Treatment of postpartum depression

Abstract

The present invention relates to 5-methoxyl-N, N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt thereof, for use in the treatment of psychiatric or nervous system disorders in a mother having an age of 18 months or less, where the 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, is administered via the 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 maternal patients diagnosed with mental or nervous system disorders, particularly breastfeeding mothers.

[0002] The psychiatric disorder is amenable to treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The treatment also improves maternal function.

[0003] Furthermore, the present invention allows for the treatment of psychiatric or neurological disorders in breastfeeding mothers without requiring a near-total interruption of breastfeeding. Background Art

[0004] Mental or neurological disorders in breastfeeding mothers can have a range of negative consequences for the mother, her baby, and her family. For example, women with mental or neurological disorders may have thoughts of harming themselves or their child, and they may be at increased risk of suicide.

[0005] Mental or neurological disorders may further contribute to disrupted interactions between mothers and their children, as exemplified by higher rates of disengagement behaviors and lower rates of visual and vocal communication between mothers and their children. Evidence also suggests a link between maternal mental or neurological disorders and child development, as shown by the fact that children of individuals with mental or neurological disorders may be at greater risk for impaired cognitive development.

[0006] Despite these issues, treatment options remain limited. In general, known treatments for mental or neurological disorders often have limited success rates, particularly for patients experiencing more than mild symptoms of the disorder.

[0007] A complicating factor in cases where the patient is a breastfeeding mother is that for many drugs, nursing women are advised to discontinue breastfeeding while taking the drug and for a period of time thereafter because the drug may be excreted in breast milk, putting the unweaned child at risk.

[0008] Furthermore, research suggests that breastfeeding mothers may be reluctant to initiate medication due to a range of concerns.

[0009] Therefore, breastfeeding patients with psychiatric or neurologic disorders may be faced with situations in which they must decide whether to discontinue breastfeeding or discontinue / withdraw treatment.

[0010] Against this backdrop, there is a need for improved treatments for mental or neurological disorders, particularly treatments that not only effectively address the symptoms of the disorder and rapidly produce a clinical response, but also avoid interfering with the patient's daily activities, particularly with regard to the care of the infant. Such treatments should improve maternal function. Furthermore, there is a need for treatments for mental or neurological disorders that do not require near-complete interruption of breastfeeding.

[0011] Despite recent interest in the use of hallucinogens to treat psychiatric disorders, treatments based on these substances have not been conducted in breastfeeding mothers to date. This is due to a general lack of clinical data that precludes conclusions about the clinical utility of hallucinogens and to concerns that their administration may be inappropriate for breastfeeding mothers.

[0012] Hallucinogens (including psychedelics) are chemical compounds, some naturally occurring and some synthetic, that, when consumed, induce sensory distortions, such as changes in auditory and visual perception, as well as mood and cognitive disturbances. The term hallucinogen encompasses a fairly broad group of psychoactive molecules with diverse modes of action. Some psychiatric disorders are, in principle, considered amenable to treatment with psychoactive molecules, such as psychedelics.

[0013] Yet no psychedelic drug has yet been approved by any regulatory body, and indeed, clinical experience with such molecules remains quite limited.

[0014] One compound that has been studied in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO 2020 / 169850 reports on tests in healthy volunteers and clinical trials involving patients with treatment-resistant depression (TRD), a form of major depressive disorder. Patients with PPD were not included in the trials.

[0015] In this context, it is an object of the present invention, in particular, to provide a therapy that is more effective than previously described therapies (i.e., a) a greater percentage of patients experience a clinical response, b) a greater mean clinical response, c) an earlier onset of clinical response, and / or d) a more durable clinical response).

[0016] It is a further object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies that have a better safety profile and / or better tolerability than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies that are more convenient than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapies and dosing regimens for said therapies that are associated with higher rates of patient compliance (including higher rates of treatment initiation) than previously described therapies. It is a still further object of the present invention to identify specific disease aspects and subgroups of specific disease aspects that benefit from such improved psychoactive therapies.

[0017] It is a still further object of the present invention to improve maternal function in patients suffering from psychiatric or neurological disorders, particularly breastfeeding mothers diagnosed with psychiatric disorders. 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 diagnosed with a mental or nervous system disorder, particularly breastfeeding mothers diagnosed with such a disorder. The disorder may in particular be a disorder characterized by depressive episodes, such as major depressive disorder (MDD), persistent depressive disorder, seasonal affective disorder and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias and substance / medication-induced anxiety disorders; somatic symptom disorder; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, fibromyalgia and migraines; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; mental disorders or neurological disorders associated with HIV, COVID sequelae or traumatic brain injury.

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

[0020] Treatment can improve maternal function.

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

[0022] The present invention also allows for treatment of breastfeeding mothers without requiring near-total interruption of breastfeeding.

[0023] The present invention also provides dosage ranges and administration regimens that can be used for the above-mentioned treatments.

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

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

[0026] definition

[0027] As used in the context of the present invention, unless otherwise indicated, 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, wherein the acid may be selected, for example, from acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered can be calculated based on the weight of the free base, assuming equimolar amounts are used.

[0028] As used in the context of the present invention, a "patient" to be treated is a mother of a child 18 months or younger, particularly 12 months or younger, who is diagnosed with a mental or neurological disorder by a licensed professional in accordance with accepted medical practice.

[0029] For example, the diagnosis of mental disorder or nervous system disorder can be carried out according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) issued by the American Psychiatric Association. In some cases, as will be apparent from the discussion of specific circumstances below, it is possible to modify or supplement standards to better define a patient or patient population that particularly benefits from treatment according to the present invention. In any case, diagnosis will be carried out by a doctor or psychologist. It is not enough for the human experimenter himself to believe that he suffers from the disorder.

[0030] As used in the context of the present invention, unless otherwise indicated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition or disorder, and include the administration of the compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition or disorder.

[0031] The patient may have a treatment-resistant disease. Treatment resistance means that the patient has not adequately improved after at least two adequate courses of treatment. In particular, the patient has not adequately improved after at least two adequate courses of treatment, wherein at least one of the two courses is medication; for example, the patient has not adequately improved after at least two adequate courses of medication. In particular, at least two prior courses of treatment were administered during the current episode of the disease, for example, if the patient has a disorder characterized by a depressive episode, during the current depressive episode.

[0032] As used in the context of this invention, "suicidal ideation" refers to thinking about, considering, or planning suicide. A doctor or psychologist will diagnose a patient with suicidal ideation using established protocols and methods for diagnosing suicidal tendencies. Generally, it is not enough for a patient to believe they have suicidal ideation. In some cases, a patient with suicidal ideation is at risk for imminent suicide or is considered to have "suicidal intent."

[0033] As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" shall mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human that is being sought by the researcher, physician, or other clinician, including alleviation of the signs and / or symptoms of the disease, condition, or disorder being treated.

[0034] "Clinical response" includes, but is not limited to, improvement on a rating scale.

[0035] The severity of the disorder and changes in severity can be assessed by the Clinical Global Impression (CGI) rating scale, which is a measure of symptom severity, treatment response, and treatment efficacy.

[0036] The CGI rating scale was developed to provide a concise, independent assessment of the clinician's perception of a patient's global functioning before and after treatment (Busner, J. and Tagrum, SD, 2007. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical Practice. Psychiatry 2007, 29-37).

[0037] The CGI severity (CGI-S) is based on a single question that clinicians must answer: “Given your overall clinical experience with this particular population, how ill is this patient currently?” Rated on a seven-point scale: 1 = normal, not ill at all; 2 = borderline ill; 3 = mildly ill; 4 = moderately ill; 5 = somewhat ill; 6 = severely ill; and 7 = the sickest patient.

[0038] The CGI-S can be used to assess treatment success by comparing scores before and after treatment.

[0039] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), which has an equally simple format. After treatment, the clinician compares the patient's overall clinical condition with their condition before treatment (the so-called baseline value). Again, there is only one question, rated on a seven-point scale: "Compared with the patient's condition at admission (before starting medication), is this patient's condition: 1 = very much improved since starting treatment; 2 = much improved; 3 = slightly improved; 4 = no change from baseline (start of treatment); 5 = slightly worse; 6 = a lot worse; 7 = very much worse since starting treatment."

[0040] The Patient Global Impression (PGI), also known as the Subject Global Impression (SGI), is the counterpart of the Clinical Global Impression (CGI). It consists of one item based on the CGI and adapted for the patient. It can measure either disease severity (PGI-S) or disease improvement (PGI-I).

[0041] The severity of the disorder, and changes in severity, can be further assessed using rating scales appropriate for the specific psychiatric or neurological disorder the patient suffers from.

[0042] Individual items as well as subcombinations of individual items of the scales as described herein can be used to assess specific disease aspects.

[0043] Maternal functioning can be assessed using the Barkin Index of Maternal Functioning (BIMF).

[0044] When clinical response is assessed at an early time point (e.g., 2 hours) after drug administration based on endpoints developed for longer recall periods (e.g., typically 7 days for MADRS), reasonable modifications to such endpoints can be made (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration).

[0045] The outlined considerations apply to early time points because, on the one hand, for the purpose of assessing clinical response, the influence of the patient's status before treatment on any score recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0046] At later time points, such as on day 1 or later, an appropriate recall period (if necessary) can usually be used to assess all items of the relevant scale used to assess clinical response, so that no pre-treatment scores need to be carried forward. For example, if the BIMF is assessed on day 7, a seven-day recall period will be used (rather than the standard 2-week recall period).

[0047] As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "applying") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient's body via any route. The active compound is administered by intravenous administration, intramuscular administration, or subcutaneous administration.

[0048] As used in the context of the present invention, unless otherwise indicated, the terms "dose," "dosage," and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined sequence of one or more separate administrations.

[0049] Mental and neurological disorders

[0050] The psychiatric and neurological disorders to be treated according to the present invention have in common that they are associated with one or more of the symptoms discussed below, including sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0051] 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 breastfeeding mother patient diagnosed with a psychiatric or neurological disorder.

[0052] The mental or nervous system disorder is suitable for treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The mental or nervous system disorder is particularly 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.

[0053] In a preferred embodiment, the psychiatric disorder is major depressive disorder.

[0054] In another preferred embodiment, the psychiatric disorder is bipolar disorder, such as bipolar disorder type II. Patients diagnosed with bipolar disorder will particularly suffer from a current major depressive episode.

[0055] All aspects of bipolar disorder, such as sleep disturbances, psychomotor retardation (reduction in energy and activity and reduced motivation), negative thinking (worthlessness; helplessness and hopelessness; guilt), anxiety, cognitive dysfunction (impaired concentration and memory) and social / emotional withdrawal or alienation (anhedonia, emotional withdrawal and emotional apathy) can be improved. Other aspects of the disease that can be improved include suicidal ideation and mixed symptoms (psychotic symptoms; irritability; instability; increased motor drive; increased speech; agitation). The improvement achieved is reflected on a clinically relevant scale.

[0056] Scales for assessing mental and neurological disorders

[0057] A variety of scales have been proposed to assess the severity of mental or neurological disorders. Such scales are based on tests that can be self-administered or administered by a clinician.

[0058] Scales for assessing mental or neurological disorders that can be used in accordance with the present invention include scales known in the art for diagnosing and / or monitoring mental or neurological disorders as discussed in more detail below.

[0059] Treatment outcomes are assessed using one or more indices or scales at one or more time points after completion of the treatment course.

[0060] The assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is generally about 2 to 3 hours after the last administration. Early assessment can generally be performed, for example, about 2 hours or about 3 hours after the last administration.

[0061] However, assessment of sleep-disrupting effects or effects on psychiatric or neurologic disorders related to sleep-disrupting effects can be performed as early as the day after treatment (ie, day 1), allowing the treated patient an opportunity to get at least one night of sleep.

[0062] Thus, an assessment on day 1 or day 1 means an assessment on the second day after administration. The assessment will be performed no earlier than 12 hours after the last administration, and in any case no earlier than one night after the last administration, and no later than 36 hours after the last administration. The assessment may be performed after about 24 hours.

[0063] Assessment on day 7 or at day 7 means assessment performed on the seventh day after administration (the day of administration is day 0). Similar definitions apply to other assessment times measured in days.

[0064] For example, when one of the scales is used to assess the severity of a mental disorder or a nervous system disorder, when the clinical response is assessed at an early time point (e.g., 2 hours) after the administration of the drug based on an endpoint developed for a longer recall period (e.g., MADRS is typically 7 days), such endpoints can be reasonably modified (e.g., the MADRS recall period is changed to 2 hours, and the sleep items recorded at the baseline before the administration of the drug are carried forward). Unless the recall period is specifically specified, the same applies to any other scale used herein for assessing the therapeutic effect of a mental or nervous system disorder.

[0065] The outlined considerations apply to early time points because, on the one hand, for the purpose of assessing clinical response, the influence of the patient's status before treatment on any score recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0066] At a later time point, such as on day 1 or later, all items of the relevant scale used to assess clinical response can generally be assessed using an appropriate recall period (if needed) so that no pre-treatment scores need to be carried forward.

[0067] Active agent

[0068] Mental or neurological disorders have several characteristics that result in a significant disease burden and warrant appropriate treatment. Therefore, treatments, particularly pharmacological interventions, are needed not only to improve the overall disease score but also to improve specific aspects of the disease.

[0069] The inventors contemplate that carefully selected hallucinogens may lead to improved treatment and may also lead to overall improvements in the disorder and maternal functioning.

[0070] The inventors also contemplate that, if treating a breastfeeding mother with a psychiatric or neurological disorder, carefully selected hallucinogens may allow breastfeeding to continue without near-total interruption.

[0071] A group of hallucinogens consists of compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families with several subtypes are described, 5-HT1 to 5-HT7). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agents are often referred to as "psychedelics," emphasizing their primary ability to induce qualitatively altered states of consciousness, such as euphoria, trance, time and space, mental experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or hyperstimulation, are minimal.

[0072] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, with the indoleamines divided into two subsets, the ergoline and the tryptamines, the latter being derived from tryptamine.

[0073] Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activities may also be modulated through interactions with other targets such as monoamine transporters and trace amine-related receptors.

[0074] Recently published studies on the use of serotonergic psychedelics, such as LSD, psilocybin, and DMT (using the shamanic infusion ayahuasca, which contains DMT), in certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for some psychiatric disorders. However, there are reports that these compounds may induce mania in patients with depressive symptoms, and this may hinder their clinical use.

[0075] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11): 1508-9) reported a case in which a patient experienced a manic episode after taking LSD or an LSD analog. The patient experienced symptoms of acute LSD intoxication, which resolved, but a typical manic episode with psychosis developed about 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4): 1-3) reported a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP and Jose MSmith, 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 man with bipolar disorder who switched to mania after consuming ayahuasca, a beverage containing DMT.

[0076] Another case report can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0077] The inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, the compound to be administered must be appropriately selected and preferably administered according to a specific dosing regimen.

[0078] The inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic drug of particular interest for therapeutic use. 5-MeO-DMT possesses unique pharmacological properties that are distinct from other psychedelic compounds.

[0079] 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 than other classic psychedelic drugs.

[0080] As further detailed in the Examples section below, the inhibitory constants (K) for psilocin dephosphate (the dephosphorylated form of psilocybin formed after ingestion of psilocybin), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brains are shown in Table 1. i The inhibitory constants (K values) of psilocybin, DMT, and 5-MeO-DMT at the 5-HT2A receptor in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while dephosphopsilin and DMT exhibit intermediate affinity. i The values ​​for 5-MeO-DMT and 5-HTP-DMT were 37, 117, and 122 nM, respectively. Thus, dephosphopsilin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0081] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits enhanced affinity for the 5-HT1A receptor, acting as a potent agonist in this setting. The contribution of 5-HT2A binding is increased in the case of dephosphopsilin and DMT relative to 5-MeO-DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Therefore, 5-HT1A binding, relative to 5-HT2A binding, plays a much larger role in 5-MeO-DMT's overall effects than in the other two compounds.

[0082] 5-HT1A agonists reportedly reduce impulsivity and aggression, while 5-HT2A agonists can cause short-term increases in these same traits. Furthermore, the dopamine system has been implicated in the development of mania, with increased dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for various dopamine receptors relative to 5-MeO-DMT.

[0083] Compared to other psychedelic drugs (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using the dosing regimens described herein without a 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), such as bipolar I and bipolar II; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders and treated according to the present invention do not experience treatment-induced mania or hypomania.

[0084] It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate the use of a wide range of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0085] The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of accompanying adverse events.

[0086] Furthermore, antidepressants have been reported to induce isolated hypomanic episodes in patients with treatment-resistant depression (TRD) (Bader, Cynthia D. and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania.

[0087] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective, described as a "loss of self," typically culminating in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after intravenous injection, compared to several hours with, for example, oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific alterations in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0088] In addition, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. The inventors used recombinant human 5-HT7 receptor, [ 3 H]LSD and serotonin were used to estimate nonspecific binding and to determine K i is 2.3nM.

[0089] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

[0090] The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis, and dendritic spine formation. It is implicated in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0091] 5-HT7 receptors are expressed particularly in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus (including the suprachiasmatic nucleus), hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0092] The suprachiasmatic nucleus (SCN) is the central pacemaker of the circadian timing system. It coordinates circadian rhythms across various brain regions. Disruption of this coordination can lead to disease states, particularly those involving sleep disturbances. Resting-state functional connectivity analysis has revealed altered functional connectivity between the SCN and regions within the default mode network in patients with sleep disturbances.

[0093] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of these receptors in regulating the sleep / wake cycle. The inventors believe that this allows for the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

[0094] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0095] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal. This is supported by the clinical results shown in the studies cited herein.

[0096] Another characteristic of 5-MeO-DMT is its short half-life.

[0097] 5-MeO-DMT is primarily inactivated through a deamination pathway mediated by monoamine oxidase A and O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

[0098] The inventors studied the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after administration.

[0099] Analysis of the pharmacokinetic properties of 5-MeO-DMT following inhalation revealed a very rapid decline in plasma concentrations. Ten minutes after administration, concentrations had fallen to 10% or less of Cmax; after two hours, concentrations were 1% or less of Cmax; and after three hours, 5-MeO-DMT was no longer detectable in plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a timeframe of one to four hours. Up-titration as disclosed herein did not result in accumulation and, therefore, did not result in higher plasma concentrations, for example, at ten minutes, two hours, or three hours after administration.

[0100] The inventors have further determined that 5-MeO-DMT has several characteristics that make it an attractive treatment for PPD. Compared to SSRIs, 5-MeO-DMT is a fast-acting agent (in the 5-MeO-DMT-TRD trial, 5 of 8 TRD patients achieved remission within 2 hours of dosing, 8 patients achieved remission on day 1, and 7 patients maintained remission on day 7). Treatment of patients with PPD with 5-MeO-DMT can rapidly improve not only depressive symptoms but also maternal functioning. In addition, 5-MeO-DMT is administered during a single day of treatment, optionally with infrequent re-dosing, thereby distinguishing it from SSRIs, which require a long-term daily dosing regimen with lower compliance, and brexanolone, which requires long-term infusions and hospitalization.

[0101] Thus, the present invention also addresses compliance and patient convenience issues.

[0102] Furthermore, the inventors have determined that treatment of PPD with 5-MeO-DMT or a pharmaceutically acceptable salt thereof allows continued breastfeeding with only brief interruptions in treatment.

[0103] 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.

[0104] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0105] A deuterated form of 5-MeO-DMT is one that has a higher deuterium content than would be expected based on the natural abundance of this isotope.

[0106] The deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

[0107] 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.

[0108] Further examples include forms of 5-MeO-DMT in which deuterium has been introduced at one or more hydrogen positions of the N-bound methyl group. Still further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is also worth noting that combinations of the above substitution patterns are also contemplated.

[0109] Methods for the preparation of these compounds are known in the art.

[0110] 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 and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

[0111] Furthermore, according to the present invention, the amount of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used is equimolar to the amount of the corresponding non-deuterated form.

[0112] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT can be converted to 5-MeO-DMT through metabolism. Therefore, when reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be substituted.

[0113] In suitable prodrugs, the hydrogen in position 1 of the indole moiety is replaced with an organic moiety that can be cleaved after administration.

[0114] An example of a suitable organic moiety is C(O)OR 1 、-C(O)R 2 、-CH(R 3 )OR 4 、-C(O)OCH(R 3 )OC(O)R 4 、-C(O)OCH(R 3 )OC(O)OR 4 、-CH(R 3 )C(O)R 4 、-CH(R 3 )OC(O)R 4 、-CH(R 3 )OC(O)OR 4 , where R 1 、R 2 、R 3 and R 4Each of is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0115] A preferred example of an organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , where R 1 、R 3 and R 4 As defined above.

