Treating postpartum depression

Abstract

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

Description

[Technical Field]

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

[0002] Psychiatric disorders can be treated with 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The treatment also improves maternal function.

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

[0004] Mental or neurological disorders in breastfeeding mothers can have a wide range of adverse effects on the affected mother, her child(ren), and her family. For example, women with mental or neurological disorders may develop thoughts of harming themselves or their child and are at increased risk of suicide.

[0005] Mental or neurological disorders may further lead to a breakdown in mother-child interaction, as indicated by higher rates of indifferent attitudes and lower rates of visual and verbal communication between mother and child. Evidence also suggests an association between maternal mental or neurological disorders and child development, as indicated by the fact that children of patients with mental or neurological disorders may be at higher risk of cognitive developmental disorders.

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

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

[0008] Furthermore, research has shown that nursing mothers may be reluctant to begin drug treatment due to a variety of concerns.

[0009] As a result, lactating patients with psychiatric or neurological disorders may be faced with a situation where they must make a decision to discontinue breastfeeding or discontinue / withdraw from treatment.

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

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

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

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

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

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

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

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

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

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

[0020] The treatment allows for improved maternal function.

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

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

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

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

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

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

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

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

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

[0030] The patient may have treatment-resistant disease.Treatment-resistant means that the patient has not seen sufficient improvement after at least two appropriate treatment courses.The patient particularly has not seen sufficient improvement after at least two appropriate treatment courses, where at least one of these two courses is drug therapy, for example, the patient has not seen sufficient improvement after at least two appropriate drug therapy courses.The at least two previous treatment courses are particularly administered in the current episode of the disease, for example, if the patient has a disorder characterized by depressive episodes, they are administered in the current depressive episode.

[0031] As used in the context of the present invention, "suicidal ideation" refers to thoughts about suicide, contemplating suicide, or planning suicide. The presence of suicidal ideation in a patient is diagnosed by a physician or psychologist using validated protocols and methods for diagnosing suicidality. Generally, it is not enough for a patient to simply consider themselves to be having suicidal ideation. In some situations, a patient experiencing suicidal ideation is considered to be at imminent risk of suicide or to have "the intention to act."

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

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

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

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

[0036] The CGI-Severity (CGI-S) is based on a single question that clinicians must answer: "Considering your overall clinical experience with this particular population, how mentally impaired is this patient at this time?" This is rated on a 7-point scale: 1 = normal, not impaired at all, 2 = borderline mentally impaired, 3 = mildly impaired, 4 = moderately impaired, 5 = markedly impaired, 6 = severely impaired, 7 = one of the most severely impaired patients.

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

[0038] Alternatively, treatment success can be assessed using the CGI-Improvement (CGI-I), a similarly simple format. After treatment, the clinician compares the patient's overall clinical condition with that before treatment (the so-called baseline value). Again, only one query is assessed on a 7-point scale: "Compared to the patient's condition at the time of entry into this project [before medication began], this patient's condition has improved greatly since the start of treatment: 1 = very much; 2 = much; 3 = slightly; 4 = no change from baseline (beginning of treatment); 5 = slightly; 6 = much; 7 = very much worse since the start of treatment."

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

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

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

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

[0043] When clinical response at an early time point (e.g., 2 hours) after drug administration is assessed based on endpoints developed for longer recall periods (e.g., typically 7 days for the MADRS), reasonable modifications of such endpoints (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration) may be applied.

[0044] On the one hand, to assess clinical response, the influence of the patient's condition before treatment on any scores recorded after treatment should be kept as low as possible, but on the other hand, sleep items cannot be assessed 2 hours after drug administration, so the considerations outlined apply to earlier time points.

[0045] At later time points, e.g., Day 1 onwards, all items on the relevant scales for assessing clinical response can typically be assessed using adapted recall periods, if necessary, so that no pre-treatment scores need to be carried forward. For example, if BIMF is assessed on Day 7, a 7-day recall period is used (instead of the standard 2-week recall period).

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

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

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

[0049] In one aspect, the present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient who is a nursing mother diagnosed with a psychiatric or nervous system disorder.

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

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

[0052] In another preferred embodiment, the psychiatric disorder is bipolar disorder, for example bipolar II disorder. Patients diagnosed with bipolar disorder are particularly those suffering from a current major depressive episode.

[0053] Various aspects of bipolar disorder can be improved, such as sleep disturbance, psychomotor retardation (reduced energy and activity, and decreased motivation), negative thoughts (worthlessness, helplessness and hopelessness, guilt), anxiety, cognitive dysfunction (concentration and memory impairment), and social / emotional withdrawal or detachment (anhedonia, emotional withdrawal, and flat affect). Further aspects of the disease that can be improved include suicidal ideation and mixed symptoms (psychotic symptoms, irritability, lability, increased motor drive, increased speech, agitation). The improvement that can be achieved is reflected in clinically relevant measures.

[0054] Scales for assessing mental and nervous system disorders Many scales have been proposed to assess the severity of psychiatric or neurological disorders, and are based on tests that may be self-administered or administered by a clinician.

[0055] Scales for assessing psychiatric or nervous system disorders that may be used in accordance with the present invention include those known in the art for diagnosing and / or monitoring psychiatric or nervous system disorders, which are discussed in more detail below.

[0056] Treatment outcome is assessed using one or more indicators or measures at one or more time points after completion of the course of treatment.

[0057] This assessment can be performed after the acute psychedelic experience has subsided. An appropriate time point for early assessment is generally about 2-3 hours after the last dose. Early assessments can generally be performed, for example, about 2 hours or about 3 hours after the last dose.

[0058] Assessment of the effect on sleep disorders, or the effect on mental or nervous system disorders related to the effect on sleep disorders, however, may be performed as early as the day after treatment (i.e., Day 1) so that the treated patient has had an opportunity to get at least one night's sleep.

[0059] Thus, evaluation at day 1 or on day 1 refers to evaluation on the day after administration. The evaluation is performed no earlier than 12 hours after the last administration, or in any event no later than overnight after the last administration, and no later than 36 hours after the last administration. The evaluation can be performed about 24 hours later.

[0060] Assessment at or on day 7 refers to assessment on the 7th day after dosing (the day of dosing is day 0). Similar definitions apply to timing of other assessments measured in days.

[0061] When evaluating the clinical response at an early time point (e.g., 2 hours) after drug administration, for example, using one of the scales for assessing the severity of psychiatric or nervous system disorders, based on an evaluation item developed for a longer recall period (e.g., typically 7 days for the MADRS), reasonable modifications of such evaluation items (e.g., changing the recall period of the MADRS to 2 hours and carrying forward the sleep items recorded at baseline before drug administration) may be applied. The same applies to any other scale used herein to evaluate the therapeutic effect on psychiatric or nervous system disorders, unless the recall period is specifically indicated.

[0062] On the one hand, to assess clinical response, the influence of the patient's condition before treatment on any scores recorded after treatment should be kept as low as possible, but on the other hand, sleep items cannot be assessed 2 hours after drug administration, so the considerations outlined apply to earlier time points.

[0063] At later time points, e.g., Day 1 and beyond, all items on the relevant scales for assessing clinical response can usually be assessed using adapted recall periods, if necessary, so there is no need to carry forward any pre-treatment scores.

[0064] Active Agent Psychiatric or neurological disorders are characterized by several aspects that in themselves constitute a significant disease burden and deserve appropriate treatment. Therefore, treatments are needed, particularly by pharmacological intervention, to improve specific aspects of the disease, rather than just improving the overall disease score.

[0065] The inventors believed that carefully selected hallucinogens may lead to improved treatment and even overall improvement in the disease and maternal functioning.

[0066] The inventors further believed that in the case of treating nursing mothers with psychiatric or neurological disorders, carefully selected hallucinogens may allow nursing to continue substantially uninterrupted.

[0067] One group of hallucinogens includes compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (there are seven families, 5-HT1 through 5-HT7, with several subtypes). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "psychedelics," emphasizing their significant ability to induce qualitatively altered states of consciousness, such as euphoria, ecstasy, transcendence of time and space, spiritual experiences, the collapse of self-boundaries, or even near-death experiences, with minimal other effects, such as sedation, narcosis, or hyperstimulation.

[0068] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, the class of indoleamines being divided into two subsets: ergolines and tryptamines, the latter derived from tryptamine.

[0069] Various serotonergic psychedelics have different binding affinities and activation capacities for various serotonin receptors, particularly 5-HT1A, 5-HT2A, and 5-HT2C, and their activity can also be modulated by interactions with other targets, such as monoamine transporters and trace amine-associated receptors.

[0070] Recently published clinical studies using serotonergic psychedelics, such as LSD, psilocybin, and DMT (using ayahuasca, a shamanic drink containing DMT), for certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds may induce mania in patients with depressive symptoms, which may preclude their clinical use.

[0071] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who experienced a manic episode after ingesting LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication, which resolved, but was followed by a typical manic episode of psychotic severity within approximately three weeks. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a manic episode after self-reported ingestion of psilocybin-containing mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a transition to mania in a man with bipolar disorder after consuming ayahuasca, a drink containing DMT.

[0072] Further case reports can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A physician's attempt to self-medicate bipolar depression with N,N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0073] The inventors have considered that in order to avoid the induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound to be administered must be appropriately selected and preferably administered in a specific dosing regimen.

[0074] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly important psychedelic for therapeutic use, which has a pharmacological profile distinct from that of other psychedelic compounds.

[0075] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with greater affinity for the 5-HT1A receptor subtype compared to other classical psychedelics.

[0076] The inhibition constants (K ) for psilocin (the dephosphorylated form of psilocybin formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brain were calculated. i The K values ​​are 48, 38, and 1.80 nM, respectively, as further detailed in the Examples section below. Thus, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit moderate affinity, for the 5-HT1A receptor. The inhibition constants (K for psilocin, DMT, and 5-MeO-DMT at the 5-HT2A receptor located in the frontal cortex of postmortem human brains were iThe agonist activity (A, B, C, D, DMT, DMT) is 37, 117, and 122 nM, respectively. Therefore, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, while DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0077] Compared to the other psychotropic compounds mentioned above, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, where it acts as a potent agonist. In the cases of psilocin and DMT, the contribution of 5-HT2A binding is greater than that of 5-MeO-DMT, with the latter showing the greatest difference in affinity between 5-HT1A and 5-HT2A among the three compounds. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than 5-HT2A binding in the other two compounds.

[0078] It has been reported that 5-HT1A agonism reduces impulsivity and aggression, while 5-HT2A agonism may increase these same traits in the short term. Furthermore, the dopamine system is implicated in contributing to mania, and increased dopamine agonism is associated with mania. LSD, psilocybin, and DMT all exhibit higher affinity for various dopamine receptors compared to 5-MeO-DMT.

[0079] Compared to other psychedelics, such as LSD, psilocybin, or DMT, 5-MeO-DMT can preferably be administered, using the administration schemes described herein, to patients without significant risk of inducing mania or hypomania in patients with psychiatric or nervous system disorders, including disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorders (BD), e.g., bipolar I disorder and bipolar II disorder, psychiatric disorders, e.g., schizophrenia, or personality disorders, e.g., schizotypal personality disorder. Patients with such psychiatric or nervous system disorders who are treated according to the present invention do not experience treatment-emergent mania or hypomania.

[0080] It is also noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use appear to indicate the use of large amounts of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD).

[0081] Our approach of sequential titration of 5-MeO-DMT significantly reduces the risk of overdosing with its attendant potential adverse events.

[0082] Furthermore, the induction of isolated hypomanic episodes by antidepressants has been reported in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. “Antidepressant-induced hypomania in treatment-resistant depression.” Journal of Psychiatric Practice 13.4 (2007):233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0083] 5-MeO-DMT can induce peak experiences, characterized by altered emotional perspectives often characterized as a "loss of self" leading to a strong sense of "oneness with the universe," much more rapidly than other psychedelics, and has a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after intravenous injection, compared with several hours for oral psilocybin and oral LSD). These characteristics of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0084] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. The present inventors have investigated the effect of 5-MeO-DMT on the 5-HT7 receptor by using recombinant human 5-HT7 receptors as a radioligand. 3 H]LSD, and serotonin were used to estimate nonspecific binding, and the Ki was 2.3 nM.

[0085] Thus, in addition to the 5-HT1A and 5-HT2A receptors described above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0086] The 5-HT7 receptor is involved in neurogenesis, synaptogenesis, and dendritic spine formation, and is associated with, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0087] 5-HT7 receptors are particularly expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0088] The suprachiasmatic nucleus is the central pacemaker of the circadian clock, coordinating circadian rhythms in various brain regions. Disruption of this coordination leads to pathologies, particularly those involving sleep disorders. Resting-state functional connectivity analysis in patients with sleep disorders reveals altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0089] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to their function in regulating the sleep / wake cycle, and the inventors believe that this may allow the treatment of patients with sleep disorders by 5-MeO-DMT, which acts on this receptor.

[0090] The inventors believe that 5-MeO-DMT binding to 5-HT7 receptors as one mediator of its pharmacological actions, along with its "resetting" of network functional connectivity and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0091] The inventors further believe that 5-HT7 receptors and 5-HT1A receptors, two mediators of 5-MeO-DMT's effects, including "resetting" functional network connectivity and neuroplasticity, may also contribute to beneficial effects in patients with other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0092] Another characteristic of 5-MeO-DMT is its short half-life.

[0093] 5-MeO-DMT is inactivated primarily through a deamination pathway mediated by monoamine oxidase A, which is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0094] When we investigated the pharmacokinetic properties of 5-MeO-DMT, we observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and shortly after administration.

[0095] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid decline in plasma concentrations. Ten minutes after administration, concentrations already fall below 10% of Cmax; two hours later, they are below 1% of Cmax; and after three hours, 5-MeO-DMT is no longer detectable in plasma. This applies across the entire dose range examined (6 mg, 12 mg, 18 mg). No accumulation is observed with repeated dosing within the 1-4 hour time frame. The titration disclosed herein does not result in accumulation and thus in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0096] The inventors further confirmed that 5-MeO-DMT exhibits various properties that make it an attractive treatment for PPD. In contrast to SSRIs, it is a fast-acting drug (in the 5-MeO-DMT-TRD study, 5 / 8 TRD patients achieved remission within 2 hours after administration, 8 / 8 patients achieved remission on day 1, and 7 / 8 patients maintained remission on day 7). Treating PPD patients with 5-MeO-DMT can not only achieve rapid improvement in depressive symptoms, but also in maternal functioning. Furthermore, 5-MeO-DMT is distinct from SSRIs because it is administered in a single treatment session and optionally re-administered at irregular intervals. SSRIs require long-term daily dosing regimens, which are associated with low compliance, and, in the case of brexanolone, require continuous infusions and hospitalization.

[0097] Thus, the present invention also addresses compliance and patient convenience.

[0098] Furthermore, the present inventors have determined that treatment of PPD with 5-MeO-DMT or a pharmaceutically acceptable salt thereof allows for continuation of breastfeeding with only a short interruption for treatment.

[0099] Isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used in accordance with the present invention. When referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0100] These variants are in particular deuterated forms of 5-MeO-DMT, and pharmaceutically acceptable salts of such forms.

[0101] The deuterated form of 5-MeO-DMT is a form with a higher deuterium content than would be expected based on the natural abundance of this isotope.

[0102] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium has been introduced at one or more defined hydrogen positions.

[0103] 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.

[0104] Further examples include forms of 5-MeO-DMT in which deuterium is introduced at one or more hydrogen positions of the N-linked methyl group. Yet further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms on the indole ring system. It is noted that combinations of the above substitution patterns are also contemplated.

[0105] Methods for preparing these compounds are known in the art.

[0106] Mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

[0107] Furthermore, according to the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in molar amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0108] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be metabolically converted to 5-MeO-DMT. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, this can be replaced with a prodrug of 5-MeO-DMT or a salt thereof.

[0109] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be cleaved off after administration.

[0110] 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 each R 1 , R 2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0111] A preferred example of the organic moiety is —CH(R 3 )OC(O)R 4 and -C(O)OR 1 where R 1 , R 3 , and R 4 is defined as above.

[0112] Prodrugs, particularly those of the above structure, may also be used in the form of pharmaceutically acceptable salts.

[0113] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, in particular ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate di-trifluoroacetate) and 5-MeO-DMT methylpivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methylpivalate).

[0114] Methods for preparing prodrugs as discussed herein are known in the art.

[0115] 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 10 mg / kg of the prodrug. max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0116] Further, in accordance with the present invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-prodrug forms.

[0117] Administration method The therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously. These routes of administration can ensure rapid onset of action. The most preferred route of administration is intravenous administration, i.e., intravenous injection.

[0118] 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration by injection, examples of excipients and vehicles for such formulations are known in the art.

[0119] Dosage regimen The present invention also provides dosage ranges, specific dosages, as well as dosage regimens (administration schemes) and suitable routes of administration.

[0120] The present invention is based, in part, on the inventors' conclusion that the acute manifestation of a peak psychedelic experience following administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, drives its therapeutic effect, either causally or as at least a surrogate behavioral marker of an underlying unknown therapeutic mechanism, in patients as defined herein who are diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder, and including those disorders associated with suicidal ideation, particularly those associated with one or more aspects as defined above.

[0121] The result is a better therapeutic profile by achieving peak experiences more quickly, in a higher percentage of patients, and with better reproducibility within individual patients compared to previously tested psychedelic agents, dosing regimens, and routes of administration.

[0122] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., no reduction or elimination of hallucinogenic effects after re-administration) as the basis for enabling dosing regimens with frequent re-administration (e.g., more than once daily or daily) designed to increase the incidence of peak experiences and thereby enhance therapeutic efficacy. Such repeated administration within a short period of time also allows for intra-individual dose optimization, which reduces the risk of overdose, which can lead to physical side effects, such as serotonin syndrome, negative psychological reactions, such as flashbacks of experiences at a later time, the induction of mania or hypomania, or a less meaningful psychedelic experience with little or no memory of the altered state (so-called "whiteout"). Furthermore, starting with a low dose generally habituates patients to the psychedelic experience, positively affecting the experience at higher doses by preparing them for the more intense symptoms that occur at higher doses. Additionally, the possibility of initiating treatment at lower doses may increase patient acceptance of this treatment modality and improve overall compliance rates at the patient population level.

[0123] Frequent re-administration of serotonergic psychedelics to improve the rate and reproducibility of peak experiences, as well as to enhance therapeutic efficacy, reduce side effects, and improve compliance rates, may not be possible with other psychedelics due to the slow onset and long duration of hallucinogenic effects, and the rapid onset of tolerance (i.e., reduced or absent hallucinogenic effects after re-administration), which may last for several days.

