponds to a 9-point or 56% improvement.

[0520] Seven days after treatment, it had decreased to 8, which corresponds to an 8-point or 50% improvement.

[0521] A BPRS item that is particularly relevant to negative thinking is "Guilt." This item concerns excessive worry or regret about past actions. Possible scores are: 1- No guilt. 2 - Very mild. Preoccupied with disappointing someone or failing at something, but not distracted. Can easily shift thoughts to other things. 3 - Mild. Somewhat preoccupied with disappointment or failure. Tends to express guilt to others. 4- Moderate. Disproportionate preoccupation with guilt, having done something wrong, or hurting others through something done or failed to do, but able to quickly shift attention elsewhere. 5 - Moderately severe. Preoccupied with guilt, disappointment, or failure; able to focus elsewhere, but only with great effort. Not delusional. 6- Severe, guilt delusions or irrational self-blame that is largely unrelated to the situation. Moderate preoccupation present. 7- Most severe. Delusions of guilt or irrational self-blame that are highly unrelated to the situation. Subject is highly preoccupied with feelings of guilt and likely to disclose or act on the delusion.

[0522] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "guilt" across all eight patients was 34 at baseline.

[0523] After 3 hours, the score had dropped to 14, which corresponds to a 20-point or 59% improvement. On the first day after treatment, it had dropped to 11, which corresponds to a 23-point or 68% improvement. On the seventh day after treatment, the score had dropped to 10, which corresponds to a 24-point or 71% improvement.

[0524] In the 12 mg group, the aggregate score for the BPRS item "guilt" across all four patients was 18 at baseline.

[0525] After 3 hours, the score had dropped to 9, which corresponds to a 9-point or 50% improvement. On the first day after treatment, it had dropped to 5, which corresponds to a 13-point or 72% improvement. On the seventh day after treatment, it had dropped to 5, which corresponds to a 13-point or 72% improvement.

[0526] Thus, scores on the MADRS scale item "Pessimistic Thinking," which is particularly related to negative thinking, are significantly improved, as are scores on the BPRS item "Guilt." The inventors conclude that 5-MeO-DMT can be used to treat negative thinking in patients, particularly those who also suffer from psychiatric or nervous system disorders, or sleep disorders (e.g., insomnia).

[0527] Thus, in accordance with the present invention, treating a patient experiencing negative thoughts with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the negative thoughts.

[0528] Maternal function In addition to the above, the inventors believe that psychiatric or nervous system disorders as defined herein, particularly disorders involving one or more symptoms selected from sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking, impair maternal functioning. Indeed, each of the described symptoms, on its own, has the potential to impair maternal functioning (and thus is independently treatable).

[0529] The first year after birth is particularly crucial for both mother and child, as in most cases the mother is the primary caregiver and therefore shoulders the majority of the work involved in childcare tasks.

[0530] Maternal functioning includes maternal competence in relation to interaction with the child(ren) and aspects of maternal self-care.

[0531] 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 of life influences child development. High levels of maternal functioning are likely to correlate with favorable child developmental outcomes. Similarly, dysfunction in the postpartum period may prevent optimal child development.

[0532] The Barkin Index of Maternal Functioning (BIMF) is designed to measure functioning during the first year after delivery. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score from 0 to 6, with a maximum total score of 120. Higher scores indicate better maternal functioning.

[0533] The BIMF identifies the main domains of maternal functioning during the postnatal period as self-care, parenting, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0534] A BIMF score of 95 or less is considered herein to represent slightly impaired maternal function, a score of 80 or less is considered herein to represent impaired maternal function, and a score of 65 or less is considered herein to represent severely impaired maternal function. The present invention particularly allows for improvement of maternal function in patients with a pre-treatment score of 80 or less, and even in patients with a score of 65 or less.

[0535] As already indicated above, the present invention allows the treatment of patients suffering from psychiatric or neurological disorders, which treatment not only results in a reduction in scores assessing the severity of depression, but also improves maternal functioning, as detailed below.

[0536] To further support the clinical application of 5-MeO-DMT in patients with psychiatric or neurological disorders, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric illness and observed specific improvements in aspects of the illness commonly observed in patients with psychiatric or neurological disorders. The inventors noted, in particular, improvements in various symptoms and symptom combinations that the inventors determined were also related to maternal function.

[0537] 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). These results have been confirmed by a recent study in patients with postpartum depression (see the Examples section below).

[0538] 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 different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, as determined by the intensity of the patient-reported hallucinatory experience.

[0539] Data collected included treated patients' assessments of 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 items comprising various scales, noting that some of the subscore items are particularly relevant to patients with psychiatric or neurological disorders and are related to maternal functioning.

[0540] Multiple patients within the recruited cohort showed significant improvement in one or more of these subscore items, 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.

[0541] The specific subscore items within each of these scales are identified in further detail below. We conclude that effectiveness in treating one or more of these symptoms results in a significant improvement in overall outcome in patients with psychiatric or nervous system disorders treated with 5-MeO-DMT.

[0542] Thus, treatment according to the present invention reduces or eliminates (or ameliorates or eliminates) aspects of the disease.

[0543] When this aspect is assessed on the MADRS scale, there is an improvement (reduction) of at least 1 point, or the patient is in complete remission (elimination) after treatment, i.e., the respective aspect is scored as 0.

[0544] When this aspect is assessed on the BPRS scale, there is an improvement (reduction) of at least 1 point, or the patient is in complete remission (elimination) after treatment, i.e., each aspect is scored as 1.

[0545] 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 score of at least 1. Preferably, the CGI-S score decreases by at least 2 and / or to a score of 0. In particular, a decrease in the CGI-S score of at least 3 and / or to a score of 0 is preferred.

[0546] The inventors further believe that improvements observed on certain MADRS items translate into improvements in aspects of maternal functioning.

[0547] Particularly relevant MADRS items are discussed in more detail below.

[0548] The MADRS item "inner tension" describes a vague feeling of discomfort, irritability, inner confusion, or mental tension (leading to either panic, fear, or anguish), which is rated according to intensity, frequency, duration, and the degree of relief sought.

[0549] A score of 0 is assigned if the patient is calm and only momentary inner tension is present. A score of 2 is assigned if irritability and vague discomfort occur occasionally. A score of 4 is assigned if there is a continuous inner tension or intermittent panic that the patient has some difficulty overcoming. A score of 6 is assigned if there is constant fear or anguish and overwhelming panic.

[0550] The inventors have determined that an increase in the score on the MADRS item "internal strain" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the infant(s) and maternal self-care). An increase in the score on the MADRS item "internal strain" impairs mother-infant interaction as assessed by the BIMF, as well as maternal psychological well-being.

[0551] Conversely, improvements on these MADRS items would lead to improvements in maternal functioning, particularly the BIMF functional domains of mother-infant interaction and / or maternal psychological well-being.

[0552] In the study identified above that included patients with TRD, in the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "internal tension" across all eight patients was 26 at baseline. After two hours, the score decreased to 11, corresponding to a 15-point or 58% improvement. One day after treatment, the score decreased to 6, corresponding to a 20-point or 77% improvement. Seven days after treatment, the score decreased to 12, corresponding to a 14-point or 54% improvement.

[0553] In the 12 mg group, the aggregate score for the MADRS item "internal tension" across all four patients was 13 at baseline. After two hours, the score decreased to 2, corresponding to an 11-point or 85% improvement. On post-treatment day 1, the score decreased to 3, corresponding to a 10-point or 77% improvement. On post-treatment day 7, the score decreased to 5, corresponding to an 8-point or 62% improvement.

[0554] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of inner tension may be achieved.

[0555] Improvement in inner tension is reflected by an improvement in the inner tension score of at least one MADRS item at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0556] Improvement in inner tension, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0558] Improvement in inner tension, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0559] The improvement in inner tension, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0560] The inventors further conclude that the reduction or elimination of inner tension achieved by treating patients with psychiatric or nervous system disorders leads to an improvement in maternal functioning, as reflected not only by a decrease in the MADRS total score but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score is also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0561] Since inner strain also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "inner strain" further contributes to a general improvement in maternal functioning.

[0562] The MADRS item "Inhibition" describes difficulty initiating or slowness in initiating and performing everyday activities.

[0563] A score of 0 means that there is almost no difficulty in starting anything and there is no inactivity. A score of 2 is assigned if the patient has difficulty initiating activities. A score of 4 means that simple activities that are usually performed are difficult to start and require effort to perform. A score of 6 is assigned if there is complete inhibition and the patient is unable to do anything without assistance.

[0564] The inventors have determined that an increased score on the "restraint" item of the MADRS negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the "restraint" item of the MADRS impairs parenting, self-care, emotional well-being, control, and adjustment.

[0565] Conversely, improvement on these MADRS items would translate to improvements in maternal functioning, particularly the BIMF functional domains of parenting, self-care, emotional fulfillment, control, and / or adjustment.

[0566] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inhibition" across all eight patients was 27 at baseline. After two hours, it decreased to 10, which corresponds to a 17-point or 63% improvement. One day after treatment, it decreased to 5, which corresponds to a 22-point or 81% improvement. Seven days after treatment, it decreased to 3, which corresponds to a 24-point or 89% improvement.