[0116] Prodrugs, especially those of the above structure, can also be used in the form of pharmaceutically acceptable salts.

[0117] Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0118] Methods for preparing prodrugs as discussed herein are known in the art.

[0119] According to the present invention, the T of the metabolite 5-MeO-DMT was measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg. max The value is preferably 1 hour or less, more preferably 0.7 hour or less, especially 0.5 hour or less.

[0120] Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

[0121] Mode of administration

[0122] Therapeutically effective amounts of 5-MeO-DMT are administered intravenously, intramuscularly, or subcutaneously. Administration via these routes ensures rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., by intravenous injection.

[0123] 5-MeO-DMT can be used in the form of a pharmaceutically acceptable salt, preferably a hydrobromide salt, or in the form of a formulation for administration via injection. Examples of excipients and vehicles for such formulations are known in the art.

[0124] Dosage regimen

[0125] The present invention also provides dosage ranges, specific dosages and dosing regimens (administration regimens) and appropriate administration routes.

[0126] The present invention is based in part on the inventors' conclusion that the peak psychedelic experience occurs during the acute phase following administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, and that this drives the therapeutic benefit of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, in patients diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorder, and including such disorder associated with suicidal ideation), particularly one or more aspects as defined above, either causally or at least as a surrogate behavioral marker of an underlying unknown therapeutic mechanism.

[0127] Therefore, achieving peak experience more quickly in a greater proportion of patients and with better reproducibility within individual patients will result in a better therapeutic profile than with previously tested psychedelics, dosing regimens, and routes of administration.

[0128] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., the absence of waning or loss of psychedelic effects upon re-administration) as a basis for enabling a dosing regimen of frequent re-administration (such as more than once daily or once daily) designed to increase the incidence of peak experiences, thereby increasing therapeutic benefit. Such repeated administrations over a short period of time also allow for intra-individual dose optimization, which reduces the risk of overdose, which may otherwise result in somatic side effects such as serotonin syndrome, negative psychotic reactions (such as flashbacks of the experience at a later time point), induction of mania or hypomania, or less significant psychedelic experiences with little or no memory of the altered state (so-called "whiteouts"). Furthermore, starting with a low dose allows the patient to become familiar with typical psychedelic experiences and allows for preparation for the more intense symptoms that occur at higher doses, which will positively impact the experience at higher doses. Furthermore, the prospect of being able to initiate treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0129] Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the reproducibility of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be achievable with other psychedelics due to the delayed onset and prolonged duration of the effects and due to the rapid development of tolerance (i.e., diminished or absent effects upon re-administration), which may persist for several days.

[0130] A patient diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder and including the disorder associated with suicidal ideation, as defined herein, is treated by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0131] In a preferred embodiment, 5-MeO-DMT is administered as monotherapy, ie, the patient is not receiving any other treatment for the diagnosed disorder.

[0132] The dosage range of 5-MeO-DMT administered to a patient diagnosed with a disorder as defined herein (including treatment-resistant forms of such a disorder and including such a disorder associated with suicidal ideation) is about 1 mg to about 10 mg, or any range therein, and is administered in the form of an administration formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT (such as the hydrobromide salt), the weight of which can be calculated based on the stated weight of 5-MeO-DMT free base, assuming the use of equimolar amounts. 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. Please note that throughout this specification, when a range is listed (such as "about 1 mg to about 10 mg"), the inventors contemplate all discrete values ​​within that range, some of which are explicitly mentioned, but not all of which are mentioned - this is merely for the sake of brevity.

[0133] In preferred embodiments, the improved methods of treating a patient diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorder, and including such disorder associated with suicidal ideation) using a therapeutically effective amount of 5-MeO-DMT comprise the onset of a clinical response no later than about 2 hours after administration of the 5-MeO-DMT.

[0134] In preferred embodiments, improved methods of treating a patient diagnosed with a disorder as defined herein, including treatment-resistant forms of such a disorder, and including such a disorder associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT include a sustained clinical response, including a clinical response that occurs no later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0135] In preferred embodiments, improved methods of treating a patient diagnosed with a disorder as defined herein (including treatment-resistant forms of such disorder, and including such disorder associated with suicidal ideation) using a therapeutically effective amount of 5-MeO-DMT comprise administering more than a single dose of 5-MeO-DMT.

[0136] In a preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0137] In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block being about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block being no less than about 6 days.

[0138] In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block being about 1 to 4 hours, preferably 1 to 2 hours, and the interval between the end of one treatment block and the beginning of the next treatment block being no less than about 6 days.

[0139] In embodiments, 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.

[0140] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and is 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 is earlier.

[0141] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg upon the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: reaching 10 mg, or all administrations within that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the treating physician determines that further dose increases are inappropriate based on observed side effects.

[0142] For embodiments in which the dose of a subsequent administration is increased, the dose of 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 dose of the previous administration. For example, if the first administration was a 1 mg dose and the dose increase is 3 mg, the second administration is a 4 mg dose unless one of the aforementioned stopping criteria has been met. Preferably, the third administration is a 7 mg dose.

[0143] In a preferred embodiment, the dose 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 dose selected from about 4 mg to about 6 mg for the second administration, and to a dose selected from about 7 mg to about 9 mg for the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Specific useful amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0144] In another preferred embodiment, the dose 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 dose selected from about 1.5 mg to about 2.5 mg for the second administration, and to a dose selected from about 2.5 mg to about 3.5 mg for the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Specific useful amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0145] In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in a first treatment block is selected from about 1 mg to about 2 mg and is then increased with each subsequent administration within the first treatment block until the earlier of: reaching 10 mg, or all administrations within the treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further dose increases are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will serve as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block was 8 mg because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 8 mg.

[0146] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient during the first administration of the first treatment block is selected from the range of about 1 mg to about 3 mg, and then, unless the patient has experienced a peak psychedelic experience during the treatment block or the attending physician determines that further increases in dose are inappropriate based on observed side effects, the second administration of the first treatment block is increased to a dose selected from the range of about 4 mg to about 6 mg, and the third administration of the first treatment block is increased to a dose selected from the range of about 7 mg to about 9 mg, wherein the highest dose in the first treatment block is used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific useful amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0147] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient during the first administration of the first treatment block is selected from the range of about 0.5 mg to about 1.5 mg, and then, unless the patient has experienced a peak psychedelic experience during the treatment block or the attending physician determines that further increases in dose are inappropriate based on observed side effects, the second administration of the first treatment block is increased to a dose selected from the range of about 1.5 mg to about 2.5 mg, and the third administration of the first treatment block is increased to a dose selected from the range of about 2.5 mg to about 3.5 mg, wherein the highest dose in the first treatment block is used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific useful amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0148] It will be understood that a pharmaceutically acceptable salt of 5-MeO-DMT is preferred for all of the above dosage regimens and that the appropriate weight of salt to be administered can be calculated based on the stated weight of the free base, assuming equimolar amounts are used.

[0149] According to the present invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0150] A patient can be identified as having a "peak psychedelic experience" by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0151] Patients experiencing a “peak psychedelic experience” can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Nowhereness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0152] According to the present invention, whether a patient has had a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 on the Peak Experience Scale (PES), also known as the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score from 0 to 100 of the patient's responses to the following three questions: 1. How intense was the experience? 2. How much loss of control was there? 3. How significant (i.e., profound and important) was the experience?

[0153] Sleep disorders

[0154] There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing sleep depth. Non-REM and REM sleep alternate during the four to five cycles of normal human sleep each night. During the early part of the night, non-REM sleep is deeper and occupies a disproportionately large amount of time, especially in the first sleep cycle. As the night progresses, non-REM sleep becomes lighter, and more of each cycle is allocated to REM sleep.

[0155] Normal, healthy sleep consists of the different stages described above, which proceed in a continuous, strictly controlled sequence throughout the night.

[0156] Disruptions in this tight control can lead to sleep disturbances.

[0157] Sleep disturbances are conditions that affect the quality, timing, or duration of sleep, whether idiopathic or occurring in the context of a medical condition (such as a psychiatric or neurological disorder). Sleep disturbances can affect a person's ability to function normally while awake.

[0158] Common forms of sleep disturbances include disorders of falling asleep and maintaining sleep (insomnias), disorders of excessive sleepiness (hypersomnias), disorders of the sleep-wake schedule (circadian rhythm disorders), disorders related to sleep, sleep stages, or partial arousals (parasomnias), disorders characterized by disturbed breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0159] Insomnia is a sleep disorder in which a person has difficulty falling asleep or staying asleep. People with insomnia have trouble falling asleep; wake up frequently during the night and have trouble falling asleep again; wake up too early in the morning; have poor sleep quality; and / or have at least one daytime problem due to poor sleep quality, such as fatigue, sleepiness, mood problems, difficulty concentrating, or accidents while working or driving.

[0160] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom found in hypersomniacs. The transition from sleep to wakefulness is difficult. Individuals who experience sleep drunkenness report feeling confused, disoriented, sluggish, and drifting back to sleep upon awakening.

[0161] Circadian rhythm disorders are characterized by chronic or recurring sleep disturbances due to alterations in an individual's internal circadian rhythm or due to a mismatch between their circadian rhythm and their desired or required work or social schedule. This missynchrony may be temporary or persistent. The resulting clinical presentation combines symptoms of insomnia and hypersomnia. Sleep duration is often shortened and disrupted, performance during desired wakefulness is impaired, and restoration of a normal sleep schedule is temporarily prevented.

[0162] Parasomnias refer to various forms of sleep disorders characterized by unusual behavioral or physiological activity (such as sleepwalking or nightmares) experienced before falling asleep, during sleep, or during the arousal period between sleep and wakefulness. There is considerable variability in the characteristics, severity, and frequency of parasomnias. Parasomnias can impair sleep quality.

[0163] Sleep-related breathing disorders are characterized by abnormal and difficult breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of the respiratory muscles and the control center in the brain. One form of sleep-related breathing disorder is central sleep apnea. This occurs, for example, when the brain stops sending signals to control breathing, depending on an underlying health condition. Central sleep apnea has potentially serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow leads to intermittent periods of hypoxia, which can fragment sleep due to micro-arousals or awakenings. The consequence can be excessive daytime sleepiness.

[0164] In sleep-related movement disorders, repetitive, relatively simple, often stereotyped movements disrupt sleep or the onset of sleep. The most common of these are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0165] Insufficient sleep quantity or quality can lead to personality changes and may not only exacerbate existing mental illnesses but also contribute to their development. Disrupted sleep can also interfere with cognitive function and lead to memory impairment. Sleep-deprived individuals may experience difficulty making decisions, irritability, poor performance, and slower reaction times. Insufficient sleep can also negatively impact life by contributing to the development of obesity, diabetes, and heart disease.

[0166] Treatment for sleep disorders varies depending on the type and underlying cause. Maintaining good sleep hygiene, a healthy sleep environment, and a consistent sleep-wake schedule are often considered first-line treatment. If unsuccessful, treatment may involve medication or psychotherapy.

[0167] Available treatments are not successful in all patients, may be associated with side effects and / or require long-term treatment to achieve a relevant therapeutic effect.

[0168] In patients with sleep disturbances associated with psychiatric or neurological disorders, known treatments for the psychiatric or neurological disorder do not necessarily improve the sleep disturbance.

[0169] For example, sleep disturbances are frequently associated with psychiatric disorders such as depression. However, treating depression does not necessarily result in an improvement in the accompanying sleep disturbances. Although most antidepressants have been shown to affect sleep architecture, some classes of antidepressants improve sleep, while other antidepressants may cause sleep impairment.

[0170] Although disrupted sleep may be considered a condition that should be treated independently of any other conditions, disorders, or symptoms an individual may have, several psychiatric and neurological disorders are associated with disrupted sleep. Notably, the relationship between sleep and psychiatric or neurological disorders is often bidirectional. Not only can psychiatric or neurological disorders negatively impact healthy sleep patterns, but disrupted sleep can also contribute to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0171] The treatment method according to the present invention can reduce or eliminate sleep disturbances and preferably also improve related psychiatric or neurological disorders.

[0172] Measuring sleep disturbances

[0173] Sleep can be assessed by measuring parameters such as sleep duration, sleep architecture, sleep latency, and the frequency and duration of wakefulness throughout the night. Quantitative indicators can be measured using objective methods, including polysomnography, actigraphy, and determination of sleep latency, or by self-report measurements (questionnaires).

[0174] Polysomnography is a technique that involves monitoring patients throughout the night in a specialist clinic. Various functions are measured throughout the night, including eye movements, brain and muscle activity, breathing effort and airflow, blood oxygen levels, body posture and movement, snoring, and heart rate.

[0175] Another quantitative measure is actigraphy. Actigraphy sensors are worn to measure motor activity, which is continuously recorded and used to assess sleep-wake cycles. This technology allows patients to continue their normal lives while recording the required data in a natural sleep environment.

[0176] Sleep latency can be measured using the Multiple Sleep Latency Test (MSLT). This test provides an objective measure to determine how long it takes a person to fall asleep after multiple test naps. An average sleep latency of approximately 10 minutes is considered normal; a latency of less than eight minutes indicates disrupted sleep (excessive daytime sleepiness). Accompanying brain activity analysis can help further diagnose sleep disorders.

[0177] The sleep assessment questionnaire captures ratings of components of sleep quality, such as perception of sleep depth, difficulty waking, and rest after sleep, as well as other factors that may influence sleep quality, such as comorbidities and medication use. Assessment of qualitative aspects of the sleep experience is important because sleep complaints can often persist despite normal quantitative sleep measures.

[0178] Questionnaires not only facilitate the rapid and accurate assessment of complex clinical problems but may also be useful in tracking patient progress.

[0179] A variety of sleep quality indices are known. The following indices include examples of questionnaires for assessing general sleep and examples of questionnaires for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias, respectively. However, the present invention is not limited to the use of a particular index or questionnaire.

[0180] Some questionnaires rely on a recall period (recall window) of several days or even weeks. While this may be suitable for diagnosing sleep disorders, it is not always suitable for assessing the effectiveness of treatment, especially the effects that occur quickly after treatment. For several questionnaires, the recall period can be modified so that the scores obtained reflect a period of time after treatment. In particular, this paper discusses questionnaires that assess the effect of treatment on sleep in patients suffering from specific conditions, which rely on a recall period that starts no earlier than the time point when the acute psychedelic experience has subsided after the last administration. In order to meet this criterion, the normally applied recall period is modified if necessary.

[0181] For example, the Sleep-50 questionnaire can be used to assess general sleep quality.

[0182] The Sleep-50 questionnaire consists of 50 items and is designed to screen for various sleep disorders in the general population. The scale consists of nine subscales, reflecting some of the most common disorders and discomforts associated with sleep and factors required for diagnosis, such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorders, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep discomfort on daily function. For each item, the respondent is given a scale from 1 ("not at all") to 4 ("very much") and is asked to indicate the extent to which the statement matches their experience in the last month or another appropriate recall window.

[0183] To diagnose a sleep disorder, not only must a specific subscale (e.g., insomnia) exceed a certain cutoff point, but the respondent must also achieve a cutoff point of at least 3 or 4 ("quite a bit" or "very much," respectively) on the subscale that assesses the impact of sleep discomfort on daily functioning (Spoormaker et al., Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005; 3(4):227-46).

[0184] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0185] A commonly used questionnaire to assess sleep disturbances is the Pittsburgh Sleep Quality Index. Other tools include the Insomnia Severity Index, the Espie Sleep Disturbance Questionnaire, and the Patient Reported Outcomes Measurement Information System (PRIME). )Sleep disorders.

[0186] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a 19-question self-assessment questionnaire that asks respondents to indicate how often they have experienced certain sleep difficulties in the past month or another appropriate recall window.

[0187] Nineteen self-rated questions assess multiple factors related to sleep quality, including estimates of sleep duration and latency and estimates of the frequency and severity of specific sleep-related problems. These 19 items are divided into seven component scores: (1) subjective sleep quality; (2) sleep latency; (3) sleep duration; (4) habitual sleep efficiency; (5) sleep disturbances; (6) use of sleeping pills; and (7) daytime dysfunction.

[0188] Each component is scored on a scale of 0 to 3. Higher scores indicate more severe sleep disturbances. Detailed scoring instructions for the Pittsburgh Sleep Quality Index can be found in the appendix of Buysse et al., The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989 May; 28(2): 193-213.

[0189] The seven component scores are then summed to create an overall score, ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A total score cutoff of 5 distinguishes those with poor sleep quality from those with good sleep quality. A total score of >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0190] If the PSQI is used to assess treatment outcomes, treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 5 or less.

[0191] The Insomnia Severity Index (ISI) is a short questionnaire that measures subjective sleep quality, symptom severity, subjective satisfaction with sleep, the degree to which insomnia interferes with daily functioning, how significant the respondent feels their insomnia is compared to other people, and the overall level of distress caused by sleep problems. Individual responses can be scored from 0 (=none) to 4 (=very); a higher total score corresponds 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 two weeks. Another appropriate recall window may also be used.

[0192] Treatment success is indicated by (i) a decrease in the score, for example a decrease of >7 points, particularly >8 points; and preferably (ii) a decrease in the score to below the cutoff for clinically significant insomnia.

[0193] The Espie Sleep Disturbance Questionnaire (SDQ) assesses the subjective experience of insomnia. The SDQ assesses restlessness / agitation, mental overactivity, consequences of insomnia, and inadequate preparation for sleep, with a particular focus on beliefs about the root causes of sleep problems. Respondents use a five-point scale to indicate how often certain statements about insomnia represent their experience. 1 means "never true," while 5 means "often true." Higher scores indicate more dysfunctional beliefs about the causes and associated factors of insomnia (A. Shahid et al., supra).

[0194] A decrease in the score indicates successful treatment.

[0195] Patient-Reported Outcomes Information System The Sleep Disturbance Tool is a general method for assessing sleep disturbances. The tool has a long form and four different short forms (e.g., 4, 6, and 8 items) and assesses self-reported sleep quality, perception of sleep depth, and any perceived difficulties with falling and staying asleep over a 7-day period.

[0196] 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.

[0197] A decrease in T score indicates successful treatment.

[0198] Excessive sleepiness or excessive sleepiness can be assessed using the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0199] The Epworth Sleepiness Scale (ESS) assesses overall daytime sleepiness. The questionnaire asks respondents to rate their likelihood of falling asleep in eight different situations, representing moments of relative inactivity, such as an afternoon nap or sitting in a car stopped in traffic. Respondents rate their likelihood of falling asleep using a scale of 0-3 (0 meaning "never doze off" and 3 meaning "very likely doze off"). Scores range from 0-24; the higher the score, the greater the severity of daytime sleepiness. A cutoff score of 10 indicates that daytime sleepiness may occur at a clinical level (A. Shahid et al., supra).

[0200] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score to 10 or less.

[0201] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses the degree of sleepiness at a particular moment. The scale consists of only one item, asking the respondent to select one of seven statements that best represents their current perceived level of sleepiness. Sleepiness levels are assessed using a scale ranging from 1 (=feeling active and energized; alert; wide awake) to 7 (=almost in a trance; falling asleep quickly; unable to stay awake) (A. Shahid et al., supra).

[0202] A decrease in the score indicates successful treatment.

[0203] Parasomnias can be assessed using the Paris Arousal Disorders Severity Scale (PADSS).

[0204] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists parasomnias, assesses their frequency, and includes an evaluation of their consequences (Arnulf et al. A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0205] Treatment success is indicated by (i) a decrease in the score, preferably (ii) a decrease in the score below a cut-off value.

[0206] A commonly used questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., supra). An appropriate recall period can also be selected.

[0207] A decrease in the score indicates successful treatment.

[0208] A commonly used questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Rating Scale. The 10-item questionnaire requires respondents to use a Likert-type rating method to indicate how severe the impact of this disorder on them has been in the past week. The questions can be divided into two categories: one of the symptoms of the disorder (nature, intensity, and frequency) and its impact (sleep problems, daily function disturbances, and resulting mood changes). Each of the ten questions requires respondents to rate their RLS experience on a scale of 0 to 4, with 4 representing the most severe and most frequent symptoms and 0 representing the least symptoms. The total score range can be 0 to 40. As a concise scale with excellent psychometric quality, the tool is applicable to a variety of research and clinical purposes, including screening and evaluating treatment outcomes. (A. Shahid et al., supra).