[0124] Patients as defined herein who are diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder, and including disorders associated with suicidal ideation, are treated by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0125] In a preferred embodiment, the 5-MeO-DMT is administered as monotherapy, ie, the patient is not receiving any other treatment for the diagnosed disorder.

[0126] The dosage of 5-MeO-DMT administered to patients diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder and disorders associated with suicidal ideation, ranges from about 1 mg to about 10 mg, or any amount within that range, and is administered in the form of a formulation for administration based on a pharmaceutically acceptable salt of 5-MeO-DMT, e.g., the hydrobromide salt, the weight of which can be calculated from the specified weight of the free base of 5-MeO-DMT, assuming equimolar amounts are used. Useful specific amounts of 5-MeO-DMT include, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Note that when a range such as "about 1 mg to about 10 mg" is given herein, the inventors contemplate all discrete values ​​within the range, some of which are specifically mentioned, but not all of which are mentioned merely for purposes of brevity.

[0127] In a preferred embodiment, the improved method for treatment of a patient as defined herein diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder, and including disorders associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT includes the onset of a clinical response within about 2 hours after administration of 5-MeO-DMT.

[0128] In a preferred embodiment, the improved method for treatment of a patient as defined herein diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder, and including disorders associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprises a clinical response, including a clinical response that occurs within about 2 hours after administration of 5-MeO-DMT, that is sustained for at least about 6 days after the last administration of 5-MeO-DMT, preferably at least 14 days after the last administration of 5-MeO-DMT, and more preferably at least about 28 days after the last administration of 5-MeO-DMT.

[0129] In a preferred embodiment, the improved method for treatment of a patient as defined herein diagnosed with a disorder as defined herein, including treatment-resistant forms of the disorder, and including disorders associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprises more than a single administration of 5-MeO-DMT.

[0130] 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 treatments, the interval between each treatment within each treatment block being at least about 1 hour and not more than about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being at least about 6 days.

[0131] 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 treatments, with the interval between each treatment within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0132] 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 treatments, with the interval between each treatment 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 start of the next treatment block being about 6 days or more.

[0133] In embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each of the administrations and each of the treatment blocks is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0134] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until it reaches 10 mg or until all administrations within that treatment block have been administered, whichever occurs first.

[0135] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and is increased thereafter with each subsequent administration within each treatment block until it reaches 10 mg or until all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a peak psychedelic experience, or until the supervising physician determines that further dose increases are not appropriate based on observed side effects.

[0136] In embodiments where the dosage is increased with each subsequent administration, the dosage for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage for the previous administration. For example, if the dosage for the first administration is 1 mg and the dosage increase is 3 mg, the dosage for the second administration will be 4 mg unless one of the aforementioned stopping criteria has been reached. Preferably, the dosage for the third administration will be 7 mg.

[0137] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration, and to a dosage selected from about 7 mg to about 9 mg for the third administration, unless the patient has already experienced a peak psychedelic experience within that treatment block or unless the supervising physician determines, based on observed side effects, that further dose increases are not appropriate. Specific amounts useful for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0138] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration, and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration, unless the patient has already experienced a peak psychedelic experience within that treatment block or unless the supervising physician determines, based on observed side effects, that further dose increases are not appropriate. Specific amounts useful for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0139] In a more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration in an initial treatment block, and is thereafter increased with each subsequent administration in the initial treatment block until it reaches 10 mg or until all administrations in that treatment block have been administered, whichever occurs first, or until the patient experiences a peak psychedelic experience, or until a supervising physician determines, based on observed side effects, that further dose increases are not appropriate, with the highest dosage in that initial treatment block being used for all subsequent treatment blocks and administrations therein. For example, if a patient experiences a peak psychedelic experience at an 8 mg dose, and therefore the highest dosage in the initial treatment block is 8 mg, then all subsequent treatment blocks and administrations therein will be 8 mg.

[0140] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 3 mg for the first administration of the first treatment block, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block, and to a dosage selected from about 7 mg to about 9 mg for the third administration of the first treatment block, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician determines, based on observed side effects, that further dose increase is not appropriate, with the highest dosage for that first treatment block being used for all subsequent treatment blocks and administrations therein. Specific amounts useful for the first, second, and third administrations of the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0141] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of the first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block, and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician determines, based on observed side effects, that further dose increase is not appropriate, with the highest dosage for that first treatment block being used for all subsequent treatment blocks and administrations therein. Specific amounts useful for the first, second, and third administrations of the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0142] Pharmaceutically acceptable salts of 5-MeO-DMT are preferably used in all of the above dosing regimens, and the appropriate weight of the salt to be administered can be calculated from the stated weight of the free base, assuming an equimolar amount is used.

[0143] In accordance with the present invention, 5-MeO-DMT is preferably not administered in combination with an MAO inhibitor.

[0144] The occurrence of a "peak psychedelic experience" in a patient can be confirmed by achieving at least 60% of the maximum possible score on each of the four subscales (mysticism, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experiences Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0145] The occurrence of a "peak psychedelic experience" in a patient can also be confirmed by the achievement of at least 60% of the maximum possible score on the Oceanic Without Boundaries (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0146] According to the present invention, the occurrence of a "peak psychedelic experience" in a patient is preferably confirmed by achieving a score of at least 75 on the Peak Experience Scale (PES), also known as the Peak Psychedelic Experience Questionnaire (PPEQ), which is the average of the patient's responses, rated from 0 to 100, to the following three questions: 1. How intense was the experience? 2. To what extent did it make you lose your mind? 3. How profound (i.e., deep and significant) was the experience?

[0147] Sleep disorders There are two basic types of sleep: rapid eye movement (REM) sleep and non-REM sleep. Non-REM sleep can be divided into four stages (I-IV). These non-REM stages correspond to increasing depths of sleep. Non-REM and REM sleep alternate during each of the four to five cycles of normal human sleep each night. Early in the night, non-REM sleep is deeper and occupies a disproportionately large portion of the time, especially within this first sleep cycle. As the night progresses, non-REM sleep becomes shallower, with a greater proportion of each cycle being allocated to REM sleep.

[0148] Normal, healthy sleep consists of the different phases outlined above that proceed in a strictly regulated sequence throughout the night.

[0149] Disruption of this tight regulation leads to sleep disorders.

[0150] A sleep disorder refers to a condition, whether idiopathic or occurring in association with a medical condition, e.g., a psychiatric or nervous system disorder, that affects the quality, timing, or duration of sleep, which affects a person's ability to function adequately while awake.

[0151] Common forms of sleep disorders include disorders of initiating and maintaining sleep (insomnia), disorders of excessive somnolence (hypersomnia), disorders of sleep-wake schedules (circadian rhythm disorders), dysfunctions related to sleep, sleep stages, or incomplete awakening (parasomnias), disorders characterized by abnormal breathing during sleep (sleep-related breathing disorders), and disorders characterized by abnormal movements during sleep (sleep-related movement disorders).

[0152] Insomnia is a sleep disorder in which it is difficult to fall asleep or stay asleep. People with insomnia have trouble falling asleep, wake up multiple times during the night and have difficulty falling asleep again, wake up early in the morning, have unrefreshing sleep, and / or experience daytime problems such as fatigue, sleepiness, mood disorders, difficulty concentrating, and accidents at work or while driving that are attributable to lack of sleep.

[0153] Hypersomnia is characterized by excessive daytime sleepiness and / or prolonged nighttime sleep. Sleep drunkenness is also a symptom seen in patients with hypersomnia. It is a difficulty in transitioning from sleep to wakefulness. People experiencing sleep drunkenness report confused awakenings, disorientation, sluggishness, and alternating periods of returning to sleep.

[0154] Circadian rhythm disorders are characterized by chronic or recurrent sleep disturbances resulting from alterations in the circadian rhythm within an individual or from a mismatch between an individual's circadian rhythm and desired or required work or social schedules. This dyssynchrony can be transient or persistent. The ensuing clinical picture combines elements of both insomnia and hypersomnia. Sleep periods are typically shortened and interrupted, the ability to remain awake during desired wakefulness is reduced, and intermittent opportunities to return to a regular sleep schedule are not achieved.

[0155] Parasomnias refer to various forms of sleep disorders characterized by abnormal behavioral or physiological activity (e.g., sleepwalking or nightmares) experienced by a person before falling asleep, during sleep, and during periods of arousal between sleep and wakefulness. There is considerable variability in characteristics, severity, and frequency. Parasomnias can impair sleep quality.

[0156] Sleep-related breathing disorders are characterized by abnormal breathing and difficulty breathing during sleep. Breathing is a complex process that relies heavily on the coordinated action of respiratory muscles and the brain (control center). One form of sleep-related breathing disorder is central sleep apnea. This occurs when the brain stops sending signals that control breathing, for example, due to an underlying disease. Central sleep apnea potentially has serious effects on sleep and the balance of oxygen and carbon dioxide in the blood. Reduced airflow causes intermittent hypoxia, which leads to sleep fragmentation due to microarousals or awakenings. This can result in excessive daytime sleepiness.

[0157] In sleep-related movement disorders, repetitive, relatively simple, usually stereotyped movements interfere with sleep or its onset, the most common of which are restless legs syndrome (RLS) and periodic limb movement disorder (PLMD).

[0158] Lack of adequate quantity or quality of sleep can lead to personality changes, and can worsen existing mental disorders, as well as trigger the onset of mental disorders.Sleep disorders can also hinder cognitive function and lead to memory impairment.Sleep-deprived subjects may experience indecisiveness, irritability, may have performance problems, and may have slow reaction times.Sleep deprivation can also negatively impact life by contributing to the development of obesity, diabetes, and heart disease.

[0159] Treatment for sleep disorders varies depending on the type and underlying condition. Good sleep hygiene, a healthy sleep environment, and maintaining a consistent sleep-wake schedule are often considered first-line treatments. If unsuccessful, treatment may also include medication or psychotherapy.

[0160] Available treatments are not successful in all patients, may be associated with side effects, and / or may require long-term treatment to achieve relevant therapeutic benefits.

[0161] In patients with sleep disorders associated with psychiatric or nervous system disorders, known treatments for the psychiatric or nervous system disorders do not always improve the sleep disorder.

[0162] For example, sleep disorders are often associated with psychiatric disorders, such as depression.However, treating depression does not necessarily improve the associated sleep disorders.Most antidepressants have been proven to affect sleep structure, and some classes of antidepressants improve sleep, while others may cause sleep disorders.

[0163] Although sleep disorders may be considered a condition worthy of treatment regardless of any other conditions, disorders, or symptoms that an individual may have, some mental and nervous system disorders are associated with sleep disorders. Notably, the relationship between sleep and mental or nervous system disorders is often bidirectional. Not only can mental or nervous system disorders adversely affect healthy sleep patterns, but sleep disorders can also contribute to the onset, progression, and prognosis of mental health or nervous system disorders.

[0164] Treatment according to the present invention reduces or eliminates sleep disorders and preferably also improves associated psychiatric or nervous system disorders.

[0165] Measurement of sleep disturbances Sleep can be assessed by measuring parameters such as sleep duration, sleep architecture, sleep onset time, and frequency and duration of awakenings throughout the night. These quantitative metrics can be measured using objective methods, including polysomnography, activity tracking, and sleep onset time measurements, or by self-report measures (questionnaires).

[0166] Polysomnography is a technique that involves overnight monitoring of patients in a specialized clinic, where various functions are measured throughout the night, including eye movement, brain and muscle activity, respiratory effort and airflow, blood oxygen levels, body posture and movements, snoring, and heart rate.

[0167] Another quantitative method is activity tracking. Patients wear activity sensors to measure motor activity, which are then recorded intermittently and used to assess sleep-wake cycles. This technology allows patients to continue their normal daily routine while recording the necessary data in a natural sleep environment.

[0168] Sleep onset time can be measured by Multiple Sleep Latency Test (MSLT). This test provides an objective measure for measuring the time it takes to fall asleep over multiple test naps. A mean sleep onset time of approximately 10 minutes is considered normal, while a time of less than 8 minutes indicates a sleep disorder (excessive daytime sleepiness). Analysis of the accompanying brain activity can further aid in the diagnosis of sleep disorders.

[0169] Sleep assessment questionnaires capture components of sleep quality, such as sleep depth, difficulty waking, and perception of restfulness after sleep, in addition to other factors that may affect sleep quality, such as comorbid conditions and medication use. Assessing the qualitative aspects of the sleep experience is important because sleep complaints can often persist despite normal values ​​on quantitative measures of sleep.

[0170] Questionnaires may be useful not only for facilitating rapid and accurate assessment of complex clinical problems but also for tracking patient progress.

[0171] Various sleep quality indices are known. The following indices each include examples of questionnaires for assessing sleep generally, and for assessing insomnia, hypersomnia, circadian rhythm disorders, and parasomnias in particular. However, the present invention is not limited to the use of any particular index or questionnaire.

[0172] Some questionnaires rely on a recall period (recall window) of several days or weeks. While this may be appropriate for diagnosing sleep disorders, it is not necessarily appropriate for assessing treatment efficacy, especially the rapid onset of effects after treatment. For some questionnaires, the recall period can be modified so that the obtained score reflects the post-treatment period. To evaluate the effectiveness of sleep treatment in patients with certain conditions, the questionnaires specifically discussed herein rely on a recall period that begins no earlier than the time when the acute psychedelic experience has subsided after the last administration. To meet this criterion, the normally applied recall period is modified as necessary.

[0173] Generally, sleep quality can be assessed, for example, with the Sleep-50 questionnaire.

[0174] The SLEEP-50 questionnaire consists of 50 items designed to screen for various sleep disorders in the general population. The scale consists of nine subscales that reflect some of the most common sleep-related disorders and complaints, as well as diagnostic factors such as sleep apnea, insomnia, narcolepsy, restless legs / periodic leg movement disorder, circadian rhythm sleep disorder, sleepwalking, nightmares, factors affecting sleep, and the impact of sleep complaints on daily functioning. For each item, respondents are provided with a scale ranging from 1 ("not at all") to 4 ("very much") and asked to indicate the degree to which the statement matches their experience over the past month or another appropriate recall window.

[0175] To diagnose a sleep disorder, not only must a particular subscale (e.g., insomnia) exceed a certain cutoff point, but respondents must also meet a cutoff of at least 3 or 4 ("somewhat much" or "very much," respectively) on subscales assessing the impact of sleep-related complaints on daily functioning (Spoormaker et al., Initial validation of the SLEEP-50 questionnaire. Behav Sleep Med. 2005;3(4):227-46).

[0176] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0177] A common questionnaire for assessing sleep disorders is the Pittsburgh Sleep Quality Index. Other measures include the Insomnia Severity Index, the Espie Sleep Disorders Questionnaire, and the Patient-Reported Outcomes Measurement Information System (PROMIS®) Sleep Disorders.

[0178] The Pittsburgh Sleep Quality Index (PSQI) assesses overall sleep quality and sleep disturbances. The PSQI is a self-assessment questionnaire consisting of 19 questions. Respondents are asked to indicate how often they have experienced certain sleep difficulties over the past month or another appropriate recall window.

[0179] These 19 self-rated questions assess a wide variety of 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 categorized into seven component scores: (1) subjective sleep quality, (2) time to fall asleep, (3) sleep duration, (4) effective sleep time, (5) sleep disturbances, (6) use of sleep aids, and (7) interference with daytime activities.

[0180] Each component is assigned a score of 0 to 3. Higher scores indicate more severe sleep disturbances. Detailed instructions for scoring on 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.

[0181] The scores for these seven components are then summed to produce a single global score ranging from 0 to 21, with "0" indicating no difficulty and "21" indicating severe difficulty in all areas. A global score cutoff of 5 distinguishes between poor and good sleepers. A global score >5 indicates that the patient has severe difficulty in at least two areas or moderate difficulty in more than three areas.

[0182] When treatment outcome is assessed using the PSQI, successful treatment is indicated by (i) a reduction in score, preferably (ii) a reduction to 5 or less.

[0183] The Insomnia Severity Index (ISI) is a short questionnaire assessing subjective sleep quality, symptom severity, subjective satisfaction with sleep, the extent to which insomnia interferes with daily functioning, how significant the respondent perceives their insomnia compared to others, and the overall level of distress caused by sleep disturbances. Individual responses can be scored from 0 (none) to 4 (very). Higher total scores correspond to more severe insomnia. A total score of 0–7 indicates "no clinically significant insomnia," 8–14 indicates "subthreshold insomnia," 15–21 indicates "moderate clinical insomnia," and 22–28 indicates "severe clinical insomnia" (A. Shahid et al. (eds.), STOP, THAT and One Hundred Other Sleep Scales, Springer Science+Business Media, LLC 2012). The recall window is 2 weeks. Other appropriate recall windows may also be used.

[0184] Successful treatment for clinically significant insomnia is indicated by (i) a reduction in score, for example, of more than 7 points, especially more than 8 points, and preferably (ii) a reduction below the cut-off value.

[0185] The Espie Sleep Disorder Questionnaire (SDQ) assesses awareness of insomnia. By assessing restlessness / agitation, mental overactivity, consequences of insomnia, and lack of readiness to fall asleep, the SDQ is particularly concerned with beliefs about the causes of sleep disturbances. Respondents use a 5-point scale to indicate how frequently certain statements about insomnia describe their experience, with 1 meaning "never true" and 5 meaning "very often true." Higher scores indicate more dysfunctional beliefs about the causes and correlates of insomnia (A. Shahid et al., ibid.).

[0186] Successful treatment is indicated by a reduction in score.

[0187] The Patient-Reported Outcomes Information System (PROMIS)® Sleep Disturbance Scale is a universal scale for assessing sleep disturbances. The scale is available as a full-length version and four different shortened versions (e.g., 4-item, 6-item, and 8-item) and assesses self-reported perceptions of sleep quality, sleep depth, and any difficulties associated with falling asleep and staying asleep over a 7-day period.

[0188] Each item on this scale is rated on a 5-point scale. The raw scores for these items are summed to obtain a total raw score. The total raw score is then converted to a standard T-score using a conversion table.

[0189] Successful treatment is indicated by a decrease in the T-score.

[0190] Hypersomnia or excessive sleepiness can be assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, or the Idiopathic Hypersomnia Severity Scale.

[0191] 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 in traffic. Using a scale of 0 to 3 (0 meaning "never falls asleep" and 3 meaning "almost always falls asleep"), respondents rate their likelihood of falling asleep. Scores range from 0 to 24, with higher scores indicating greater severity of daytime sleepiness. A cutoff score of 10 identifies potentially clinical levels of daytime sleepiness (A. Shahid et al., ibid.).