[0567] In the 12 mg group, the aggregate score for the "inhibition" item on the MADRS across all four patients was 16 at baseline. After two hours, it decreased to 10, which corresponds to a 6-point or 38% improvement. On day 1 after treatment, it decreased to 0, which corresponds to a 16-point or 100% improvement. On day 7 after treatment, it decreased to 3, which corresponds to a 13-point or 81% improvement.

[0568] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of inhibition may be achieved.

[0569] Improved inhibition is reflected by an improvement in inhibition scores for at least the MADRS items at about 2 hours, day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0570] Improvement in inhibition, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0571] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0572] Improvement in inhibition, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0573] The improvement in inhibition, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0574] The inventors further conclude that the reduction or elimination of inhibition achieved by treatment of patients with psychiatric or nervous system disorders leads not only to a decrease in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is rapid, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score is also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28. Because inhibition also affects other aspects of psychiatric or nervous system disorders, the inventors conclude that the improvement observed in the "Inhibition" item on the MADRS further contributes to an overall improvement in maternal functioning.

[0575] The MADRS item "Inability to have emotions" describes the subjective experience of decreased interest in one's surroundings or in activities that usually give pleasure. One has a diminished ability to respond to situations or people with appropriate emotions.

[0576] A score of 0 indicates normal interest in surroundings and other people, a score of 2 indicates a diminished ability to enjoy things that normally interest one. A score of 4 is assigned in cases of loss of interest in surroundings and loss of emotion toward friends and acquaintances. A score of 6 reflects the experience of emotional numbness and an inability to experience feelings of anger, deep sadness, or joy, and a complete or painful inability to sympathize with close relatives and friends.

[0577] The inventors have determined that an increased score on the MADRS item "unable to have emotions" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the MADRS item "unable to have emotions" impairs mother-child interaction and emotional well-being.

[0578] Conversely, improvement on these MADRS items leads to improvement in maternal functioning, particularly in the BIMF functional domains of mother-child interaction and / or psychological well-being.

[0579] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inability to Have Emotions" across all eight patients was 36 at baseline. After two hours, it decreased to 12, which corresponds to a 24-point or 67% improvement. One day after treatment, it decreased to 2, which corresponds to a 34-point or 94% improvement. Seven days after treatment, the score decreased to 6, which corresponds to a 30-point or 83% improvement.

[0580] In the 12 mg group, the aggregate score for the MADRS item "Inability to Have Emotions" across all four patients was 16 at baseline. After two hours, it decreased to 9, which corresponds to a 7-point or 44% improvement. On day 1 after treatment, it decreased to 1, which corresponds to a 15-point or 94% improvement. On day 7 after treatment, the score decreased to 1, which corresponds to a 15-point or 94% improvement.

[0581] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of the inability to have emotions may be achieved.

[0582] Improvement in unaffectedness is reflected by at least an improvement in the unaffectedness score on the MADRS item at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0583] Improvement in affective disorders, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0584] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0585] Improvement in inability to feel, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0586] The improvement in emotional inability, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0587] The inventors further conclude that the reduction or elimination of emotional incapacity following treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the MADRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is rapid, i.e., within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 7, 14, and / or 28. 13 Because emotional incapacity impacts other aspects of psychiatric or nervous system disorders, the inventors conclude that the improvement observed in the MADRS item "emotional incapacity" further contributes to an overall improvement in maternal functioning.

[0588] The MADRS item "Difficulty concentrating" describes difficulty organizing thoughts, leading to a lack of concentration that is so severe it interferes with normal functioning.

[0589] If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty gathering thoughts, the score is 2. If there is difficulty concentrating and sustaining thoughts, and the ability to read or sustain a conversation is reduced, a score of 4 is assigned. If the patient cannot read or speak without great difficulty, the score is 6.

[0590] The inventors have determined that an increased score on the MADRS item "Difficulty concentrating" negatively impacts both aspects of maternal functioning (maternal ability to interact with infant(s) and maternal self-care). An increased score on the MADRS item "Difficulty concentrating" impairs the ability to care for and even manage the infant.

[0591] Conversely, improvement on this MADRS item translates to improvement in maternal functioning, particularly in the BIMF functional domain of infant care and / or management.

[0592] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Difficulty concentrating" across all eight patients was 30 at baseline. After two hours, the score decreased to 11, corresponding to a 19-point or 63% improvement. One day after treatment, the score decreased to 1, corresponding to a 29-point or 97% improvement. Seven days after treatment, the score decreased to 9, corresponding to a 21-point or 70% improvement.

[0593] In the 12 mg group, the aggregate score for the MADRS item "Difficulty concentrating" across all four patients was 16 at baseline. After two hours, the score had decreased to 7, corresponding to a 9-point or 56% improvement. On day 1 after treatment, the score had decreased to 2, corresponding to a 14-point or 88% improvement. On day 7 after treatment, it had decreased to 3, corresponding to a 13-point or 81% improvement.

[0594] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of concentration difficulties may be achieved.

[0595] Improvement in difficulty concentrating is reflected by an improvement in the difficulty concentrating score on at least the MADRS item at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0596] Improvement in concentration difficulties, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0597] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

[0599] The improvement in concentration difficulties, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0600] The inventors further conclude that the reduction or elimination of concentration difficulties resulting from treatment of patients with psychiatric or nervous system disorders results in an improvement in maternal functioning, as reflected not only by a decrease in the MADRS total score but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 7, 14, and / or 28.

[0601] Because difficulty concentrating also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "difficulty concentrating" further contributes to a general improvement in maternal functioning.

[0602] The MADRS item "negative thinking" refers to thoughts of guilt, inferiority, self-blame, guilt, regret, and doom and gloom.

[0603] A score of 0 is assigned if there are no pessimistic thoughts. A score of 2 is assigned if there are fluctuating thoughts of failure, self-blame, or self-deprecation. A score of 3 is assigned if there are persistent self-blame or obvious but reasonable thoughts of guilt or guilt, and the patient is increasingly pessimistic about the future. A score of 6 is assigned if there are delusions of doom, remorse, or irredeemable guilt, and irrational, unwavering self-blame.

[0604] The inventors have determined that an increased score on the MADRS item "pessimistic thinking" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the infant(s) and maternal self-care). An increased score on the MADRS item "pessimistic thinking" impairs emotional well-being, social support and control.

[0605] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly in the BIMF functional domains of emotional well-being, social support, and / or control.

[0606] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Pessimistic Thinking" across all eight patients was 28 at baseline. After two hours, it had decreased to 7, which corresponds to a 21-point or 75% improvement. One day after treatment, it had decreased to 4, which corresponds to a 24-point or 86% improvement. Seven days after treatment, it had decreased to 3, which corresponds to a 25-point or 89% improvement.

[0607] In the 12 mg group, the aggregate score for the MADRS item "pessimistic thinking" across all four patients was 16 at baseline. After two hours, it was reduced to 8, which corresponds to an 8-point or 50% improvement. On day 1 after treatment, it was reduced to 7, which corresponds to a 9-point or 56% improvement. On day 7 after treatment, it was reduced to 8, which corresponds to an 8-point or 50% improvement.

[0608] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of negative thinking may be achieved.

[0609] Improvement in negative thinking is reflected by an improvement in the negative thinking score on the MADRS item at least about 2 hours, on day 1 (e.g., about 24 hours), on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0610] Improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0611] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0612] Improvement in negative thinking, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0613] The improvement in negative thinking, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0614] The inventors further conclude that the reduction or elimination of negative thinking through treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the MADRS total score but also 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28.

[0615] Because pessimistic thinking also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "pessimistic thinking" further contributes to a general improvement in maternal functioning.

[0616] The MADRS item "Decreased Sleep" describes the experience of decreased sleep duration or depth compared to the subject's own normal pattern when well.

[0617] A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects slight difficulty falling asleep or slightly short, light, or intermittent sleep. A score of 4 means reduced or interrupted sleep for at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0618] The inventors have determined that an increased score on the MADRS item "Decreased Sleep" negatively impacts both aspects of maternal functioning (maternal competence in interacting with child(ren) and maternal self-care). An increased score on the MADRS item "Decreased Sleep" impairs self-care, emotional well-being, and control.

[0619] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly in the BIMF functional domains of self-care, emotional well-being, and / or control.

[0620] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Decreased Sleep" across all eight patients was 25 at baseline. By day 1 after treatment (the earliest time point to assess the treatment's impact on sleep), the score had decreased to 12, representing a 13-point or 52% improvement. By day 7 after treatment, the score had decreased to 9, representing a 16-point or 64% improvement.

[0621] In the 12 mg group, the aggregate score for the MADRS item "Decreased Sleep" across all four patients was 12 at baseline. One day after treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. Seven days after treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0622] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of sleep deprivation may be achieved.

[0623] The reduction or elimination of sleep deprivation is reflected by an improvement in the sleep deprivation score for at least the MADRS item at 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0624] Improvement in sleep reduction, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0625] Improvement in sleep reduction, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0626] The improvement in sleep reduction, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0627] The inventors further conclude that the reduction or elimination of sleep loss due to treatment of patients with psychiatric or nervous system disorders results in an improvement in maternal functioning, as reflected not only by a decrease in the MADRS total score but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score is also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0628] Because sleep loss also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "sleep loss" further contributes to an overall improvement in maternal functioning.