[0209] The response to treatment can be assessed by a decrease in the score.

[0210] Resting-state networking and sleep disturbances

[0211] Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0212] Functional images of the brain were acquired over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of this spontaneous signal revealed regions with correlated and inversely correlated fluctuations.

[0213] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0214] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0215] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0216] RSNs have been shown to be responsible for various aspects of complex brain function, and these connected networks have been found to be impaired in various disease states. Such disease states are associated with altered functional connectivity within specific resting-state networks and / or between one or more regions in one or more additional resting-state networks.

[0217] Altered resting-state networks have been found in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0218] A key network involved in sleep is the default mode network (DMN). Generally speaking, the DMN is deactivated during tasks and activated during rest. It is involved in a variety of cognitive processes, such as higher-level cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given the importance of the DMN to sleep physiology, altered DMN activity is particularly relevant to sleep disorders.

[0219] As discussed further in this article, impaired resting-state networks can also be found in psychiatric or neurological disorders.

[0220] Resting-state networks associated with sleep disturbances can also be affected by psychiatric or neurological disorders caused by certain medical health conditions.

[0221] In patients with insomnia, functional connectivity impairments have been observed within the default mode network (DMN) and the salience network, which are associated with the detection and integration of emotional and sensory stimuli. Studies have shown that these networks contain key areas for integrating emotional and physical states, and that functional connectivity impairments within and / or between these networks and other brain regions may contribute to patients' alertness, subjective distress, and poor sleep continuity.

[0222] 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 changes, and functional connectivity within the DMN is correlated with self-reported sleepiness severity.

[0223] A study examining the differences between night and day shift nurses revealed that circadian rhythm disturbances promote changes in resting-state function in the cerebellum, which is involved in sleep regulation and cognitive functions such as reactivity and alertness. Furthermore, the functional connectivity of the DMN is fundamentally different in early and late circadian rhythm phenotypes. Like other forms of sleep disturbances, circadian rhythm disturbances can lead to changes in brain functional connectivity. Changes in resting-state brain functional connectivity have been reported in various diseases with circadian rhythm disturbances.

[0224] Although performing functional brain imaging during parasomnia events is technically difficult, differences in the precuneus have been observed in arousal disorders representing non-REM parasomnias.

[0225] The precuneus is involved in analyzing and integrating visual, auditory, and somatosensory information, as well as monitoring movement. It is a subregion of the DMN. Therefore, the default mode network is affected in patients with parasomnias.

[0226] Resting-state fMRI studies of patients with sleep-related breathing disorders, such as central sleep apnea, have demonstrated profound global and regional connectivity deficits, particularly in the default mode network (DMN) and in regions involved in arousal and sensorimotor systems.

[0227] Sleep-related movement disorders, such as periodic limb movements during sleep, were reflected by alterations in the prefrontal motor control pathway, a subregion of the default mode network. Furthermore, activity was observed in the cerebellum and thalamus, as well as additional activation in the red nucleus and brainstem.

[0228] In many cases, abnormal functional connectivity of resting-state networks associated with sleep disturbances is also associated with the aforementioned disorders. Therefore, according to the present invention, influencing these networks by the therapy according to the present invention will lead to an improvement in sleep disturbances and, if the patient being treated suffers from a psychiatric or neurological disorder, also to an improvement in said disorder.

[0229] Treatment of sleep disorders and psychiatric and neurological disorders

[0230] According to the present invention, idiopathic sleep disorders and sleep disorders in patients suffering from mental disorders or nervous system disorders can be treated. In patients suffering from sleep disorders associated with mental disorders or nervous system disorders, the treatment of sleep disorders according to the present invention leads to improvement of diseases associated with sleep disorders.

[0231] In many cases, the resting-state networks associated with sleep disturbances are also implicated in these disorders.

[0232] 5-MeO-DMT disrupts established functional connectivity patterns in resting-state networks. This disruption leads to the reset of pathological, malconnected brain connections as the network rewires. New, healthy functional connections are established, with lasting effects.

[0233] The persistent nature of these effects may be explained by 5-MeO-DMT's neuroplasticity-promoting properties. 5-MeO-DMT specifically promotes structural and functional plasticity at synapses, the sites where neurons connect and communicate with each other. 5-MeO-DMT modulates the morphogenesis and maturation of dendritic spines, thereby initiating the formation of new synaptic connections. These new connections are then strengthened, weakened, or even eliminated, depending on activity.

[0234] The resulting formation of new synapses, in turn, influences the activity patterns of neurons. The inventors conclude that such reciprocal structural and functional modifications contribute to the proper establishment of networks and the persistence of the effects following administration of 5-MeO-DMT.

[0235] From a biochemical point of view, 5-MeO-DMT interacts with, among other things, the 5-HT receptor.

[0236] 5-HT receptors, receptors for the neurotransmitter serotonin or 5-hydroxytryptamine (5-HT), are found throughout the central and peripheral nervous systems. A variety of physiological and pathological functions are mediated by these receptors.

[0237] In the brain, seven types of 5-HT receptors are expressed, which can be further divided into several subtypes. The various types and subtypes exhibit different spatial distributions.

[0238] 5-MeO-DMT interacts with several 5-HT receptors, which have been implicated in mediating its effects on resting-state networks and neuroplasticity.

[0239] In addition to the 5-HT1A and 5-HT2A discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

[0240] The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis, and dendritic spine formation. It is implicated in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0241] 5-HT7 receptors are expressed particularly in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus (including the suprachiasmatic nucleus), hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0242] The suprachiasmatic nucleus (SCN) is the central pacemaker of the circadian timing system. It coordinates circadian rhythms across various brain regions. Disruption of this coordination can lead to disease states, particularly those involving sleep disturbances. Resting-state functional connectivity analysis has revealed altered functional connectivity between the SCN and regions within the default mode network in patients with sleep disturbances.

[0243] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of these receptors in regulating the sleep / wake cycle. The inventors believe that this allows for the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

[0244] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0245] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal. This is supported by the clinical results shown in the studies mentioned herein.

[0246] Treatment according to the invention will result in an improvement in sleep disturbances and, if the patient being treated suffers from a psychiatric or neurological disorder, will also result in an improvement in said disorder.

[0247] Clinical data from studies of patients with treatment-resistant depression (TRD) or postpartum depression (PPD) demonstrate that sleep disturbances can be successfully treated by administering 5-MeO-DMT.

[0248] In the TRD study described in more detail in the Examples section below, the MADRS item "Sleep reduction" reflecting insomnia was assessed, among others.

[0249] The MADRS item "Sleep reduction" represents the experience of reduced sleep duration or depth compared to the participant's normal sleep pattern when healthy. A score of 0 indicates normal sleep. A score of 2 reflects mild difficulty falling asleep or slightly reduced, shallow, or fragmented sleep. A score of 4 indicates reduced or interrupted sleep of at least two hours. A score of 6 indicates sleep duration of less than two or three hours.

[0250] In the study group that received the individualized dosing regimen, all eight patients had a total score of 25 for the MADRS item "Sleep reduction" at baseline. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score had decreased to 12, corresponding to an improvement of 13 points, or 52%. On day 7 after treatment, the score had decreased to 9, corresponding to an improvement of 16 points, or 64%.

[0251] In the 12 mg group, all four patients had a total score of 12 for the MADRS item "Sleep reduction" at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

[0252] Therefore, the score of the scale item "sleep loss" which is particularly related to sleep disturbance was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat sleep disturbance, especially in patients suffering from mental disorders or neurological disorders.

[0253] Cognitive dysfunction

[0254] Cognition includes the skills needed for thinking, memory, attention, and problem-solving. Loss or decline in these skills can lead to cognitive impairment, a term used in this article to refer to deficits or impairments in any cognitive domain. Cognitive impairment may be a manifestation of an underlying medical condition.

[0255] The DSM-5 defines six key areas of cognitive function: complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition.

[0256] Cognitive dysfunction can affect one or more of these areas. In fact, cognitive abilities are highly correlated, and it is not uncommon for more than one area to be affected.

[0257] For example, the domain complex attention has the subdomains sustained attention (often called “concentration” or “focus”), divided attention, selective attention, and processing speed.

[0258] Therefore, complex attention clearly encompasses aspects that are crucial for a variety of cognitive tasks, such as executive function, learning, and memory. Cognitive control, or executive function, is essentially attention. Furthermore, perception and decision-making are also significantly influenced by attentional capacity.

[0259] Therefore, attention can be tested not only in isolation but also through cognitive control tasks / executive function. If attention is impaired, other types of cognitive abilities may also be impaired. Before one can understand language, perceive visual-spatial relationships, remember information, or solve problems, one must pay attention to stimuli.

[0260] Cognitive impairment (the term used herein to refer to an acquired disorder and thus represents a decline from a previously achieved level of function) can be related to a variety of processes.

[0261] In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained during aging and can even improve over time. However, even in the absence of any pathological conditions, aging can lead to a decline in abilities such as abstract thinking, reasoning, and decision-making. These deteriorations are associated with potential age-related deficits in processing speed, attention, memory, and executive function (which indicate cognitive aging).

[0262] In addition to normal aging, cognitive impairment may be associated with psychiatric or neurological disorders or some other medical conditions.

[0263] Mental or neurological disorders such as those discussed herein can cause or be associated with cognitive impairment.

[0264] Additionally, cognitive impairment occurs in disorders that present with characteristic symptoms of a neurocognitive disorder that causes clinically significant distress or impairment in social, occupational, or other important areas of functioning but does not meet full criteria for any etiologically relevant disorder.

[0265] Cognitive dysfunction can manifest in the form of neurocognitive disorders.

[0266] Mild neurocognitive disorder, also known as mild cognitive impairment, is characterized by a slight decline in cognitive ability compared to previous performance levels in one or more cognitive domains. Affected individuals are still able to maintain independence and perform daily tasks. However, functioning is typically suboptimal. Daily tasks become more strenuous as compensatory strategies are employed to maintain independence.

[0267] In severe neurocognitive impairment, a significant decline in cognitive ability compared to previous performance levels is observed in one or more cognitive domains. Cognitive deficits interfere with independence in daily activities.

[0268] Measuring cognitive impairment

[0269] Cognitive impairment can be assessed using questionnaires or neuropsychological assessments.

[0270] Questionnaires assess a patient's mental status based on observations by the patient, a caregiver, or the clinician who administers the questionnaire. Questionnaires used to assess patients for specific mental or neurological disorders may include items related to cognitive function.

[0271] A neuropsychological assessment is a comprehensive evaluation of a person's cognitive, psychological / emotional, and behavioral functioning. A core component of a neuropsychological assessment is the administration of neuropsychological tests to formally assess cognitive function.

[0272] Performance on these tests is compared to standards appropriate for the patient's age, education, and cultural background. Testing typically uses a set of performance-based questions, also called a neuropsychological battery.

[0273] The abilities tested include language processing, visuospatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive function, processing speed, and sensory perception.

[0274] Common tests for assessing cognitive impairment include the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), and the Mini-Cog TM , Screening for Cognitive Impairment in Psychiatry (SCIP) and MATRICS Consensus Cognitive Battery (MCCB).

[0275] The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment for detecting cognitive impairment. It evaluates different cognitive domains: short-term memory; visuospatial abilities; executive function; attention, concentration, and working memory; language; and orientation to time and space. The total possible score is 30, with 26 or above considered normal, 18-25 mild, 10-17 moderate, and less than 10 severe.

[0276] The Mini-Mental State Examination (MMSE) is an 11-question measurement tool that tests five areas of cognitive function: orientation, recording, attention and calculation, recall, and language. The maximum score is 30. The original score may also need to be modified based on education level and age.

[0277] This article uses four cutoff levels 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 means severe cognitive impairment.

[0278] Used repeatedly, the MMSE is suitable for measuring changes in cognitive status.

[0279] Mini-Cog TM This is a brief questionnaire to screen for cognitive impairment. It combines a three-word recall test with a clock drawing test. The clock drawing test assesses a number of cognitive areas that may be affected, such as executive function, visuospatial abilities, motor programming, and attention. After taking the clock drawing test, one point is awarded for each three words correctly recalled; each correct drawing of a clock is worth two points. A score of less than 4 indicates cognitive impairment.

[0280] The Screening for Cognitive Impairment in Psychiatry (SCIP) is a well-evaluated screening tool used to examine cognitive performance in patients with psychiatric disorders.

[0281] The SCIP consists of five subscales: the Verbal Learning Test-Immediate (VLT-I), the Working Memory Test (WMT), the Verbal Fluency Test (VFT), the Verbal Learning Test-Delayed (VLT-D), and the Processing Speed ​​Test (PST). Three different test formats are used to facilitate repeated testing, which can reduce learning effects. A subscale score is calculated for each of the five tests, and a total score is calculated by summing the subscale scores. A total score below 70 indicates cognitive impairment.

[0282] Cognitive impairment can also be assessed using the MCCB (MATRICS Consensus Cognitive Battery) or one or more of its subtests. These subtests include: Trail Making Test Part A (processing speed); Brief Assessment of Cognitive Abilities in Schizophrenia, Symbol Coding Subtest (processing speed); Hopkins Verbal Learning Test-Revised, Immediate Recall, Only Three Learning Trials (verbal learning); Wechsler Memory Scale-3, Spatial Span Subtest (working memory (non-verbal)); Letter-Digit 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 Quotient Test, Managing Emotions Branch (social cognition); and Sustained Performance Test, Paired Version (attention / vigilance).

[0283] The test battery is suitable for measuring cognitive changes.

[0284] Further tests included the Verbal Recognition Memory (VRM) test, Rapid Visual Processing (RVP) test, Spatial Working Memory (SWM) test, and Digit Symbol Substitution Test (DSST).

[0285] Potential mechanisms of cognitive impairment

[0286] Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0287] Functional images of the brain were acquired over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of this spontaneous signal revealed distributed regions with correlated and inversely correlated fluctuations.

[0288] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0289] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0290] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0291] RSNs have been shown to be responsible for various aspects of complex brain function, and these connected networks have been found to be impaired in various disease states. Such disease states, including certain forms of cognitive impairment, are associated with altered functional connectivity within specific resting-state networks and / or between one or more regions in one or more additional resting-state networks.

[0292] Resting-state fMRI is particularly advantageous when studying populations affected by cognitive impairment because it enables the examination of functional connectivity while removing task demands that may be confounded by underlying cognitive or motor impairments.

[0293] Cognitive processes are reflected by the functional connectivity of certain brain regions within and / or between regions located in different networks.

[0294] Specifically, certain core networks, also called “higher-order cognitive networks,” appear to be crucial for most mental activities.

[0295] The frontoparietal control network (FPCN), also known as the frontoparietal network (FPN), the central executive network (CEN), or the executive network (EN), is often associated with executive functions. These functions include holding and updating relevant information in working memory, inhibiting impulsive responses, and using flexible problem-solving strategies to guide decision-making and goal-directed behavior.

[0296] Another core network is the default mode network (DMN). The DMN contains regions of 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 free thought unrelated to the task.

[0297] The third network is the salience network, also known as the cingulo-opercular network. This network is involved in identifying salient stimuli and events—those that other brain networks should pay attention to. This network plays a central role in controlling mental processes and behavior.

[0298] The fourth network is the dorsal attention network (DAN). The DAN is associated with top-down, goal-directed attention processes.

[0299] The aforementioned networks do not operate independently. In fact, there are countless connections between them. Cooperation between networks is crucial for the functionality of specific tasks.

[0300] Throughout the lifespan, brain networks undergo functional reorganization, with concurrent impacts on cognition. During healthy aging, age-related alterations have been observed in higher-order cognitive networks.

[0301] Compared with age-matched healthy controls, patients with cognitive impairment showed altered functional connectivity within and / or between resting-state networks. Alterations were observed within and / or between the default mode network, executive network, salience network, and dorsal attention network.

[0302] In many cases, resting-state networks involved in cognition are affected by psychiatric or neurological disorders as discussed herein.

[0303] Resting-state networks involved in cognition can also be affected by psychiatric or neurological disorders, as a consequence of certain medical health conditions, as well as unspecified neurocognitive disorders.

[0304] Furthermore, resting-state networks involved in cognition are affected by sleep disturbances such as insomnia. In fact, cognitive dysfunction and sleep impairment are correlated.

[0305] Patients with disturbed sleep have worse cognitive function, and patients with cognitive impairment often also have impaired sleep.

[0306] Treatment of cognitive impairment

[0307] According to the present invention, the cognitive dysfunction that occurs in the patient suffering from mental disorder or nervous system disorder or the medical health disorder that causes relevant mental or nervous system disorder can be treated.In addition, the cognitive dysfunction that occurs in the patient suffering from sleep disorder (such as insomnia) can be treated.

[0308] Cognitive dysfunction in unspecified neurocognitive disorders can also be treated.

[0309] In patients suffering from cognitive dysfunction associated with another disorder detailed above, treatment of cognitive dysfunction according to the invention results in an improvement of the disorder associated with the cognitive dysfunction.

[0310] Treatment according to the present invention is by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0311] Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the reset of pathological, dysfunctional connections as the networks rewire. New, healthy functional connections are established, with lasting effects.

[0312] Thus, according to the present invention, affecting these networks through therapies as described herein will result in improvements in cognitive dysfunction and, if the patient being treated suffers from a psychiatric or neurological disorder, will also result in improvements in that disorder; if the patient being treated suffers from a medical health condition that causes the relevant psychiatric or neurological disorder, will also result in improvements in the relevant psychiatric or neurological disorder; if the patient being treated suffers from a sleep disorder (e.g., insomnia), will also result in improvements in the sleep disorder (e.g., insomnia); if the patient suffers from an unspecified neurocognitive disorder, will also result in improvements in one or more other symptoms of that disorder.

[0313] To further support the clinical utility of 5-MeO-DMT in patients suffering from cognitive impairment, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in cognitive impairment, which is also commonly observed in patients with other disorders.

[0314] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below.) While TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to the design of treatments for other disorders associated with cognitive dysfunction.

[0315] In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group of interest was the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR), which allowed for multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the patient-reported psychedelic experience.

[0316] The collected data included assessments of the treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy by improving the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items (such as those related to cognitive dysfunction) were associated with other disorders in which cognitive dysfunction was based on similar altered functional connectivity within and / or between the default mode network, executive control network, salience network, and dorsal attention network.

[0317] Several patients in the recruited cohort demonstrated significant improvements, confirming the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

[0318] More specifically, one aspect that can be treated by administering 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.

[0319] The MADRS item particularly relevant to impaired concentration and memory is "difficulty concentrating." This item represents difficulty collecting one's thoughts, which leads to an inability to focus, and is scored on a scale of 0 to 6. If the patient has no difficulty concentrating, the score is 0. If they occasionally have difficulty concentrating their thoughts, the score is 2. If difficulty concentrating and maintaining thoughts leads to reduced ability to read or converse, the score is 4. If the patient cannot read or converse easily, the score is 6.

[0320] In the study group that received the individualized dosing regimen, all eight patients had a total score of 30 for the MADRS item "difficulty concentrating" at baseline.

[0321] After 2 hours, the score had dropped to 11, which corresponded to a 19-point or 63% improvement. On the first day after treatment, the score had dropped to 1, which corresponded to a 29-point or 97% improvement. On the seventh day after treatment, the score had dropped to 9, which corresponded to a 21-point or 70% improvement.

[0322] In the 12 mg group, all four patients had a total score of 16 for the MADRS item "difficulty concentrating" at baseline.

[0323] After 2 hours, the score dropped to 7, which corresponds to a 9-point or 56% improvement. On the first day after treatment, the score dropped to 2, which corresponds to a 14-point or 88% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to a 13-point or 81% improvement.

[0324] Thus, 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.

[0325] More specifically, according to the present invention, treatment of a patient suffering from cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction, wherein the cognitive dysfunction is a deficit or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, sensorimotor function, and social cognition. For example, if the cognitive dysfunction affects the cognitive domain complex attention, such as one or more subdomains of the cognitive domain complex attention selected from sustained attention, divided attention, selective attention, and processing speed, in particular sustained attention, the cognitive dysfunction is reduced or eliminated.

[0326] In patients suffering from cognitive dysfunction associated with a psychiatric disorder or a nervous system disorder, the treatment of cognitive dysfunction according to the present invention results in an improvement of the symptoms associated with the cognitive dysfunction.

[0327] Although cognitive impairment may be considered a condition that should be treated independently of any other conditions, disorders, or symptoms an individual may have, several psychiatric and neurological disorders are associated with cognitive impairment. Notably, the relationship between cognitive impairment and psychiatric disorders is often bidirectional. Not only can psychiatric disorders negatively impact cognitive function, but cognitive impairment can also contribute to the onset, progression, and prognosis of psychiatric or neurological disorders.