[0192] Successful treatment is indicated by (i) a reduction in score, preferably (ii) a reduction to 10 or less.

[0193] The Stanford Sleepiness Scale is a subjective measure of sleepiness that assesses sleepiness at a particular moment. This single-item scale requires respondents to select one of seven statements that best describes their current perceived level of sleepiness. Levels of sleepiness are rated using a scale ranging from 1 (= feeling active and energetic, alert, wide awake) to 7 (= mostly dreamy, falls asleep easily, makes no effort to stay awake) (A. Shahid et al., ibid.).

[0194] Successful treatment is indicated by a reduction in score.

[0195] Parasomnias can be assessed by the Paris Awake Disorders Severity Scale (PADSS).

[0196] The Paris Arousal Disorders Severity Scale (PADSS) is a self-rating scale that lists abnormal sleep behaviors and includes an outcome assessment (Arnulf et al., A scale for assessing the severity of arousal disorders. Sleep. 2014 Jan 1;37(1):127-36).

[0197] Successful treatment is indicated by (i) a decrease in score, preferably (ii) a decrease below the cutoff value.

[0198] A common questionnaire for assessing sleep-related breathing disorders is the Berlin Questionnaire (A. Shahid et al., ibid.). An appropriate recall period can also be selected.

[0199] Successful treatment is indicated by a reduction in score.

[0200] A common questionnaire for assessing sleep-related movement disorders is the International Restless Legs Syndrome Study Group Severity Scale. This 10-item questionnaire asks respondents to indicate, using a Likert-type rating, how severely the disorder has affected them over the past week. Questions are divided into two categories: the disorder's symptoms (nature, intensity, and frequency) and their impact (sleep disturbances, impairment of daily functioning, and resulting mood changes). Each of the 10 questions requires respondents to rate their experience of RLS on a scale of 0 to 4, with 4 representing the most severe and frequent symptoms and 0 representing the least severe. Total scores can range from 0 to 40. As a brief scale with good psychometric qualities, this scale may be suitable for a variety of research and clinical purposes, including screening and evaluation of treatment outcomes (A. Shahid et al., ibid.).

[0201] Treatment response can be assessed by a reduction in score.

[0202] Resting-state networks and sleep disorders Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0203] Functional images of the brain are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signal are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0204] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal change are called resting-state networks (RSNs).

[0205] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the activity patterns seen in resting-state networks and task-based fMRI experiments.

[0206] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional architecture, which has been characterized as encompassing aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0207] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been shown to be impaired in various pathological conditions that are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0208] Alterations in the resting-state network can be seen in insomnia, hypersomnia, circadian rhythm disorders, parasomnias, sleep-related breathing disorders, and sleep-related movement disorders.

[0209] The primary network involved in sleep is the default mode network (DMN). Generally, the DMN is deactivated during task activity and activated during rest. It is involved in multiple cognitive processes, including higher cognition, emotion, and interoception. During sleep, its overall activity level decreases. Given the importance of the DMN to sleep physiology, changes in DMN activity are particularly important in the context of sleep disturbances.

[0210] Resting-state network impairments may also be seen in psychiatric or neurological disorders, as discussed further herein.

[0211] Resting-state networks involved in sleep disorders are also influenced by mental or neurological conditions that are the result of certain medical conditions.

[0212] In patients with insomnia, abnormal functional connectivity has been observed within the default mode network (DMN) and the salience network, which are involved in the detection and integration of emotional and sensory stimuli. Research has shown that these networks contain important regions that integrate emotional and physical states, and that abnormal functional connectivity within these networks and / or between these networks and other brain regions may underlie patients' vigilance, subjective distress, and poor sleep continuity.

[0213] The default mode network is affected in patients with hypersomnia. For example, in idiopathic hypersomnia, distinct DMN hubs, the precuneus and medial prefrontal cortex, show significant alterations, and functional connectivity in the DMN correlates with the severity of self-reported sleepiness.

[0214] A study investigating differences between night-shift and day-shift nurses revealed that circadian rhythm disorders contribute to altered resting-state function in the cerebellum, which is involved in sleep regulation, and cognitive functions, such as reactivity and attention. Furthermore, functional connectivity of the DMN is fundamentally different between early and late circadian phenotypes. Similar to other forms of sleep disorders, circadian rhythm disorders may result in alterations in brain functional connectivity. Alterations in resting-state brain functional connectivity have been reported in various diseases associated with circadian rhythm disorders.

[0215] Although it is technically difficult to perform functional brain imaging during a parasomnia event, differences in the precuneus have been observed in disturbances of arousal representing non-REM parasomnia.

[0216] The precuneus is involved in analyzing and integrating visual, auditory, and somatic information, as well as monitoring movement. The precuneus is a subregion of the DMN. Therefore, in patients with parasomnia, the default mode network is affected.

[0217] Resting-state fMRI studies in patients with sleep-related breathing disorders, such as central sleep apnea, show significant global and regional connectivity deficits, particularly in the default mode network (DMN) and regions involved in arousal and sensorimotor systems.

[0218] Sleep-related movement disorders, such as periodic limb movements during sleep, are reflected by alterations in the motor control pathways of the prefrontal lobe, a subregion of the default mode network, and activity in the cerebellum and thalamus can be observed, along with additional activity in the red nucleus and brainstem.

[0219] Abnormalities in the functional connectivity of resting-state networks involved in sleep disorders are often also involved in these conditions, and therefore, in accordance with the present invention, affecting these networks with therapies according to the present invention results in the improvement of sleep disorders and, if the patient being treated has a psychiatric or neurological disorder, also results in the improvement of that disorder.

[0220] Treatment of sleep disorders and mental and nervous system disorders The present invention can treat idiopathic sleep disorders and sleep disorders in patients with psychiatric or nervous system disorders. In patients with sleep disorders associated with psychiatric or nervous system disorders, treatment of the sleep disorder with the present invention improves the conditions associated with the sleep disorder.

[0221] In many cases, the resting state networks involved in sleep disorders are also involved in the above conditions.

[0222] 5-MeO-DMT has the ability to disrupt established resting-state functional connectivity patterns. This disruption resets pathological, maladaptive brain connections while simultaneously reconnecting the network. New, healthy functional connections are established with lasting effects.

[0223] The persistence of this effect can be explained by the neuroplasticity-promoting properties of 5-MeO-DMT. 5-MeO-DMT promotes structural and functional plasticity, particularly at synapses, i.e., the sites where neurons connect and communicate with each other. 5-MeO-DMT regulates the morphogenesis and maturation of dendritic spines, thereby initiating the formation of new synaptic connections. These new connections can be strengthened, weakened, or even eliminated, depending on the activity.

[0224] The resulting new synapses then influence patterns of neuronal activity, and we conclude that such reciprocal structural and functional modifications contribute to the establishment of appropriate networks and sustained effects following 5-MeO-DMT administration.

[0225] From a biochemical point of view, 5-MeO-DMT interacts specifically with the 5-HT receptor.

[0226] 5-HT receptors, receptors for the neurotransmitters serotonin or 5-hydroxytryptamine (5-HT), are found throughout the central and peripheral nervous systems. A wide range of physiological and pathological functions are mediated through these receptors.

[0227] Seven types of 5-HT receptors are expressed in the brain, which can be further divided into several subtypes. These various types and subtypes show distinct spatial distributions.

[0228] 5-MeO-DMT interacts with several 5-HT receptors, which are involved in mediating the effects of 5-MeO-DMT on resting-state networks and neuroplasticity.

[0229] In addition to the 5-HT1A and 5-HT2A receptors mentioned above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0230] The 5-HT7 receptor is involved in neurogenesis, synaptogenesis, and dendritic spine formation, and is associated with, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0231] 5-HT7 receptors are particularly expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0232] The suprachiasmatic nucleus is the central pacemaker of the circadian clock, coordinating circadian rhythms in various brain regions. Disruption of this coordination leads to pathologies, particularly those involving sleep disorders. Resting-state functional connectivity analysis in patients with sleep disorders reveals altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0233] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to their function in regulating the sleep / wake cycle, and the inventors believe that this may allow the treatment of patients with sleep disorders by 5-MeO-DMT, which acts on this receptor.

[0234] The inventors believe that 5-MeO-DMT binding to 5-HT7 receptors as one mediator of its pharmacological actions, along with its "resetting" of network functional connectivity and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients with sleep disorders.

[0235] The inventors further believe that 5-HT7 receptors and 5-HT1A receptors, two mediators of 5-MeO-DMT's effects, including "resetting" functional network connectivity and neuroplasticity, may also contribute to beneficial effects in patients with other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0236] Treatment according to the present invention results in improvement of the sleep disorder and, if the patient being treated has a psychiatric or nervous system disorder, also results in improvement of that disorder.

[0237] Clinical data from studies of patients with treatment-resistant depression (TRD) or postpartum depression (PPD) confirm that sleep disorders can be successfully treated with the administration of 5-MeO-DMT.

[0238] The TRD study, described in more detail in the Examples section below, assessed, among other things, the MADRS item "Decreased Sleep," which reflects insomnia.

[0239] The MADRS item "Sleep Decreased" describes the experience of decreased sleep duration or depth compared to the subject's normal pattern during good times. A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects slight difficulty falling asleep or slightly short, shallow, or intermittent sleep. A score of 4 means sleep is shortened or interrupted by at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0240] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Decreased Sleep" across all eight patients was 25 at baseline. By day 1 after treatment, the earliest time point for assessing the treatment's impact on sleep, it had decreased to 12, representing a 13-point or 52% improvement. By day 7 after treatment, it had decreased to 9, representing a 16-point or 64% improvement.

[0241] In the 12 mg group, the aggregate score for the MADRS item "Decreased Sleep" across all four patients was 12 at baseline. One day after treatment, it decreased to 10, which corresponds to a 2-point or 17% improvement. Seven days after treatment, it decreased to 6, which corresponds to a 6-point or 50% improvement.

[0242] Thus, the score for "decreased sleep," a measure particularly relevant to sleep disorders, is significantly improved. The inventors conclude that 5-MeO-DMT may be used to treat patients with sleep disorders, particularly psychiatric or nervous system disorders.

[0243] Cognitive dysfunction Cognition includes the skills required for thinking, memory, attention and problem solving.The loss or decline of these skills leads to cognitive dysfunction, and this term is used herein to refer to the defect or impairment of any cognitive domain.Cognitive dysfunction can be one of the symptoms of the patient's underlying disease.

[0244] The DSM-5 defines six major domains of cognitive function: complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition.

[0245] Cognitive dysfunction can affect one or more of these domains; indeed, cognitive abilities are highly interrelated, and it is not uncommon for multiple domains to be affected.

[0246] For example, the domain of complex attention has the subdomains of sustained attention (commonly called "concentration" or "focus"), divided attention, selective attention, and processing speed.

[0247] Complex attention therefore clearly encompasses aspects important for a variety of cognitive tasks, such as executive function and learning and memory. Cognitive control or executive function is essentially related to attention, and perception and decision-making are greatly influenced by attentional abilities.

[0248] As a result, attention is not only tested in isolation, but also by, for example, cognitive control tasks / executive functions. If attention is impaired, other types of cognitive abilities are likely impaired as well. Before language can be understood, visuospatial relationships recognized, information memorized, or problems solved, attention must be paid to a stimulus.

[0249] Cognitive dysfunction, a term used herein to refer to an acquired condition and thus to a decline from a previously achieved level of functioning, may be associated with a variety of processes.

[0250] In healthy individuals, certain cognitive abilities, such as accumulated knowledge and vocabulary, are maintained with aging and may even improve over time. However, even in the absence of any pathological condition, aging leads to declines in abilities such as abstract thinking, reasoning, and decision-making. These declines are associated with fundamental age-related impairments in processing speed, attention, memory, and executive function, which are indicative of cognitive aging.

[0251] Apart from normal aging, cognitive dysfunction may be associated with a psychiatric or neurological disorder or some other medical condition.

[0252] The psychiatric or nervous system disorders discussed herein result in or are associated with cognitive dysfunction.

[0253] Cognitive dysfunction also occurs in disorders that exhibit symptoms characteristic of neurocognitive disorders, which cause clinically significant distress or impairment in social, occupational, or other important areas of functioning, but do not meet the full criteria for any etiologically related disorder.

[0254] Cognitive dysfunction can take the form of neurocognitive disorders.

[0255] Mild neurocognitive impairment, also known as mild cognitive impairment, is characterized by a mild cognitive decline from a previous level of ability in one or more cognitive domains. Affected patients are able to remain independent and perform everyday tasks. However, these patients usually function at suboptimal levels. Daily tasks become more demanding due to the engagement of compensatory strategies to maintain independence.

[0256] Dementia is characterized by a significant cognitive decline from a previous level of ability in one or more cognitive domains. Cognitive impairment impairs independence in daily activities.

[0257] Measuring cognitive dysfunction Cognitive dysfunction can be assessed by questionnaire or neuropsychological assessment.

[0258] The questionnaire assesses the patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient has a specific psychiatric or neurological disorder may include items related to cognitive function.

[0259] A neuropsychological evaluation is a process in which a person's cognitive, psychological / emotional, and behavioral functioning are comprehensively evaluated. A central part of a neuropsychological evaluation is the administration of neuropsychological tests for the formal evaluation of cognitive function.

[0260] Performance on these tests is compared to norms appropriate for the patient's age, education, and cultural background. The tests often use a series of ability-based questions, also known as a neuropsychological test battery.

[0261] Abilities tested include language processing, visual-spatial processing, attention / concentration, verbal learning and memory, visual learning and memory, executive function, processing speed, and sensory-cognitive function.

[0262] Common tests to assess cognitive impairment are the Montreal Cognitive Assessment (MoCA), the Mini-Mental State Examination (MMSE), the Mini-Cog™, the Screening for Cognitive Impairment in Psychiatry (SCIP), and the MATRICS Consensus Cognitive Assessment Battery (MCCB).

[0263] The Montreal Cognitive Assessment (MoCA) is a widely used screening assessment to detect cognitive impairment. It evaluates different cognitive domains: short-term memory, visuospatial ability, executive function, attention, concentration, and working memory, language, and spatial and temporal orientation. The maximum total score is 30. A score of 26 or higher is considered normal, a score of 18-25 is considered mild cognitive impairment, a score of 10-17 is considered moderate cognitive impairment, and a score of less than 10 is considered severe cognitive impairment.

[0264] The Mini-Mental State Examination (MMSE) is an 11-question measure that tests five areas of cognitive function: orientation, memory, attention and calculation, recall, and language. The maximum score is 30. Raw scores may need to be adjusted for education and age.

[0265] Herein, four cutoff levels are used to classify the severity of cognitive impairment: 24-30 means no cognitive impairment, 19-23 means mild cognitive impairment, 10-18 means moderate cognitive impairment, and 9 means severe cognitive impairment.

[0266] With repeated use, the MMSE is suitable for measuring changes in cognitive status.

[0267] The Mini-Cog™ is a short cognitive impairment screening questionnaire. It combines a three-word recall and a clock-drawing test. The clock-drawing test assesses many cognitive domains that may be affected, such as executive function, visuospatial ability, motor programming, and attention. 1 point is awarded for each of the three words correctly recalled after performing the clock-drawing test, and an accurately drawn clock is worth 2 points. A score below 4 indicates cognitive impairment.

[0268] The Screening for Cognitive Impairment in Psychiatry (SCIP) is a highly regarded screening instrument for examining the cognitive abilities of psychiatric patients.

[0269] The SCIP consists of five subscales: the Verbal Learning Test-Immediate (VLT-I), Working Memory Test (WMT), Verbal Fluency Test (VFT), Verbal Learning Test-Delayed (VLT-D), and Processing Speed ​​Test (PST). Three different test formats exist to facilitate repetition of the test and thus reduce learning effects. Subscale scores are calculated for each of the five tests, and a total score is calculated from the sum of the subscale scores. A total score of less than 70 indicates cognitive dysfunction.

[0270] Cognitive dysfunction may also be assessed by the MCCB (MATRICS Consensus Cognitive Assessment Battery) or by one or more of its various subtests, including the Trail Making Test, Part A (a test of processing speed), the Brief Cognitive Assessment Scale in Schizophrenia, the Signing Subtest (processing speed), the Hopkins Verbal Learning Scale-Revised, Immediate Recall, Three Trials Only (verbal learning), the Wechsler Scales, Third Edition, the Spatial Span Subtest (non-verbal working memory), the Letter Span Test (verbal working memory), the Neuropsychological Assessment Battery, the Maze Subtest (logical thinking and problem solving), the Brief Visuospatial Memory Test-Revised (visual learning), the Category Fluency Test, Animal Names (processing speed), the Multifactor Emotional Intelligence Scale, Emotion Management Branch (social cognition), and the Sustained Processing Task, Identical Pairs Version (attention / vigilance).

[0271] Test batteries are suitable for measuring cognitive change.

[0272] Further tests include the Verbal Recognition Memory (VRM) test, the Rapid Visual Processing (RVP) test, the Spatial Working Memory (SWM) test, and the Digit Symbol Substitution Test (DSST).

[0273] Mechanisms of cognitive dysfunction Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0274] Functional images of the brain are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signal are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0275] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal change are called resting-state networks (RSNs).

[0276] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the activity patterns seen in resting-state networks and task-based fMRI experiments.

[0277] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional architecture, which has been characterized as encompassing aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0278] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been shown to be impaired in various pathological conditions, including certain forms of cognitive dysfunction, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0279] Resting-state fMRI is particularly advantageous when testing populations affected by cognitive dysfunction, as it allows for the examination of functional connectivity while eliminating task demands that may be confounded by underlying cognitive or motor impairments.

[0280] Cognitive processes are reflected by the functional connectivity of certain brain regions within and / or between regions located in different networks.

[0281] In particular, certain core networks, also called "higher-order cognitive networks," appear to be essential for most mental activities.

[0282] The frontoparietal control network (FPCN), also known as the frontoparietal network (FPN), central executive network (CEN), or executive network (EN), is typically associated with executive functions, including holding and updating relevant information in working memory, inhibiting impulsive responses, and using flexible problem-solving strategies to guide decisions and goal-directed behavior.

[0283] Another core network is the default mode network (DMN). The DMN contains areas in the brain that are most active when a person's attention is not focused on any specific task. DMN activity is associated with introspection, episodic memory, memory consolidation, social and self-related cognition, the integration of cognitive and emotional processing, and task-irrelevant free-thinking mind-wandering.