[0629] A further aspect of psychiatric or nervous system disorders that may be treated by administration of 5-MeO-DMT is suicidal ideation. 5-MeO-DMT may be administered to a patient with a psychiatric or nervous system disorder to reduce or eliminate suicidal ideation in that patient.

[0630] In the clinical trials mentioned above involving the administration of 5-MeO-DMT, the MADRS item "suicidal thoughts" was assessed, among other things.

[0631] "Suicidal thoughts" refers to feeling that there is no point in living, that one is ready to die naturally at any time, having suicidal thoughts, and / or making preparations to commit suicide. A suicide attempt itself should not affect the rating of this MADRS item.

[0632] A score of 0 means that the patient is enjoying life. A score of 2 is assigned if the patient with a psychiatric or nervous system disorder is bored with life and / or has only fleeting suicidal thoughts. A score of 4 means that the patient wishes they were dead, has frequent suicidal thoughts, and considers suicide a possible solution, but the patient has no specific plan or intent. A score of 6 is assigned if the patient has a clear plan to attempt suicide and / or is actively preparing.

[0633] This item on the MADRS scale is particularly relevant to suicidal ideation.

[0634] The inventors have determined that an increased score on the MADRS item "suicidal thoughts" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the MADRS item "suicidal thoughts" impairs self-care, emotional well-being, and control.

[0635] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly in the BIMF functional domains of self-care, emotional well-being, and / or control.

[0636] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Suicidal Thoughts" across all eight patients was 11 at baseline. After two hours, the score had fallen to 3, which corresponds to an 8-point or 73% improvement. One day after treatment, it had fallen to 1, which corresponds to a 10-point or 91% improvement. Seven days after treatment, the score had fallen to 3, which corresponds to an 8-point or 73% improvement.

[0637] Aggregating scores for the MADRS item "suicidal ideation" across all four patients in the 12 mg group showed a baseline of 8. After two hours, the score had decreased to 3, corresponding to a 5-point or 63% improvement. On the first day after treatment, it had decreased to 5, corresponding to a 3-point or 38% improvement. On the seventh day after treatment, the score had decreased to 7, corresponding to a 1-point or 13% improvement.

[0638] Thus, scores for the "suicidal thoughts" scale item, which is specifically related to suicidal ideation, are significantly improved in patients on at least an individualized dosing regimen. We conclude that 5-MeO-DMT may be used to treat suicidal ideation in patients with psychiatric or nervous system disorders.

[0639] Thus, in accordance with the present invention, treating a patient with a psychiatric or nervous system disorder who is experiencing suicidal ideation reduces or eliminates the suicidal ideation.

[0640] The reduction or elimination of suicidal ideation is reflected by at least an improvement in the scores for the suicidal thoughts on the MADRS item at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0641] If the patient is suffering from 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 last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0642] Improvement in suicidal ideation, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0643] Alternatively, the decrease in Clinical Global Impression-Severity (CGI-S) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0644] Improvement in suicidal ideation, as assessed by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0645] The improvement in suicidal ideation, as assessed by a reduction in CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0646] The inventors further conclude that the reduction or elimination of suicidal thoughts through treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the MADRS total score but also 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28.

[0647] Because suicidal thoughts also impact other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "suicidal thoughts" further contributes to an overall improvement in maternal functioning.

[0648] The BPRS item "Emotional Withdrawal" relates to a deficit in the patient's ability to engage emotionally in interview situations. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. Lack of affective engagement is indicated by an occasional failure to return feedback, appearing distracted at times, or smiling awkwardly, but the individual spontaneously engages with the interviewer most of the time. 3- Mild. Lack of emotional engagement is indicated by a noticeable inability to return feedback, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4- Moderate. Emotional contact is absent for much of the interview because the subject does not elaborate on responses, fails to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychotic content. 5 - Moderately severe. Same as 4, but emotional contact is absent for most of the interview. 6- Severe. Actively avoids emotional involvement. Often does not respond or gives yes / no responses (not solely due to paranoia). Responds with very little emotion. 7- Most severe. Consistently avoids emotional involvement. Does not respond or gives yes / no responses (not solely due to paranoia). May walk out during the interview or not respond at all.

[0649] The inventors determined that an increased score on the BPRS item "emotional withdrawal" adversely affects both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the BPRS item "emotional withdrawal" impairs emotional well-being, mother-child interaction, and social support.

[0650] Conversely, improvement on this BPRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of emotional well-being, mother-infant interaction, and / or social support.

[0651] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After three hours, the score had decreased to 8, which corresponds to a 5-point or 38% improvement. On the first day after treatment, it had decreased to 8, which corresponds to a 5-point or 38% improvement. On the seventh day after treatment, the score had decreased to 8, which corresponds to a 5-point or 38% improvement.

[0652] In the 12 mg group, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score decreased to 11, corresponding to a 2-point or 15% improvement. On post-treatment day 1, the score decreased to 8, corresponding to a 5-point or 38% improvement. On post-treatment day 7, the score decreased to 6, corresponding to a 7-point or 54% improvement.

[0653] We conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of emotional withdrawal may be achieved.

[0654] The reduction or elimination of emotional withdrawal is reflected by at least an improvement in the score on the emotional withdrawal item of the BPRS at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0655] Improvement in emotional withdrawal, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0656] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0657] Improvement in emotional withdrawal, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0658] The improvement in emotional withdrawal, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0659] The inventors further conclude that the reduction or elimination of emotional withdrawal by treating patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28.

[0660] Because emotional withdrawal also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "emotional withdrawal" further contributes to a general improvement in maternal functioning.

[0661] The BPRS item "affective blunting" relates to a restricted range of emotional expression in face, voice, and body language, as well as a marked indifference or flatness, even when discussing distressing topics. Possible scores are: 1- No emotional blunting. 2- Very mild. Emotional range is somewhat subdued or reserved, but facial expressions and tone of voice are within the normal range and appropriate. 3- Mild. Overall range of emotions is reduced, inhibited, or reserved, and spontaneous and appropriate emotional responses are rare. Voice tone is slightly monotonous. 4- Moderate. The range of affect is significantly reduced; the patient does not show emotion or smile, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Expressions or gestures of emotion are usually followed by a return to a flat affect. 5- Moderately severe. The range of affect is extremely reduced, the patient does not show emotion or smile, or responds minimally to distressing topics, gestures very little, and facial expression rarely changes. The tone of voice is monotonous most of the time. 6- Severe. Little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression is constant. Tone of voice is monotonous most of the time. 7- Most severe. Virtually no emotional range or expression, stiff movements. Monotonous tone of voice throughout.

[0662] The inventors have determined that elevated scores on the BPRS item "flattened affect" negatively impact both aspects of maternal functioning (maternal competence related to communication with infant(s) and maternal self-care). Elevated scores on the BPRS item "flattened affect" impair emotional well-being and mother-infant communication.

[0663] Conversely, improvement on this BPRS item would translate to improved maternal functioning, particularly in the BIMF domain of functioning, psychological well-being and / or mother-child communication.

[0664] The aggregate score for the BPRS item "blunted affect" was 15 at baseline. After 3 hours, the score decreased to 11, which corresponds to a 4-point or 27% improvement. On day 1 after treatment, it decreased to 8, which corresponds to a 7-point or 47% improvement. On day 7 after treatment, the score decreased to 8, which corresponds to a 7-point or 47% improvement.

[0665] In the 12 mg group, the total score for the BPRS item "blunted affect" was 11 at baseline. After 3 hours, the score had decreased to 8, corresponding to a 3-point or 27% improvement. On the first day after treatment, it had decreased to 6, corresponding to a 5-point or 45% improvement. On the seventh day after treatment, the score had decreased to 5, corresponding to a 6-point or 55% improvement.

[0666] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of affective blunting may be achieved.

[0667] The reduction or elimination of blunted affect is reflected by at least an improvement in the score on the blunted affect component of the BPRS at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0668] Improvement in affective blunting, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0669] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0670] Improvement in affective blunting, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0671] The improvement in affective blunting, as reflected by a reduction in the CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0672] The inventors further conclude that the reduction or elimination of blunted affect resulting from treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score, but also 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28.

[0673] Because affective blunting also affects other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "affective blunting" further contributes to a general improvement in maternal functioning.

[0674] The BPRS item "Guilt" concerns excessive preoccupation with or remorse for past actions. Possible scores are:

[0675] 1- No guilt.

[0676] 2 - Very mild. Preoccupied with disappointing someone or failing at something, but not distracted. Can easily shift thoughts to other things.

[0677] 3 - Mild. Somewhat preoccupied with disappointment or failure. Tends to express guilt to others.

[0678] 4 - Moderate. Disproportionate preoccupation with guilt, having done something wrong, or hurting others through something done or failed to do, but able to quickly shift attention elsewhere.

[0679] 5 - Moderately severe. Preoccupied with guilt, disappointment, or failure; able to focus elsewhere, but only with great effort. Not delusional.

[0680] 6 - Severe. Delusional guilt or irrational self-blame that is largely unrelated to the situation. Moderately distracted.

[0681] 7 - Most severe. Delusions of guilt or irrational self-blame that are highly unrelated to the situation. Subject is highly preoccupied with feelings of guilt and likely to disclose or act on the delusion.

[0682] The inventors have determined that an increased score on the BPRS item "guilt" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the BPRS item "guilt" impairs self-care, mother-child interaction, emotional well-being, and control.