[0328] In many cases, resting-state networks implicated in cognitive dysfunction are also implicated in these disorders.

[0329] 5-MeO-DMT disrupts established functional connectivity patterns in resting-state networks. This disruption leads to the resetting of pathological, dysfunctional brain connections as the network rewires. New, healthy functional connections are established, with lasting effects.

[0330] anxiety

[0331] Anxiety is sometimes defined as "the apprehensive anticipation of future danger or misfortune, accompanied by feelings of dysphoria or physical symptoms of tension."

[0332] Anxiety is characterized by intense, excessive, and persistent worry and fear about situations that are perceived only subjectively as threatening, often accompanied by muscle tension, restlessness, fatigue, difficulty breathing, abdominal tightness, nausea, and difficulty concentrating.

[0333] In an anxiety disorder or other anxiety-related mental or neurological disorder, feelings of anxiety are difficult to control and interfere with daily activities.

[0334] Anxiety is a core feature of anxiety disorders, including separation anxiety disorder, specific phobias, social anxiety disorder (social phobia), panic disorder, generalized anxiety disorder (GAD), agoraphobia, and substance / medication-induced anxiety disorders.

[0335] In addition, anxiety is associated with several other psychiatric and neurological disorders. Anxiety is also associated with sleep disturbances.

[0336] Measuring anxiety

[0337] Several rating scales for assessing anxiety are known in the art, and anxiety symptoms are also assessed as part of various rating scales used to assess psychiatric and neurological disorders.

[0338] The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. The scale is administered by a clinician. The scale has 14 items and can be divided into a mental group (items 1-6 and 14), which specifically measures mental agitation and psychological distress, and a somatic group (items 7-13), which specifically measures physical discomfort associated with anxiety.

[0339] The HAM-A items are shown in the table below.

[0340]

[0341] The interviewer rated each item on a scale of 0 to 4: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.

[0342] The total score is obtained by summing the 14 items. The total score range is 0–56. Higher scores indicate more severe anxiety.

[0343] A score of 7 or less was considered to indicate no or very low anxiety; a score of 8–14 indicated mild anxiety; a score of 15–23 indicated moderate anxiety; and a score of 24 or more indicated severe anxiety.

[0344] The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire developed to assess anxiety, with a focus on somatic symptoms. Items are rated on a four-point Likert scale, ranging from zero (not at all) to three (severely: I can hardly stand it). Total scores range from 0 to 63.

[0345] The term "subthreshold anxiety" as used herein specifically means that the patient scores at least 9 but less than 18 on the Hamilton Anxiety Rating Scale (HAM-A) and / or at least 11 but less than 16 on the Beck Anxiety Inventory (BAI).

[0346] Potential mechanisms of anxiety

[0347] Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0348] Functional images of the brain were acquired over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of this spontaneous signal revealed distributed regions with correlated and inversely correlated fluctuations.

[0349] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0350] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0351] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0352] RSNs have been shown to be responsible for various aspects of complex brain function, and these connected networks have been found to be impaired in various disease states. Such disease states, including certain forms of anxiety, are associated with altered functional connectivity within specific resting-state networks and / or between one or more regions in one or more additional resting-state networks.

[0353] Based on these studies, multiple brain regions have been implicated in anxiety and anxiety disorders. Thus, the pathophysiology of anxiety and anxiety disorders involves abnormal connectivity between the amygdala-frontal region and the frontal-striatal region. Anxiety and anxiety disorders are associated with specific alterations in resting-state networks.

[0354] Anxiety and anxiety disorders exhibit abnormalities within and / or between the default mode network, the salience network, and the sensorimotor network. The resting-state balance within and / or between each of these networks differs in different anxiety disorders.

[0355] Treatment of anxiety

[0356] According to the present invention, anxiety that occurs in patients suffering from anxiety disorders or other psychiatric disorders or neurological disorders related to anxiety can be treated. In addition, anxiety that occurs in patients suffering from sleep disorders (such as insomnia) can be treated.

[0357] In patients suffering from anxiety associated with another psychiatric or neurological disorder or a sleep disorder (eg insomnia), the anxiety treatment according to the present invention results in an improvement in the anxiety-related symptoms.

[0358] Treatment according to the present invention is by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0359] Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the reset of pathological, dysfunctional connections as the networks rewire. New, healthy functional connections are established, with lasting effects.

[0360] Thus, according to the present invention, affecting these networks through therapies as described herein will result in improved anxiety, and if the patient being treated suffers from another psychiatric or neurological disorder related to anxiety, that disorder will also be improved; if the patient being treated suffers from a sleep disorder, such as insomnia, that sleep disorder (e.g., insomnia) will also be improved.

[0361] To further support the clinical utility of 5-MeO-DMT in patients suffering from anxiety, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in anxiety, which is also commonly observed in patients with other disorders.

[0362] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below.) While TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for anxiety disorders and other anxiety-related disorders.

[0363] In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group of interest was the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR), which allowed for multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the patient-reported psychedelic experience.

[0364] The data collected included assessments of the treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the trial focused on demonstrating treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items, such as those related to anxiety, were associated with other disorders where anxiety was based on similarly altered functional connectivity within and / or between resting-state networks.

[0365] Several patients in the recruited cohort demonstrated significant improvements, confirming the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

[0366] More specifically, one aspect that can be treated by administering 5-MeO-DMT is anxiety. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's anxiety.

[0367] A particularly relevant BPRS item in this context is "Anxiety." This item relates to reported worry, tension, fear, panic, or concern. Possible scores are:

[0368] 1- No anxiety

[0369] 2 - Very Mild. Reports some discomfort due to worry or infrequent worry that occurs more frequently than in most normal individuals.

[0370] 3 - Mild. Frequent worrying but able to easily shift attention to other things.

[0371] 4 - Moderate. Worrying most of the time and unable to easily shift attention to other things, but functioning is not impaired; or anxiety occasionally occurs with autonomic symptoms, but functioning is not impaired.

[0372] 5 - Moderate to severe. Frequent (but not daily) anxiety with autonomic symptoms, or some areas of functioning are disrupted by anxiety or worry.

[0373] 6 - Severe. Anxiety occurs daily with autonomic symptoms, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or persistent worry.

[0374] 7 - Extreme. Anxiety with autonomic symptoms persists throughout the day, or most areas of functioning are disrupted by anxiety or persistent worry.

[0375] In the study group that received the individualized dosing regimen, the total score for the BPRS item "anxiety" was 37 at baseline for all eight patients.

[0376] After 3 hours, the score had dropped to 19, which corresponded to an 18-point or 49% improvement. On the first day after treatment, the score had dropped to 16, which corresponded to a 21-point or 57% improvement. On the seventh day after treatment, the score had dropped to 17, which corresponded to a 20-point or 54% improvement.

[0377] In the 12 mg group, the total score of the BPRS item "anxiety" was 25 at baseline for all four patients.

[0378] After 3 hours, the score had dropped to 11, which corresponds to a 14-point or 56% improvement. On the first day after treatment, the score had dropped to 6, which corresponds to a 19-point or 76% improvement. On the seventh day after treatment, the score had dropped to 6, which corresponds to a 19-point or 76% improvement.

[0379] The inventors have concluded that 5-MeO-DMT can be used to treat anxiety in patients, such as patients suffering from anxiety disorders and patients suffering from mental or neurological disorders and associated anxiety.

[0380] Thus, according to the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.

[0381] The MADRS item "Inner Tension" represents feelings of vague discomfort, irritability, inner confusion, and mental tension that escalate into panic, fear, or distress. It is rated based on intensity, frequency, duration, and the degree of reassurance required.

[0382] If the patient is calm and has only brief bouts of inner tension, the score is 0. If there are occasional feelings of irritability and vague discomfort, the score is 2. If there is constant inner tension or intermittent panic that the patient has difficulty controlling, the score is 4. If there is constant fear or distress and overwhelming panic, the score is 6.

[0383] In the aforementioned trial involving patients with TRD, the total score for the MADRS item "Inner Tension" for all eight patients in the study group who received the personalized dosing regimen was 26 at baseline. After 2 hours, the score had dropped to 11, which corresponds to an improvement of 15 points, or 58%. On the first day after treatment, the score had dropped to 6, which corresponds to an improvement of 20 points, or 77%. On the seventh day after treatment, the score had dropped to 12, which corresponds to an improvement of 14 points, or 54%.

[0384] In the 12 mg group, all four patients had a total score of 13 for the MADRS item "Inner Tension" at baseline. Two hours later, the score dropped to 2, corresponding to an 11-point, or 85%, improvement. On the first day after treatment, the score dropped to 3, corresponding to a 10-point, or 77% improvement. On the seventh day after treatment, the score dropped to 5, corresponding to an 8-point, or 62% improvement.

[0385] These results further support the inventors' conclusion that treatment according to the present invention reduces or eliminates the symptoms of anxiety.

[0386] Treatment according to the present invention results in a clinical response in patients suffering from anxiety symptoms as reflected by a decrease in HAM-A scores of at least 50% compared to the corresponding scores before treatment at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g., about 24 hours; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0387] The clinical response in patients suffering from anxiety symptoms (as reflected by a decrease of at least 50% in the HAM-A score compared to the corresponding score before treatment) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response in patients suffering from anxiety symptoms (as reflected by a decrease of at least 50% in the HAM-A score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0388] Relief 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; on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0389] Relief of anxiety symptoms in patients suffering from anxiety symptoms (as reflected by a HAM-A score of 7 or less) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety symptoms in patients suffering from anxiety symptoms (as reflected by a HAM-A score of 7 or less) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0390] Thus, according to the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the anxiety.

[0391] Psychomotor retardation

[0392] Key aspects observed in patients suffering from psychomotor retardation are decreased energy and activity and reduced motivation.

[0393] Psychomotor retardation involves slower thinking and decreased physical movement. Psychomotor impairment may result in noticeably slower physical and emotional reactions.

[0394] Psychomotor retardation may be associated with a psychiatric or neurological disorder or some other medical condition.

[0395] Mental or neurological disorders that cause or are associated with psychomotor retardation include disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; postpartum depression (PPD); seasonal affective disorder and persistent depressive disorder; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; and chronic fatigue syndrome.

[0396] Psychomotor retardation may also occur in patients with sleep disorders such as insomnia.

[0397] Measuring psychomotor retardation

[0398] Psychomotor retardation can be assessed by measuring various aspects. These can 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.

[0399] For example, in the line connection test (TMT), the subject must connect 25 circles containing numbers (TMT A) or numbers and letters (TMT B) in ascending order. The task requirement of TMT-B is similar, except that the subject must alternate between numbers and letters (1, A, 2, B, 3, C, etc.). Therefore, the test evaluates processing speed (TMT A) or cognitive flexibility (TMT B). The scoring of each part represents the time required to complete the task.

[0400] Another test involving graphomotor ability is the Gibson Spiral Maze (GSM), which assesses only psychomotor speed and is not influenced by cognitive ability. To complete the GSM, subjects must correctly trace a spiral maze from the start to the end without touching the borders.

[0401] The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of digit-symbol pairs and lists of numbers. Under each number, the subject should write the corresponding symbol as quickly as possible. The score is determined by the number of symbols reported correctly within 90 seconds. Another example of a motor test is the finger tapping test.

[0402] Therefore, some tests combine measures of both motor and cognitive aspects of psychomotor retardation, whereas other tests assess only the motor aspects.

[0403] Speech analysis can serve as a further indicator of psychomotor retardation.

[0404] The main scales that can be used for assessment and measurement include the severity of psychomotor retardation, the Salpêtrière Slowness Rating Scale (SRRS), and the Motor Agitation and Retardation Scale (MARS).

[0405] The Salpêtrière Slowness Rating Scale (SRRS) was developed to assess cognitive and motor aspects through fifteen items. The first three indicators measure movement, especially the quality of stride and the slowness of movements of the limbs, trunk, head and neck. The next three items focus on speech, including speech fluency, intonation and length of answers. Two items were designed to objectively measure cognitive function. These questions are based on interview dialogues and measure the patient's ability to approach and expand on topics. Further items are subjective and assess contemplation, fatigue, interest level, time perception, memory and attention. The last item of the scale is related to the overall assessment of the patient's psychomotor retardation. Based on the severity of the symptoms presented, the items are scored from 0 (no symptoms) to 4 (severe), with a total score ranging from 0 to 60.

[0406] The Motor Agitation and Retardation Scale (MARS) assesses motor aspects only. It is designed to assess psychomotor disturbances in depressive disorders. Psychomotor disturbances are divided into five physical categories: eyes, face, voice, limbs, and trunk, with a total of 19 items on the scale. Items in the eyes category include gaze direction, number of blinks, gaze, and eye movements. Items related to the face category include facial expression and facial expressivity. The voice category has items including volume, slurredness, pitch, and onset time. Items under the limb category include movements of the hands, feet, and legs, stride length, slowness of movement, and tension in the hands. Items under 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. Of these 19 items, 9 are related to motor agitation, and 10 items assess bradykinesia. The MARS scale includes abnormal gait, trunk / proximal limb immobility, postural collapse, and slow movements (i.e., limb and trunk categories); lack of facial expressivity and downcast gaze (i.e., eyes and face categories); and lowered voice, slurred speech, delayed speech, and monotonous speech (i.e., voice categories). The MARS scale allows for a rapid clinical assessment of motor signs.

[0407] Resting-state networking and psychomotor retardation

[0408] Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0409] Functional images of the brain were acquired over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of this spontaneous signal revealed distributed regions with correlated and inversely correlated fluctuations.

[0410] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0411] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0412] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0413] RSNs have been shown to be responsible for various aspects of complex brain function, and these connected networks have been found to be impaired in various disease states. Such disease states, including certain forms of psychomotor retardation, are associated with altered functional connectivity within specific resting-state networks and / or between one or more regions in one or more additional resting-state networks.

[0414] For example, abnormal functional connectivity from the somatosensory motor network (SMN) to the visual (VN), dorsal attention (DAN), and default mode networks has been reported to be associated with psychomotor retardation and agitation in depressive disorders.

[0415] In many cases, resting-state networks involved in psychomotor retardation are affected by psychiatric or neurological disorders characterized by depressive episodes, such as major depressive disorder (MDD); bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; postpartum depression (PPD); seasonal affective disorder and persistent depressive disorder; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and Parkinson's disease dementia; Parkinson's disease; and chronic fatigue syndrome.

[0416] Resting-state networks involved in psychomotor retardation are also affected by sleep disturbances such as insomnia. In fact, psychomotor retardation is associated with sleep impairment.

[0417] Treatment of psychomotor retardation and mental or neurological disorders

[0418] According to the present invention, psychomotor retardation in patients suffering from mental disorders or nervous system disorders can be treated. In addition, psychomotor retardation occurring in patients suffering from sleep disorders (such as insomnia) can be treated.

[0419] In patients suffering from psychomotor retardation associated with another disorder detailed above, the treatment of psychomotor retardation according to the invention results in an improvement of the disorder associated with the psychomotor retardation.

[0420] Treatment according to the present invention is by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0421] Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the reset of pathological, dysfunctional connections as the networks rewire. New, healthy functional connections are established, with lasting effects.

[0422] Thus, according to the present invention, affecting these resting-state networks through therapies as described herein will result in improvements in psychomotor retardation, and if the patient being treated suffers from a psychiatric or neurological disorder, the disorder will also be improved; if the patient being treated suffers from a sleep disorder (e.g., insomnia), the sleep disorder (e.g., insomnia) will also be improved.

[0423] To further support the clinical utility of 5-MeO-DMT in patients suffering from psychomotor retardation, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in psychomotor retardation, which is also commonly observed in patients with other disorders.

[0424] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below.) While TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for other disorders associated with psychomotor retardation.

[0425] In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group of interest was the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR), which allowed for multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the patient-reported psychedelic experience.

[0426] The data collected included assessments of the treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items (such as those related to psychomotor retardation) were associated with other disorders in which psychomotor retardation was based on similar altered functional connectivity within and / or between the somatomotor / sensorimotor networks, the visual network, the dorsal attention network, and the default mode network.

[0427] Several patients in the recruited cohort demonstrated significant improvements, confirming the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

[0428] More specifically, one aspect that can be treated by administering 5-MeO-DMT is psychomotor retardation. 5-MeO-DMT can be administered to a patient to reduce or eliminate psychomotor retardation in the patient.

[0429] The item in the MADRS scale that is particularly relevant to psychomotor retardation is “slouching,” which represents difficulty starting or slowness in initiating and performing daily activities.

[0430] A score of 0 means almost no difficulty starting and no slowness. If the patient has trouble starting an activity, the score is 2. A score of 4 means difficulty starting simple daily activities that require effort. If the patient is completely lazy and unable to do anything without help, the score is 6.

[0431] In the study group that received the personalized dosing regimen, all eight patients had a total score of 27 for the MADRS item "laziness" at baseline.

[0432] After 2 hours, the score dropped to 10, which corresponds to a 17-point or 63% improvement. On the first day after treatment, the score dropped to 5, which corresponds to a 22-point or 81% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to a 24-point or 89% improvement.

[0433] In the 12 mg group, the total score for the MADRS item "sluggishness" was 16 at baseline for all four patients. After 2 hours, the score dropped to 10, which corresponds to a 6-point or 38% improvement. On the first day after treatment, the score dropped to 0, which corresponds to a 16-point or 100% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to a 13-point or 81% improvement.

[0434] Thus, the score of the scale item "sluggishness", which is particularly relevant to psychomotor retardation, was significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat psychomotor retardation in patients, especially those who also suffer from mental disorders or neurological disorders or sleep disorders (such as insomnia).

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

[0436] Social / emotional withdrawal or alienation

[0437] Symptoms such as anhedonia, emotional withdrawal, and affective flattening are categorized herein as social / emotional withdrawal or alienation. Reduced social engagement is another aspect related to social / emotional withdrawal or alienation.

[0438] Anhedonia is the inability to experience pleasure. If the subjective ability to experience pleasure in daily activities is not diminished, the patient does not suffer from anhedonia. Anhedonia is mild if the pleasure derived from normally pleasurable activities is slightly diminished; moderate if the pleasure derived from normally pleasurable activities is significantly diminished, or some pleasure derived from isolated activities is preserved; or severe if the inability to experience pleasure is complete.

[0439] Anhedonia consists of both consumptive (or liking) and anticipatory (or wanting) components. Consumptive hedonia refers to the "instant" pleasure experienced when a subject directly participates in a pleasurable activity, while anticipatory hedonia refers to the pleasurable experience associated with future activities.

[0440] Affective flattening characterizes the subjective perception of a decrease in the intensity or range of feelings or emotions. If no decrease in the intensity or range of feelings or emotions is perceived, the subject does not exhibit affective flattening. Affective flattening is mild if the range of emotions is slightly reduced, or if the range or intensity of feelings is temporarily reduced. Affective flattening is moderate if the range or intensity of feelings is significantly reduced, but some emotions are retained, such as the inability to cry. Affective flattening is severe if the range of emotions is significantly and pervasively reduced, or if the inability to experience usual emotions is present.

[0441] Emotional withdrawal or detachment refers to an inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes an item related to emotional withdrawal, which characterizes a subject's impairment in expressing emotion during the interview. According to this BPRS item, if lack of emotional engagement is absent, as evidenced by occasional failure to respond to comments, occasional absentmindedness, or a forced smile, but spontaneous interaction with the interviewer most of the time, emotional withdrawal is absent. If lack of emotional engagement is present, as evidenced by a clear failure to respond to comments, absentmindedness, or lack of enthusiasm, but responding when approached by the interviewer, mild emotional withdrawal is present. If emotional engagement is absent during most interviews, as evidenced by the subject not responding in detail, not making eye contact, seeming unconcerned about whether the interviewer is listening, or perhaps being immersed in the psychotic material, emotional withdrawal is moderate. Alternatively, if emotional engagement is absent during most interviews, emotional withdrawal is moderate to severe. A severe form is present if the subject actively avoids emotional engagement, or if the subject frequently fails to respond, responds with yes / no answers, or responds only minimally emotionally. Affective withdrawal was considered extreme if the subject consistently avoided emotional engagement, did not respond or responded with yes / no answers, or was likely to walk away during the interview or not respond at all.