[0284] 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 need to pay attention to. This network plays a central role in governing mental processes and behavior.

[0285] The fourth network is the dorsal attention network (DAN), which is involved in top-down, goal-directed attention processes.

[0286] The above networks do not operate independently; in fact, there are many connections between them. Cooperation between networks is essential for task-specific function.

[0287] Throughout life, brain networks undergo functional reorganization that is simultaneously relevant to cognition. In healthy aging, age-related changes are observed in higher-order cognitive networks.

[0288] Patients with cognitive dysfunction exhibit altered functional connectivity within and / or between resting-state networks when compared to age-matched healthy controls. Alterations are observed within and / or between the default mode network, executive network, salience network, and dorsal attention network.

[0289] Resting-state networks involved in cognition are often affected by psychiatric or neurological disorders, as discussed herein.

[0290] Resting-state networks involved in cognition are also affected by psychiatric or neurological conditions that are the result of certain medical conditions, and in neurocognitive disorders not otherwise specified.

[0291] Furthermore, resting-state networks involved in cognition are affected by sleep disorders, such as insomnia, and indeed cognitive dysfunction and sleep disorders are correlated.

[0292] Cognitive function is impaired in patients with sleep disorders, and patients with cognitive dysfunction often also have sleep disorders.

[0293] Treating cognitive dysfunction The present invention can treat cognitive dysfunction occurring in patients suffering from a medical condition leading to a psychiatric or nervous system disorder or related psychiatric or nervous system condition, and can also treat cognitive dysfunction occurring in patients suffering from a sleep disorder, such as insomnia.

[0294] Cognitive dysfunction in neurocognitive disorder not otherwise specified can be similarly treated.

[0295] In patients with cognitive dysfunction associated with another condition detailed above, treatment of the cognitive dysfunction according to the present invention results in an improvement in the condition associated with the cognitive dysfunction.

[0296] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0297] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption resets pathological, maladaptive connections as networks reconnect. New, healthy functional connections are established with lasting effects.

[0298] Thus, in accordance with the present invention, influencing these networks by the treatment methods described in the present invention will result in an improvement in cognitive dysfunction, and, if the patient being treated has a psychiatric or nervous system disorder, an improvement in the disorder, and, if the patient being treated has a medical health condition that leads to an associated psychiatric or nervous system condition, an improvement in the associated psychiatric or nervous system condition, and, if the patient being treated has a sleep disorder, e.g., insomnia, an improvement in the sleep disorder, e.g., insomnia, and, if the patient being treated has an unspecified neurocognitive disorder, an improvement in one or more other symptoms of the disorder.

[0299] To further support the clinical application of 5-MeO-DMT in patients with cognitive dysfunction, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in cognitive dysfunction that are also commonly observed in patients with other disorders.

[0300] These data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific condition, as discussed in more detail below, the inventors have determined that certain clinical observations made in this study may be relevant for devising treatments for other conditions associated with cognitive dysfunction.

[0301] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, determined by the intensity of the patient-reported psychedelic experience.

[0302] Data collected included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvements in the overall MADRS score, we focused on the items that make up the various scales and found that certain subscores, such as those related to cognitive dysfunction, are associated with other conditions. In this case, cognitive dysfunction is based on similar changes in functional connectivity within and / or between the default mode network, executive control network, salience network, and dorsal attention network.

[0303] Multiple patients within the recruited cohort showed significant improvement, and the results support our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0304] More specifically, an aspect that may be treated by administration of 5-MeO-DMT is cognitive dysfunction, particularly difficulty concentrating. 5-MeO-DMT may be administered to a patient to reduce or eliminate cognitive dysfunction, particularly difficulty concentrating, in said patient.

[0305] The MADRS item that is particularly relevant to concentration and memory problems is "Difficulty concentrating." This item represents anything from difficulty organizing thoughts to inability to concentrate and is scored on a scale ranging from 0 to 6. A score of 0 is assigned if the patient has no difficulty concentrating. A score of 2 is assigned if the patient has occasional difficulty organizing thoughts. A score of 4 is assigned if difficulty concentrating and sustaining thoughts impairs the ability to read or speak. A score of 6 is assigned if the patient is unable to read or speak without great difficulty.

[0306] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Difficulty concentrating" across all eight patients was 30 at baseline.

[0307] After 2 hours, it had decreased to 11, which corresponds to a 19-point or 63% improvement. One day after treatment, it had decreased to 1, which corresponds to a 29-point or 97% improvement. Seven days after treatment, it had decreased to 9, which corresponds to a 21-point or 70% improvement.

[0308] In the 12 mg group, the combined score for the MADRS item "Difficulty concentrating" across all four patients was 16 at baseline.

[0309] After 2 hours, it had decreased to 7, which corresponds to a 9-point or 56% improvement. One day after treatment, it had decreased to 2, which corresponds to a 14-point or 88% improvement. Seven days after treatment, it had decreased to 3, which corresponds to a 13-point or 81% improvement.

[0310] Thus, in accordance with the present invention, treating a patient suffering from cognitive dysfunction with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction.

[0311] More specifically, according to the present invention, treating a patient with cognitive dysfunction, which is a deficit or impairment in one or more cognitive domains selected from complex attention, executive function, learning and memory, language, perceptual-motor function, and social cognition, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the cognitive dysfunction. For example, the cognitive dysfunction is reduced or eliminated when it affects the cognitive domain of complex attention, e.g., one or more subdomains of the cognitive domain of complex attention selected from sustained attention, divided attention, selective attention, and processing speed, particularly sustained attention.

[0312] In patients suffering from cognitive dysfunction associated with a psychiatric or nervous system disorder, treating the cognitive dysfunction according to the present invention results in an improvement in cognition associated with the cognitive dysfunction.

[0313] Although cognitive dysfunction may be considered a condition worthy of treatment regardless of any other conditions, disorders, or symptoms that an individual may have, some mental and nervous system disorders are associated with cognitive dysfunction. Notably, the relationship between cognitive dysfunction and mental disorders is bidirectional. Not only can mental disorders adversely affect cognitive function, but cognitive dysfunction can also contribute to the onset, progression, and prognosis of mental or nervous system disorders.

[0314] In many cases, the resting-state networks involved in cognitive dysfunction are also involved in the above conditions.

[0315] 5-MeO-DMT has the ability to disrupt established resting-state functional connectivity patterns. This disruption resets pathological, maladaptive brain connections while simultaneously reconnecting the network. New, healthy functional connections are established with lasting effects.

[0316] anxiety Anxiety may be defined as "the apprehensive anticipation of future danger or misfortune accompanied by physical symptoms of discomfort or tension."

[0317] Anxiety is characterized by intense, excessive, and persistent worry and fear about situations that are only subjectively viewed as threatening, and is often accompanied by muscle tension, restlessness, fatigue, breathlessness, abdominal tightness, nausea, and difficulty concentrating.

[0318] In anxiety disorders or other anxiety-related mental or nervous system disorders, feelings of anxiety are difficult to control and interfere with daily activities.

[0319] Anxiety is a cardinal feature of anxiety disorders, including separation anxiety disorder, specific phobia, social anxiety disorder (social phobia), panic disorder, generalized anxiety disorder (GAD), agoraphobia, and substance / medication-induced anxiety.

[0320] Anxiety is also associated with several other mental and nervous system disorders. Anxiety is also associated with sleep disorders.

[0321] Measuring anxiety Several rating scales for assessing anxiety are known in the art, and anxiety symptoms are further assessed as part of various rating scales used to assess psychiatric and nervous system disorders.

[0322] The Hamilton Anxiety Rating Scale (HAM-A) is designed to assess anxiety symptoms. This scale is administered by a clinician. It has 14 items divided into a psychological group (items 1-6 and 14) that specifically measure mental agitation and psychological distress, and a somatic group (items 7-13) that specifically measure somatic complaints related to anxiety.

[0323] The HAM-A items are shown in the table below. [Table 1] Each item is rated by the interviewer on a scale of 0 to 4: 0 = absent, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.

[0324] A total score is obtained by summing these 14 items, with the range of the total score being 0 to 56. Higher scores indicate greater anxiety.

[0325] A score of 7 is considered to represent no or minimal anxiety, scores of 8-14 mild anxiety, scores of 15-23 moderate anxiety, and a score of 24 severe anxiety.

[0326] The Beck Anxiety Inventory (BAI) is a 21-item self-report questionnaire developed to assess anxiety, focusing on somatic symptoms. These items are rated on a 4-point Likert scale ranging from 0 (not at all) to 3 (severe: barely tolerable). Total scores range from 0 to 63.

[0327] The term subthreshold anxiety as used herein specifically means that the patient has a Hamilton Anxiety Rating Scale (HAM-A) score of at least 9 but less than 18 and / or a Beck Anxiety Inventory (BAI) score of at least 11 but less than 16.

[0328] Mechanisms of anxiety Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0329] Functional images of the brain are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signal are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0330] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal change are called resting-state networks (RSNs).

[0331] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the activity patterns seen in resting-state networks and task-based fMRI experiments.

[0332] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional architecture, which has been characterized as encompassing aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0333] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been shown to be impaired in various pathological conditions, including certain forms of anxiety, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0334] According to such studies, several brain regions are involved in anxiety and anxiety disorders. Thus, the pathophysiology of anxiety and anxiety disorders involves abnormal connections between the frontal amygdala and the frontostriatal region. Anxiety and anxiety disorders are associated with specific changes in the resting-state network.

[0335] Anxiety and anxiety disorders exhibit abnormalities within and / or between the default mode network, salience network, and sensorimotor network. The resting balance within and / or between each of these networks differs in anxiety disorders.

[0336] Treating anxiety The present invention can be used to treat anxiety in patients with an anxiety disorder or another psychiatric or nervous system disorder associated with anxiety, and can also be used to treat anxiety in patients with sleep disorders, such as insomnia.

[0337] In patients with anxiety associated with another psychiatric or nervous system disorder or sleep disorder, such as insomnia, treatment of anxiety according to the present invention will result in an improvement in the anxiety-related condition.

[0338] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0339] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption resets pathological, maladaptive connections as networks reconnect. New, healthy functional connections are established with lasting effects.

[0340] Thus, in accordance with the present invention, influencing these networks by the treatment methods described herein results in an improvement in anxiety, and, if the patient being treated has another psychiatric or nervous system disorder that is associated with anxiety, also results in an improvement in that disorder, and, if the patient being treated has a sleep disorder, e.g., insomnia, also results in an improvement in the sleep disorder, e.g., insomnia.

[0341] To further support the clinical application of 5-MeO-DMT in patients with anxiety, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in anxiety that are also commonly observed in patients with other disorders.

[0342] These data are derived from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific condition, as discussed in more detail below, the inventors have determined that certain clinical observations made in this study are relevant for devising treatments for anxiety disorders and other anxiety-related conditions.

[0343] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, determined by the intensity of the patient-reported psychedelic experience.

[0344] Data collected included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvements in the overall MADRS score, we focused on the items that make up the various scales and found that certain subscore items, such as those related to anxiety, are related to other conditions. In this case, anxiety is based on similar changes in functional connectivity within and / or between resting-state networks.

[0345] Multiple patients within the recruited cohort showed significant improvement, and the results support our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0346] More specifically, an aspect that may be treated by administration of 5-MeO-DMT is anxiety. 5-MeO-DMT may be administered to a patient to reduce or eliminate anxiety in that patient.

[0347] A particularly relevant BPRS item in this context is "Anxiety." This item concerns reported anxiety, tension, fear, panic, or worry. Possible scores are: 1-No anxiety 2 - Very mild. Reports some discomfort due to worry or frequent worrying that occurs more than usual for most healthy people. 3 - Mild. Frequent anxiety, but able to quickly redirect attention elsewhere. 4 - Moderate. Worried most of the time and unable to easily attend to other things, but not interfering with function, or occasional involuntary anxiety, but not interfering with function. 5 - Moderately severe. Frequent but not constant involuntary anxiety, or some areas of functioning are disrupted by anxiety or worry. 6 - Severe. Constant involuntary anxiety, but not all day long, or many areas of functioning are disrupted by anxiety or persistent worry. 7 - Severe. Involuntary anxiety lasts all day or most areas of functioning are disrupted by anxiety or persistent worry.

[0348] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "anxiety" across all eight patients was 37 at baseline.

[0349] After 3 hours, it had decreased to 19, which corresponds to an 18-point or 49% improvement. One day after treatment, it had decreased to 16, which corresponds to a 21-point or 57% improvement. Seven days after treatment, it had decreased to 17, which corresponds to a 20-point or 54% improvement.

[0350] In the 12 mg group, the aggregate score for the BPRS item "anxiety" across all four patients was 25 at baseline.

[0351] After 3 hours, it had decreased to 11, which corresponds to a 14-point or 56% improvement. One day after treatment, it had decreased to 6, which corresponds to a 19-point or 76% improvement. Seven days after treatment, it had decreased to 6, which corresponds to a 19-point or 76% improvement.

[0352] The inventors conclude that 5-MeO-DMT may be used to treat anxiety in patients, for example, those suffering from anxiety disorders and those suffering from psychiatric or nervous system disorders associated with anxiety.

[0353] Thus, in accordance with the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0354] The MADRS item "Inner tension" describes a vague feeling of discomfort, irritability, inner confusion, or mental tension (ranging from panic, fear, or distress) that is rated according to intensity, frequency, duration, and need for reassurance.

[0355] A score of 0 is assigned if the patient is calm and only momentary inner tension is present. A score of 2 is assigned if irritability and vague discomfort occur occasionally. A score of 4 is assigned if there is a continuous inner tension or intermittent panic that the patient has some difficulty overcoming. A score of 6 is assigned if there is intense fear or anguish and insurmountable panic.

[0356] In the study involving patients with TRD, the aggregate score for the "internal tension" item on the MADRS across all eight patients in the study group receiving the individualized dosing regimen was 26 at baseline. After two hours, it had decreased to 11, corresponding to a 15-point or 58% improvement. One day after treatment, it had decreased to 6, corresponding to a 20-point or 77% improvement. Seven days after treatment, it had decreased to 12, corresponding to a 14-point or 54% improvement.

[0357] In the 12 mg group, the aggregate score for the MADRS item "internal tension" across all four patients was 13 at baseline. After two hours, it had decreased to 2, which corresponds to an 11-point or 85% improvement. One day after treatment, it had decreased to 3, which corresponds to a 10-point or 77% improvement. Seven days after treatment, it had decreased to 5, which corresponds to an 8-point or 62% improvement.

[0358] These results further support our conclusion that treatment according to the present invention reduces or eliminates symptoms of anxiety.

[0359] Treatment according to the present invention results in a clinical response in patients experiencing anxiety symptoms, reflected by at least a 50% reduction in the HAM-A score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, compared to the respective score before treatment.

[0360] The clinical response, reflected by at least a 50% reduction in the HAM-A score in a patient experiencing anxiety symptoms compared to their respective pre-treatment scores, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The clinical response, reflected by at least a 50% reduction in the HAM-A score in a patient experiencing anxiety symptoms, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0361] Amelioration of anxiety symptoms in a patient experiencing anxiety symptoms is reflected by a HAM-A score of 7 or less at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0362] In a patient experiencing anxiety symptoms, remission of anxiety symptoms, as reflected by a HAM-A score of 7 or less, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Remission of anxiety symptoms, as reflected by a HAM-A score of 7 or less, in a patient experiencing anxiety symptoms, persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0363] Thus, in accordance with the present invention, treating a patient suffering from anxiety with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0364] psychomotor inhibition The main aspects observed in patients with psychomotor depression are decreased energy and activity and decreased motivation.

[0365] Psychomotor retardation involves slowed thinking and reduced movement in an individual. Psychomotor impairment can cause noticeable slowing of physical and emotional responses.

[0366] Psychomotor retardation may be associated with a psychiatric or nervous system disorder or some other medical condition.

[0367] Mental or nervous system disorders leading to or associated with psychomotor depression include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depressive disorder, mental and behavioral disorders resulting from psychoactive substance use, such as substance use disorders (SUD), psychiatric disorders, such as schizophrenia, dementia, such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia and Parkinson's disease dementia, Parkinson's disease, chronic fatigue syndrome.

[0368] Psychomotor depression can also occur in patients suffering from sleep disorders, such as insomnia.

[0369] Measurement of psychomotor inhibition Psychomotor inhibition can be assessed by measuring various aspects, including various types of drawing tasks and tests, such as the Trail Making Test (TMT), the Digit Symbol Substitution Test (DSST), or the Gibson Spiral Maze Test (GSM), and others known in the art.

[0370] In the Trail Making Test (TMT), for example, subjects must connect 25 circles containing either numbers (TMT A) or number-letter combinations (TMT B) in ascending order. The task requirements are similar for TMT-B, except that subjects must alternate between numbers and letters (1, A, 2, B, 3, C, etc.). Thus, this test assesses processing speed (TMT A) or cognitive flexibility (TMT B). The score for each part represents the time taken to complete the task.

[0371] Another test that involves grapheme skills is the Gibson Spiral Maze (GSM), which assesses only psychomotor speed and is not affected by cognitive ability. To achieve the GSM, subjects must accurately trace a spiral maze from start to finish without touching the borders.

[0372] The Digit Symbol Substitution Test (DSST) also measures psychomotor speed and consists of number-symbol pairs and symbol lists. Subjects must write the corresponding symbol under each number as quickly as possible. The score consists of the number of symbols correctly reported in 90 seconds. A further example of a motor test is the finger tapping test.

[0373] Thus, certain tests combine measures of both the motor and cognitive aspects of psychomotor inhibition, while still other tests assess only the motor aspect.

[0374] Analysis of speech may be a further indicator of psychomotor retardation.

[0375] The main scales available for assessment and measurement include the severity of psychomotor depression, the Salpetriere Retardation Rating Scale (SRRS), and the Motor Agitation and Retardation Scale (MARS).

[0376] The Salpetriere Retardation Rating Scale (SRRS), developed by Widlocher, assesses cognitive and motor aspects with 15 items. The first three items measure the quality of movement, specifically the stride and slowness of limb, trunk, head, and neck movements. The next three items focus on speech, including speech flow, tone of voice, and duration of responses. Two items are designed to objectively measure cognitive function. These questions are based on interview conversations and measure the patient's ability to approach and develop a topic. Further items are subjective and assess rumination, fatigue, interest level, sense of time, memory, and concentration. The final item on this scale relates to an overall assessment of the patient's psychomotor retardation. These items are rated based on the severity of the presenting symptoms, ranging from 0 (no symptoms) to 4 (severe symptoms), with a total score ranging from 0 to 60.