[0683] Conversely, improvement on these BPRS items would translate to improvements in maternal functioning, particularly the BIMF functional domains of self-care, mother-infant interaction, emotional well-being, and / or control.

[0684] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "Guilt" across all eight patients was 34 at baseline. After three hours, the score had fallen to 14, corresponding to a 20-point or 59% improvement. One day after treatment, it had fallen to 11, corresponding to a 23-point or 68% improvement. Seven days after treatment, the score had fallen to 10, corresponding to a 24-point or 71% improvement.

[0685] In the 12 mg group, the aggregate score for the BPRS item "guilt" across all four patients was 18 at baseline. After 3 hours, the score had decreased to 9, which corresponds to a 9-point or 50% improvement. On day 1 after treatment, it had decreased to 5, which corresponds to a 13-point or 72% improvement. On day 7 after treatment, it had decreased to 5, which corresponds to a 13-point or 72% improvement.

[0686] We conclude that by using 5-MeO-DMT to treat patients with psychiatric or neurological disorders, a reduction or elimination of guilt may be achieved.

[0687] The reduction or elimination of guilt is reflected by an improvement in the score on the guilt item of the BPRS at least about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0688] Improvement in guilt, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0689] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0690] Improvement in guilt, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0691] The improvement in guilt, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0692] The inventors further conclude that the reduction or elimination of guilt through treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28.

[0693] Because guilt also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "guilt" further contributes to a general improvement in maternal functioning.

[0694] The BPRS item "Anxiety" relates to reported apprehension, tension, fear, panic, or worry. Possible scores are:

[0695] 1- No anxiety.

[0696] 2 - Very mild. Reports discomfort due to worry that occurs more frequently than most healthy people or occasional worry.

[0697] 3 - Mild. Frequent anxiety, but able to quickly redirect attention elsewhere.

[0698] 4 - Moderate. Worried most of the time and unable to easily focus on other things, but does not impair functioning, or occasional autonomic anxiety, but does not impair functioning.

[0699] 5 - Moderately severe. There are frequent but not daily periods of autonomic anxiety, or some areas of functioning are impaired by anxiety or worry.

[0700] 6 - Severe. Autonomic anxiety occurs daily but not all day long, or many areas of functioning are impaired by anxiety or constant worry.

[0701] 7 - Most severe. Anxiety with autonomic symptoms persists throughout the day or most areas of functioning are impaired by anxiety or constant worry.

[0702] The inventors determined that elevated scores on the BPRS item "Anxiety" negatively impact both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the BPRS item "Anxiety" impair emotional well-being, social support, and control.

[0703] Conversely, improvement on this BPRS item would translate to improved emotional well-being, social support, and / or control in maternal functioning, particularly in the BIMF functioning domain.

[0704] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "Anxiety" across all eight patients was 37 at baseline. After three hours, the score decreased to 19, corresponding to an 18-point or 49% improvement. One day after treatment, the score decreased to 16, corresponding to a 21-point or 57% improvement. Seven days after treatment, the score decreased to 17, corresponding to a 20-point or 54% improvement.

[0705] In the 12 mg group, the BPRS "anxiety" item score was aggregated across all four patients, with a baseline of 25. After 3 hours, the score had decreased to 11, corresponding to a 14-point or 56% improvement. On day 1 after treatment, the score had decreased to 6, corresponding to a 19-point or 76% improvement. On day 7 after treatment, the score had decreased to 6, corresponding to a 19-point or 76% improvement.

[0706] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of anxiety may be achieved.

[0707] The reduction or elimination of anxiety is reflected by an improvement in the score on the anxiety item of the BPRS at least about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0708] Improvement in anxiety, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0709] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGIS) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0710] Improvement in anxiety, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0711] The improvement in anxiety, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0712] The inventors further conclude that the reduction or elimination of anxiety by treating patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28.

[0713] Because anxiety also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "anxiety" further contributes to a general improvement in maternal functioning.

[0714] The BPRS item "tension" relates to observable physical and motor signs of tension, "nervousness," and agitation. Possible scores are:

[0715] 1- No tension.

[0716] 2 - Very mild. Excessive restlessness but within normal limits. Some transient signs of nervousness, such as nail biting, paw shaking, head scratching, or finger tapping.

[0717] 3 - Mild. Same as "2" but with more frequent or exaggerated signs of tension.

[0718] 4 - Moderate. Signs of motor tightness are numerous and frequent, and one or more signs may occur simultaneously, e.g., clenching hands together while rocking feet. Signs of tightness may be absent.

[0719] 5 - Moderately severe. Frequent exertional strain accompanied by one or more symptoms often occurs simultaneously. Rarely, strain symptoms may be absent.

[0720] 6 - Severe. Same as 5, but signs of tension are persistent.

[0721] 7 - Most severe. Multiple motor signs of tension are present in succession, e.g., continuous pacing and clenching of hands.

[0722] The inventors have determined that elevated scores on the BPRS item "strain" negatively impact both aspects of maternal functioning (maternal competence related to communication with infant(s) and maternal self-care). Elevated scores on the BPRS item "strain" impair mother-infant communication and emotional well-being.

[0723] Conversely, improvement on this BPRS item would translate to improved maternal functioning, particularly mother-child communication and / or emotional well-being in the BIMF functional domain.

[0724] In the study group receiving the individualized dosing plan, the aggregated scores for the "tension" item on the BPRS across all eight patients had a baseline of 16. After three hours, the score had fallen to 11, which corresponds to a 5-point or 31% improvement. On the first day after treatment, it had fallen to 11, which corresponds to a 5-point or 31% improvement. On the seventh day after treatment, the score had fallen to 10, which corresponds to a 6-point or 38% improvement.

[0725] In the 12 mg group, the BPRS "tension" item score, aggregated across all four patients, had a baseline of 14. After three hours, the score had decreased to 9, corresponding to a 5-point or 36% improvement. On the first day after treatment, it had decreased to 6, corresponding to an 8-point or 57% improvement. On the seventh day after treatment, the score had decreased to 6, corresponding to an 8-point or 57% improvement.

[0726] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of tension may be achieved.

[0727] The reduction or elimination of tension is reflected by at least an improvement in the score on the tension item of the BPRS at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0728] Improvement in tone, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0729] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0730] 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0731] The improvement in tone, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0732] The inventors further conclude that reduction or elimination of tension through treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28.

[0733] Since strain also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "strain" further contributes to a general improvement in maternal functioning.

[0734] Improvement in one or more aspects of the psychiatric or nervous system disorder also leads to a general improvement. Preferably, treatment results in remission.

[0735] Remission of depressive symptoms may be reflected by a MADRS score of 10 or less, with onset within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, occurring on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0736] Further alternatively, or in addition, remission of depressive symptoms may be reflected by a HAM-D score of 7 or less, with onset within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and with onset on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0737] In light of the above, it follows that treating 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 confirmed by clinical data, as discussed in the Examples section below.

[0738] Improvement in maternal functioning includes improvements in the self-care domain of functioning. For example, an improvement in the MADRS items of inhibition and / or sleep reduction leads to an increase in the score of the BIMF scale, which reflects 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%.

[0739] Improvement in maternal functioning includes improvement in the parenting function domain. For example, improvement in the inhibition and / or concentration difficulties items of the MADRS results in an increase in the score of the BIMF scale reflecting parenting. The improvement in the cumulative score of the BIMF scale items reflecting self-management is preferably at least 15%, more preferably at least 25%.

[0740] The improvement of maternal function includes the improvement in the functional domain of mother-child interaction. For example, the improvement of the MADRS items of emotional incapacity and inner tension leads to an increase in the score of the BIMF scale reflecting mother-child interaction. The improvement of the cumulative score of the BIMF scale items reflecting mother-child interaction is preferably at least 5%, more preferably at least 15%.

[0741] Improvement in maternal functioning includes improvement in the functional domain of psychological well-being. For example, improvement in the MADRS items of inhibition, pessimistic thinking, emotional inability, inner tension, and / or decreased sleep leads to an increase in the score of the BIMF scale 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%.

[0742] The improvement of maternal function includes the improvement in the functional domain of social support.For example, the improvement of the pessimistic thinking of the MADRS item leads to the increase of the BIMF scale score that reflects social support.The cumulative score of the BIMF scale item that reflects social support preferably improves by at least 10%, more preferably by at least 20%.

[0743] Improvements in maternal functioning include improvements in the functional domain of control. For example, improvements in the MADRS items inhibition, pessimistic thinking, and / or difficulty concentrating result in an increase in the score on the BIMF scale reflecting control. The improvement in the cumulative score on the BIMF scale items reflecting control is preferably at least 20%, more preferably at least 30%.

[0744] Improvement in maternal functioning includes improvement in the functional domain of adaptation. For example, improvement in the inhibition of MADRS items leads to an increase in the score of the BIMF scale, which reflects adaptation. The cumulative score improvement of the BIMF scale items, which reflects adaptation, is preferably at least 5%, more preferably at least 15%.

[0745] The improvement in maternal functioning is associated with one or more, particularly two or more, functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, parenting, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0746] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0747] Breastfeeding As used herein, the term "lactation" refers to the process of feeding human breast milk to a child. Breastfeeding includes feeding milk directly from the breast, as well as pre-expressing breast milk and then bottle-feeding the breast milk to a child.