[0442] Decreased social engagement represents a subjective report of decreased social and interpersonal participation or interaction. If there is no report of decreased social and interpersonal participation or interaction, then there is no decreased social engagement. Decreased social engagement is mild if social engagement is slightly decreased but social or interpersonal functioning is not impaired; moderate if social engagement is significantly decreased and accompanied by some functional sequelae, such as avoidance of some social engagements or conversations; and severe if social interactions are significantly decreased or nearly all forms of social contact are avoided, such as refusing to answer the phone or see friends or family.

[0443] Social / emotional withdrawal or alienation may be associated with a psychiatric or neurological disorder or some other medical condition.

[0444] Mental or neurological disorders that cause or are associated with social / emotional withdrawal or alienation include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD), such as bipolar I and bipolar II, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); and post-traumatic stress disorder. These include post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders due to psychoactive substance use, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementias, such as Alzheimer's disease dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0445] Social / emotional withdrawal or detachment may also occur in patients with sleep disorders such as insomnia.

[0446] Social / emotional withdrawal or alienation may also occur in patients with medical health conditions that result in associated psychiatric or neurological disorders, including traumatic brain injury (TBI).

[0447] Measuring social / emotional withdrawal or alienation

[0448] Social / emotional withdrawal or alienation (generally referred to herein as social / emotional withdrawal) or its individual aspects, such as anhedonia, emotional withdrawal, and affective apathy, can be assessed by different tools, such as questionnaires or scales.

[0449] Questionnaires assess a patient's mental state based on observation by the patient, a caregiver, or the clinician who administers the questionnaire. Questionnaires used to assess patients for specific mental or neurological disorders may include items related to social / emotional withdrawal or alienation.

[0450] The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale that measures anhedonia, or the inability to experience pleasure. The items cover areas including: social interaction, food and drink, sensory experiences, and interests / pastures. A score of 2 or less constitutes a "normal" score, while a score of 3 or more is defined as an "abnormal" score. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Any "disagree" response is scored as one point, and any "agree" response is scored as zero. Therefore, the final score range is 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. The SHAPS has been used to measure anhedonia in depression, but it is also frequently used to assess anhedonia in other patient groups.

[0451] In principle, the SHAPS uses 14 hypothetically formulated items to measure hedonic tone over the past few days. However, due to the hypothetical nature of the items, an appropriately shorter recall period can also be used to assess earlier time points.

[0452] Alternatively or additionally, the Dimensional Anhedonia Rating Scale (DARS) can be used to assess anhedonia, which measures interest, motivation, effort, and consumptive pleasure in four domains (hobbies, food / beverages, social activities, and sensory experiences). The scale includes 17 items that assess current state anhedonia. The DARS is rated on a five-point Likert scale, ranging from 0 (not at all) to 4 (very much), with higher values ​​indicating less anhedonia. The total score for all items ranges from 0 to 68. For the four hedonic domains, namely hobbies (four items, total score 0-16), food / beverages (four items, total score 0-16), social activities (four items, total score 0-16), and sensory experiences (5 items, total score 0-20), participants were asked to provide two or three of their own favorite examples.

[0453] The Personality Inventory for DSM-5 (PID-5) - Adult is a 220-item self-assessment of personality traits for adults aged 18 years and older. It assesses 25 personality trait facets, including anhedonia, anxiety, attention-seeking, callousness, deceitfulness, depression, distractibility, eccentricity, emotional instability, grandiosity, hostility, impulsivity, intimacy avoidance, irresponsibility, manipulativeness, perceptual dysregulation, stubbornness, emotional restriction, rigid perfectionism, risk-taking, separation insecurity, submissiveness, suspiciousness, unusual beliefs and experiences, and withdrawal, with each facet consisting of 4 to 14 items.

[0454] The Anhedonic Trait Facet contains items 1, 23, 26, 30R, 124, 155R, 157, 189 (reverse-scored items are marked with the letter "R"), the Withdrawal Trait Facet contains items 10, 20, 75, 82, 136, 146, 147, 161, 182, 186, and the Intimacy Avoidance Trait Facet contains items 89, 97R, 108, 120, 145, 203. These three trait facets can be combined to produce a broader trait domain designated Distancing.

[0455] The measure is completed by the individual before visiting a clinician. Each item requires the individual to rate how well the item describes him or her overall.

[0456] Each item in the measure is rated on a 4-point scale. Response categories for each item are: 0 = Very false or often false; 1 = Sometimes or somewhat false; 2 = Sometimes or somewhat true; 3 = Very true or often true. Items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215 were reverse coded before being included in the scale score calculation.

[0457] The scores for the items within each trait facet should be summed and entered into the appropriate raw facet score box. In addition, the clinician is asked to calculate and use the average score for each facet and domain. The average score reduces the total score and the score for each domain to a 4-point scale, which allows the clinician to think about the individual's personality dysfunction relative to the observed norm. The average facet score is calculated by dividing the raw facet score by the number of items in the facet (for example, if all items within the "anhedonia" facet are rated as "sometimes or somewhat true," the average facet score would be 16 / 8 = 2, indicating moderate anhedonia). The average domain score is calculated by adding the scores for the three facets that primarily contribute to a particular domain and then averaging them. For example, if the average facet score for anhedonia, avoidance of intimacy, and withdrawal (the scale that primarily indexes alienation) is 2, the sum of these scores would be 6, and the average domain score would be 6 / 3 = 2. Higher average scores indicate more severe dysfunction in a particular personality trait facet or domain.

[0458] High scores on aspects or domains may indicate significant and problematic areas for the individual receiving care, which may require further assessment, treatment, and follow-up.

[0459] Resting-state networking and social / emotional withdrawal or alienation

[0460] Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0461] Functional images of the brain were acquired over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of this spontaneous signal revealed distributed regions with correlated and inversely correlated fluctuations.

[0462] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0463] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0464] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0465] RSNs have been shown to be responsible for various aspects of complex brain function, and these connected networks have been found to be impaired in various disease states. Such disease states, including certain forms of social / emotional withdrawal or alienation, are associated with altered functional connectivity within specific resting-state networks and / or between one or more regions in one or more additional resting-state networks.

[0466] Alterations in the RSN also implicate anhedonia, a key aspect of social / emotional withdrawal or alienation. More specifically, anhedonia is associated with hyperconnectivity in the visual network and expansion of the visual network, the dorsal attention network (DAN), and the default mode network (DMN). Anhedonia also involves decreased network connectivity between the DMN, salience, DAN, somatomotor, and visual networks.

[0467] In addition, the emotional alienation of adult psychosis is associated with structural abnormalities in the dorsal DMN. Because the dorsal DMN has functions related to psychosis, it is particularly interesting in the development of psychosis. Specifically, the dorsal DMN and its connected areas (medial prefrontal cortex and posterior cingulate cortex (PCC)) support emotional, social and moral processing. In adult psychosis, microstructural abnormalities in the dorsal DMN are associated with the emotional and interpersonal differences that define the disorder.

[0468] Thus, compared to age-matched healthy controls, patients suffering from social / emotional withdrawal or alienation exhibited altered functional connectivity within and / or between RSNs. Alterations were observed within and / or between the DMN, salience, DAN, somatomotor, and visual networks.

[0469] In many cases, RSN involving social / emotional withdrawal or alienation is influenced by a psychiatric or neurological disorder, such as disorders characterized by depressive episodes, for example, major depressive disorder (MDD), bipolar disorder (BD), such as bipolar I and bipolar II, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); Post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain and fibromyalgia; mental and behavioral disorders due to psychoactive substance use, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementias, such as Alzheimer's disease dementia (AD); dementia with Lewy bodies (DLB); vascular dementia and frontotemporal dementia (FTD); Parkinson's disease (PD); eating disorders; autism spectrum disorder (ASD); attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0470] Resting-state networks involved in social / emotional withdrawal or alienation can also be affected by psychiatric or neurological disorders as a result of certain medical health conditions, such as traumatic brain injury (TBI).

[0471] Resting-state networks involved in social / emotional withdrawal or alienation are also affected by sleep disturbances such as insomnia. In fact, social / emotional withdrawal or alienation is associated with sleep impairment.

[0472] Treatment of social / emotional withdrawal or alienation and psychiatric or neurological disorders

[0473] According to the present invention, social / emotional withdrawal or alienation occurring in patients suffering from psychiatric or neurological disorders can be treated. In addition, social / emotional withdrawal or alienation occurring in patients suffering from sleep disorders (e.g., insomnia) can be treated.

[0474] In patients suffering from social / emotional withdrawal or alienation associated with another disorder detailed above, treatment of social / emotional withdrawal or alienation according to the present invention results in an improvement of the disorder associated with the social / emotional withdrawal or alienation.

[0475] Treatment according to the present invention is by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0476] Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the reset of pathological, dysfunctional connections as the networks rewire. New, healthy functional connections are established, with lasting effects.

[0477] Thus, according to the present invention, influencing these networks through therapies as described herein will result in improved social / emotional withdrawal or alienation, and if the patient being treated suffers from a psychiatric or neurological disorder, the disorder will also be improved; if the patient being treated suffers from a sleep disorder (e.g., insomnia), the sleep disorder (e.g., insomnia) will also be improved.

[0478] To further support the clinical utility of 5-MeO-DMT in patients suffering from social / emotional withdrawal or detachment, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in social / emotional withdrawal or detachment, which is also commonly observed in patients with other disorders.

[0479] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below.) While TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for other disorders associated with social / emotional withdrawal or alienation.

[0480] In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group of interest was the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR), which allowed for multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the patient-reported psychedelic experience.

[0481] The data collected included assessments of the treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items (such as items related to social / emotional withdrawal or alienation) were associated with other disorders in which social / emotional withdrawal or alienation was based on similar altered functional connectivity within and / or between the default mode network, the salience network, the dorsal attention network, the somatomotor network, and the visual network.

[0482] Several patients in the recruited cohort demonstrated significant improvements, confirming the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

[0483] More specifically, one aspect that can be treated by administering 5-MeO-DMT is social / emotional withdrawal or alienation, particularly anhedonia, emotional withdrawal, and / or apathy. Another aspect that can be treated is decreased social engagement. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's social / emotional withdrawal or alienation, particularly anhedonia, emotional withdrawal, and / or apathy. In addition, decreased social engagement is ameliorated, i.e., reduced or eliminated.

[0484] The MADRS item "Anorexia," which is particularly relevant to social / emotional withdrawal or detachment, represents the subjective experience of decreased interest in one's surroundings or in activities that would normally bring pleasure. It also refers to a reduced ability to respond adequately emotionally to situations or people.

[0485] A score of 0 indicates normal interest in one's surroundings and other people, while a score of 2 indicates a reduced ability to enjoy everyday interests. A score of 4 indicates a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects emotional numbness, an inability to feel anger, sadness, or pleasure, and a complete and even painful loss of affection for friends and family.

[0486] In the study group that received the personalized dosing regimen, the total score for the MADRS item "loss of sensation" for all eight patients was 36 at baseline. After 2 hours, the score dropped to 12, which corresponds to a 24-point improvement, or 67%. On the first day after treatment, the score dropped to 2, which corresponds to a 34-point improvement, or 94%. On the seventh day after treatment, the score dropped to 6, which corresponds to a 30-point improvement, or 83%.

[0487] In the 12 mg group, the total score for the MADRS item "loss of sensation" was 16 at baseline for all four patients. After 2 hours, the score dropped to 9, which corresponds to an improvement of 7 points, or 44%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points, or 94%. On the seventh day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points, or 94%.

[0488] BPRS items that are particularly relevant to social / emotional withdrawal or alienation are “emotional withdrawal” and “emotional blunting.”

[0489] The BPRS item "Emotional Withdrawal" relates to the patient's deficit in expressing emotions during the interview. Possible scores are:

[0490] 1- No emotional withdrawal.

[0491] 2 - Very Mild. Lack of emotional engagement, as evidenced by occasional failure to respond to comments, occasional absent-mindedness, or a stiff smile, but mostly spontaneous interaction with the interviewer.

[0492] 3 - Mild. Lack of emotional engagement, as evidenced by a marked failure to respond to comments, appearing distracted or lacking enthusiasm, but responding when approached by the interviewer.

[0493] 4 - Moderate. Emotional engagement is absent during most of the interview, as the subject does not respond in detail, makes no eye contact, does not seem to care whether the interviewer is listening, or may be immersed in the psychotic material.

[0494] 5 - Moderately severe. Same as 4, but emotional contact was absent during most of the interview.

[0495] 6 - Severe. Actively avoids emotional engagement. Frequently fails to respond or responds with yes / no answers (not solely due to persecutory delusions). Or responds with minimal emotion.

[0496] 7 - Extreme. Consistently avoids emotional engagement. Does not respond or responds with yes / no answers (not solely due to persecutory delusions). May walk away or not respond at all during the interview.

[0497] The total score for the BPRS item "Emotional Withdrawal" was 13 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%.

[0498] In the 12 mg group, the total score for the BPRS item "Emotional Withdrawal" was 13 at baseline. After 3 hours, the score dropped to 11, which corresponds to a 2-point or 15% improvement. On the first day after treatment, the score dropped to 8, which corresponds to a 5-point or 38% improvement. On the seventh day after treatment, the score dropped to 6, which corresponds to a 7-point or 54% improvement.

[0499] The BPRS item "Blunting of Emotion" involves a restricted range of emotional expressiveness in the face, voice, and gestures, as well as apparent apathy or indifference even when discussing painful topics. Possible scores are:

[0500] 1- No emotional blunting.

[0501] 2 - Very mild. Emotional range is slightly suppressed or reserved, but facial expressions and voice intonation are appropriate and within normal range.

[0502] 3 - Mild. Emotional range is generally diminished, inhibited, or reserved, without many spontaneous and appropriate emotional responses. Voice and intonation are slightly monotonous.

[0503] 4 - Moderate. Emotional range is markedly diminished, and except in rare cases, the patient does not express emotion, smile, or respond to distressing topics. Speech may be monotonous or spontaneous movements may be markedly reduced. Displays of emotion or gestures often result in a return to apathy.

[0504] 5 - Moderate to severe. The emotional range is very diminished. The patient does not show emotion, smile, or respond to painful topics. Facial expression does not change often, except for minimal, infrequent gestures. The voice is monotonous most of the time.

[0505] 6 - Severe. Emotional range or expression is very limited. Speech and gestures are mechanical most of the time. Facial expression remains unchanged. Voice intonation is monotonous most of the time.

[0506] 7 - Extreme. There is little emotional range or expressiveness, and movements are stiff. The voice and intonation are monotonous at all times.

[0507] The total score for the BPRS item "Blunting" was 15 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 4 points or 27%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%.

[0508] In the 12 mg group, the total score for the BPRS item "Bluntness of Emotion" was 11 at baseline. After 3 hours, the score dropped to 8, which corresponds to a 3-point improvement, or 27%. On the first day after treatment, the score dropped to 6, which corresponds to a 5-point improvement, or 45%. On the seventh day after treatment, the score dropped to 5, which corresponds to a 6-point improvement, or 55%.

[0509] Thus, the scores of the scale items particularly related to social / emotional withdrawal or alienation, namely "loss of sensation" (MADRS), "withdrawal of affect" (BPRS), and "blunt affect" (BPRS), were significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat social / emotional withdrawal or alienation in patients, especially those who also suffer from psychiatric or neurological disorders or sleep disorders (such as insomnia).

[0510] Thus, according to the present invention, treatment of a patient suffering from social / emotional withdrawal or alienation with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or alienation.

[0511] negative thinking

[0512] Symptoms such as pessimism, feelings of worthlessness, helplessness, and hopelessness, as well as pathological, excessive, or inappropriate guilt are categorized here as negative thinking.

[0513] Helplessness and hopelessness (also referred to simply as helplessness and hopelessness) characterize subjective feelings of pessimism or hopelessness about the future, an inability to cope, or a loss of control. If the patient does not experience these feelings, helplessness and hopelessness are not present. Helplessness and hopelessness are mild if there are occasional mild feelings of being unable to cope as usual or pessimism; moderate if the patient frequently feels unable to cope or has significant feelings of helplessness or hopelessness that sometimes disappear; or severe if there is a marked and persistent feeling of pessimism, helplessness, or hopelessness.

[0514] Worthlessness (also simply referred to as worthlessness) describes subjective feelings or thoughts of diminished self-worth or self-worth. If patients do not have these feelings, they do not experience worthlessness. Worthlessness can be mild, with a slightly diminished sense of self-worth; moderate, with some thoughts of worthlessness and diminished self-worth; or severe, with marked, pervasive, or persistent feelings of worthlessness, such as a feeling that others would be better off without them and an inability to appreciate positive qualities.

[0515] Guilt (also simply referred to as guilt) characterizes subjective feelings of self-blame, failure, or regret for past real or imagined mistakes. If the patient does not have such feelings, guilt is not present. Guilt is mild if there is a slight decrease in self-esteem or increased self-criticism; moderate if there are significant thoughts of failure, self-criticism, inability to cope, or rumination about past failures and their impact on others; and if excess is recognized; or severe if there is obvious, pervasive, or persistent guilt, such as a feeling of deserving punishment; or if excess is not clearly recognized.

[0516] Negative thinking may be associated with a mental or neurological disorder or some other medical condition.

[0517] Mental or neurological disorders that cause or are associated with negative thinking include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorder (BD), such as bipolar I and bipolar II, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorders (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease dementia (AD); eating disorders; attention deficit hyperactivity disorder (ADHD); and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0518] Negative thinking may also occur in patients with sleep disorders such as insomnia.

[0519] Negative thinking may also occur in patients with medical conditions that lead to associated psychiatric or neurological disorders, including traumatic brain injury (TBI).

[0520] Measuring negative thinking

[0521] Negative thinking or its individual aspects, such as worthlessness, helplessness and hopelessness, and guilt, can be assessed by different instruments, such as questionnaires or scales.

[0522] Questionnaires assess a person's mental state based on observation by the person, their caregiver, or the clinician who administers the questionnaire. Questionnaires used to assess patients for specific mental or neurological disorders may include items related to negative thinking.

[0523] Instruments that assess aspects related to negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Scale-Expanded (PANAS-X), or the State Hope Scale (SHS).

[0524] The State Shame and Guilt Scale (SSGS) is a self-assessment scale for current (state) shame and guilt experiences. It consists of two subscales: the Shame subscale and the Guilt subscale. 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 assessed using a 5-point Likert scale. The scale contains statements that may or may not describe the patient's current feelings. Higher scores indicate stronger feelings of shame or guilt.

[0525] The Positive and Negative Affect Scale-Extended (PANAS-X) is an expanded version of the 60-item PANAS. The PANAS-X measures 11 specific emotions: fear, sadness, guilt, hostility, shyness, fatigue, surprise, happiness, confidence, concentration, and calmness. Thus, the PANAS-X provides two different levels of emotional measurement. The basic negative affect scale is fear, hostility, guilt, and sadness, while the guilt scale contains six items: guilt, shame, blameworthiness, anger at oneself, disgust with oneself, and dissatisfaction with oneself. Each answer should be rated on the following scale: 1 = very slightly or not at all; 2 = a little; 3 = moderately; 4 = quite a bit; or 5 = extremely. However, researchers facing stricter time constraints may select and evaluate only the scales most relevant to their study.

[0526] The stronger the guilt, the higher the score reflected on the guilt scale.

[0527] The PANAS-X is simple and easy to administer. Most subjects complete the entire 60-item scale in 10 minutes or less. This scale consists of many words and phrases describing various feelings and emotions. While it should indicate the extent to which patients have felt these feelings over the past few weeks, trait scores on the PANAS-X scales, including "now," "today," and "past few days," have been found to be stable over time, indicating that appropriately shorter recall periods can be used.

[0528] The State Hope Scale (SHS) consists of three agency items and three pathway items, in which respondents describe themselves based on their "current" situation. The agency subscale score is calculated by summing items 2, 4, and 6, which relate to the perceived ability to use one's pathways to achieve desired goals. The pathway subscale score is calculated by summing items 1, 3, and 5, which relate to the thinking used to identify possible ways to achieve goals. The total State Hope Scale score is calculated by summing the three agency items and the three pathway items. Scores can range from a low of 6 to a high of 48, with higher scores on this scale reflecting greater hope.

[0529] Negative thinking or aspects thereof are also reflected in other scales such as HAM-D, MADRS, BPRS or BDRS, wherein the relevant items of the scales can be generally applied to assess negative thinking or aspects thereof.

[0530] Resting-state networks and negative thinking

[0531] Brain processes can be studied using functional magnetic resonance imaging (fMRI). Brain activity is correlated with blood flow, and the temporal correlation of spontaneous blood oxygenation level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0532] Functional images of the brain were acquired over several minutes. Low-frequency BOLD signal oscillation patterns were observed throughout the brain. Decomposition of this spontaneous signal revealed distributed regions with correlated and inversely correlated fluctuations.