[0377] The Motor Agitation and Retardation Scale (MARS) assesses only motor aspects. It was designed to assess psychomotor impairments in depressive disorders. Psychomotor impairments are divided into five major physical categories, including eyes, face, voice, limbs, and trunk, and the scale contains a total of 19 items. Items in the eye category include gaze direction, blink rate, gaze, and eye movements. Items associated with the face category include facial expression and facial expressivity. The voice category includes items such as voice volume, clarity, tone, and onset time. Items in the limb category include hand, foot, and leg movements, stride, slowness of movement, and hand tension. Items in the trunk category include posture, immobility, and axial movement. The severity of each item ranges from 1 to 4, with 4 being the most severe. Nine of the 19 items relate to motor agitation, and 10 assess motor inhibition. Inhibitory items include abnormal gait, trunk / proximal limb immobility, postural collapse, slowness of movement (i.e., limb and trunk category), lack of facial expressiveness, downcast gaze (i.e., eyes and face category), and reduced vocal volume, slurred speech, delayed speech initiation, monotonous speech (i.e., voice category). The MARS scale provides a rapid clinical assessment of motor signs.

[0378] Resting-state networks and psychomotor inhibition Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0379] Functional images of the brain are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signal are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0380] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal change are called resting-state networks (RSNs).

[0381] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the activity patterns seen in resting-state networks and task-based fMRI experiments.

[0382] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional architecture, which has been characterized as encompassing aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0383] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been shown to be impaired in various pathological conditions, including certain forms of psychomotor depression, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0384] For example, abnormalities in functional connectivity from the somatosensory-motor network (SMN) to the visual (VN), dorsal attention (DAN), and default mode networks have been reported, which correlated with both psychomotor inhibition and agitation in depressive disorders.

[0385] In many instances, resting-state networks involved in psychomotor inhibition are affected by psychiatric or nervous system disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), including bipolar I and II disorders, postpartum depression (PPD), seasonal affective disorder, and persistent depressive disorder, mental and behavioral disorders resulting from psychoactive substance use, including substance use disorders (SUDs), psychiatric disorders, such as schizophrenia, dementia, including Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia, and Parkinson's disease, Parkinson's disease, and chronic fatigue syndrome.

[0386] Resting-state networks involved in psychomotor inhibition are also affected by sleep disorders, such as insomnia, and indeed psychomotor inhibition and sleep disorders are correlated.

[0387] Treatment of psychomotor depression and mental or nervous system disorders According to the present invention, psychomotor retardation can be treated in patients suffering from psychiatric or nervous system disorders, and also in patients suffering from sleep disorders, such as insomnia.

[0388] In patients suffering from psychomotor depression associated with another condition detailed above, treatment of psychomotor depression according to the present invention will result in improvement of the condition associated with psychomotor depression.

[0389] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0390] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption resets pathological, maladaptive connections as networks reconnect. New, healthy functional connections are established with lasting effects.

[0391] Thus, in accordance with the present invention, influencing these resting state networks by the treatment methods described in the present invention results in an improvement in psychomotor inhibition, and in the case where the treated patient has a psychiatric or nervous system disorder, also results in an improvement in the disorder, and in the case where the treated patient has a sleep disorder, e.g., insomnia, also results in an improvement in the sleep disorder, e.g., insomnia.

[0392] To further support the clinical application of 5-MeO-DMT in patients suffering from psychomotor depression, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in psychomotor depression that are also commonly observed in patients with other disorders.

[0393] These data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific condition, as discussed in detail below, the inventors have determined that certain clinical observations made in this study are relevant for devising treatments for other conditions associated with psychomotor slowing.

[0394] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, determined by the intensity of the patient-reported psychedelic experience.

[0395] Data collected included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS). While the focus of this study was to demonstrate treatment efficacy through improvements in the overall MADRS score, we focused on the items that make up the various scales and found that certain subscores, such as those related to psychomotor inhibition, are related to other conditions. In this case, psychomotor inhibition is based on similar changes in functional connectivity within and / or between the somatomotor / sensorimotor network, visual network, dorsal attention network, and default mode network.

[0396] Multiple patients within the recruited cohort showed significant improvement, and the results support our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0397] More specifically, an aspect that may be treated by administration of 5-MeO-DMT is psychomotor depression. 5-MeO-DMT may be administered to a patient to reduce or eliminate psychomotor depression in that patient.

[0398] The MADRS scale item that is particularly relevant to psychomotor inhibition is "inhibition," which describes difficulty initiating or slowness in initiating and performing everyday activities.

[0399] A score of 0 means that there is almost no difficulty in starting anything and no slowness. A score of 2 is assigned if the patient has difficulty initiating activities. A score of 4 means that simple activities that are usually performed are difficult to start and require effort to perform. A score of 6 is assigned if there is complete inhibition and the patient is unable to do anything without assistance.

[0400] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "inhibition" across all eight patients was 27 at baseline.

[0401] After 2 hours, it had decreased to 10, which corresponds to a 17-point or 63% improvement. One day after treatment, it had decreased to 5, which corresponds to a 22-point or 81% improvement. Seven days after treatment, it had decreased to 3, which corresponds to a 24-point or 89% improvement.

[0402] In the 12 mg group, the aggregate score for the MADRS item "inhibition" across all four patients was 16 at baseline. After two hours, it decreased to 10, which corresponds to a 6-point or 38% improvement. One day after treatment, it decreased to 0, which corresponds to a 16-point or 100% improvement. Seven days after treatment, it decreased to 3, which corresponds to a 13-point or 81% improvement.

[0403] Thus, the score for "inhibition," a scale item particularly related to psychomotor retardation, is significantly improved. The inventors conclude that 5-MeO-DMT may be used to treat psychomotor retardation in patients, particularly those who also suffer from a psychiatric or nervous system disorder or a sleep disorder, such as insomnia.

[0404] Thus, in accordance with the present invention, treating a patient suffering from psychomotor depression with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the psychomotor depression.

[0405] Social / emotional withdrawal or detachment Symptoms such as anhedonia, emotional withdrawal, and flat affect are grouped together herein as social / emotional withdrawal or detachment. Decreased social engagement is a further aspect associated with social / emotional withdrawal or detachment.

[0406] Anhedonia is the inability to experience pleasure. A patient does not have anhedonia if they have no subjectively diminished ability to experience pleasure in usual activities. Anhedonia is mild if pleasure from normally pleasurable activities is slightly diminished, moderate if pleasure from normally pleasurable activities is greatly diminished or some pleasure from isolated activities is maintained, and severe if there is a complete inability to experience pleasure.

[0407] Anhedonia contains elements of completion (or liking) and anticipation (or wanting). Completion pleasure refers to the "in-the-moment" pleasure experienced by subjects directly involved in an enjoyable activity, while anticipatory pleasure refers to the experience of pleasure related to a future activity.

[0408] Flattened affect is characterized by a perceived decrease in the intensity or range of sensations or emotions. A subject does not exhibit flattened affect if they have no sensation of a decrease in the intensity or range of sensations or emotions. Mild affect is defined as a slight suppression of the range of emotions or a temporary decrease in the range or intensity of emotions; moderate affect is defined as a significant suppression of the range or intensity of emotions but with some emotion preserved, e.g., an inability to cry; and severe affect is defined as a marked and pervasive suppression of the range of emotions or an inability to experience normal emotions.

[0409] Emotional withdrawal or detachment is an inability or unwillingness to connect with others on an emotional level. For example, the BPRS includes an item regarding emotional withdrawal, which is characterized as a subject's lack of ability to relate emotionally during the interview situation. According to this BPRS item description, emotional withdrawal is not present if there is a lack of emotional engagement indicated by an occasional failure to comment reciprocally, an occasional absent-minded appearance, or a stiff smile, but spontaneous engagement with the interviewer most of the time. A mild form of emotional withdrawal is present if there is a lack of emotional engagement indicated by a noticeable failure to comment reciprocally, an absent-minded appearance, or a lack of warmth, but a response when approached by the interviewer. A moderate form of emotional withdrawal is present if emotional engagement is absent for much of the interview because the subject does not elaborate on their responses, fails to make eye contact, does not seem concerned about whether the interviewer is listening, or may be distracted by psychotic content. Furthermore, a moderately severe form is present if emotional engagement is absent for most of the interview. Severe is present when emotional engagement is actively avoided by the subject, or when the subject frequently does not respond, or responds with yes / no answers, or responds with minimal affect. Extremely severe is when the subject consistently avoids emotional engagement, is unresponsive, or responds with yes / no answers, or may drop out of the interview or not respond at all.

[0410] Reduced social engagement characterizes subjective reports of reduced social and interpersonal engagement or interaction. Reduced social engagement is absent when there is no report of reduced social and interpersonal engagement or interaction. It is mild, which is a slight reduction in social engagement without impairment of social or interpersonal functioning; moderate, which is a marked reduction in social engagement with some functional sequelae, e.g., avoidance of some social engagement or conversation; and severe, which is a marked reduction in social interaction or avoidance of nearly all forms of social contact, e.g., refusing to answer the phone or meet with people or family.

[0411] Social / emotional withdrawal or detachment may be associated with a psychiatric or neurological disorder or some other medical condition.

[0412] Mental or nervous system disorders leading to or associated with social / emotional withdrawal or detachment include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depressive disorder, anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD), obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD), post-traumatic stress disorder (PTSD), pain, and the like. Pain disorders, such as chronic pain and fibromyalgia, mental and behavioral disorders resulting from psychoactive substance use, such as substance use disorders (SUDs), psychiatric disorders, such as schizophrenia, dementia, such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia and frontotemporal dementia (FTD), Parkinson's disease (PD), eating disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0413] Social / emotional withdrawal or detachment can also manifest in patients with sleep disorders, eg, insomnia.

[0414] Social / emotional withdrawal or detachment can also occur in patients with medical health conditions that lead to related psychiatric or neurological conditions, including traumatic brain injury (TBI).

[0415] Measuring social / emotional withdrawal or detachment Social / emotional withdrawal or detachment (often referred to herein as social / emotional withdrawal), or its individual aspects, e.g., anhedonia, emotional withdrawal, and flat affect, can be assessed by different instruments, e.g., questionnaires or scales.

[0416] Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient has a specific mental or neurological disorder may include items related to social / emotional withdrawal or detachment.

[0417] The Snaith-Hamilton Pleasure Scale (SHAPS) is a 14-item scale measuring anhedonia, or the inability to experience pleasure. These items span the domains of social interaction, food and drink, sensory experience, and interests / recreation. A score of 2 or less constitutes a "normal" score, while an "abnormal" score is defined as 3 or greater. Each item has four possible responses: strongly disagree, disagree, agree, or strongly agree. Any "disagree" response scores 1, and any "agree" response scores 0. Thus, final scores range from 0 to 14. The SHAPS has adequate construct validity and satisfactory test-retest reliability. High internal consistency has also been reported. While the SHAPS has been used to measure anhedonia in depression, it is also frequently used to assess anhedonia in other patient populations.

[0418] In principle, SHAPS measures hedonic tone over the past few days using 14 hypothetical items, however, the hypothetical nature of the items allows for an appropriate shorter recall period to be applied at earlier assessment times.

[0419] Alternatively or additionally, anhedonia can be assessed using the Dimensional Anhedonia Rating Scale (DARS), which measures interest, motivation, effort, and pleasure of completion across four domains: hobbies, food / drink, social activities, and sensory experiences. It contains 17 items assessing current anhedonia. The DARS is rated on a 5-point Likert scale ranging from 0 (not at all) to 4 (very much), with higher scores indicating less anhedonia. All items are summed to obtain a total score ranging from 0 to 68. For each of the four hedonic domains, namely, hobbies (4 items, total score 0–16), food / drink (4 items, total score 0–16), social activities (4 items, total score 0–16), and sensory experiences (5 items, total score 0–20), participants are asked to provide two or three examples of their preferences.

[0420] The Personality Inventory for DSM-5 (PID-5)-Adult is a 220-item self-rating personality trait scale for adults aged 18 years and older. It assesses 25 personality trait dimensions, including anhedonia, anxiety, attention-seeking, callousness, deceptiveness, depression, distractibility, eccentricity, emotional lability, grandiosity, hostility, impulsivity, avoidance of intimacy, irresponsibility, manipulativeness, dysfunctional perceived control, perseverance, limited affect, rigid perfectionism, reckless risk-taking, separation anxiety, submissiveness, suspiciousness, unusual beliefs and experiences, and social withdrawal, with each dimension consisting of 4 to 14 items.

[0421] The trait dimension of anhedonia includes items 1, 23, 26, 30R, 124, 155R, 157, and 189 (reversed items are marked with the letter "R"), the trait dimension of withdrawal includes items 10, 20, 75, 82, 136, 146, 147, 161, 182, and 186, and the trait dimension of intimacy avoidance includes items 89, 97R, 108, 120, 145, and 203. These three trait dimensions can be combined to obtain a broader trait domain designated as detachment.

[0422] The measure is completed by individuals prior to visiting a clinician. Each item asks individuals to rate how well the item describes them generally.

[0423] Each item on this scale is rated on a 4-point scale. Response categories for these items are: 0 = very incorrect or often incorrect; 1 = sometimes or somewhat incorrect; 2 = sometimes or somewhat correct; and 3 = very correct or often correct. For items 7, 30, 35, 58, 87, 90, 96, 97, 98, 131, 142, 155, 164, 177, 210, and 215, these items are reverse coded before being used to calculate the scale score.

[0424] Scores for items within each trait dimension should be summed and placed in the appropriate raw dimension score box. Additionally, clinicians are asked to calculate and use mean scores for each dimension and domain. These mean scores reduce the overall and domain scores to a 4-point scale, allowing clinicians to assess an individual's personality dysfunction relative to observed norms. The mean dimension score is calculated by dividing the raw dimension score by the number of items within that dimension (e.g., if all items within the "anhedonia" dimension are rated "sometimes or somewhat true," the mean dimension score would be 16 / 8 = 2, indicating moderate anhedonia). The mean domain score is calculated by summing and then averaging the three dimension scores that primarily contribute to a particular domain. For example, if the mean dimension scores for anhedonia, intimacy avoidance, and withdrawal (a measure primarily indicative of detachment) are all 2, the sum of these scores would be 6, and the mean domain score would be 6 / 3 = 2. A higher mean score indicates greater dysfunction within a particular personality trait dimension or domain.

[0425] High scores on any aspect or domain may indicate an area of ​​importance and problem for the individual receiving care, which may require further assessment, treatment, and follow-up.

[0426] Resting-state networks and social / emotional withdrawal or detachment Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0427] Functional images of the brain are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signal are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0428] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal change are called resting-state networks (RSNs).

[0429] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the activity patterns seen in resting-state networks and task-based fMRI experiments.

[0430] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional architecture, which has been characterized as encompassing aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0431] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks are known to be impaired in various pathological conditions, including certain forms of social / emotional withdrawal or detachment, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0432] Alterations in the RSNs are also involved in anhedonia, a key aspect of social / emotional withdrawal or detachment. More specifically, anhedonia is associated with hyperconnectivity in the visual network and expansion of the visual network, dorsal attention network (DAN), and default mode network (DMN). Anhedonia is also accompanied by decreased inter-network connectivity between the DMN, salience, DAN, somatomotor, and visual networks.

[0433] Furthermore, emotional detachment in adult psychopathy is associated with structural abnormalities in the dorsal DMN. The dorsal DMN is particularly important in the development of psychopathy due to its associated functions. Specifically, the dorsal DMN and the regions it connects with (the medial prefrontal cortex and posterior cingulate cortex (PCC)) support emotional, social, and moral processing. In adult psychopathy, microstructural abnormalities within the dorsal DMN are associated with the emotional and interpersonal differences that define this disorder.

[0434] Thus, patients with social / emotional withdrawal or detachment exhibit altered functional connectivity within and / or between RSNs when compared to age-matched healthy controls. Alterations are observed within and / or between the DMN, salience, DAN, somatomotor, and visual networks.

[0435] In many instances, RSNs involved in social / emotional withdrawal or detachment are associated with psychiatric or nervous system disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorders (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depressive disorder, anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD), obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD), post-traumatic stress disorder (PTSD), pain, and the like. These include sexual disorders such as chronic pain and fibromyalgia, mental and behavioral disorders resulting from psychoactive substance use such as substance use disorders (SUDs), psychiatric disorders such as schizophrenia, dementia such as Alzheimer's disease (AD), dementia with Lewy bodies (DLB), vascular dementia and frontotemporal dementia (FTD), Parkinson's disease (PD), eating disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and personality disorders such as schizotypal personality disorder and borderline personality disorder (BPD).

[0436] Resting-state networks involved in social / emotional withdrawal or detachment are also affected by mental or neurological conditions that are the result of certain medical health conditions, such as traumatic brain injury (TBI).

[0437] Resting-state networks involved in social / emotional withdrawal or detachment are also affected by sleep disorders, such as insomnia, and indeed, social / emotional withdrawal or detachment and sleep disorders are correlated.

[0438] Treatment of social / emotional withdrawal or detachment and mental or nervous system disorders According to the present invention, social / emotional withdrawal or detachment occurring in patients with psychiatric or nervous system disorders can be treated, and also in patients with sleep disorders, such as insomnia.

[0439] In patients with social / emotional withdrawal or detachment associated with another condition detailed above, treatment of social / emotional withdrawal or detachment according to the present invention results in improvement of the condition associated with the social / emotional withdrawal or detachment.

[0440] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0441] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption resets pathological, maladaptive connections as networks reconnect. New, healthy functional connections are established with lasting effects.

[0442] Thus, in accordance with the present invention, influencing these networks by the treatment methods described in the present invention results in an improvement in social / emotional withdrawal or detachment, and in the case where the patient being treated has a psychiatric or nervous system disorder, also results in an improvement in the disorder, and in the case where the patient being treated has a sleep disorder, such as insomnia, also results in an improvement in the sleep disorder, such as insomnia.

[0443] To further support the clinical application of 5-MeO-DMT in patients with social / emotional withdrawal or detachment, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and found specific improvements in social / emotional withdrawal or detachment that are also commonly observed in patients with other disorders.

[0444] These data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific condition, as discussed in more detail below, the inventors have determined that certain clinical observations made in this study may be relevant for designing treatments for other conditions related to social / emotional withdrawal or detachment.

[0445] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, determined by the intensity of the patient-reported psychedelic experience.