[0748] As noted above, for many medications, breastfeeding patients may be faced with the decision to discontinue breastfeeding or discontinue / withdraw from treatment.

[0749] If a decision is made to discontinue breastfeeding in order to undergo treatment, this decision negatively impacts maternal functioning, particularly impairing the functional domains of mother-child interaction and psychological well-being.

[0750] The present invention also addresses the need for treatment of psychiatric or nervous system disorders in nursing mothers without substantially interrupting breastfeeding.

[0751] According to the present invention, breastfeeding can be resumed immediately after treatment.

[0752] The present inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT in an effort to determine at what point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, breast-feeding could be initiated without exposing the infant to any associated risks.

[0753] Additionally, breast milk was collected from lactating patients treated for PPD with 5-MeO-DMT. As described in more detail in the Examples section, lactating patients suffering from PPD were administered a 6 mg dose of 5-MeO-DMT, followed one hour later by an additional 12 mg dose of 5-MeO-DMT.

[0754] After the final dose of 5-MeO-DMT, breast milk samples, as well as serum and urine samples, were analyzed at several time points to confirm the presence of 5-MeO-DMT, bufotenin (the major metabolite of 5-MeO-DMT), and 5-MIAA (the final metabolite of 5-MeO-DMT).

[0755] For the administered compound, 5-MeO-DMT itself, absorption and distribution are rapid, with maximum concentrations and pharmacological effects observed during and shortly after administration, for example, by inhalation or injection.

[0756] Plasma protein binding is low (13-23%).

[0757] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid decline in plasma concentrations. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. The titration disclosed herein does not result in accumulation, and therefore does not result in high plasma concentrations of 5-MeO-DMT, for example, at 10 minutes, 2 hours, or 3 hours after administration.

[0758] The rapid decline in plasma concentrations results in only a short period of time during which 5-MeO-DMT can enter breast milk, resulting in 5-MeO-DMT only being present in breast milk for a short period of time.

[0759] The patient data obtained confirmed that 5-MeO-DMT concentrations in breast milk declined rapidly (see Example 12). No 5-MeO-DMT was detected in measurements taken after 24 hours.

[0760] When determining the potential effects of maternal drug administration on breastfed infants, it is standard practice to calculate the relative infant dose (RID) (Bennett, PN, and LJ Notarianni. “Risk from drugs in breast milk: an analysis by relative dose.” Br J Clin Pharmacol 42.5 (1996): P673-4). The RID is the dose to which the infant is exposed through breast milk ingestion (μg / kg / day) divided by the dose received by the mother (μg / kg / day).

[0761] Estimates of daily breast milk intake and frequency of breastfeeding, as well as measured breast milk concentrations, can be used to determine infant exposure.

[0762] For example, a published estimate of daily breast milk intake as a function of infant weight is 150 ml / kg / day. To model exposure, a 5 kg infant is assumed to be breastfed three times over a 24-hour period, with 250 ml of breast milk per feeding. 5-MeO-DMT concentrations are assumed to be 2167.0 pg / ml (measured at hour 1) in the first feeding, 560.6 pg / ml (measured at hour 2.5) in the second feeding, and 42.1 pg / ml (measured at hour 8.5) in the third feeding. Based on this, the infant's total exposure (daily infant dose, DID) would be 692425 pg 5-MeO-DMT / day (0.000692425 mg / day), which corresponds to 0.000138485 mg / kg / day.

[0763] For maternal 5-MeO-DMT exposure, the total dose is 18 mg (6 mg as the first dose and 12 mg as the second dose according to the applicable titration scheme).

[0764] Also, because the amount actually delivered to the patient may be less than the prescribed dose, the RID calculation is performed assuming that the actual delivered amount is only 50% of the prescribed dose to avoid any possibility of underestimating the infant's exposure.

[0765] Assuming a typical maternal weight of 60 kg, the resulting RIDs are 0.092% (based on a maternal exposure of 9 mg) to 0.046% (based on a maternal exposure of 18 mg).

[0766] The threshold for recognition of "low risk" RID is 10%. From the calculations, it is clear that the 5-MeO-DMT RID is well below this threshold.

[0767] Furthermore, it should be noted that the 0.046% to 0.092% range is a conservative estimate. It assumes that 5-MeO-DMT concentrations remain constant between feedings (even though actual concentrations decline rapidly), ignoring the fact that with more than three feedings per day likely occurring and each feeding being smaller, infants are exposed to decreasing 5-MeO-DMT concentrations over time.

[0768] Furthermore, the estimate assumes that breast milk is not expressed or discarded.

[0769] Therefore, the actual RID will be less than the estimated value.

[0770] Possible metabolites of 5-MeO-DMT in humans were identified and the potential relevance of such metabolites was evaluated. In an in vitro metabolic characterization 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]

[0771] Of note, subsequent assays repeatedly failed to detect the presence of 5-methoxytryptophol, but reproducibly demonstrated the presence of 5-MIAA as the major metabolite, which likely plays no significant role in vivo.

[0772] The metabolites listed in the table above are formed via three different pathways.

[0773] 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 to form acetaldehyde: [ka] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0774] The secondary amines, primary amines, and aldehydes were not identified, indicating that they were not present in high concentrations at any time.

[0775] This aldehyde intermediate metabolite undergoes two separate biotransformations in human hepatocytes: it is either oxidized to 5-methoxyindoleacetic acid (5-MIAA) or reduced to 5-methoxyindole-3-ethanol. [ka] Both resulting metabolites are endogenous substances and are formed in the human body (e.g., 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).

[0776] Because the primary pathway for the metabolism of 5-MeO-DMT rapidly leads to metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the oxidative deamination of 5-MeO-DMT does not involve metabolites that require restrictions regarding breastfeeding.

[0777] Furthermore, as detailed in the Examples section, incubation of 5-methoxytryptophol with human hepatocytes showed high turnover, 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).

[0778] Thus, plasma concentrations of 5-methoxytryptophol, if formed at all, decline rapidly to reach endogenous levels.

[0779] 5-MIAA has been identified as the major human metabolite.

[0780] Incubation of 5-MIAA with human hepatocytes showed low turnover, with 75-82% of 5-MIAA remaining after 72 hours. 5-MIAA is thought to be the final metabolic product of 5-MeO-DMT.

[0781] 5-MIAA exhibits a relatively low plasma binding rate (mean unbound fraction (Fu)) of approximately 50% (see Examples section), yet it remains in the circulation subject to renal clearance.

[0782] If we ignore the endogenous production of 5-MIAA and assume that 5-MIAA is formed instantaneously from 5-MeO-DMT after administration of a single dose of the compound, a standard glomerular filtration rate of 90–120 ml / min suggests that 5-MIAA would be cleared from the circulation due to urinary excretion in approximately 1–2 h.

[0783] For example, the urinary concentration of 5-MIAA measured after 2.5 hours was 12,980,501 pg / ml (approximately 12.98 mg / l), indicating that most of the formed 5-MIAA was rapidly excreted.

[0784] As a result, plasma concentrations of 5-MIAA decline rapidly.

[0785] To more accurately estimate changes in plasma concentrations of 5-MIAA, several factors must be considered, including the patient's size and the increased blood volume that occurs during pregnancy. It is understood that there is interindividual variability in the glomerular filtration rate and the rate of metabolism of 5-MeO-DMT.

[0786] Furthermore, although the formation of 5-MIAA is rapid, pharmacokinetic data from healthy volunteers and even PPD patients indicate that small amounts of 5-MeO-DMT (equivalent to less than 10% of Cmax) may still be present after approximately 1 hour, resulting in the actual formation of 5-MIAA over a period of time following administration of 5-MeO-DMT.

[0787] Furthermore, when more than one dose of 5-MeO-DMT is administered, there is no accumulation of 5-MeO-DMT if the doses are spaced at least about one hour apart, although there is still measurable amounts of 5-MIAA in the serum after 2.5 hours, indicating some accumulation of this metabolite if subjects take doses one hour apart.

[0788] 5-MIAA is a weak acid and exists in plasma in an ionized form, reducing the tendency of the compound to pass into breast milk.

[0789] Nevertheless, it can be assumed that some 5-MIAA enters breast milk, especially during the limited period when plasma concentrations of 5-MIAA are relatively high.

[0790] Further information on the concentration-time profile is obtained from the measured breast milk concentrations of 5-MIAA as outlined in Example 12. These data can be used to calculate an estimate of the infant's exposure to 5-MIAA.

[0791] The 5-MIAA concentration is assumed to be 13945.2 pg / ml (measured at 1 hour) in the first 250 ml lactation, 13240.9 pg / ml (measured at 2.5 hours) in the second lactation, and 359.4 pg / ml (measured at 8.5 hours) in the third lactation. Based on this, the total exposure to the infant (DID) would be 0.00688638 mg 5-MIAA / day, which corresponds to 0.00137728 mg / kg / day.

[0792] Of note, 5-MIAA concentrations in breast milk at 24 hours are nearly 400-fold lower than at 1 hour, so there is no relevant exposure after 1 day.

[0793] Maternal exposure to 5-MIAA can be estimated based on the amount of 5-MeO-DMT administered and the proportion of 5-MeO-DMT converted to 5-MIAA.