[0533] In this way, resting-state fMRI can be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are a set of spatially distinct brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns characterize a network of brain regions with coherent patterns of signal changes, which are called resting-state networks (RSNs).

[0534] Different resting-state networks have been identified and named, primarily based on spatial similarities between resting-state networks and activation patterns observed in task-related fMRI experiments.

[0535] Therefore, resting-state fMRI can be used to assess the intrinsic functional organization of the brain. Resting-state networks have been characterized for aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0536] RSNs have been shown to be responsible for various aspects of complex brain function, and these connected networks have been found to be impaired in various disease states. Such disease states, including certain forms of negative thinking, have been associated with altered functional connectivity within specific resting-state networks and / or between one or more regions in one or more additional resting-state networks.

[0537] Major depressive disorder (MDD) is a disorder characterized by high levels of negative affect and lower levels of positive affect. More specifically, lower levels of positive affect (such as hope) mean higher levels of hopelessness and higher levels of negative affect (such as guilt). MDD has always been a research focus in the field of rs-fMRI, showing that MDD is a disorder characterized by extensive network dysfunction. This dysfunction mainly occurs in networks and regions related to emotion regulation. These networks and regions include the default mode network (DMN), the salience network, the affect network, and the prefrontal cortex. Therefore, different aspects of negative thinking may be related to abnormal resting state networks.

[0538] Patients with repetitive negative thinking (RNT) have been reported to have functional connectivity disturbances in resting-state networks, including altered connectivity between the left executive control network and the anterior salience network and the ventral default mode network.

[0539] Thus, compared to age-matched healthy controls, patients with negative thinking exhibited altered functional connectivity within and / or between resting-state networks. Alterations were observed within and / or between at least the default mode network, executive control network, salience network, affective network, and prefrontal cortex.

[0540] In many cases, RSNs involving negative thinking are affected by psychiatric or neurological disorders, such as disorders characterized by depressive episodes, for example, major depressive disorder (MDD), bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder; anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD); obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; dementia, such as Alzheimer's disease dementia (AD); eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0541] Resting-state networks involved in negative thinking can also be affected by psychiatric or neurological disorders as a result of certain medical health conditions, such as traumatic brain injury (TBI).

[0542] Resting-state networks involved in negative thinking are also affected by sleep disturbances such as insomnia. In fact, negative thinking is associated with impaired sleep.

[0543] Treatment of negative thinking and mental or neurological disorders

[0544] According to the present invention, negative thinking occurring in patients suffering from mental disorders or nervous system disorders can be treated. In addition, negative thinking occurring in patients suffering from sleep disorders (such as insomnia) can be treated.

[0545] In a patient suffering from negative thinking associated with another disorder detailed above, treatment of negative thinking according to the invention results in an improvement in the disorder associated with the negative thinking.

[0546] Treatment according to the present invention is by administering 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] Administration of 5-MeO-DMT to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption leads to the reset of pathological, dysfunctional connections as the networks rewire. New, healthy functional connections are established, with lasting effects.

[0548] Thus, according to the present invention, influencing these networks through therapies as described herein will result in improvements in negative thinking, and if the patient being treated suffers from a psychiatric or neurological disorder, said disorder will also be improved; if the patient being treated suffers from a sleep disorder (e.g., insomnia), said sleep disorder (e.g., insomnia) will also be improved.

[0549] To further support the clinical utility of 5-MeO-DMT in patients suffering from negative thinking, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in negative thinking, which is also commonly observed in patients with other disorders.

[0550] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below.) While TRD is a specific disorder, as discussed in detail below, the inventors determined that certain clinical observations made in the trial are relevant to designing treatments for other disorders associated with negative thinking.

[0551] In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group of interest was the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR), which allowed for multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the patient-reported psychedelic experience.

[0552] The data collected included assessments of the treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that specific sub-score items, such as those related to negative thinking, were associated with other disorders in which negative thinking is based on similar altered functional connectivity within and / or between the default mode network, executive control network, salience network, affective network, and prefrontal cortex.

[0553] Several patients in the recruited cohort demonstrated significant improvements, confirming the inventors' findings that 5-MeO-DMT is a suitable compound for the treatment of patients experiencing these symptoms.

[0554] More specifically, one aspect that can be treated by administering 5-MeO-DMT is negative thinking, particularly feelings of worthlessness, helplessness, hopelessness, and / or guilt. 5-MeO-DMT can be administered to a patient to reduce or eliminate the patient's negative thinking, particularly feelings of worthlessness, helplessness, hopelessness, and / or guilt.

[0555] The MADRS item that is particularly relevant to negative thinking is “pessimistic thinking,” which represents thoughts of guilt, low self-esteem, self-blame, sin, regret, and destruction.

[0556] If there are no pessimistic thoughts, the score is 0. If there are fluctuating thoughts of failure, self-blame, or self-deprecation, the score is 2. The score indicates persistent self-accusations, or clear but still justified thoughts of guilt or sin, and the patient's increasing pessimism about the future. If there are delusions of annihilation, remorse, or irreparable guilt, and absurd and unshakable self-accusations, the score is 6.

[0557] In the study group that received the personalized dosing regimen, all eight patients had a total score of 28 at baseline for the MADRS item "pessimistic thinking."

[0558] After 2 hours, the score dropped to 7, which corresponds to a 21-point or 75% improvement. On the first day after treatment, the score dropped to 4, which corresponds to a 24-point or 86% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to a 25-point or 89% improvement.

[0559] In the 12 mg group, all four patients had a combined score of 16 for the MADRS item "pessimistic thoughts" at baseline. After 2 hours, the score dropped to 8, which corresponds to an improvement of 8 points or 50%. On the first day after treatment, the score dropped to 7, which corresponds to an improvement of 9 points or 56%.

[0560] On day 7 after treatment, the score dropped to 8, which corresponds to an improvement of 8 points or 50%.

[0561] The BPRS item that is particularly relevant to negative thinking is "Guilt." This item is related to excessive focus on or regret for past actions. Possible scores are:

[0562] 1- No guilt.

[0563] 2 - Very Mild. Worry about disappointing someone or failing at something, but not preoccupied. Can easily shift thoughts to other things.

[0564] 3-Mild. Fear of disappointing someone or failing can cause some distraction. Tends to express guilt to others.

[0565] 4 - Moderate. Preoccupied with guilt, wrongdoing, or hurting others through actions or omissions, but easily shifts focus to other matters.

[0566] 5 - Moderate to severe. Obsessing over guilt, disappointing someone, or failing at something. Can shift focus to other things, but only with considerable effort. Not delusional.

[0567] 6 - Severe; Delusional guilt or unjustified self-blame that is grossly disproportionate to the circumstances. Moderate absent-mindedness is present.

[0568] 7 - Extreme. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. The subject is extremely preoccupied with guilt and may disclose it to others or act on it.

[0569] In the study group that received the individualized dosing regimen, the total score for the BPRS item "guilt" was 34 at baseline for all eight patients.

[0570] After 3 hours, the score had dropped to 14, which corresponds to a 20-point or 59% improvement. On the first day after treatment, the score 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.

[0571] In the 12 mg group, the total score of the BPRS item “guilt” was 18 at baseline for all four patients.

[0572] After 3 hours, the score dropped to 9, which corresponds to a 9-point or 50% improvement. On the first day after treatment, the score dropped to 5, which corresponds to a 13-point or 72% improvement. On the seventh day after treatment, the score dropped to 5, which corresponds to a 13-point or 72% improvement.

[0573] As a result, the score of the MADRS scale item "pessimistic thinking," which is particularly related to negative thinking, was significantly improved, and the score of the BPRS item "guilt" was also significantly improved. The inventors concluded that 5-MeO-DMT can be used to treat negative thinking in patients, especially those who also suffer from mental disorders, neurological disorders, or sleep disorders (such as insomnia).

[0574] Thus, according to the present invention, treating a patient suffering from negative thinking with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the negative thinking.

[0575] Mother's function

[0576] In addition to the above, the inventors believe that mental or neurological 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, can impair maternal functioning. In fact, each of the symptoms listed has the potential to impair maternal functioning (and therefore should be treated independently).

[0577] The first year after childbirth, in particular, is a critical window for both mother and child. In most cases, the mother is the primary caregiver and is therefore responsible for most tasks related to infant care.

[0578] Maternal functioning includes aspects of maternal competence related to interaction with the infant and maternal self-care.

[0579] Maternal functioning, including the emotional aspects of motherhood, is also important for child development. In fact, the quality of mother-child interactions in the first year of life can influence infant development. High levels of maternal functioning may be associated with positive infant developmental outcomes. Similarly, impaired functioning in the postpartum period may hinder optimal infant development.

[0580] The Barkin Index of Maternal Functioning (BIMF) is designed to measure functioning within one year after childbirth. The BIMF is a 20-item self-report measure of maternal functioning. Each item is scored on a scale of 0 to 6, for a maximum total score of 120. The higher the score, the better the assessment of maternal functioning.

[0581] The BIMF identifies key areas of maternal functioning during the postpartum period as: self-care, infant care, mother-infant interaction, maternal psychological well-being, social support, management, and regulation.

[0582] A BIMF score of 95 or less is considered herein to represent mild impairment of 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 can particularly improve maternal function in patients with a pre-treatment score of 80 or less and in patients with a pre-treatment score of 65 or less.

[0583] As described above, the present invention allows for the treatment of patients suffering from psychiatric or neurological disorders. Said treatment not only results in a reduction in scores assessing depression severity, but also improves maternal functioning, as discussed in detail below.

[0584] To further support the clinical utility of 5-MeO-DMT in patients suffering from psychiatric or neurological disorders, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in aspects of the disease, which are also commonly observed in patients suffering from psychiatric or neurological disorders. The inventors particularly noted improvements in various symptoms and combinations of symptoms, which the inventors determined were also associated with maternal functioning.

[0585] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). A more recent trial conducted in patients with postpartum depression confirmed these results (see the Examples section below).

[0586] In the TRD clinical trial, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, the group of interest was the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR), which allowed for multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day based on the intensity of the patient-reported psychedelic experience.

[0587] The data collected included assessments of the treated patients on several scales, including the Montgomery Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy by improving the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that several sub-score items were particularly relevant to patients with mental or neurological disorders and were related to maternal functioning.

[0588] Multiple patients in the recruited cohort demonstrated significant improvements in one or more of these subscores, confirming the inventors' findings that 5-MeO-DMT is a compound suitable for treating patients with psychiatric or neurological disorders and for improving maternal function in those patients.

[0589] The specific sub-score items within each scale are identified in more detail below. The inventors have concluded that efficacy in treating one or more of these symptoms will result in a significant improvement in the overall outcome for patients with psychiatric or neurological disorders treated with 5-MeO-DMT.

[0590] Thus, treatment according to the invention alleviates or eliminates (or ameliorates or eliminates) one aspect of the disease.

[0591] If the aspect is assessed according to the MADRS scale, there is at least one point of improvement (reduction) or the patient is completely relieved (eliminated) after treatment, that is, the corresponding aspect score is 0.

[0592] If the aspect is assessed according to the BPRS scale, there is at least one point of improvement (reduction) or the patient is completely relieved (eliminated) after treatment, that is, the corresponding aspect score is 1.

[0593] A clinical response can also be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S score is reduced by at least 1 point. Preferably, the CGI-S score is reduced by at least 2 points and / or to 0 points. Particularly preferably, the CGI-S score is reduced by at least 3 points and / or to 0 points.

[0594] The inventors further believe that the improvements observed in certain MADRS items will translate into improvements in maternal functioning.

[0595] Particularly relevant MADRS items are discussed in more detail below.

[0596] The MADRS item "Inner Tension" represents feelings of vague discomfort, irritability, inner confusion, and mental tension that escalate into panic, fear, or distress. It is rated based on intensity, frequency, duration, and the degree of reassurance required.

[0597] If the patient is calm and has only brief bouts of inner tension, the score is 0. If there are occasional feelings of irritability and vague discomfort, the score is 2. If there is constant inner tension or intermittent panic that the patient has difficulty controlling, the score is 4. If there is constant fear or distress and overwhelming panic, the score is 6.

[0598] The inventors have determined that an increase in the score of the MADRS item "Internal Tension" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). As assessed by the BIMF, an increase in the score of the MADRS item "Internal Tension" impairs mother-infant interaction and maternal psychological well-being.

[0599] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF domains of mother-child interaction and / or maternal psychological well-being.

[0600] In the aforementioned trial involving patients with TRD, the total score for the MADRS item "Inner Tension" for all eight patients in the study group who received the personalized dosing regimen was 26 at baseline. After 2 hours, the score had dropped to 11, which corresponds to an improvement of 15 points, or 58%. On the first day after treatment, the score had dropped to 6, which corresponds to an improvement of 20 points, or 77%. On the seventh day after treatment, the score had dropped to 12, which corresponds to an improvement of 14 points, or 54%.

[0601] In the 12 mg group, all four patients had a total score of 13 for the MADRS item "Inner Tension" at baseline. Two hours later, the score dropped to 2, corresponding to an 11-point, or 85%, improvement. On the first day after treatment, the score dropped to 3, corresponding to a 10-point, or 77% improvement. On the seventh day after treatment, the score dropped to 5, corresponding to an 8-point, or 62% improvement.

[0602] The inventors have concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve a reduction or elimination of internal tension.

[0603] The improvement in inner tension is reflected in at least an improvement in the score of the MADRS item inner tension at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0604] Improvement in internal tension, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0605] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0606] Improvement in internal tension (as reflected at least by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0607] The improvement in inner tension (as reflected by a decrease in the CGI-S score or at least by a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0608] The inventors also concluded that the reduction or elimination of internal tension achieved by treating patients with mental or nervous system disorders not only leads to a decrease in the total MADRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0609] Since internal tension may also influence other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "internal tension" item of the MADRS would additionally contribute to the overall improvement in maternal functioning.

[0610] The MADRS item “sluggishness” represents difficulty getting started or slowness in initiating and performing daily activities.

[0611] A score of 0 means almost no difficulty starting and no slowness. If the patient has trouble starting an activity, the score is 2. A score of 4 means difficulty starting simple daily activities that require effort. If the patient is completely lazy and unable to do anything without help, the score is 6.

[0612] The inventors have determined that an increase in the score for the MADRS item "lazy" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score for the MADRS item "lazy" impairs infant care, self-care, psychological health, management, and regulation.

[0613] Conversely, improvements on this MADRS item led to improvements in maternal functioning, particularly in the BIMF functional domains of infant care, self-care, psychological well-being, management, and regulation.

[0614] In the study group that received the personalized dosing regimen, the total score for the MADRS item "sluggishness" for all eight patients was 27 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 17 points, or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 22 points, or 81%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 24 points, or 89%.

[0615] In the 12 mg group, the total score for the MADRS item "sluggishness" was 16 at baseline for all four patients. After 2 hours, the score dropped to 10, which corresponds to a 6-point or 38% improvement. On the first day after treatment, the score dropped to 0, which corresponds to a 16-point or 100% improvement. On the seventh day after treatment, the score dropped to 3, which corresponds to a 13-point or 81% improvement.

[0616] The inventors have concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to reduce or eliminate lethargy.

[0617] Improvement in sluggishness is reflected in at least an improvement in the MADRS item sluggishness score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0618] Improvement in sluggishness, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0619] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0620] Improvement in sluggishness (as reflected at least by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0621] The improvement in laziness (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0622] The inventors also concluded that the reduction or elimination of lethargy achieved by treating patients with mental or neurological disorders not only results in a decrease in the total MADRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the first day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the seventh day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Because lethargy can also affect other aspects of mental or neurological disorders, the inventors concluded that the observed improvement in the "lethargy" item in the MADRS will also contribute to the overall improvement in maternal function.

[0623] The MADRS item "Anesthesia" represents the subjective experience of decreased interest in one's surroundings or in activities that normally bring pleasure. It also describes a reduced ability to respond fully emotionally to situations or people.

[0624] A score of 0 indicates normal interest in one's surroundings and other people, while a score of 2 indicates a reduced ability to enjoy everyday interests. A score of 4 indicates a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects emotional numbness, an inability to feel anger, sadness, or pleasure, and a complete and even painful loss of affection for friends and family.

[0625] The inventors have determined that an increase in the score for the MADRS item "sensory loss" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score for the MADRS item "sensory loss" impairs mother-child interaction and psychological well-being.

[0626] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF domains of mother-child interaction and / or psychological well-being.

[0627] In the study group that received the personalized dosing regimen, the total score for the MADRS item "loss of sensation" for all eight patients was 36 at baseline. After 2 hours, the score dropped to 12, which corresponds to a 24-point improvement, or 67%. On the first day after treatment, the score dropped to 2, which corresponds to a 34-point improvement, or 94%. On the seventh day after treatment, the score dropped to 6, which corresponds to a 30-point improvement, or 83%.

[0628] In the 12 mg group, the total score for the MADRS item "loss of sensation" was 16 at baseline for all four patients. After 2 hours, the score dropped to 9, which corresponds to an improvement of 7 points, or 44%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points, or 94%. On the seventh day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points, or 94%.

[0629] The inventors have concluded that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of sensory deficits.

[0630] The improvement in anesthesia is reflected in at least an improvement in the score for the MADRS item anesthesia at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0631] Improvement in anesthesia, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0632] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0633] Improvement in anesthesia (as reflected at least by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0634] The improvement in anesthesia (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0635] The inventors also concluded that the reduction or elimination of sensory impairment achieved by treating patients with mental or neurological disorders not only results in a reduction in the total MADRS score, but also results in an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within approximately 2 hours, and an increase in the BIMF score will also be observed on day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 13 Because sensory impairment can also affect other aspects of mental or neurological disorders, the inventors concluded that the observed improvement in the "sensory impairment" item on the MADRS will additionally contribute to the overall improvement in maternal function.

[0636] The MADRS item “difficulty concentrating” represents difficulty collecting one’s thoughts, resulting in an inability to concentrate.

[0637] If the patient has no difficulty concentrating, the score is 0. If the patient occasionally has difficulty collecting their thoughts, the score is 2. If the patient has difficulty concentrating and maintaining thoughts, resulting in reduced ability to read or converse, the score is 4. If the patient cannot read or converse easily, the score is 6.

[0638] The inventors have determined that increased scores on the MADRS item "Difficulty Concentrating" have a negative impact on two aspects of maternal functioning: maternal ability related to interaction with the infant and maternal self-care. Increased scores on the MADRS item "Difficulty Concentrating" impair infant care and management.

[0639] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domain infant care and / or management.

[0640] In the study group that received the personalized dosing regimen, all eight patients had a total score of 30 for the MADRS item "Difficulty Concentrating" at baseline. After two hours, the score dropped to 11, which corresponds to a 19-point improvement, or 63%. On the first day after treatment, the score dropped to 1, which corresponds to a 29-point improvement, or 97%. On the seventh day after treatment, the score dropped to 9, which corresponds to a 21-point improvement, or 70%.

[0641] In the 12 mg group, the total score for the MADRS item "Difficulty Concentrating" was 16 at baseline for all four patients. After 2 hours, the score dropped to 7, which corresponds to an improvement of 9 points, or 56%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 14 points, or 88%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points, or 81%.

[0642] The inventors have concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to reduce or eliminate difficulty concentrating.

[0643] The improvement in difficulty concentrating is reflected in at least an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0644] Improvement in difficulty concentrating, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0645] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0646] Improvement in difficulty concentrating (as reflected at least by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0647] The improvement in difficulty concentrating (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0648] The inventors also concluded that the reduction or elimination of difficulty concentrating achieved by treating patients with mental or neurological disorders not only results in a decrease in the total MADRS score, but also results in an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0649] Since difficulty concentrating may also affect other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "difficulty concentrating" item of the MADRS would additionally contribute to the overall improvement in maternal functioning.

[0650] The MADRS item “pessimistic thoughts” represents thoughts of guilt, inferiority, self-blame, sin, regret, and destruction.

[0651] If there are no pessimistic thoughts, the score is 0. If there are fluctuating thoughts of failure, self-blame, or self-deprecation, the score is 2. The score indicates persistent self-accusations, or clear but still justified thoughts of guilt or sin, and the patient's increasing pessimism about the future. If there are delusions of annihilation, remorse, or irreparable guilt, and absurd and unshakable self-accusations, the score is 6.