[0446] Data collected included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvements in the overall MADRS score, we focused on the items that make up the various scales and found that certain subscores, such as those related to social / emotional withdrawal or detachment, are associated with other conditions. In this case, social / emotional withdrawal or detachment is based on similar changes in functional connectivity within and / or between the default mode network, salience, dorsal attention, somatomotor, and visual networks.

[0447] Multiple patients within the recruited cohort showed significant improvement, and the results support our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0448] More specifically, the aspect that can be treated by administering 5-MeO-DMT is social / emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and / or flattened affect. A further aspect that can be treated is reduced social engagement. 5-MeO-DMT can be administered to a patient to reduce or eliminate social / emotional withdrawal or detachment, particularly anhedonia, emotional withdrawal, and / or flattened affect, in the patient. Furthermore, reduced social engagement is improved, i.e., it is reduced or eliminated.

[0449] The MADRS scale item "Inability to have emotions," which is particularly relevant to social / emotional withdrawal or detachment, refers to a perceived diminished interest in one's surroundings or in normally enjoyable activities. There is a diminished ability to respond emotionally to situations or people in one's surroundings.

[0450] A score of 0 indicates normal interest in surroundings and other people, a score of 2 indicates a diminished ability to enjoy things that normally interest one. A score of 4 is assigned in cases of loss of interest in surroundings and loss of emotion toward friends and acquaintances. A score of 6 reflects an experience of emotional numbness, an inability to feel anger, deep sadness, or joy, and a complete or distressing inability to care for close relatives and friends.

[0451] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inability to Have Emotions" across all eight patients was 36 at baseline. After two hours, it was reduced to 12, which corresponds to a 24-point or 67% improvement. One day after treatment, it was reduced to 2, which corresponds to a 34-point or 94% improvement. Seven days after treatment, it was reduced to 6, which corresponds to a 30-point or 83% improvement.

[0452] In the 12 mg group, the aggregate score for the MADRS item "Inability to Have Emotions" across all four patients was 16 at baseline. After two hours, it was reduced to 9, which corresponds to a 7-point or 44% improvement. After one day of treatment, it was reduced to 1, which corresponds to a 15-point or 94% improvement. After seven days of treatment, it was reduced to 1, which corresponds to a 15-point or 94% improvement.

[0453] Items on the BPRS scale that are particularly relevant to social / emotional withdrawal or detachment are "emotional withdrawal" and "affective blunting."

[0454] The BPRS item "Emotional Withdrawal" relates to the patient's lack of ability to relate emotionally in the interview situation. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. There is a lack of emotional engagement indicated by occasional failure to comment reciprocally, an occasional absent-minded look, or a stiff smile, but most of the time there is spontaneous engagement with the interviewer. 3 - Mild. Lack of emotional engagement indicated by a noticeable failure to comment reciprocally, appearing absent-minded, or lacking warmth but responding when approached by the interviewer. 4 - Moderate. Emotional contact is absent for much of the interview because the subject does not elaborate on responses, fails to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychotic content. 5 - Moderately severe. Same as 4, but emotional contact is absent for most of the interview. 6 - Severe. Actively avoids emotional involvement. Frequently does not respond or responds with yes / no answers (not simply due to paranoia). Responds with minimal affect. 7 - Most severe. Consistently avoids emotional involvement. Does not respond or responds with yes / no answers (not simply due to paranoia). May abandon interview or not respond at all.

[0455] The aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, it was reduced to 8, which corresponds to a 5-point or 38% improvement. After 1 day of treatment, it was reduced to 8, which corresponds to a 5-point or 38% improvement. After 7 days of treatment, it was reduced to 8, which corresponds to a 5-point or 38% improvement.

[0456] In the 12 mg group, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, it decreased to 11, which corresponds to a 2-point or 15% improvement. After 1 day of treatment, it decreased to 8, which corresponds to a 5-point or 38% improvement. After 7 days of treatment, it decreased to 6, which corresponds to a 7-point or 54% improvement.

[0457] The BPRS item "Bluted Affect" concerns a restricted range of emotional expression in face, voice, and body language, and a marked indifference or flatness even when discussing distressing topics. Possible scores are: 1- No emotional blunting. 2 - Very mild. Emotional range is somewhat subdued or reserved, but facial expression and tone of voice are within the normal range and appropriate. 3 - Mild. Overall range of emotion is reduced, inhibited, or reserved, with few spontaneous and appropriate emotional responses. Voice tone is slightly monotonous. 4 - Moderate. The range of affect is significantly reduced; the patient does not show emotion or smile, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Expressive emotion or gestures usually are followed by a return to flat affect. 5 - Moderately severe. The range of emotion is severely reduced; the patient does not show emotion or smile, or responds minimally to distressing topics, gestures very little, and facial expression rarely changes. The tone of voice is often monotonous. 6 - Severe. Little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expressions are constant. Voice tone is monotonous most of the time. 7 - Most severe. Virtually no emotional range or expression, stiff movements, monotonous tone of voice throughout the entire time.

[0458] The aggregate score for the BPRS item "blunted affect" was 15 at baseline. After 3 hours, it decreased to 11, which corresponds to a 4-point or 27% improvement. After 1 day of treatment, it decreased to 8, which corresponds to a 7-point or 47% improvement. After 7 days of treatment, it decreased to 8, which corresponds to a 7-point or 47% improvement.

[0459] In the 12 mg group, the aggregate score for the BPRS item "blunted affect" was 11 at baseline. After 3 hours, it decreased to 8, which corresponds to a 3-point or 27% improvement. After 1 day of treatment, it decreased to 6, which corresponds to a 5-point or 45% improvement. After 7 days of treatment, it decreased to 5, which corresponds to a 6-point or 55% improvement.

[0460] Thus, scores on scales specifically related to social / emotional withdrawal or detachment, i.e., "unable to have emotions" (MADRS), "emotional withdrawal" (BPRS), and "blunted affect" (BPRS), are significantly improved. The inventors conclude that 5-MeO-DMT may be used to treat social / emotional withdrawal or detachment in patients, particularly those who also suffer from psychiatric or nervous system disorders or sleep disorders, such as insomnia.

[0461] Thus, in accordance with the present invention, treating a patient suffering from social / emotional withdrawal or detachment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the social / emotional withdrawal or detachment.

[0462] Negative thinking Symptoms such as pessimism, feelings of worthlessness, powerlessness and hopelessness, as well as pathological, excessive or inappropriate guilt, are grouped together herein as negative thoughts.

[0463] Helplessness and hopelessness (also simply referred to as helplessness and despair) are characterized by subjective pessimism or worry about the future, a sense of inability to cope, or a lack of control. If the patient does not have such feelings, helplessness and despair are not present. Helplessness and despair are mild when there is an occasional mild feeling of not being able to cope as usual or pessimism; moderate when the patient often feels unable to cope or has significant feelings of helplessness or despair with occasional relief; and severe when the pessimism, helplessness, or despair are markedly and persistently present.

[0464] Feelings of worthlessness (also simply called worthlessness) are characterized by awareness or thoughts of decreased self-worth or self-esteem. If the patient does not have such feelings, there is no worthlessness. They may be mild, i.e., a slightly reduced sense of self-worth; moderate, i.e., some thoughts of worthlessness and decreased self-esteem; or severe, i.e., a pronounced, pervasive, or persistent feeling of worthlessness, e.g., feeling that others would be better off without you, being unable to recognize your positive qualities.

[0465] Guilt (also simply called guilt) is characterized by a sense of self-blame, failure, or remorse for real or imagined past wrongdoings. If the patient does not have such feelings, there is no guilt. Mild is characterized by a slight decrease in self-esteem or a slight increase in self-criticism; moderate is characterized by significant thoughts of failure, self-criticism, inability to cope, or rumination about past failures and the impact on others, perceived as excessive; and severe is characterized by marked, pervasive, or persistent guilt, e.g., a sense of deserving punishment, or a lack of clear perception that it is excessive.

[0466] Negative thoughts may be associated with a psychiatric or neurological disorder or some other medical condition.

[0467] Mental or nervous system disorders leading to or associated with negative thinking include disorders characterized by depressive episodes, such as major depressive disorder (MDD), bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depressive disorder, anxiety disorders, such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD), obsessive-compulsive 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 resulting from psychoactive substance use, such as substance use disorders (SUD), psychiatric disorders, such as schizophrenia, dementia, such as Alzheimer's disease (AD), eating disorders, attention deficit hyperactivity disorder (ADHD), personality disorders, such as schizotypal personality disorder and borderline personality disorder (BPD).

[0468] Negative thinking can also occur in patients with sleep disorders, such as insomnia.

[0469] Negative thinking can also occur in patients with medical health conditions that lead to related mental or neurological conditions, including traumatic brain injury (TBI).

[0470] Measuring negative thinking Negative thoughts or individual aspects thereof, such as worthlessness, powerlessness and hopelessness, and guilt, can be assessed by different instruments, such as questionnaires or scales.

[0471] Questionnaires assess a patient's mental state based on observations made by the patient, their caregiver, or the clinician administering the questionnaire. Questionnaires used to assess whether a patient has a particular mental or nervous system disorder may include items related to negative thinking.

[0472] Scales assessing relevant aspects of negative thinking include, for example, the State Shame and Guilt Scale (SSGS), the Positive and Negative Affect Schedule-Expanded Form (PANAS-X), or the State Hope Scale (SHS).

[0473] The State Shame and Guilt Scale (SSGS) is a self-assessment scale of momentary (state) feelings of shame and guilt. It contains two subscales: the shame and guilt 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 rated on a 5-point Likert scale. It includes several statements that may or may not describe how the patient is currently feeling. Higher scores indicate stronger feelings of shame or guilt.

[0474] The Positive and Negative Affect Schedule-Expanded Form (PANAS-X) is a 60-item expanded version of the PANAS. The PANAS-X measures 11 specific emotions: fear, sadness, guilt, hostility, shyness, fatigue, surprise, enjoyment, confidence, concentration, and calmness. Thus, the PANAS-X provides a measure of mood at two distinct levels. The basic negative affect scales are fear, hostility, guilt, and sadness, and the guilt scale encompasses six items: guilt, shame, blameworthiness, anger at self, self-hatred, and dissatisfaction with self. Each response is scored as 1 = very little or not at all, 2 = slightly, 3 = moderate, 4 = quite a bit, or 5 = extremely. However, researchers facing more severe time constraints may choose to select and assess only those measures most relevant to their study.

[0475] Stronger feelings of guilt are reflected by higher scores on the guilt scale.

[0476] The PANAS-X is simple and easy to administer. Most subjects complete the entire 60-item schedule in 10 minutes or less. The scale consists of many words and phrases that describe various sensations and emotions. Although patients are required to indicate the extent to which they have felt this way over the past few weeks, trait scores on the PANAS-X scale have been found to be stable over time, including between "at this time," "today," and "the past few days," indicating that an adequately short recall period can be applied.

[0477] The State Hope Scale (SHS) has three intention and three planning items, on which respondents describe how they feel "right now." The intention subscale score is obtained by summing items 2, 4, and 6, which relate to the perceived ability to use plans to achieve desired goals, and the planning subscale score is obtained by adding items 1, 3, and 5, which relate to the thoughts used to identify possible ways to achieve goals. The State Hope Scale total score is obtained by summing the three intention and three planning items. Scores can range from a minimum of 6 to a maximum of 48, with higher hope reflected by a higher score on this scale.

[0478] Negative thinking or aspects thereof are also reflected in other scales, such as the HAM-D, MADRS, BPRS, or BDRS, whose relevant items may be generally applicable to assessing negative thinking or aspects thereof.

[0479] Resting-state network and negative thoughts Brain processes can be investigated by functional magnetic resonance imaging (fMRI): brain activity is related to blood flow, and temporal correlations of spontaneous blood oxygen level-dependent (BOLD) signal fluctuations between different brain regions can be measured.

[0480] Functional images of the brain are acquired over several minutes. Oscillatory patterns of low-frequency BOLD signal are observed throughout the brain. Decomposition of this spontaneous signal reveals distributed regions with correlated and anticorrelated fluctuations.

[0481] Resting-state fMRI can thus be used to characterize large-scale functional networks, so-called resting-state networks (RSNs), which are spatially distinct sets of brain regions that exhibit coordinated activity in the absence of any explicit cognitive task (i.e., at rest). The observed patterns that characterize networks of brain regions with coherent patterns of signal change are called resting-state networks (RSNs).

[0482] Distinct resting-state networks have been identified and named primarily based on spatial similarities between the activity patterns seen in resting-state networks and task-based fMRI experiments.

[0483] Resting-state fMRI can therefore be used to assess the brain's intrinsic functional architecture, which has been characterized as encompassing aspects of attention, memory, cognitive control, default mode, motor, and sensory systems.

[0484] RSNs have been shown to be responsible for various aspects of complex brain function, and these connectivity networks have been shown to be impaired in various pathological conditions, including certain forms of negative thinking, which are associated with altered functional connectivity between one or more regions within a particular resting-state network and / or within one or more additional resting-state networks.

[0485] Major depressive disorder (MDD) is a disorder broadly characterized by high levels of negative affect and low levels of positive affect. More specifically, low levels of positive affect, e.g., hope, are associated with high levels of despair and high levels of negative affect, e.g., guilt. MDD has been the focus of research in the field of rs-fMRI, which indicates that MDD is a disorder characterized by large-scale network dysfunction. This dysfunction has been observed primarily in networks and regions related to emotion regulation. These include the default mode network (DMN), salience network, affect network, and prefrontal cortex. Therefore, different aspects of negative thinking may be associated with abnormal resting-state networks.

[0486] Functional connectivity abnormalities in resting-state networks have also been reported in patients with repetitive negative thinking (RNT), including altered connectivity between the left executive control network and the anterior salience network and ventral default mode network.

[0487] Thus, patients with negative thinking exhibit altered functional connectivity within and / or between resting-state networks when compared to age-matched healthy controls, with alterations observed within and / or between at least the default mode network, executive control network, salience network, emotion network, and prefrontal cortex.

[0488] In many instances, RSNs involved in negative thinking are affected by mental or nervous system disorders, such as disorders characterized by depressive episodes, e.g., major depressive disorder (MDD), bipolar disorders (BD), e.g., bipolar I disorder and bipolar II disorder, postpartum depression (PPD), seasonal affective disorder and persistent depressive disorder, anxiety disorders, e.g., generalized anxiety disorder (GAD) and social anxiety disorder (SAD), obsessive-compulsive disorder and related disorders, e.g., obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD), post-traumatic stress disorder (PTSD), pain disorders, e.g., chronic pain, mental and behavioral disorders resulting from psychoactive substance use, e.g., substance use disorder (SUD), psychiatric disorders, e.g., schizophrenia, dementia, e.g., Alzheimer's disease (AD), eating disorders, attention-deficit hyperactivity disorder (ADHD), personality disorders, e.g., schizotypal personality disorder and borderline personality disorder (BPD).

[0489] Resting-state networks involved in negative thinking are also affected by mental or neurological conditions that are the result of certain medical health conditions, such as traumatic brain injury (TBI).

[0490] The resting-state network involved in negative thinking is also affected by sleep disorders, such as insomnia, and in fact, negative thinking and sleep disorders are correlated.

[0491] Treatment of negative thinking and mental or nervous system disorders According to the present invention, negative thoughts occurring in patients with mental disorders or nervous system disorders can be treated, and further, negative thoughts occurring in patients with sleep disorders, such as insomnia, can be treated.

[0492] In patients with negative thoughts associated with another condition detailed above, treatment of the negative thoughts in accordance with the present invention will result in an improvement in the condition associated with the negative thoughts.

[0493] Treatment according to the present invention is by administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0494] 5-MeO-DMT administered to patients disrupts established functional connectivity patterns within and / or between resting-state networks. This disruption resets pathological, maladaptive connections as networks reconnect. New, healthy functional connections are established with lasting effects.

[0495] Thus, in accordance with the present invention, influencing these networks by the treatment methods described in the present invention results in an improvement in negative thinking, and in the case where the patient being treated has a psychiatric or nervous system disorder, also results in an improvement in the disorder, and in the case where the patient being treated has a sleep disorder, e.g., insomnia, also results in an improvement in the sleep disorder, e.g., insomnia.

[0496] To further support the clinical application of 5-MeO-DMT in patients with negative thinking, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric disorders and observed specific improvements in negative thinking that are also commonly observed in patients with other disorders.

[0497] These data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. While TRD is a specific condition, as discussed in more detail below, the inventors have determined that certain clinical observations made in this study may be relevant for devising treatments for other conditions associated with negative thinking.

[0498] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, determined by the intensity of the patient-reported psychedelic experience.

[0499] Data collected included assessments of treated patients on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various scales and found that certain subscores, such as those related to negative thinking, are associated with other conditions. In this case, negative thinking is based on similar changes in functional connectivity within and / or between the default mode network, executive control network, salience network, emotion network, and prefrontal cortex.

[0500] Multiple patients within the recruited cohort showed significant improvement, and the results support our findings that 5-MeO-DMT is a suitable compound for treating patients with these conditions.

[0501] More specifically, aspects that may be treated by administration of 5-MeO-DMT are negative thoughts, particularly feelings of worthlessness, helplessness and hopelessness, and / or guilt. 5-MeO-DMT may be administered to a patient to reduce or eliminate negative thoughts, particularly feelings of worthlessness, helplessness and hopelessness, and / or guilt in the patient.

[0502] The item on the MADRS scale that is particularly relevant to negative thinking is "pessimistic thinking," which refers to thoughts of guilt, inferiority, self-blame, guilt, regret, and doom and gloom.

[0503] A score of 0 is assigned if there are no pessimistic thoughts. A score of 2 is assigned if there are fluctuating thoughts of failure, self-blame, or self-deprecation. A score of 3 is assigned if there are persistent self-blame or clear but reasonable thoughts of guilt or guilt, and the patient is increasingly pessimistic about the future. A score of 6 is assigned if there are delusions of destruction, remorse, or irredeemable guilt, and irrational, unwavering self-blame.

[0504] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "pessimistic thinking" across all eight patients was 28 at baseline.

[0505] After 2 hours, it had decreased to 7, which corresponds to a 21-point or 75% improvement. One day after treatment, it had decreased to 4, which corresponds to a 24-point or 86% improvement. Seven days after treatment, it had decreased to 3, which corresponds to a 25-point or 89% improvement.

[0506] In the 12 mg group, the aggregate score for the MADRS item "pessimistic thinking" across all four patients was 16 at baseline. After two hours, it had decreased to 8, which corresponds to an 8-point or 50% improvement. One day after treatment, it had decreased to 7, which corresponds to a 9-point or 56% improvement.