[0794] In the metabolism experiment described above, the mixture contains approximately 60% 5-MIAA after 2 hours. Because metabolism is not complete, the actual percentage of 5-MeO-DMT converted to 5-MIAA will be higher. It can be assumed that more than 60%, and up to nearly 100%, of 5-MeO-DMT is converted to 5-MIAA as a final metabolic product, which is then excreted.

[0795] Considering the molecular weights (218.29 g / mol for 5-MeO-DMT and 205.21 g / mol for 5-MIAA), a total 18 mg 5-MeO-DMT dose would yield 10.15 mg 5-MIAA (60% conversion) to 16.92 mg 5-MIAA (100% conversion). Assuming only 9 mg of 5-MeO-DMT is delivered, as above, 5.08 mg 5-MIAA (60% conversion) to 8.46 mg 5-MIAA (100% conversion) would be formed.

[0796] Therefore, maternal exposure ranges from 0.085 mg / kg / day to 0.282 mg / kg / day, yielding estimated RID values ​​of 0.49% to 1.62%.

[0797] As shown, the accepted threshold for a "low risk" RID is 10%, and it is clear from the calculations, which represent conservative estimates, that the 5-MIAA RID is significantly below this threshold.

[0798] Moreover, the risk profile of 5-MIAA is low considering not only its subthreshold daily RID values ​​but also the fact that this compound is formed endogenously as a metabolite of certain natural tryptophan derivatives (e.g., serotonin).

[0799] Finally, levels of bufotenin, the major metabolite of 5-MeO-DMT, were assessed in urine, serum, and breast milk as described in Example 12. Notably, bufotenin was not detected in serum or breast milk at any time point, and was only detected in urine at the 2.5 hour time point (32.3 pg / ml). This data further demonstrates that bufotenin does not increase the risk profile of 5-MeO-DMT.

[0800] The above calculations are based on a titration regimen including doses of 6 mg and 12 mg of 5-MeO-DMT, and the conclusions reached are valid for single doses up to 12 mg, which would result in lower exposure to 5-MeO-DMT and its metabolites.

[0801] Extrapolating to higher doses and assuming a linear relationship between dose increment and increasing breast milk concentration, and therefore infant exposure, leads to the conclusion that the RID of 5-MeO-DMT, and also of 5-MIAA, is still significantly below 10% for lactating mothers treated with higher doses of 5-MeO-DMT, e.g., 18 mg or 25 mg as a single dose or as the final dose in an ascending dose scheme.

[0802] This is true even when taking into account the storage effect of 5-MIAA in breast milk.

[0803] Linear extrapolation is justified based on the observed linear pharmacokinetic profile of 5-MeO-DMT.

[0804] Finally, when considering risks to infants, daily dosing should be considered, as in chronic treatment regimes, because this eliminates the need to consider cumulative exposure of the infant over time.

[0805] A further identified metabolite, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The formed metabolite then undergoes glucuronidation catalyzed by UGTs. [ka] As part of pharmacokinetic studies, we determined that bufotenin was barely detectable in human serum. In any case, it was not detectable 15 minutes after administration of 5-MeO-DMT. Small amounts were detected in urine 2.5 hours later (Example 12).

[0806] Bufotenin glucuronide cannot bind to the receptor and exerts no effect. Furthermore, its concentration is so low that it was not detected in the hepatocyte assay. Bufotenin glucuronide is further converted to 5-hydroxyindoleacetic acid: [ka] 5-Hydroxyindoleacetic acid is an endogenous substance, occurring, for example, in the metabolism of melatonin and serotonin (references given above).

[0807] The O-demethylation pathway of 5-MeO-DMT plays a minor role and leads to the major metabolite, bufotenin, which is rapidly removed from plasma and further metabolized to compounds present only in very low concentrations, ultimately leading to metabolites that are also part of endogenous metabolic pathways. The present inventors have determined that O-demethylation of 5-MeO-DMT does not involve metabolites that require restrictions regarding breastfeeding.

[0808] The third metabolic pathway involves N-oxidation: [ka] In silico modeling of the metabolites formed, 5-MeO-DMT-N-oxide was determined to be nongenotoxic, consistent with the negative in vitro genotoxicity assessment of the parent molecule. This compound is water-soluble and subject to rapid excretion, as confirmed by observations in rats (Sitaram, B.R., Lockett, L., Blackman, G.L., McLeod, W.R., 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine, and their N-oxides in the rat. Biochemical Pharmacology 36: 2235-2231). Because the metabolic pathway of 5-MeO-DMT involving N-oxidation plays a minor role and results in a low proportion of rapidly excreted metabolites without apparent toxicity, we determined that N-oxidation of 5-MeO-DMT does not involve metabolites that require restrictions regarding lactation.

[0809] Based on the above, the inventors have determined that breastfeeding can be resumed immediately after treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0810] It is safe for nursing patients to simply temporarily discontinue breastfeeding. Typically, breastfeeding is not normally permitted during the actual treatment, i.e., during administration of 5-MeO-DMT or its pharmaceutically acceptable salts, and for the duration of the subsequent hallucinogenic experience. However, once the immediate effects of administration have ceased, nursing patients may safely resume breastfeeding.

[0811] Early resumption of breastfeeding represents a significant benefit to the breastfeeding patient, their health, and the health of their infant.

[0812] The mother undergoing treatment may be advised, for example, to temporarily discontinue breastfeeding for a certain period of time or until a particular event occurs.

[0813] Cessation of breastfeeding means that the baby cannot be breastfed, or even expressed breast milk if breastfeeding is not recommended, although previously collected breast milk can be bottle-fed. The crucial point is when the breast milk is expressed (not when the child is fed).

[0814] Breastfeeding can be resumed for the indicated period or immediately after the event.

[0815] For example, mothers are encouraged to temporarily discontinue breastfeeding only for the duration of the actual procedure (e.g., until the Clinical Assessment of Readiness for Discharge (CADR) indicates readiness for discharge).

[0816] A Clinical Assessment of Readiness for Discharge (CADR) is performed to determine if there are any clinical barriers that would prevent the patient from returning home.

[0817] Readiness for discharge according to CADR requires that the following be observed: all adverse events have resolved or, if not resolved, do not prevent discharge; the patient is fully oriented; the patient has no hallucinations or perceptual distortions; the patient is alert (promptly responds to name-calling in a normal tone, and has a modified observer alertness / sedation rating of 5); vital signs have not changed clinically significantly compared to baseline; and in the treating physician's opinion, the patient is ready for discharge.

[0818] CADR may be administered approximately 1 hour after the last dose. Alternatively, a qualified professional may perform an independent discharge readiness assessment based on relevant factors such as the patient's vital signs and / or alertness / sedation.

[0819] Patients may be advised not to resume breastfeeding before 6 hours after discharge from the hospital or the last dose, whichever is later, preferably 3 hours after discharge from the hospital or the last dose, whichever is later, more preferably 2 hours after discharge from the hospital or the last dose, whichever is later, and especially 1 hour after discharge from the hospital or the last dose, whichever is later.

[0820] It is also possible to wait longer before resuming breastfeeding (eg, until the concentration of 5-MeO-DMT and / or its metabolites in breast milk samples falls below a certain threshold).

[0821] For example, breastfeeding may be temporarily discontinued until the 5-MeO-DMT concentration in breast milk samples falls to less than 2000 pg / ml, 500 pg / ml, or 75 pg / ml, and / or the 5-MIAA concentration in breast milk falls to less than 14000 pg / ml, 2000 pg / ml, or 75 pg / ml.

[0822] Alternatively, breast milk may be pumped until the concentration of 5-MeO-DMT and / or 5-MIAA falls below the indicated level and then discarded.

[0823] Furthermore, breastfeeding may be temporarily discontinued for a certain period of time, based on, for example, clinical experience regarding the concentration of 5-MeO-DMT and / or its metabolites in breast milk. In one example, a patient is advised to discontinue breastfeeding until 48 hours after receiving the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Patients are advised to discontinue breastfeeding preferably until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and more preferably until 12 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Even more preferably, breastfeeding needs to be discontinued for only 6 hours, even more preferably for only 3 hours, particularly for only 2 hours, and most preferably for only 1 hour after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0824] This short interruption, and the corresponding possibility of resuming breastfeeding immediately after the procedure, contributes to the success of the procedure, in particular to maternal function and health and the development of the infant(s).

[0825] To avoid any associated risks to the infant, it is desirable to keep the concentrations of 5-MeO-DMT and / or 5-MIAA in breast milk as low as possible. As long as the concentrations of 5-MeO-DMT and / or 5-MIAA in breast milk exceed a predetermined threshold, any associated risks to the infant can be avoided by discarding any expressed breast milk or by resuming breastfeeding only when the 5-MeO-DMT and / or 5-MIAA concentrations in breast milk fall below the predetermined threshold. In a preferred embodiment, the threshold for 5-MeO-DMT in breast milk is as low as possible. In a further preferred embodiment, the threshold for 5-MIAA in breast milk is as low as possible. In a most preferred embodiment, the threshold for both 5-MeO-DMT and 5-MIAA in breast milk is as low as possible.