[0652] The inventors have determined that increased scores on the MADRS item "pessimistic thinking" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). Increased scores on the MADRS item "pessimistic thinking" can impair psychological health, social support and management.

[0653] Conversely, improvements on this MADRS item will lead to improvements in maternal functioning, particularly in the BIMF functioning domains of psychological well-being, social support, and / or management.

[0654] In the study group that received the personalized dosing regimen, the total score for the MADRS item "pessimistic thinking" was 28 at baseline for all eight patients. After 2 hours, the score dropped to 7, which corresponds to a 21-point improvement, or 75%. On the first day after treatment, the score dropped to 4, which corresponds to a 24-point improvement, or 86%. On the seventh day after treatment, the score dropped to 3, which corresponds to a 25-point improvement, or 89%.

[0655] In the 12 mg group, the total score for the MADRS item "pessimistic thoughts" was 16 at baseline for all four patients. After 2 hours, the score dropped to 8, which corresponds to an improvement of 8 points or 50%. On the first day after treatment, the score dropped to 7, which corresponds to an improvement of 9 points or 56%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 8 points or 50%.

[0656] The inventors concluded that 5-MeO-DMT could be used to treat patients with mental or neurological disorders to reduce or eliminate pessimistic thoughts.

[0657] The improvement in pessimistic thoughts is reflected in at least an improvement in the score of the MADRS item pessimistic thoughts at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0658] Improvement in pessimistic thoughts, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurred no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0659] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0660] Improvement in pessimistic thoughts (as reflected at least by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0661] The improvement in pessimistic thinking (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0662] The inventors also concluded that the reduction or elimination of pessimistic thoughts achieved by treating patients with mental or neurological disorders not only leads to a decrease in the total MADRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the first day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0663] Since negative thoughts may also affect other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "negative thoughts" item of the MADRS would additionally contribute to the overall improvement in maternal functioning.

[0664] The MADRS item "sleep reduction" represents the experience of a decrease in sleep duration or depth compared to the subject's normal pattern when healthy.

[0665] A score of 0 indicates normal sleep. A score of 2 reflects mild difficulty falling asleep or slightly reduced, shallow, or intermittent sleep. A score of 4 means sleep was reduced or interrupted for at least two hours. A score of 6 means sleep was less than two or three hours.

[0666] The inventors have determined that increased scores on the MADRS item "Sleep Reduction" have a negative impact on two aspects of maternal functioning: maternal ability related to interaction with the infant and maternal self-care. Increased scores on the MADRS item "Sleep Reduction" impair self-care, psychological well-being, and management.

[0667] Conversely, improvements on this MADRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychological well-being, and / or management.

[0668] In the study group that received the personalized dosing regimen, all eight patients had a total score of 25 on the MADRS item "Sleep reduction" at baseline. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score had dropped to 12, corresponding to an improvement of 13 points, or 52%. On day 7 after treatment, the score had dropped to 9, corresponding to an improvement of 16 points, or 64%.

[0669] In the 12 mg group, all four patients had a total score of 12 for the MADRS item "Sleep reduction" at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

[0670] The inventors conclude that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of sleep loss.

[0671] Reduction or elimination of sleep loss is reflected in at least an improvement in the score for the MADRS item sleep loss on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0672] Improvement in sleep loss, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0673] Improvement in sleep loss (as reflected at least by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0674] The improvement in sleep loss (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0675] The inventors also concluded that reducing or eliminating sleep loss achieved by treating patients with mental or neurological disorders not only results in a decrease in the MADRS total score, but also results in an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 24 hours, and an increase in the BIMF score is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; 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.

[0676] Since sleep reduction may also affect other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "sleep reduction" item of the MADRS would additionally contribute to the overall improvement in maternal functioning.

[0677] Another aspect of a mental or nervous system disorder that can be treated by administering 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to a patient with a mental or nervous system disorder to reduce or eliminate suicidal ideation in the patient.

[0678] In the above-mentioned clinical studies involving 5-MeO-DMT administration, the MADRS item “suicidal thoughts” was assessed, among others.

[0679] "Suicidal ideation" represents a feeling that life is not worth living, that a natural death is desirable, suicidal thoughts, and / or preparations for suicide. A suicide attempt itself should not influence the assessment of this MADRS item.

[0680] A score of 0 means the patient enjoys life. If the patient with a mental or neurological disorder feels bored with life and / or has only brief suicidal thoughts, the score is 2. A score of 4 means the patient feels death would be better, suicidal thoughts are common, and suicide is considered a possible solution, but the patient has no specific plan or intention. If the patient has a clear suicide plan and / or is actively preparing for it, the score is 6.

[0681] This MADRS item is particularly relevant to suicidal ideation.

[0682] The inventors have determined that increased scores on the MADRS item "suicidal thoughts" have a negative impact on two aspects of maternal functioning: maternal ability to interact with the infant and maternal self-care. Increased scores on the MADRS item "suicidal thoughts" impair self-care, psychological well-being, and management.

[0683] Conversely, improvements on this MADRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychological well-being, and / or management.

[0684] In the study group that received the personalized dosing regimen, all eight patients had a total score of 11 on the MADRS item "Suicidal thoughts" at baseline. After 2 hours, the score dropped to 3, which corresponds to an improvement of 8 points, or 73%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 10 points, or 91%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 8 points, or 73%.

[0685] In the 12 mg group, all four patients had a total score of 8 on the MADRS item "suicidal thoughts" at baseline. After 2 hours, the score dropped to 3, which corresponds to an improvement of 5 points or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 3 points or 38%. On the seventh day after treatment, the score dropped to 7, which corresponds to an improvement of 1 point or 13%.

[0686] Thus, the score on the scale item "suicidal ideation," which is particularly relevant to suicidal ideation, was significantly improved, at least in patients who received the individualized dosing regimen. The inventors concluded that 5-MeO-DMT can be used to treat suicidal ideation in patients with mental or neurological disorders.

[0687] Thus, according to the present invention, treatment of a patient suffering from a mental or neurological disorder suffering from suicidal ideation can reduce or eliminate suicidal ideation.

[0688] Reduction or elimination of suicidal ideation is reflected in at least an improvement in the score of the MADRS item Suicidal Thoughts at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0689] If the patient suffers from suicidal ideation, improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0690] Improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0691] Alternatively, the decrease in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, eg, about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0692] Improvement in suicidal ideation (as assessed by at least a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0693] The improvement in suicidal ideation (assessed as a decrease in the CGI-S score or at least as a "much improved" score in the CGI-I score or the PGI-I score) is preferably maintained until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0694] The inventors also concluded that the reduction or elimination of suicidal thoughts achieved by treating patients with mental or neurological disorders not only results in a decrease in the total MADRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the first day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0695] Since suicidal thoughts may also affect other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "suicidal thoughts" item of the MADRS would additionally contribute to an overall improvement in maternal functioning.

[0696] The BPRS item "Emotional Withdrawal" relates to the patient's deficit in expressing emotions during the interview. Possible scores are:

[0697] 1- No emotional withdrawal.

[0698] 2 - Very Mild. Lack of emotional engagement, as evidenced by occasional failure to respond to comments, occasional absent-mindedness, or a stiff smile, but mostly spontaneous interaction with the interviewer.

[0699] 3 - Mild. Lack of emotional engagement, as evidenced by a marked failure to respond to comments, appearing distracted or lacking enthusiasm, but responding when approached by the interviewer.

[0700] 4 - Moderate. Emotional engagement is absent during most of the interview, as the subject does not respond in detail, makes no eye contact, does not seem to care whether the interviewer is listening, or may be immersed in the psychotic material.

[0701] 5 - Moderately severe. Same as 4, but emotional contact was absent during most of the interview.

[0702] 6 - Severe. Actively avoids emotional engagement. Frequently fails to respond or responds with yes / no answers (not solely due to persecutory delusions). Or responds with minimal emotion.

[0703] 7 - Extreme. Consistently avoids emotional engagement. Does not respond or responds with yes / no answers (not solely due to persecutory delusions). May walk away or not respond at all during the interview.

[0704] The inventors have determined that increased scores on the BPRS item "emotional withdrawal" have a negative impact on two aspects of maternal functioning: maternal ability related to interaction with the infant and maternal self-care. Increased scores on the BPRS item "emotional withdrawal" impair psychological health, mother-child interaction, and social support.

[0705] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being, mother-child interaction, and / or social support.

[0706] In the group receiving the individualized dosing regimen, the total score for the BPRS item "Emotional Withdrawal" was 13 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 5 points, or 38%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points, or 38%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points, or 38%.

[0707] In the 12 mg group, the total score for the BPRS item "Emotional Withdrawal" was 13 at baseline. After 3 hours, the score dropped to 11, corresponding to a 2-point or 15% improvement. On the first day after treatment, the score dropped to 8, corresponding to a 5-point or 38% improvement. On the seventh day after treatment, the score dropped to 6, corresponding to a 7-point or 54% improvement.

[0708] The inventors have concluded that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve a reduction or elimination of emotional withdrawal.

[0709] Reduction or elimination of affective withdrawal is reflected in at least an improvement in the score of the BPRS item affective withdrawal about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0710] Improvement in affective withdrawal, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0711] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0712] Improvement in affective withdrawal (as reflected at least by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0713] The improvement in affective withdrawal (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0714] The inventors also concluded that the reduction or elimination of emotional withdrawal achieved by treating patients with mental or neurological disorders not only results in a decrease in the BPRS total score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the first day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0715] Since emotional withdrawal may also influence other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "emotional withdrawal" item of the BPRS would additionally contribute to an overall improvement in maternal functioning.

[0716] The BPRS item "Blunting of Emotion" involves a restricted range of emotional expressiveness in the face, voice, and gestures, as well as apparent apathy or indifference even when discussing painful topics. Possible scores are:

[0717] 1- No emotional blunting.

[0718] 2 - Very Mild. Emotional range is slightly suppressed or reserved, but facial expressions and voice intonation are appropriate and within normal range.

[0719] 3 - Mild. Emotional range is generally diminished, inhibited, or reserved, without many spontaneous and appropriate emotional responses. Voice and intonation are slightly monotonous.

[0720] 4 - Moderate. Emotional range is markedly diminished, and except in rare cases, the patient does not express emotion, smile, or respond to distressing topics. Speech may be monotonous or spontaneous movements may be markedly reduced. Displays of emotion or gestures often result in a return to apathy.

[0721] 5 - Moderate to severe. The emotional range is very diminished. The patient does not show emotion, smile, or respond to painful topics. Facial expression does not change often, except for minimal, infrequent gestures. The voice is monotonous most of the time.

[0722] 6 - Severe. Emotional range or expression is very limited. Speech and gestures are mechanical most of the time. Facial expression remains unchanged. Voice intonation is monotonous most of the time.

[0723] 7 - Extreme. There is little emotional range or expressiveness, and movements are stiff. The voice and intonation are monotonous at all times.

[0724] The inventors have determined that increased scores on the BPRS item "Emotional Blunting" have a negative impact on two aspects of maternal functioning: maternal ability related to interaction with the infant and maternal self-care. Increased scores on the BPRS item "Emotional Blunting" impair psychological health and mother-child interaction.

[0725] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being and / or mother-child interaction.

[0726] The total score for the BPRS item "Blunting" was 15 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 4 points or 27%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%.

[0727] In the 12 mg group, the total score for the BPRS item "Bluntness of Emotion" was 11 at baseline. After 3 hours, the score dropped to 8, which corresponds to a 3-point improvement, or 27%. On the first day after treatment, the score dropped to 6, which corresponds to a 5-point improvement, or 45%. On the seventh day after treatment, the score dropped to 5, which corresponds to a 6-point improvement, or 55%.

[0728] The inventors have concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve a reduction or elimination of affective blunting.

[0729] Reduction or elimination of blunting is reflected in at least an improvement in the score for the BPRS item Blunting at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0730] Improvement in blunted affect, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0731] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0732] Improvement in affective blunting (as reflected at least by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0733] The improvement in affective blunting (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0734] The inventors also concluded that the reduction or elimination of blunted affect achieved by treating patients with mental or neurological disorders results not only in a decrease in the BPRS total score, but also in an improvement in maternal function, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; 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.

[0735] Since blunting of affect may also affect other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "bluntness of affect" item of the BPRS would additionally contribute to the overall improvement in maternal functioning.

[0736] The BPRS item "Guilt" is related to excessive concern or regret about past behavior. Possible scores are:

[0737] 1- No guilt.

[0738] 2 - Very Mild. Worry about disappointing someone or failing at something, but not preoccupied. Can easily shift thoughts to other things.

[0739] 3-Mild. Fear of disappointing someone or failing can cause some distraction. Tends to express guilt to others.

[0740] 4 - Moderate. Preoccupied with guilt, wrongdoing, or hurting others through actions or omissions, but easily shifts focus to other matters.

[0741] 5 - Moderate to severe. Obsessing over guilt, disappointing someone, or failing at something. Can shift focus to other things, but only with considerable effort. Not delusional.

[0742] 6 - Severe. Delusional guilt or unjustified self-blame that is highly disproportionate to the circumstances. Moderate absent-mindedness is present.

[0743] 7 - Extreme. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. The subject is extremely preoccupied with guilt and may disclose it to others or act on it.

[0744] The inventors have determined that increased scores on the BPRS item "Guilt" have a negative impact on two aspects of maternal functioning: maternal ability related to interaction with the infant and maternal self-care. Increased scores on the BPRS item "Guilt" impair self-care, mother-child interaction, psychological well-being, and management.

[0745] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, mother-child interaction, psychological well-being, and / or management.

[0746] In the study group that received the personalized dosing regimen, the total score for the BPRS item "Guilt" was 34 at baseline for all eight patients. After 3 hours, the score had dropped to 14, which corresponds to a 20-point, or 59%, improvement. On the first day after treatment, the score 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.

[0747] In the 12 mg group, the total score for the BPRS item "Guilt" was 18 at baseline for all four patients. Three hours later, the score dropped to 9, corresponding to a 9-point or 50% improvement. On the first day after treatment, the score dropped to 5, corresponding to a 13-point or 72% improvement. On the seventh day after treatment, the score dropped to 5, corresponding to a 13-point or 72% improvement.

[0748] The inventors have concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve a reduction or elimination of guilt.

[0749] The reduction or elimination of guilt is reflected in at least an improvement in the score of the BPRS item Guilt at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0750] Improvement in guilt feelings, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0751] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0752] Improvement in guilt feelings (as reflected at least by a rating of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0753] The improvement in guilt feelings (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0754] The inventors also concluded that the reduction or elimination of guilt achieved by treating patients with mental or neurological disorders not only leads to a decrease in the BPRS total score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved rapidly, that is, within about 2 hours, and an increase in the BIMF score will be observed on the first day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0755] Since guilt can also influence other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvements in the "guilt" item of the BPRS would additionally contribute to the overall improvement in maternal functioning.

[0756] The BPRS item "Anxiety" relates to reports of worry, tension, fear, panic, or concern. Possible scores are:

[0757] 1- No anxiety.

[0758] 2 - Very Mild. Reports some discomfort due to worry or infrequent worry that occurs more frequently than in most normal individuals.

[0759] 3 - Mild. Frequent worrying but able to easily shift attention to other things.

[0760] 4 - Moderate. Worrying most of the time and unable to easily shift attention to other things, but functioning is not impaired; or anxiety occasionally occurs with autonomic symptoms, but functioning is not impaired.

[0761] 5 - Moderate to severe. Frequent (but not daily) anxiety with autonomic symptoms, or some areas of functioning are disrupted by anxiety or worry.

[0762] 6 - Severe. Anxiety occurs daily with autonomic symptoms, but does not persist throughout the day, or many areas of functioning are disrupted by anxiety or persistent worry.

[0763] 7 - Extreme. Anxiety with autonomic symptoms persists throughout the day, or most areas of functioning are disrupted by anxiety or persistent worry.

[0764] The inventors have determined that increased scores on the BPRS item "Anxiety" have a negative impact on two aspects of maternal functioning: maternal ability related to interaction with the infant and maternal self-care. Increased scores on the BPRS item "Anxiety" can impair psychological health, social support, and management.

[0765] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functioning domains of psychological well-being, social support, and / or management.

[0766] In the study group that received the personalized dosing regimen, the total score for the BPRS item "Anxiety" was 37 at baseline for all eight patients. After 3 hours, the score dropped to 19, which corresponds to an improvement of 18 points, or 49%. On the first day after treatment, the score dropped to 16, which corresponds to an improvement of 21 points, or 57%. On the seventh day after treatment, the score dropped to 17, which corresponds to an improvement of 20 points, or 54%.

[0767] In the 12 mg group, the total score for the BPRS "Anxiety" subscale was 25 at baseline for all four patients. Three hours later, the score had dropped to 11, corresponding to a 14-point, or 56%, improvement. On the first day after treatment, the score had dropped to 6, corresponding to a 19-point, or 76% improvement. On the seventh day after treatment, the score had dropped to 6, corresponding to a 19-point, or 76% improvement.

[0768] The inventors have concluded that 5-MeO-DMT can be used to treat patients with psychiatric or neurological disorders to achieve reduction or elimination of anxiety.

[0769] The reduction or elimination of anxiety is reflected in at least an improvement in the score of the BPRS item Anxiety at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0770] Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0771] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0772] Improvement in anxiety (as reflected at least by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0773] The improvement in anxiety (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0774] The inventors also concluded that the reduction or elimination of anxiety achieved by treating patients with mental or neurological disorders not only results in a decrease in the BPRS total score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the first day, for example, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0775] Since anxiety may also influence other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvements in the "anxiety" item of the BPRS would additionally contribute to the overall improvement in maternal functioning.

[0776] The BPRS item "nervousness" is related to observable physical and motor manifestations of tension, "nervousness," and agitation. Possible scores are

[0777] 1- No tension.

[0778] 2 - Very Mild. More irritable than most people but within normal limits. Some brief signs of nervousness, such as picking at nails, rocking feet, excessive scalp scratching, or finger tapping.

[0779] 3 - Mild. Same as "2", but with more frequent or exaggerated signs of tension.

[0780] 4 - Moderate. Signs of motor nervousness are numerous and frequent, sometimes with one or more signs occurring simultaneously, e.g., shaking the feet while twisting the hands. Sometimes no signs of nervousness are present.

[0781] 5 - Moderate to severe. Numerous and frequent signs of motor strain, often with one or more signs present simultaneously. Rarely, no signs of strain may be present.

[0782] 6 - Severe. Same as 5, but signs of nervousness are persistent.

[0783] 7 - Extreme. Multiple motor signs of nervousness persist, such as constant pacing and hand twisting.

[0784] The inventors have determined that increased scores on the BPRS item "Strain" have a negative impact on two aspects of maternal functioning: interaction with the infant and maternal self-care. Increased scores on the BPRS item "Strain" impair mother-child interaction and psychological well-being.

[0785] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of mother-child interaction and / or psychological well-being.

[0786] In the study group that received the personalized dosing regimen, the total score for the BPRS item "Tension" was 16 at baseline for all eight patients. After 3 hours, the score had dropped to 11, corresponding to a 5-point, or 31%, improvement. On the first day after treatment, the score had dropped to 11, corresponding to a 5-point, or 31% improvement. On the seventh day after treatment, the score had dropped to 10, corresponding to a 6-point, or 38% improvement.

[0787] In the 12 mg group, the total score for the BPRS item "Tense" was 14 at baseline for all four patients. After 3 hours, the score dropped to 9, which corresponds to an improvement of 5 points or 36%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 8 points or 57%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 8 points or 57%.

[0788] The inventors have concluded that 5-MeO-DMT can be used to treat patients with mental or neurological disorders to achieve the reduction or elimination of stress.

[0789] The reduction or elimination of stress is reflected in at least an improvement in the score of the BPRS item stress at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0790] Improvement in stress, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0791] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0792] Improvement in stress (at least as reflected by a score of "much improved" on the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0793] The improvement in stress (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0794] The inventors also concluded that the reduction or elimination of stress achieved by treating patients with mental or neurological disorders not only results in a decrease in the BPRS total score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0795] Since stress may also influence other aspects of psychiatric or neurological disorders, the inventors concluded that the observed improvement in the "stress" item of the BPRS would additionally contribute to the overall improvement in maternal functioning.

[0796] Improvement in one or more aspects of the mental or nervous system disorder will also result in overall improvement.Preferably, treatment results in remission.