[0507] Seven days after treatment, it had decreased to 8, which corresponds to an 8-point or 50% improvement.

[0508] The BPRS item that is particularly relevant to negative thinking is "Guilt." This item concerns excessive preoccupation with or remorse for past actions. Possible scores are: 1- No guilt. 2 - Very mild. Preoccupied with disappointing someone or failing at something, but not distracted. Can easily shift thoughts to other things. 3 - Mild. Somewhat preoccupied with disappointment or failure. Tends to express guilt to others. 4 - Moderate. Disproportionate preoccupation with guilt, having done something wrong, or hurting others through something done or failed to do, but able to quickly shift attention elsewhere. 5 - Moderately severe. Preoccupied with guilt, disappointment, or failure; able to focus elsewhere, but only with great effort. Not delusional. 6 - Severe, delusions of guilt or irrational self-blame that is largely unrelated to the situation. Moderate preoccupation is present. 7 - Severe. Delusions of guilt or irrational self-blame that is highly unrelated to the situation. Subject is so preoccupied with guilt that they may reveal or act on their delusions.

[0509] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "guilt" across all eight patients was 34 at baseline.

[0510] After 3 hours, it had decreased to 14, which corresponds to a 20-point or 59% improvement. One day after treatment, it had decreased to 11, which corresponds to a 23-point or 68% improvement. Seven days after treatment, it had decreased to 10, which corresponds to a 24-point or 71% improvement.

[0511] In the 12 mg group, the aggregate score for the BPRS item "guilt" across all four patients was 18 at baseline.

[0512] After 3 hours, it was reduced to 9, which corresponds to a 9-point or 50% improvement. After 1 day of treatment, it was reduced to 5, which corresponds to a 13-point or 72% improvement. After 7 days of treatment, it was reduced to 5, which corresponds to a 13-point or 72% improvement.

[0513] Thus, the MADRS scale item "Pessimistic thinking," which is particularly related to negative thinking, significantly improves, as does the score for the BPRS item "Guilt." The inventors conclude that 5-MeO-DMT may be used to treat negative thinking in patients, particularly those who also suffer from psychiatric or nervous system disorders or sleep disorders, such as insomnia.

[0514] Thus, in accordance with the present invention, treating a patient experiencing negative thoughts with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates the negative thoughts.

[0515] Maternal function In addition to the above, the inventors believe that psychiatric or nervous system disorders as defined herein, particularly disorders involving one or more symptoms selected from sleep disturbances, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking, impair maternal functioning. Indeed, each of the described symptoms, on its own, has the potential to impair maternal functioning (and thus is independently treatable).

[0516] The first year after birth is particularly crucial for both mother and child, as in most cases the mother is the primary caregiver and therefore shoulders the majority of the childcare tasks.

[0517] Maternal functioning includes maternal competence in relation to interaction with the child(ren) and aspects of maternal self-care.

[0518] Maternal functioning, including the emotional aspects of motherhood, is also important for child development. Indeed, the quality of mother-infant interactions during the first year of life influences child development. High levels of maternal functioning are likely to correlate with favorable child developmental outcomes. Similarly, dysfunction in the postpartum period may prevent optimal child development.

[0519] The Barkin Index of Maternal Functioning (BIMF) is designed to measure functioning during the first year after delivery. The BIMF is a 20-item self-report measure of functioning. Each item is assigned a score from 0 to 6, with a maximum total score of 120. Higher scores indicate better maternal functioning.

[0520] The BIMF identifies the main domains of maternal functioning during the postnatal period as self-care, parenting, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0521] A BIMF score of 95 or less is considered herein to represent slightly impaired maternal function, a score of 80 or less is considered herein to represent impaired maternal function, and a score of 65 or less is considered herein to represent severely impaired maternal function. The present invention particularly allows for improvement of maternal function in patients with a pre-treatment score of 80 or less, and even in patients with a score of 65 or less.

[0522] As already indicated above, the present invention allows the treatment of patients suffering from psychiatric or neurological disorders, which treatment not only results in a reduction in scores assessing the severity of depression, but also improves maternal functioning, as detailed below.

[0523] To further support the clinical application of 5-MeO-DMT in patients with psychiatric or neurological disorders, the inventors evaluated clinical data related to the use of 5-MeO-DMT in patients treated for psychiatric illness and observed specific improvements in aspects of the illness commonly observed in patients with psychiatric or neurological disorders. The inventors noted, in particular, improvements in various symptoms and symptom combinations that the inventors determined were also related to maternal function.

[0524] These data come from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). These results have been confirmed by a recent study in patients with postpartum depression (see the Examples section below).

[0525] In this TRD clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, as determined by the intensity of the patient-reported psychedelic experience.

[0526] Data collected included treated patients' ratings on several scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of this study was to demonstrate treatment efficacy through improvement in the overall MADRS score, the inventors focused on the items that make up the various scales and found that some subscore items were particularly relevant to patients with psychiatric or neurological disorders and to maternal functioning.

[0527] Multiple patients within the recruited cohort showed significant improvement in one or more of these subscore items, and the results support our findings that 5-MeO-DMT is a suitable compound for treating patients with psychiatric or neurological disorders and for improving maternal function in these patients.

[0528] The specific subscore items within each of these scales are identified in more detail below. We conclude that effectiveness in treating one or more of these symptoms results in a significant improvement in overall outcome in patients with psychiatric or nervous system disorders treated with 5-MeO-DMT.

[0529] Thus, treatment according to the present invention reduces or eliminates (or ameliorates or eliminates) aspects of the disease.

[0530] When this aspect is assessed on the MADRS scale, there is an improvement (reduction) of at least 1 point, or the patient is in complete remission (elimination) after treatment, i.e., the respective aspect is scored as 0.

[0531] When this aspect is assessed on the BPRS scale, there is an improvement (reduction) of at least 1 point, or the patient is in complete remission (elimination) after treatment, i.e., each aspect is scored as 1.

[0532] Clinical response may also be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S score of at least 1. Preferably, the CGI-S score decreases by at least 2 and / or to a score of 0. In particular, a decrease in the CGI-S score of at least 3 and / or to a score of 0 is preferred.

[0533] The inventors further believe that improvements observed on certain MADRS items translate into improvements in aspects of maternal functioning.

[0534] Particularly relevant MADRS items are discussed in more detail below.

[0535] The MADRS item "Inner tension" describes a vague feeling of discomfort, irritability, inner confusion, or mental tension (ranging from panic, fear, or distress) that is rated according to intensity, frequency, duration, and need for reassurance.

[0536] A score of 0 is assigned if the patient is calm and only momentary inner tension is present. A score of 2 is assigned if irritability and vague discomfort occur occasionally. A score of 4 is assigned if there is a continuous inner tension or intermittent panic that the patient has some difficulty overcoming. A score of 6 is assigned if there is intense fear or anguish and insurmountable panic.

[0537] The inventors have determined that an increase in the score on the "internal strain" item of the MADRS negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increase in the score on the "internal strain" item of the MADRS impairs mother-child interaction and maternal psychological well-being as assessed by the BIMF.

[0538] Conversely, improvement on these MADRS items leads to improvement in maternal functioning, particularly in the BIMF functional domains of mother-infant interaction and / or maternal psychological well-being.

[0539] In the study involving patients with TRD, the aggregate score for the "internal tension" item on the MADRS across all eight patients in the study group receiving the individualized dosing regimen was 26 at baseline. After two hours, it had decreased to 11, corresponding to a 15-point or 58% improvement. One day after treatment, it had decreased to 6, corresponding to a 20-point or 77% improvement. Seven days after treatment, it had decreased to 12, corresponding to a 14-point or 54% improvement.

[0540] In the 12 mg group, the aggregate score for the MADRS item "internal tension" across all four patients was 13 at baseline. After two hours, it had decreased to 2, which corresponds to an 11-point or 85% improvement. One day after treatment, it had decreased to 3, which corresponds to a 10-point or 77% improvement. Seven days after treatment, it had decreased to 5, which corresponds to an 8-point or 62% improvement.

[0541] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of inner tension may be achieved.

[0542] Improvement in inner tone is reflected by an improvement in the inner tone score of at least the MADRS item at about 2 hours, day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0543] Improvement in inner tension, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0544] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0545] Improvement in inner tension, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0546] The improvement in inner tension, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] The inventors further conclude that the reduction or elimination of inner tension achieved by treating patients with psychiatric or nervous system disorders leads to an improvement in maternal functioning, as reflected not only by a decrease in the MADRS total score but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score is also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0548] Since inner strain also influences other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "inner strain" further contributes to a general improvement in maternal functioning.

[0549] The MADRS item "Inhibition" refers to difficulty initiating or slowness in initiating and performing daily activities.

[0550] A score of 0 means that there is almost no difficulty in starting anything and no slowness. A score of 2 is assigned if the patient has difficulty initiating activities. A score of 4 means that simple activities that are usually performed are difficult to start and require effort to perform. A score of 6 is assigned if there is complete inhibition and the patient is unable to do anything without assistance.

[0551] The inventors have determined that an increased score on the "restraint" item of the MADRS negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the "restraint" item of the MADRS impairs parenting, self-care, emotional well-being, control, and adjustment.

[0552] Conversely, improvement on these MADRS items would translate to improvements in maternal functioning, particularly the BIMF functional domains of parenting, self-care, emotional fulfillment, control, and / or adjustment.

[0553] In the study group receiving the individualized dosing regimen, the aggregate score for the "inhibition" item on the MADRS across all eight patients was 27 at baseline. After two hours, it decreased to 10, which corresponds to a 17-point or 63% improvement. One day after treatment, it decreased to 5, which corresponds to a 22-point or 81% improvement. Seven days after treatment, it decreased to 3, which corresponds to a 24-point or 89% improvement.

[0554] In the 12 mg group, the aggregate score for the MADRS item "inhibition" across all four patients was 16 at baseline. After two hours, it decreased to 10, which corresponds to a 6-point or 38% improvement. One day after treatment, it decreased to 0, which corresponds to a 16-point or 100% improvement. Seven days after treatment, it decreased to 3, which corresponds to a 13-point or 81% improvement.

[0555] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of inhibition may be achieved.

[0556] Improved inhibition is reflected by an improvement in inhibition scores for at least the MADRS items at about 2 hours, day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] Improvement in inhibition, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0558] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0559] Improved inhibition, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0560] The improvement in inhibition, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0561] The inventors further conclude that the reduction or elimination of inhibition achieved by treatment of patients with psychiatric or nervous system disorders leads not only to a decrease in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is rapid, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score is also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28. Because inhibition also affects other aspects of psychiatric or nervous system disorders, the inventors conclude that the improvement observed in the "Inhibition" item on the MADRS further contributes to an overall improvement in maternal functioning.

[0562] The MADRS item "Inability to have emotions" refers to awareness of a decreased interest in one's surroundings or in normally enjoyable activities. There is a decreased ability to respond emotionally to situations or people around one's surroundings.

[0563] A score of 0 indicates normal interest in surroundings and other people, a score of 2 indicates a diminished ability to enjoy things that normally interest one. A score of 4 is assigned in cases of loss of interest in surroundings and loss of emotion toward friends and acquaintances. A score of 6 reflects an experience of emotional numbness, an inability to feel anger, deep sadness, or joy, and a complete or distressing inability to care for close relatives and friends.

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

[0565] Conversely, improvement on these MADRS items leads to improvement in maternal functioning, particularly in the BIMF functional domains of mother-child interaction and / or psychological well-being.

[0566] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inability to Have Emotions" across all eight patients was 36 at baseline. After two hours, it was reduced to 12, which corresponds to a 24-point or 67% improvement. One day after treatment, it was reduced to 2, which corresponds to a 34-point or 94% improvement. Seven days after treatment, it was reduced to 6, which corresponds to a 30-point or 83% improvement.

[0567] In the 12 mg group, the aggregate score for the MADRS item "Inability to Have Emotions" across all four patients was 16 at baseline. After two hours, it was reduced to 9, which corresponds to a 7-point or 44% improvement. After one day of treatment, it was reduced to 1, which corresponds to a 15-point or 94% improvement. After seven days of treatment, it was reduced to 1, which corresponds to a 15-point or 94% improvement.

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

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

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

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

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

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

[0574] The inventors further conclude that the reduction or elimination of emotional incapacity following treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the MADRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is rapid, i.e., within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 7, 14, and / or 28. 13 Because emotional incapacity impacts other aspects of psychiatric or nervous system disorders, the inventors conclude that the improvement observed in the MADRS item "emotional incapacity" further contributes to an overall improvement in maternal functioning.

[0575] The MADRS item "Difficulty concentrating" represents symptoms ranging from difficulty organizing thoughts to inability to concentrate.

[0576] A score of 0 is assigned if the patient has no difficulty concentrating. A score of 2 is assigned if there is occasional difficulty in organizing thoughts. A score of 4 is assigned if difficulty concentrating and sustaining thoughts impairs the ability to read or speak. A score of 6 is assigned if the patient is unable to read or speak without great difficulty.

[0577] The inventors have determined that an increased score on the MADRS item "Difficulty concentrating" adversely affects both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the MADRS item "Difficulty concentrating" impairs caregiving and care.

[0578] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of parenting and / or management.

[0579] In the study group receiving the individualized dosing regimen, the aggregate score for the "Difficulty concentrating" item on the MADRS across all eight patients was 30 at baseline. After two hours, it had decreased to 11, which corresponds to a 19-point or 63% improvement. One day after treatment, it had decreased to 1, which corresponds to a 29-point or 97% improvement. Seven days after treatment, it had decreased to 9, which corresponds to a 21-point or 70% improvement.

[0580] In the 12 mg group, the aggregate score for the MADRS item "Difficulty concentrating" across all four patients was 16 at baseline. After two hours, it had decreased to 7, which corresponds to a 9-point or 56% improvement. One day after treatment, it had decreased to 2, which corresponds to a 14-point or 88% improvement. Seven days after treatment, it had decreased to 3, which corresponds to a 13-point or 81% improvement.

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

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

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

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

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

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

[0587] The inventors further conclude that the reduction or elimination of concentration difficulties resulting from treatment of patients with psychiatric or nervous system disorders results in an improvement in maternal functioning, as reflected not only by a decrease in the MADRS total score but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within approximately 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on days 7, 14, and / or 28.

[0588] Because difficulty concentrating also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "difficulty concentrating" further contributes to a general improvement in maternal functioning.

[0589] The MADRS item "negative thinking" refers to thoughts of guilt, inferiority, self-blame, guilt, regret, and doom and gloom.

[0590] A score of 0 is assigned if there are no pessimistic thoughts. A score of 2 is assigned if there are fluctuating thoughts of failure, self-blame, or self-deprecation. A score of 3 is assigned if there are persistent self-blame or clear but reasonable thoughts of guilt or guilt, and the patient is increasingly pessimistic about the future. A score of 6 is assigned if there are delusions of destruction, remorse, or irredeemable guilt, and irrational, unwavering self-blame.

[0591] The inventors have determined that an increase in the score on the MADRS item "pessimistic thinking" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-control). An increase in the score on the MADRS item "pessimistic thinking" impairs emotional well-being, social support, and control.

[0592] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of emotional well-being, social support, and / or control.

[0593] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Pessimistic Thinking" across all eight patients was 28 at baseline. After two hours, it was reduced to 7, which corresponds to a 21-point or 75% improvement. One day after treatment, it was reduced to 4, which corresponds to a 24-point or 86% improvement. Seven days after treatment, it was reduced to 3, which corresponds to a 25-point or 89% improvement.

[0594] In the 12 mg group, the aggregate score for the MADRS item "pessimistic thinking" across all four patients was 16 at baseline. After two hours, it was reduced to 8, which corresponds to an 8-point or 50% improvement. After one day of treatment, it was reduced to 7, which corresponds to a 9-point or 56% improvement. After seven days of treatment, it was reduced to 8, which corresponds to an 8-point or 50% improvement.

[0595] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of negative thinking may be achieved.

[0596] Improvement in negative thinking is reflected by an improvement in the negative thinking score for at least one MADRS item at about 2 hours, day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0597] Improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0598] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0599] Improvement in negative thinking, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0600] The improvement in negative thinking, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0601] The inventors further conclude that the reduction or elimination of negative thinking through treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the MADRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0602] Because pessimistic thinking also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "pessimistic thinking" further contributes to a general improvement in maternal functioning.

[0603] The MADRS item "Decreased Sleep" describes the experience of decreased sleep duration or depth compared to the subject's own normal pattern when well.

[0604] A score of 0 is assigned if the subject sleeps normally. A score of 2 reflects slight difficulty falling asleep or slightly short, light, or intermittent sleep. A score of 4 means sleep is shortened or interrupted by at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0605] The inventors have determined that an increased score on the MADRS item "Decreased Sleep" negatively impacts both aspects of maternal functioning (maternal competence in interacting with child(ren) and maternal self-care). An increased score on the MADRS item "Decreased Sleep" impairs self-care, emotional well-being, and control.

[0606] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of self-care, emotional well-being, and / or control.

[0607] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Decreased Sleep" across all eight patients was 25 at baseline. By day 1 after treatment, the earliest time point for assessing the treatment's impact on sleep, it had decreased to 12, representing a 13-point or 52% improvement. By day 7 after treatment, it had decreased to 9, representing a 16-point or 64% improvement.

[0608] In the 12 mg group, the aggregate score for the MADRS item "Decreased Sleep" across all four patients was 12 at baseline. One day after treatment, it decreased to 10, which corresponds to a 2-point or 17% improvement. Seven days after treatment, it decreased to 6, which corresponds to a 6-point or 50% improvement.

[0609] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of sleep deprivation may be achieved.

[0610] The reduction or elimination of sleep deprivation is reflected by an improvement in the sleep deprivation score for at least the MADRS item at 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0611] Improvement in sleep reduction, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0612] Improvement in sleep reduction, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

[0614] The inventors further conclude that the reduction or elimination of sleep loss due to treatment of patients with psychiatric or nervous system disorders results in an improvement in maternal functioning, as reflected not only by a decrease in the MADRS total score but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score is also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0615] Because sleep loss also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "sleep loss" further contributes to an overall improvement in maternal functioning.

[0616] A further aspect of psychiatric or nervous system disorders that may be treated by administration of 5-MeO-DMT is suicidal ideation. 5-MeO-DMT may be administered to a patient with a psychiatric or nervous system disorder to reduce or eliminate suicidal ideation in that patient.

[0617] In the clinical trials mentioned above involving the administration of 5-MeO-DMT, the MADRS item "suicidal thoughts" was assessed, among other things.