[0826] Various preferred threshold values ​​for 5-MeO-DMT and / or 5-MIAA in expressed breast milk are provided below. [Table 3]

[0827] Delivered Infant Dose (DID) for 5-MeO-DMT and / or 5-MIAA The delivered infant dose (DID) for 5-MeO-DMT and / or 5-MIAA should be kept as low as possible. In a preferred embodiment, the DID for 5-MeO-DMT is kept as low as possible. In a more preferred embodiment, the DID for 5-MIAA is kept as low as possible. In a most preferred embodiment, the DID for both 5-MeO-DMT and 5-MIAA is kept as low as possible.

[0828] The relevant DIDs for 5-MeO-DMT and / or 5-MIAA of the present invention are as follows: [Table 4] Achieving the DID requires adaptation of breastfeeding, which can be an appropriate time for resumption of breastfeeding, an appropriate number of breastfeeds during the first 24 hours after resumption of breastfeeding, an appropriate period of pumping and discarding breast milk, or a combination of these measures.

[0829] Relative Infant Dose (RID) for 5-MeO-DMT and / or 5-MIAA The relative infant dose (RID) for 5-MeO-DMT and / or 5-MIAA should be as low as possible. In a preferred embodiment, the RID for 5-MeO-DMT is kept as low as possible. In a more preferred embodiment, the RID for 5-MIAA is kept as low as possible. In a most preferred embodiment, the RID for both 5-MeO-DMT and 5-MIAA is kept as low as possible.

[0830] The relevant RIDs for 5-MeO-DMT and / or 5-MIAA of the present invention are as follows: [Table 5]

[0831] Achieving the RID requires adaptation of breastfeeding, which can be an appropriate time for resumption of breastfeeding, an appropriate number of breastfeeds during the first 24 hours after resumption of breastfeeding, an appropriate period of pumping and discarding breast milk, or a combination of these measures.

[0832] Delivered Infant Dose (DID) and Relative Infant Dose (RID) Combinations for 5-MeO-DMT and / or 5-MIAA It has been explained that the DID and RID for 5-MeO-DMT and / or 5-MIAA are related aspects of the present invention. While each individual aspect is related as such, in a preferred embodiment of the present invention, both aspects of the DID for 5-MeO-DMT and / or 5-MIAA and the RID for 5-MeO-DMT and / or 5-MIAA should be considered in combination. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0833] In one embodiment, a DID for 5-MeO-DMT and a RID for 5-MeO-DMT are combined. In a preferred embodiment, the DID and RID for 5-MeO-DMT are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0834] In a further embodiment, a DID for 5-MIAA and a RID for 5-MIAA are combined. In a preferred embodiment, the DID and RID for 5-MIAA are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0835] In a further embodiment, a DID for 5-MeO-DMT and a RID for 5-MIAA are combined. In a preferred embodiment, the DID for 5-MeO-DMT and the RID for 5-MIAA are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0836] In a further embodiment, a RID for 5-MeO-DMT and a DID for 5-MIAA are combined. In a preferred embodiment, the RID for 5-MeO-DMT and the DID for 5-MIAA are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0837] In a more preferred embodiment, the DIDs for 5-MeO-DMT and 5-MIAA, and the RIDs for 5-MeO-DMT and 5-MIAA, are combined. In a preferred embodiment, the DIDs for 5-MeO-DMT and 5-MIAA, and the RIDs for 5-MeO-DMT and 5-MIAA, are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0838] Treatment of mental or nervous system conditions Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0839] A depressive episode is a period of depressed mood and / or loss of enjoyment in most activities.

[0840] For example, according to the DSM-V, a major depressive episode is characterized by the presence of five or more symptoms during the same two-week period and represents a change from past functioning, with at least one of these symptoms being either (1) depressed mood or (2) loss of interest or pleasure.

[0841] Patients suffering from a disorder characterized by depressive episodes may have a treatment-resistant form of the disorder.

[0842] Disorders characterized by depressive episodes are accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor slowing, social / emotional withdrawal, and negative thinking.

[0843] Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0844] In patients suffering from disorders characterized by depressive episodes, alterations in functional connectivity are observed within and / or between several brain regions involved in processing, regulation, and emotional memory; cognitive processes related to rumination; impaired concentration and physiological arousal.

[0845] Treating a patient suffering from a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the disorder characterized by depressive episodes.

[0846] 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 last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0847] The improvement in the patient's disorder characterized by depressive episodes, as reflected by a decrease in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by depressive episodes, as reflected by a decrease in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0848] 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.

[0849] 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the patient's 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 last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0850] Improvement in the disorder characterized by depressive episodes, 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.

[0851] 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the patient's 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 last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0852] Improvement in maternal functioning in patients with a disorder characterized by depressive episodes is reflected by an improvement in at least the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0853] The improvement in maternal functioning in patients with a disorder characterized by depressive episodes, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal functioning, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0854] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest, which affects the way a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0855] The patient may have 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 the patient may have 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.

[0856] Patients with MDD may have a treatment-resistant form (TRD) of the disorder.

[0857] MDD is accompanied by one or more of the following symptoms: sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0858] Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0859] In patients suffering from 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, and functional connectivity differs significantly from that observed in healthy controls.

[0860] Treating patients suffering from the disorder, including treatment-resistant forms of MDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the MDD.

[0861] Improvement in MDD, as reflected by a decrease 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 last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0862] The improvement in the patient's MDD, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the 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 last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0863] Improvement in MDD, as reflected by a decrease 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.

[0864] The improvement in MDD in the patient, as reflected by a reduction in the MADRS score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and 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 last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0865] ...

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of a psychiatric or nervous system disorder in a nursing mother, a dosage of about 1 mg to about 10 mg of 5-MeO-DMT or an equimolar amount of said pharmaceutically acceptable salt is administered as a single dose or as a top dose in an escalating scheme with an interval between doses of at least about 1 hour; the 5-MeO-DMT or the pharmaceutically acceptable salt thereof is administered via an intravenous, intramuscular, or subcutaneous route; The patient is advised to temporarily discontinue breast-feeding, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for the above uses.

2. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily stop breastfeeding at least one hour before receiving the first dose and not resume breastfeeding until at least 24 hours after the last dose.

3. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily stop breastfeeding at least one hour before receiving the first dose and not resume breastfeeding until at least 12 hours after the last dose.

4. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily stop breastfeeding at least one hour before receiving the first dose and not resume breastfeeding until at least six hours after the last dose.

5. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily stop breastfeeding at least one hour before receiving the first dose and not resume breastfeeding until at least two hours after the last dose.

6. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily stop breastfeeding at least one hour before receiving the first dose and not resume breastfeeding until at least one hour after the last dose.

7. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and not resume breastfeeding until at least 24 hours after the last dose.

8. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and not resume breastfeeding until at least 12 hours after the last dose.

9. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and not resume breastfeeding until at least 6 hours after the last dose.

10. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and not resume breastfeeding until at least two hours after the last dose.

11. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily discontinue breastfeeding immediately prior to receiving the first dose and not resume breastfeeding until at least one hour after the last dose.

12. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient is advised to temporarily discontinue breastfeeding only for the duration of the actual treatment.

13. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 12, wherein the patient is advised to temporarily discontinue breastfeeding from just before receiving the first dose until the patient is ready to be discharged from the hospital.

14. 14. The 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 13, wherein the determination of readiness for discharge is made about 1 hour after the last dose.

15. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 13 or 14, wherein the patient is recommended not to resume breastfeeding until discharged from the hospital or 6 hours after the last dose, whichever is later.

16. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 15, wherein the patient is recommended not to resume breastfeeding until discharged from the hospital or three hours after the last dose, whichever is later.

17. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 15, wherein the patient is recommended not to resume breastfeeding until discharged from the hospital or two hours after the last dose, whichever is later.

18. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 15, wherein the patient is recommended not to resume breastfeeding until discharged from the hospital or one hour after the last dose, whichever is later.

19. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 18, wherein the patient is advised to temporarily cease breastfeeding from immediately before administering the first dose until at least 24 hours after the last dose and to discard all expressed breast milk during that 24-hour period.

20. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 18, wherein the patient is advised to temporarily cease breastfeeding from immediately before administering the first dose until at least 2.5 hours after the last dose, and to express and discard breast milk 2.5 hours after the last dose.

21. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 20, wherein the patient is advised to express and discard breast milk 24 hours after the last dose before reinitiating breastfeeding.

22. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 21, wherein the patient is recommended not to breastfeed their child more than twice during the first 12 hours after the last dose.

23. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 22, wherein any expressed breast milk is discarded as long as the concentration of 5-MeO-DMT and / or 5-MIAA in the breast milk exceeds a predetermined threshold.

24. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the threshold for 5-MeO-DMT is 2000 pg.

25. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the threshold for 5-MeO-DMT is 500 pg.

26. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 23, wherein the threshold for 5-MeO-DMT is 75 pg.

27. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 23 to 26, wherein the threshold for 5-MIAA is 14,000 pg.

28. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 23 to 26, wherein the threshold for 5-MIAA is 2000 pg.

29. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 23 to 26, wherein the threshold for 5-MIAA is 75 pg.

30. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 22, wherein lactation is resumed when the 5-MeO-DMT concentration and / or the 5-MIAA concentration in breast milk fall below a predetermined threshold.

31. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 30, wherein the threshold for 5-MeO-DMT is 2000 pg.

32. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 30, wherein the threshold for 5-MeO-DMT is 500 pg.

33. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claim 30, wherein the threshold for 5-MeO-DMT is 75 pg.

34. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 30 to 33, wherein the threshold for 5-MIAA is 14,000 pg.

35. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 30 to 33, wherein the threshold for 5-MIAA is 2000 pg.

36. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 30 to 33, wherein the threshold for 5-MIAA is 75 pg.

37. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 36, wherein the breastfeeding is adapted so that the DID of 5-MeO-DMT per kg of infant body weight during breastfeeding in the first 24 hours after resumption of breastfeeding is 1 μg / kg / day or less, and said adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

38. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 36, wherein the breastfeeding is adapted so that the DID of 5-MeO-DMT per kg of infant body weight during breastfeeding in the first 24 hours after resumption of breastfeeding is 0.4 μg / kg / day or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

39. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 36, wherein the breastfeeding is adapted so that the DID of 5-MeO-DMT per kg of infant body weight during breastfeeding in the first 24 hours after resumption of breastfeeding is 0.2 μg / kg / day or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

40. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 39, wherein the breastfeeding is adapted so that the RID of 5-MeO-DMT during breastfeeding in the first 24 hours after resumption of breastfeeding is 10% or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

41. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 39, wherein the breastfeeding is adapted so that the RID of 5-MeO-DMT during breastfeeding in the first 24 hours after resumption of breastfeeding is 5% or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

42. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 39, wherein the breastfeeding is adapted so that the RID of 5-MeO-DMT during breastfeeding in the first 24 hours after resumption of breastfeeding is 1% or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

43. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 42, wherein the breastfeeding is adapted so that the DID of the terminal metabolite 5-MIAA per kg of infant body weight during breastfeeding in the first 24 hours after resumption of breastfeeding is 4 μg / kg / day or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

44. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 42, wherein the breastfeeding is adapted so that the DID of the terminal metabolite 5-MIAA per kg of infant body weight during breastfeeding in the first 24 hours after resumption of breastfeeding is 2 μg / kg / day or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

45. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 42, wherein the breastfeeding is adapted so that the DID of the terminal metabolite 5-MIAA per kg of infant body weight during breastfeeding in the first 24 hours after resumption of breastfeeding is 1 μg / kg / day or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these measures.

46. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 45, wherein the breastfeeding is adapted so that the RID of the terminal metabolite 5-MIAA during breastfeeding in the first 24 hours after resumption of breastfeeding is 4% or less, and the adaptation is achieved by selecting an appropriate time for resumption of breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these means.

47. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 45, wherein the breastfeeding is adapted so that the RID of the terminal metabolite 5-MIAA during breastfeeding in the first 24 hours after resumption of breastfeeding is 2% or less, and the adaptation is achieved by selecting an appropriate time for resuming breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these means.

48. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 45, wherein the breastfeeding is adapted so that the RID of the terminal metabolite 5-MIAA during breastfeeding in the first 24 hours after resumption of breastfeeding is 1% or less, and the adaptation is achieved by selecting an appropriate time for resuming breastfeeding and an appropriate number of breastfeedings during the first 24 hours after resumption of breastfeeding, by expressing and discarding breast milk for an appropriate period of time, or by a combination of these means.

49. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 48, wherein the patient is suffering from PPD.

50. 50. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 49, wherein remission of depressive symptoms as assessed by a MADRS score of 10 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

51. 51. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 50, wherein remission of depressive symptoms as assessed by a HAM-D score of 7 or less occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

52. 52. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 51, wherein maternal function is improved as reflected by improvements in the Birkin Index of Maternal Function (BIMF) functional domains of mother-infant interaction and psychological well-being.

53. 53. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 52, wherein the improvement in the cumulative score of BIMF scale items reflecting psychological well-being is at least 25% and the improvement in the cumulative score of BIMF scale items reflecting mother-infant interaction is at least 5%.

54. 54. ...

55. 55. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 54, wherein the patient suffers from a psychiatric or nervous system disorder accompanied by one or more symptoms selected from sleep disorders and anxiety, each of which symptoms impairs maternal function.

56. 56. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 55, wherein the patient is suffering from a psychiatric or nervous system disorder accompanied by symptoms of anxiety, and wherein treatment reduces or eliminates the symptoms of anxiety, in particular symptoms of inner tension.

57. 57. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 56, wherein the treatment results in a clinical response reflected by at least a 50% decrease in HAM-A score, compared to the respective score before treatment, about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

58. 58. ...

59. 59. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 56 to 58, wherein the treatment results in a clinical response reflected by at least a 50% reduction in HAM-A score 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, compared to the respective score before treatment.

60. 60. 50 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 56 to 59, wherein the treatment results in a clinical response reflected by at least a 50% reduction in HAM-A score 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, compared to the respective score before treatment.

61. 61. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 56 to 60, wherein the treatment results in a clinical response reflected by at least a 50% reduction in HAM-A score 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, compared to the respective score before treatment.

62. 62. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 55 to 61, wherein the patient is suffering from a psychiatric or nervous system disorder accompanied by symptoms of a sleep disorder, and treatment reduces or eliminates the symptoms of the sleep disorder.

63. 63. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 62, wherein the patient suffers from a sleep disorder as reflected by a Pittsburgh Sleep Quality Index (PSQI) total score >5.

64. 64. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 62 or 63, wherein the treatment reduces or eliminates sleep disturbances, said reduction or elimination of sleep disturbances reflected by an improvement in Pittsburgh Sleep Quality Index (PSQI) total score 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and wherein the recall period ranges from the time the acute hallucinatory experience abated after the last administration to the time of assessment.

65. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 62 to 64, wherein the success of the treatment is indicated by a decrease in the PSQI total score.

66. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 62 to 65, wherein the success of the treatment is indicated by a reduction in at least four of the seven-component score of the PSQI.

67. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 62 to 66, wherein the success of the treatment is indicated by a reduction in the PSQI total score to 5 or less.

68. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 62 to 67, wherein the sleep disorder is insomnia.

69. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 68, administered at a dose or dosage regimen that causes the patient to experience a peak hallucinatory experience.

70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69, wherein a dosage of about 2 mg, or about 5 mg, or about 8 mg is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

71. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69, wherein a dosage of about 1 mg, or about 2 mg, or about 3 mg is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

72. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69, wherein a dosage of about 2 mg, or about 4 mg, or about 6 mg is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

73. 70. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69, wherein the 5-MeO-DMT or a salt thereof is administered at a first dosage for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration unless the patient experiences a peak hallucinatory experience.

74. 74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69 or 73, wherein the 5-MeO-DMT is administered at a dosage of about 1 mg to about 3 mg for a first administration, thereafter increased to a dosage of about 4 mg to about 6 mg for a second administration, and thereafter increased to a dosage of about 7 mg to about 9 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

75. 75. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 74, wherein the first dosage of 5-MeO-DMT is about 2 mg, the second dosage of 5-MeO-DMT is about 5 mg, and the third dosage of 5-MeO-DMT is about 8 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

76. 74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69 or 73, wherein the 5-MeO-DMT is administered at a dosage of about 0.5 mg to about 1.5 mg for a first administration, thereafter increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, and thereafter increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

77. 77. The 5-MeO-DMT or pharmaceutically acceptable salt thereof for use according to claim 76, wherein the first dosage of 5-MeO-DMT is about 1 mg, the second dosage of 5-MeO-DMT is about 2 mg, and the third dosage of 5-MeO-DMT is about 3 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

78. 74. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69 or 73, wherein the 5-MeO-DMT is administered at a dosage of about 2 mg to about 3 mg for a first administration, thereafter increased to a dosage of about 4 mg to about 5 mg for a second administration, and thereafter increased to a dosage of about 6 mg to about 7.5 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

79. 79. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 78, wherein the first dosage of 5-MeO-DMT is about 2 mg, the second dosage of 5-MeO-DMT is about 4 mg, and the third dosage of 5-MeO-DMT is about 6 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

80. 80. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 73 to 79, wherein the interval between two administrations is at least 1 hour and at most 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

81. a dosage of about 1 mg to about 5 mg of 5-MeO-DMT or an equimolar amount of said pharmaceutically acceptable salt is administered as a single dose or as a top dose in an escalating scheme with an interval between doses of at least about 1 hour; the 5-MeO-DMT or the pharmaceutically acceptable salt thereof is administered via an intravenous, intramuscular, or subcutaneous route; 70. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to claims 1 to 69, wherein the patient is advised to temporarily discontinue breastfeeding.

82. 82. The use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof according to claim 81, wherein a dosage of about 1 mg, or about 5 mg is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

83. 83. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 82, wherein the 5-MeO-DMT or a salt thereof is administered at a first dosage for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration unless the patient experiences a peak hallucinatory experience.

84. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 83, wherein the interval between two administrations is at least 1 hour and at most 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

85. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 69 to 84, wherein the manifestation of a peak hallucinatory experience is confirmed by achievement of at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and indescribable) of the 30-item Revised Mystical Experiences Questionnaire (MEQ30), or by achievement of at least 60% of the maximum possible score on the Oceanic Without Boundaries (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achievement of a total score of at least 75 on the Peak Experiences Scale (PES).

86. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 85, wherein said onset of a peak hallucinatory experience is confirmed by achievement of a Peak Experience Scale (PES) total score of at least 75.

87. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 86, which is administered by intravenous injection.

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