[0797] Remission of depressive symptoms can be reflected by a MADRS score of 10 or less and occurring no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0798] Further, alternatively or additionally, relief of depressive symptoms can be reflected by a HAM-D score equal to or less than 7 and occurring no later than 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 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0799] As can be seen from the above, treatment of patients with mental or neurological disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results not only in a reduction in MADRS scores (including, in particular, the subscores as detailed above), but also in improvements in the BIMF scale domains. As discussed in the Examples section below, clinical data confirms both a reduction in MADRS scores and an improvement in maternal function.

[0800] The improvement of maternal function includes the improvement of self-care function domain.For example, the improvement of MADRS project laziness and / or sleep reduction can lead to the increase of BIMF scale score reflecting self-care.The improvement of the cumulative score of BIMF scale project reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0801] The improvement of maternal function includes the improvement of infant care function domain.For example, the improvement of MADRS project lazy and / or difficulty concentrating can lead to the increase of BIMF scale score reflecting infant care.The improvement of the cumulative score of BIMF scale project reflecting self-care is preferably at least 15%, more preferably at least 25%.

[0802] The improvement of maternal function includes the improvement of mother-child interaction function domain.For example, the improvement of MADRS project sense loss and inner tension can lead to the increase of BIMF scale score reflecting mother-child interaction.The improvement of the cumulative score of BIMF scale project reflecting mother-child interaction is preferably at least 5%, more preferably at least 15%.

[0803] The improvement of maternal function includes the improvement of mental health function domain.For example, the improvement of MADRS project laziness, pessimistic thoughts, sensory loss, inner tension and / or sleep reduction can lead to the increase of BIMF scale score reflecting mental health.The improvement of the cumulative score of BIMF scale project reflecting mental health is preferably at least 25%, more preferably at least 35%.

[0804] The improvement of maternal function includes the improvement of social support function domain.For example, the improvement of pessimistic thinking of MADRS project can lead to the increase of BIMF scale score reflecting social support.The improvement of the cumulative score of BIMF scale project reflecting social support is preferably at least 10%, more preferably at least 20%.

[0805] The improvement of maternal function includes the improvement of management function domain.For example, the improvement of MADRS project laziness, pessimistic thoughts and / or difficulty concentrating attention can lead to the increase of BIMF scale score reflecting management.The improvement of the cumulative score of BIMF scale project reflecting management is preferably at least 20%, more preferably at least 30%.

[0806] The improvement of maternal function includes the improvement of regulation function domain.For example, the improvement of MADRS project laziness can lead to the increase of BIMF scale score reflecting regulation.The improvement of the cumulative score of BIMF scale project reflecting regulation is preferably at least 5%, more preferably at least 15%.

[0807] Improvement in maternal functioning relates to one or more, in particular two or more, domains of functioning selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

[0808] The BIMF total score improves by 10% or more, preferably by 20% or more.

[0809] Breastfeeding

[0810] As mentioned above, for many medications, a breastfeeding patient may be faced with having to decide whether to discontinue breastfeeding or discontinue / withdraw treatment.

[0811] If a decision is made to stop breastfeeding in order to receive treatment, this decision will have a negative impact on maternal functioning, particularly impairing the areas of functioning such as mother-child interaction and psychological well-being.

[0812] The present invention also addresses the need for treating psychiatric or neurological disorders in breastfeeding mothers without nearly complete interruption of breastfeeding.

[0813] According to the present invention, breastfeeding can be resumed shortly after treatment.

[0814] The inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT to determine the time point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt at which breastfeeding can be initiated without exposing the breastfed infant to any associated risks.

[0815] Absorption and distribution of inhaled 5-MeO-DMT are rapid, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

[0816] The plasma protein binding rate is low (13-23%).

[0817] Analysis of the pharmacokinetic properties of 5-MeO-DMT following inhalation revealed a very rapid decline in plasma concentrations. Ten minutes after administration, concentrations had fallen to 10% or less of Cmax; after two hours, concentrations were 1% or less of Cmax; and after three hours, 5-MeO-DMT was no longer detectable in plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a timeframe of one to four hours. Up-titration as disclosed herein did not result in accumulation and, therefore, did not result in higher plasma concentrations, for example, at ten minutes, two hours, or three hours after administration.

[0818] To identify 5-MeO-DMT metabolites that may occur in humans and to assess their potential relevance, in vitro metabolic characterization studies were conducted in human hepatocytes, incubating 5-MeO-DMT free base at 10 μM for up to 120 minutes. The identified compounds and their relative proportions are shown in Table 1 below:

[0819] Table 1

[0820] Compound Relative proportion Bufotenine (5-OH-DMT) 5％ 5-MeO-DMT 7％ 5-MeO-DMT-N-oxide 1％ 5-Methoxyindole-3-ethanol (5-methoxytryptol) 25％ 5-Methoxyindoleacetic acid (5-MIAA) 61％

[0821] Notably, subsequent assays repeatedly failed to detect the presence of 5-methoxytryptol but reproducibly demonstrated the presence of 5-MIAA as the major metabolite. Therefore, 5-methoxytryptol is unlikely to play any significant role in vivo.

[0822] The metabolites listed in the table above are formed via three different pathways.

[0823] The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed by oxidative deamination. This involves enzymatic removal of the N-methyl group and oxidation to form acetaldehyde:

[0824]

[0825] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0826] No secondary amines, primary amines, or aldehydes were identified, indicating that they were not present in significant concentrations at any time.

[0827] The aldehyde intermediate metabolite undergoes two independent biotransformations in human hepatocytes: it is oxidized to 5-methoxyindoleacetic acid or reduced to 5-methoxyindole-3-ethanol.

[0828]

[0829] Both resulting metabolites are endogenous substances and are formed in the human body, for example, during the synthesis and metabolism of melatonin and serotonin (see, for example, Chapter 3 in Melatonin and the Mammalian Pineal Gland. Biochemistry of the Pineal. Arendt J (ed.) Chapman & Hall, 1995; Chapter 3 in Slominski R and Slominski AT. Melatonin in the Promotion of Health. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Watson RR (ed.) CRC Press 2012).

[0830] Because the major pathway of 5-MeO-DMT metabolism rapidly produces 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 would require restrictions on breastfeeding.

[0831] Furthermore, as described in detail in the Examples section, incubation of 5-methoxytryptol with human hepatocytes showed a high metabolic turnover rate, with the compound completely eliminated within 24 hours. At a test concentration of 1 μM, the in vitro intrinsic clearance of 5-methoxytryptol was 16.2 μl / min / million cells (half-life 142 minutes).

[0832] Therefore, the plasma concentration of 5-methoxytryptol (to the extent that it is formed) will decline rapidly and reach endogenous levels.

[0833] 5-MIAA is a weak acid that exists in plasma in an ionized form, which reduces the possibility of the compound entering breast milk.

[0834] Incubation of 5-MIAA with human hepatocytes showed a low metabolic turnover rate, with the remaining 5-MIAA concentration being 75-82% after 72 h. 5-MIAA is considered the final metabolite of 5-MeO-DMT.

[0835] 5-MIAA exhibits a relatively low plasma binding of approximately 50% (mean unbound fraction (Fu); see Examples). After renal clearance, 5-MIAA remains in the circulation. Given a standard glomerular filtration rate of 90-120 ml / min, this means that all traces of 5-MIAA are cleared from the circulation for urinary excretion within approximately 1-2 hours (depending on the patient's size and taking into account the increase in blood volume during pregnancy).

[0836] As a result, the plasma concentration of 5-MIAA also decreases rapidly.

[0837] Together with the rapid clearance of 5-MeO-DMT (<1 hour), this supports the notion that the administered therapy and all associated metabolites are cleared from the circulation within approximately 2 hours.

[0838] Another identified metabolite, bufotoxin, is the result of O-demethylation catalyzed by CYP2D6. The resulting metabolite is then glucuronidated by UGTs:

[0839]

[0840] As part of the pharmacokinetic studies, it was determined that bufotoxin was virtually undetectable in human serum. In any case, bufotoxin was undetectable 15 minutes after administration of 5-MeO-DMT.

[0841] Toad serotonin glucuronide cannot bind to receptors and has no effect. In addition, the concentration of toad serotonin glucuronide is so low that it cannot be detected in hepatocyte assays. Toad serotonin glucuronide is further converted to 5-hydroxyindoleacetic acid:

[0842]

[0843] 5-Hydroxyindoleacetic acid is an endogenous substance that is present, for example, in the metabolism of melatonin and serotonin (see above).

[0844] Because the O-demethylation pathway of 5-MeO-DMT produces the major metabolite bufotoxin, which is rapidly cleared from plasma and further metabolized to compounds present only at very low concentrations and ultimately to metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the O-demethylation of 5-MeO-DMT does not involve metabolites that would require restrictions on breastfeeding.

[0845] The third metabolic pathway involves N-oxidation:

[0846]

[0847] In computer simulations of the metabolites formed, 5-MeO-DMT-N-oxide was found to be non-genotoxic, consistent with the negative in vitro genotoxicity assessment of the parent molecule. As confirmed by observations in rats, the compound is water-soluble and rapidly excreted (Sitaram, BR, Lockett, L., Blackman, GL, McLeod, WR, 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine and their N-oxides in the rat. Biochemical Pharmacology 36:2235-2231). Because the 5-MeO-DMT metabolic pathway involving N-oxidation plays only a minor role and results in a low proportion of non-apparently toxic metabolites that are rapidly excreted, the inventors determined that N-oxidation of 5-MeO-DMT does not involve metabolites that would require restrictions on breastfeeding.

[0848] Based on the above, the inventors determined that breastfeeding can be resumed shortly after treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0849] Therefore, if the patient is a breastfeeding mother, she is advised to discontinue breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Specifically, she is advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0850] Preferably, breastfeeding must be interrupted for only 6 hours, more preferably for only 3 hours, and most preferably for only 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0851] This brief interruption and the possibility of resuming breastfeeding soon after treatment contribute to the success of the treatment and, in particular, to the functioning of the mother and the health and development of the baby.

[0852] Treatment of mental or nervous system disorders

[0853] Disorders characterized by depressive episodes

[0854] Several disorders are characterized by depressive episodes.

[0855] A depressive episode is a period of depressed mood and / or loss of interest in most activities.

[0856] For example, according to DSM-V, a major depressive episode is characterized by the presence of five or more symptoms within the same 2-week period that represent a change from previous functioning; at least one of the symptoms is (1) depressed mood or (2) loss of interest or pleasure.

[0857] Patients suffering from a disorder characterized by depressive episodes may suffer from a treatment-resistant form of the disorder.

[0858] Disorders characterized by depressive episodes involve one or more of sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0859] For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0860] In patients with disorders characterized by depressive episodes, altered functional connectivity is observed within and / or between several brain regions associated with processing, regulating, and emotional memory; cognitive processes related to rumination; and impaired concentration and physiological arousal.

[0861] Treatment of 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 an improvement in the disorder characterized by depressive episodes.

[0862] Improvement in the disorder characterized by a depressive episode (as reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after; on day 7; on day 14; and / or on day 28.

[0863] The patient's improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0864] Improvement in the disorder characterized by a depressive episode (as reflected by a decrease in MADRS score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0865] The patient's improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the MADRS score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0866] Improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the HAM-D score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0867] The patient's improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by a depressive episode (as reflected by a decrease in the HAM-D score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0868] Improvement in maternal function in a patient suffering from a disorder characterized by a depressive episode is reflected in at least an improvement in the BIMF total score on day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0869] Improvement in maternal function (as reflected in an improvement in the BIMF total score) in patients suffering from a disorder characterized by a depressive episode occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected in an improvement in the BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0870] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. MDD affects how a person feels, thinks, and behaves and can lead to a variety of emotional and physical problems.

[0871] Patients may have moderate or severe MDD, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 17 or higher. Patients may further be considered to have severe major depressive disorder, as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 25 or higher.

[0872] Patients suffering from MDD may suffer from a treatment-resistant form of the disorder (TRD).

[0873] MDD involves one or more of sleep disturbances, cognitive impairment, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0874] For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0875] In patients with MDD, functional connectivity impairments and modulations were observed within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network. Functional connectivity differed significantly from that observed in healthy controls.

[0876] Treatment of patients suffering from MDD, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the MDD.

[0877] Improvement in MDD (as reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0878] The patient's improvement in MDD (as reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD (as reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0879] Improvement in MDD (as reflected by a decrease in MADRS score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0880] The patient's improvement in MDD (as reflected by a decrease in MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD (as reflected by a decrease in MADRS score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0881] Improvement in MDD (as reflected by a decrease in HAM-D score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0882] The patient's improvement in MDD (as reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in MDD (as reflected by a decrease in the HAM-D score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0883] Improvement in maternal function in a patient suffering from MDD is reflected in at least an improvement in the BIMF total score on day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0884] Improvement in maternal function (as reflected in an improvement in the BIMF total score) in patients suffering from MDD occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected in an improvement in the BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0885] persistent depressive disorder

[0886] Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. It is diagnosed if depression is present most of the time, most of the time, for at least two years. Any symptom-free period is less than two months.

[0887] To be considered depressed, two or more of the following symptoms must be present: 1. Hopelessness; 2. Lack of energy or fatigue; 3. Low self-esteem; 4. Decreased sleep (insomnia) or increased sleep (hypersomnia); 5. Loss of appetite or overeating; 6. Difficulty making decisions or concentrating.

[0888] Patients suffering from persistent depressive disorder may suffer from a treatment-resistant form of the disorder.

[0889] Persistent depressive disorder involves one or more of sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0890] For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0891] In patients with persistent depressive disorder, altered functional connectivity was observed within and / or between several brain regions associated with processing, regulating, and emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal. Functional connectivity impairments were observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity differed significantly from that observed in healthy controls.

[0892] Treatment of patients suffering from persistent depressive disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the persistent depressive disorder.

[0893] Improvement in persistent depressive disorder (as reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0894] Improvement in the patient's persistent depressive disorder (as reflected by a decrease in the CGI-S score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the persistent depressive disorder (as reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0895] Improvement in persistent depressive disorder (as reflected by a decrease in MADRS score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0896] Improvement in the patient's persistent depressive disorder (as reflected by a decrease in the MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the persistent depressive disorder (as reflected by a decrease in the MADRS score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0897] Improvement in persistent depressive disorder (as reflected by a decrease in HAM-D score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0898] Improvement in the patient's persistent depressive disorder (as reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in the persistent depressive disorder (as reflected by a decrease in the HAM-D score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0899] Improvement in maternal function in patients suffering from persistent depressive disorder is reflected in at least an improvement in the BIMF total score on day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0900] Improvement in maternal function (as reflected by improvement in the BIMF total score) in patients suffering from persistent depressive disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected by improvement in the BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0901] Seasonal affective disorder

[0902] Seasonal affective disorder is a mood disorder with a seasonal pattern, with symptoms typically beginning in the fall and easing in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0903] Patients suffering from seasonal affective disorder may suffer from a treatment-resistant form of the disorder.

[0904] Seasonal affective disorder involves one or more of sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0905] For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0906] In patients with seasonal affective disorder, altered functional connectivity was observed within and / or between several brain regions associated with processing, regulating, and emotional memory; cognitive processes related to rumination; impaired concentration; and physiological arousal. Impaired functional connectivity was observed within and / or between the DMN, salience network, executive control network, and limbic network. The functional connectivity differed significantly from that observed in healthy controls.

[0907] Treatment of patients suffering from seasonal affective disorder, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of seasonal affective disorder.

[0908] Improvement in seasonal affective disorder (as reflected by a decrease in CGI-S score) is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours after; on day 7; on day 14; and / or on day 28.

[0909] The improvement in seasonal affective disorder (as reflected by a decrease in the CGI-S score) in the patient occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in seasonal affective disorder (as reflected by a decrease in the CGI-S score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0910] Improvement in seasonal affective disorder (as reflected by a decrease in MADRS score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0911] Improvement in the patient's seasonal affective disorder (as reflected by a decrease in the MADRS score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder (as reflected by a decrease in the MADRS score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0912] Improvement in seasonal affective disorder (as reflected by a decrease in HAM-D score) is observed on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; 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.

[0913] Improvement in the patient's seasonal affective disorder (as reflected by a decrease in the HAM-D score) occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in seasonal affective disorder (as reflected by a decrease in the HAM-D score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0914] Improvement in maternal function in patients suffering from seasonal affective disorder is reflected in at least an improvement in the BIMF total score on day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0915] Improvement in maternal function (as reflected in an improvement in the BIMF total score) in patients suffering from seasonal affective disorder occurs no later than about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function (as reflected in an improvement in the BIMF total score) preferably persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0916] Bipolar disorder

[0917] Bipolar disorder (BD) is a mental health condition characterized by severe mood swings, including periods of low moods (major depressive episodes) and high moods (manic or hypomanic episodes). BD is a relapsing, chronic disorder that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0918] Patients suffering from BD may suffer from treatment-resistant forms of the disorder.

[0919] If there is at least one manic episode (with or without a depressive episode), BD is classified as bipolar I. If there is at least one hypomanic episode (but not a full-blown manic episode) and one major depressive episode, BD is classified as bipolar II. If these symptoms are caused by medications or medical problems, the symptoms are not diagnosed as bipolar disorder.

[0920] Patients with BD, whether diagnosed with bipolar II or bipolar I, are particularly susceptible to experiencing a current major depressive episode.

[0921] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient may have a total score equal to or greater than 19, such as greater than or equal to 24, in particular greater than or equal to 37.

[0922] Alternatively or additionally, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as greater than or equal to 24, in particular greater than or equal to 37.

[0923] BD involves one or more of sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0924] For example, severity and treatment success can be assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HAM-D), or the Bipolar Depression Rating Scale (BDRS).

[0925] The BDRS is designed to measure the severity of depressive symptoms in bipolar depression. The BDRS has been validated by trained assessors for clinical use. Based on clinical interviews, the BDRS items assess the severity of depressive and / or mixed symptoms that a patient exhibits currently and over the past few days. If current symptoms are inconsistent with symptoms over the past few days, the assessment should reflect the current symptoms. The scale contains 20 questions and the maximum possible score is 60. Higher scores indicate greater severity.

[0926] The problems addressed include depressed mood; sleep disturbances; appetite disturbances; decreased social engagement; decreased energy and activity; decreased motivation; impaired concentration and memory; anxiety; anhedonia; emotional flattening; feelings of worthlessness; helplessness and hopeles...

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a mental or nervous system disorder in a mother with a child 18 months of age or younger, wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the mental or nervous system disorder involves one or more symptoms selected from sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal and negative thinking.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1 or 2, wherein the patient suffers from a treatment-resistant form of the disorder.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 3, wherein an improvement in the disorder, as reflected by a decrease in the CGI-S score, is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours; at day 7; at day 14; and / or at day 28.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 3, wherein the improvement of the disorder occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement is reflected in a decrease in the CGI-S score.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 3 or 5, wherein the improvement of the disorder persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said improvement being reflected in a decrease in the CGI-S score.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 6, wherein the patient also suffers from mildly impaired, impaired or severely impaired maternal function.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 7, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 95 or less, such as 80 or less, in particular 65 or less.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 8, wherein said treatment improves maternal function.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 9, wherein the improvement relates to one or more, in particular two or more, functional areas selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 8 to 10, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 11, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 12, wherein a dose of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 12, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 12, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 13, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein, Unless the patient is experiencing a peak psychedelic experience, each subsequent administration uses a higher dose than the previous one.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 13 or 16, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for a first administration, then increased to a dose of about 4 mg to about 6 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 17, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 13 or 16, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 19, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 16 to 20, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 12 to 21, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Ocean-like Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 22, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 23, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

25. 5-MeO-DMT for use as claimed in claims 1 to 24, wherein the disorder is a disorder characterized by depressive episodes, such as major depressive disorder (MDD), persistent depressive disorder, seasonal affective disorder and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias and substance / medication induced anxiety disorders; somatic symptom disorders; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD); OCD) and body dysmorphic disorder (BDD); post-traumatic stress disorder (PTSD); pain disorders, such as chronic pain, fibromyalgia, and migraines; mental and behavioral disorders due to the use of psychoactive substances, such as substance use disorder (SUD); psychotic disorders, such as schizophrenia; eating disorders; attention deficit hyperactivity disorder (ADHD); personality disorders, such as schizotypal personality disorder and borderline personality disorder; autism spectrum disorder; chronic fatigue syndrome; and mental or neurological disorders related to HIV, COVID sequelae, or traumatic brain injury.

26. 5-MeO-DMT for use as claimed in claims 1 to 25, wherein the patient suffers from a sleep disorder.

27. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 26, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 26, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 26, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

30. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 26, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

31. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 26, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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