[0618] "Suicidal thoughts" refers to feeling that there is no point in living, that one is ready to die naturally at any time, having suicidal thoughts, and / or making preparations to commit suicide. Suicide attempts themselves should not influence the rating of this MADRS item.

[0619] A score of 0 means the patient is enjoying life. A score of 2 is assigned if the patient with a psychiatric or nervous system disorder is bored with life and / or has only fleeting suicidal thoughts. A score of 4 means the patient often has suicidal thoughts, wishes they were dead, and considers suicide a possible solution, but the patient has no specific plan or intent. A score of 6 is assigned if the patient has a clear plan and / or is actively preparing to attempt suicide.

[0620] This MADRS scale item is particularly relevant to suicidal ideation.

[0621] The inventors have determined that an increase in the score on the MADRS item "suicidal thoughts" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increase in the score on the MADRS item "suicidal thoughts" impairs self-care, emotional well-being, and control.

[0622] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of self-care, emotional well-being, and / or control.

[0623] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "suicidal thoughts" across all eight patients was 11 at baseline. After two hours, it was reduced to 3, which corresponds to an 8-point or 73% improvement. One day after treatment, it was reduced to 1, which corresponds to a 10-point or 91% improvement. Seven days after treatment, it was reduced to 3, which corresponds to an 8-point or 73% improvement.

[0624] In the 12 mg group, the aggregate score for the MADRS item "suicidal thoughts" across all four patients was 8 at baseline. After 2 hours, it was reduced to 3, which corresponds to a 5-point or 63% improvement. After 1 day of treatment, it was reduced to 5, which corresponds to a 3-point or 38% improvement. After 7 days of treatment, it was reduced to 7, which corresponds to a 1-point or 13% improvement.

[0625] Thus, scores for the "suicidal thoughts" scale item, which is specifically related to suicidal ideation, are significantly improved in patients on at least an individualized dosing regimen. We conclude that 5-MeO-DMT may be used to treat suicidal ideation in patients with psychiatric or nervous system disorders.

[0626] Thus, in accordance with the present invention, treating a patient with a psychiatric or nervous system disorder who is experiencing suicidal ideation reduces or eliminates the suicidal ideation.

[0627] Reduction or elimination of suicidal ideation is reflected by an improvement in the suicidal ideation score for at least one MADRS item at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0628] If the patient is experiencing suicidal ideation, improvement in suicidal ideation is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0629] Improvement in suicidal ideation, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0630] Alternatively, the decrease in Clinical Global Impression-Severity (CGI-S) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0631] Improvement in suicidal ideation, as assessed by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0632] The improvement in suicidal ideation, as assessed by a reduction in CGI-S score or a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0633] The inventors further conclude that the reduction or elimination of suicidal thoughts through treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the MADRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and an increase in the BIMF score is also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0634] Because suicidal thoughts also impact other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the MADRS item "suicidal thoughts" further contributes to an overall improvement in maternal functioning.

[0635] The BPRS item "Emotional Withdrawal" relates to the patient's lack of ability to relate emotionally in the interview situation. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. There is a lack of emotional engagement indicated by occasional failure to comment reciprocally, an occasional absent-minded look, or a stiff smile, but most of the time there is spontaneous engagement with the interviewer. 3 - Mild. Lack of emotional engagement indicated by a noticeable failure to comment reciprocally, appearing absent-minded, or lacking warmth but responding when approached by the interviewer. 4 - Moderate. Emotional contact is absent for much of the interview because the subject does not elaborate on responses, fails to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychotic content. 5 - Moderately severe. Same as 4, but emotional contact is absent for most of the interview. 6 - Severe. Actively avoids emotional involvement. Frequently does not respond or responds with yes / no answers (not simply due to paranoia). Responds with minimal affect. 7 - Most severe. Consistently avoids emotional involvement. Does not respond or responds with yes / no answers (not simply due to paranoia). May abandon interview or not respond at all.

[0636] The inventors determined that an increased score on the BPRS item "emotional withdrawal" adversely affects both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the BPRS item "emotional withdrawal" impairs emotional well-being, mother-child interaction, and social support.

[0637] Conversely, improvement on this BPRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of emotional well-being, mother-infant interaction, and / or social support.

[0638] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, it was reduced to 8, which corresponds to a 5-point or 38% improvement. After 1 day of treatment, it was reduced to 8, which corresponds to a 5-point or 38% improvement. After 7 days of treatment, it was reduced to 8, which corresponds to a 5-point or 38% improvement.

[0639] In the 12 mg group, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, it decreased to 11, which corresponds to a 2-point or 15% improvement. After 1 day of treatment, it decreased to 8, which corresponds to a 5-point or 38% improvement. After 7 days of treatment, it decreased to 6, which corresponds to a 7-point or 54% improvement.

[0640] We conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of emotional withdrawal may be achieved.

[0641] The reduction or elimination of emotional withdrawal is reflected by an improvement in the emotional withdrawal score on at least one BPRS item at about 2 hours, day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

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

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

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

[0646] The inventors further conclude that the reduction or elimination of emotional withdrawal resulting from treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0647] Because emotional withdrawal also impacts other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "emotional withdrawal" further contributes to a general improvement in maternal functioning.

[0648] The BPRS item "Bluted Affect" concerns a restricted range of emotional expression in face, voice, and body language, and a marked indifference or flatness even when discussing distressing topics. Possible scores are: 1- No emotional blunting. 2 - Very mild. Emotional range is somewhat subdued or reserved, but facial expression and tone of voice are within the normal range and appropriate. 3 - Mild. Overall range of emotion is reduced, inhibited, or reserved, with few spontaneous and appropriate emotional responses. Voice tone is slightly monotonous. 4 - Moderate. The range of affect is significantly reduced; the patient does not show emotion or smile, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Expressive emotion or gestures usually are followed by a return to flat affect. 5 - Moderately severe. The range of emotion is severely reduced; the patient does not show emotion or smile, or responds minimally to distressing topics, gestures very little, and facial expression rarely changes. The tone of voice is often monotonous. 6 - Severe. Little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expressions are constant. Voice tone is monotonous most of the time. 7 - Most severe. Virtually no emotional range or expression, stiff movements, monotonous tone of voice throughout the entire time.

[0649] The inventors have determined that an increase in the score on the BPRS item "affective blunting" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increase in the score on the BPRS item "affective blunting" impairs emotional well-being and mother-child interaction.

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

[0651] The aggregate score for the BPRS item "blunted affect" was 15 at baseline. After 3 hours, it decreased to 11, which corresponds to a 4-point or 27% improvement. After 1 day of treatment, it decreased to 8, which corresponds to a 7-point or 47% improvement. After 7 days of treatment, it decreased to 8, which corresponds to a 7-point or 47% improvement.

[0652] In the 12 mg group, the aggregate score for the BPRS item "blunted affect" was 11 at baseline. After 3 hours, it decreased to 8, which corresponds to a 3-point or 27% improvement. After 1 day of treatment, it decreased to 6, which corresponds to a 5-point or 45% improvement. After 7 days of treatment, it decreased to 5, which corresponds to a 6-point or 55% improvement.

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

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

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

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

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

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

[0659] The inventors further conclude that the reduction or elimination of blunted affect resulting from treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

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

[0661] The BPRS item "Guilt" concerns excessive preoccupation with or remorse for past actions. Possible scores are: 1- No guilt. 2 - Very mild. Preoccupied with disappointing someone or failing at something, but not distracted. Can easily shift thoughts to other things. 3 - Mild. Somewhat preoccupied with disappointment or failure. Tends to express guilt to others. 4 - Moderate. Disproportionate preoccupation with guilt, having done something wrong, or hurting others through something done or failed to do, but able to quickly shift attention elsewhere. 5 - Moderately severe. Preoccupied with guilt, disappointment, or failure; able to focus elsewhere, but only with great effort. Not delusional. 6 - Severe. Delusions of guilt or irrational self-blame that is largely unrelated to the situation. Moderate preoccupation is present. 7 - Severe. Delusions of guilt or irrational self-blame that is highly unrelated to the situation. Subject is so preoccupied with guilt that they may reveal or act on their delusions.

[0662] The inventors have determined that an increased score on the BPRS item "guilt" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increased score on the BPRS item "guilt" impairs self-care, mother-child interaction, emotional well-being, and control.

[0663] Conversely, improvement on these BPRS items would translate to improvements in maternal functioning, particularly the BIMF functional domains of self-care, mother-infant interaction, emotional well-being, and / or control.

[0664] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "guilt" across all eight patients was 34 at baseline. After three hours, it had decreased to 14, which corresponds to a 20-point or 59% improvement. One day after treatment, it had decreased to 11, which corresponds to a 23-point or 68% improvement. Seven days after treatment, it had decreased to 10, which corresponds to a 24-point or 71% improvement.

[0665] In the 12 mg group, the aggregate score for the BPRS item "guilt" across all four patients was 18 at baseline. After 3 hours, it was reduced to 9, which corresponds to a 9-point or 50% improvement. After 1 day of treatment, it was reduced to 5, which corresponds to a 13-point or 72% improvement. After 7 days of treatment, it was reduced to 5, which corresponds to a 13-point or 72% improvement.

[0666] We conclude that by using 5-MeO-DMT to treat patients with psychiatric or neurological disorders, a reduction or elimination of guilt may be achieved.

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

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

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

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

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

[0672] The inventors further conclude that the reduction or elimination of guilt through treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

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

[0674] The BPRS item "Anxiety" relates to reported anxiety, tension, fear, panic, or worry. Possible scores are: 1- No anxiety. 2 - Very mild. Reports some discomfort due to worry or frequent worrying that occurs more than usual for most healthy people. 3 - Mild. Frequent anxiety, but able to quickly redirect attention elsewhere. 4 - Moderate. Worried most of the time and unable to easily attend to other things, but not interfering with function, or occasional involuntary anxiety, but not interfering with function. 5 - Moderately severe. Frequent but not constant involuntary anxiety, or some areas of functioning are disrupted by anxiety or worry. 6 - Severe. Constant involuntary anxiety, but not all day long, or many areas of functioning are disrupted by anxiety or persistent worry. 7 - Severe. Involuntary anxiety lasts all day or most areas of functioning are disrupted by anxiety or persistent worry.

[0675] The inventors have determined that an increased score on the BPRS item "Anxiety" negatively impacts both aspects of maternal functioning (maternal competence regarding interactions with child(ren) and maternal self-control). An increased score on the BPRS item "Anxiety" impairs emotional well-being, social support, and control.

[0676] Conversely, improvement on this BPRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of emotional well-being, social support, and / or control.

[0677] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "anxiety" across all eight patients was 37 at baseline. After three hours, it was reduced to 19, which corresponds to an 18-point or 49% improvement. One day after treatment, it was reduced to 16, which corresponds to a 21-point or 57% improvement. Seven days after treatment, it was reduced to 17, which corresponds to a 20-point or 54% improvement.

[0678] In the 12 mg group, the aggregate score for the BPRS item "anxiety" across all four patients was 25 at baseline. After 3 hours, it was reduced to 11, which corresponds to a 14-point or 56% improvement. After 1 day of treatment, it was reduced to 6, which corresponds to a 19-point or 76% improvement. After 7 days of treatment, it was reduced to 6, which corresponds to a 19-point or 76% improvement.

[0679] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of anxiety may be achieved.

[0680] The reduction or elimination of anxiety is reflected by an improvement in anxiety scores on at least one BPRS item at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0681] Improvement in anxiety, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0682] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0683] Improvement in anxiety, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0684] The improvement in anxiety, as reflected by a reduction in the CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0685] The inventors further conclude that the reduction or elimination of anxiety resulting from treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0686] Because anxiety also affects other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "anxiety" further contributes to a general improvement in maternal functioning.

[0687] The BPRS item "tension" relates to observable physical and motor signs of tension, "nervousness," and agitation. Possible scores are: 1- No tension. 2 - Very mild. Excessive restlessness but within normal limits. Some transient signs of nervousness, such as nail biting, paw shaking, head scratching, or finger tapping. 3 - Mild. Same as "2", but signs of tension are more frequent or exaggerated. 4 - Moderate. Many frequent signs of exertional strain, e.g., hands clasping while swinging legs, occasionally accompanied by one or more other signs occurring simultaneously. Signs of strain may be absent. 5 - Moderately severe. Frequent exertional strain accompanied by one or more symptoms often occurs simultaneously. Rarely, strain symptoms may be absent. 6 - Severe. Same as 5, but with persistent signs of tension. 7 - Most severe. Multiple motor symptoms are present in succession, e.g., continuous walking and rubbing of hands.

[0688] The inventors have determined that an increase in the score on the BPRS item "strain" negatively impacts both aspects of maternal functioning (maternal competence in interacting with the child(ren) and maternal self-care). An increase in the score on the BPRS item "strain" impairs mother-child interaction and psychological well-being.

[0689] Conversely, improvement on these BPRS items would lead to improvements in maternal functioning, particularly in the BIMF functional domains of mother-child interaction and / or psychological well-being.

[0690] In the study group receiving the individualized dosing regimen, the aggregate score for the BPRS item "tension" across all eight patients was 16 at baseline. After three hours, it had decreased to 11, which corresponds to a 5-point or 31% improvement. One day after treatment, it had decreased to 11, which corresponds to a 5-point or 31% improvement. Seven days after treatment, it had decreased to 10, which corresponds to a 6-point or 38% improvement.

[0691] In the 12 mg group, the aggregate score for the BPRS item "tension" across all four patients was 14 at baseline. After 3 hours, it was reduced to 9, which corresponds to a 5-point or 36% improvement. After 1 day of treatment, it was reduced to 6, which corresponds to an 8-point or 57% improvement. After 7 days of treatment, it was reduced to 6, which corresponds to an 8-point or 57% improvement.

[0692] The inventors conclude that by using 5-MeO-DMT to treat patients with psychiatric or nervous system disorders, a reduction or elimination of tension may be achieved.

[0693] The reduction or elimination of tension is reflected by an improvement in the tension score of at least one BPRS item at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0694] Improvement in tone, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0695] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0696] Improvement in tone, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0697] The improvement in tone, as reflected by a reduction in CGI-S score or a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0698] The inventors further conclude that the reduction or elimination of tension resulting from treatment of patients with psychiatric or nervous system disorders results in not only a decrease in the BPRS total score but also an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and increases in the BIMF score are also observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0699] Because strain also affects other aspects of psychiatric or neurological disorders, we conclude that the improvement observed in the BPRS item "strain" further contributes to a general improvement in maternal functioning.

[0700] Improvement in one or more aspects of the psychiatric or nervous system disorder also leads to an overall improvement. Preferably, treatment results in remission.

[0701] Remission of depressive symptoms may be reflected by a MADRS score of 10 or less, with onset within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, occurring on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0702] Further alternatively, or in addition, remission of depressive symptoms may be reflected by a HAM-D score of 7 or less, with onset within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and with onset on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28.

[0703] In light of the above, it follows that treating patients with psychiatric or nervous system disorders with 5-MeO-DMT or a pharmaceutically acceptable salt thereof not only leads to a reduction in MADRS scores, including in particular the subscores detailed above, but also to improvements in domains of the BIMF scale. The reduction in MADRS scores and improvement in maternal functioning are confirmed by clinical data, as discussed in the Examples section below.

[0704] Improvement in maternal functioning includes improvements in the self-care domain of functioning. For example, an improvement in the MADRS items of inhibition and / or sleep reduction leads to an increase in the score of the BIMF scale, which reflects self-care. The improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0705] Improvement in maternal functioning includes improvement in the parenting function domain. For example, improvement in the inhibition and / or concentration difficulties items of the MADRS results in an increase in the score of the BIMF scale reflecting parenting. The improvement in the cumulative score of the BIMF scale items reflecting self-management is preferably at least 15%, more preferably at least 25%.

[0706] The improvement of maternal function includes the improvement in the functional domain of mother-child interaction. For example, the improvement of the MADRS items of emotional incapacity and inner tension leads to an increase in the score of the BIMF scale reflecting mother-child interaction. The improvement of the cumulative score of the BIMF scale items reflecting mother-child interaction is preferably at least 5%, more preferably at least 15%.

[0707] Improvement in maternal functioning includes improvement in the functional domain of psychological well-being. For example, improvement in the MADRS items of inhibition, pessimistic thinking, emotional inability, inner tension, and / or decreased sleep leads to an increase in the score of the BIMF scale reflecting psychological well-being. The improvement in the cumulative score of the BIMF scale items reflecting psychological well-being is preferably at least 25%, more preferably at least 35%.

[0708] The improvement of maternal function includes the improvement in the functional domain of social support.For example, the improvement of the pessimistic thinking of the MADRS item leads to the increase of the BIMF scale score that reflects social support.The cumulative score of the BIMF scale item that reflects social support preferably improves by at least 10%, more preferably by at least 20%.

[0709] Improvements in maternal functioning include improvements in the functional domain of control. For example, improvements in the MADRS items inhibition, pessimistic thinking, and / or difficulty concentrating result in an increase in the score on the BIMF scale reflecting control. The improvement in the cumulative score on the BIMF scale items reflecting control is preferably at least 20%, more preferably at least 30%.

[0710] Improvement in maternal functioning includes improvement in the functional domain of adaptation. For example, improvement in the inhibition of MADRS items leads to an increase in the score of the BIMF scale, which reflects adaptation. The cumulative score improvement of the BIMF scale items, which reflects adaptation, is preferably at least 5%, more preferably at least 15%.

[0711] The improvement in maternal functioning is associated with one or more, particularly two or more, functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, parenting, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0712] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0713] Breastfeeding As noted above, with many medications, breastfeeding patients may be faced with a situation where they must make the decision to discontinue breastfeeding or discontinue / withdraw from treatment.

[0714] If a decision is made to discontinue breastfeeding in order to receive treatment, this decision negatively impacts maternal functioning, particularly impairing the functional domains of mother-child interaction and psychological well-being.

[0715] The present invention also addresses the need for treatment of psychiatric or nervous system disorders in nursing mothers without substantially interrupting breastfeeding.

[0716] According to the present invention, breastfeeding can be resumed immediately after treatment.

[0717] The present inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT in an effort to determine when breast-feeding is possible after administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof without exposing the infant to the associated risks.

[0718] Absorption and distribution of inhaled 5-MeO-DMT was rapid, with peak concentrations and pharmacological effects observed during and shortly after administration.

[0719] Plasma protein binding is low (13-23%).

[0720] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid decline in plasma concentrations. Ten minutes after administration, concentrations already fall below 10% of Cmax; two hours later, they are below 1% of Cmax; and after three hours, 5-MeO-DMT is no longer detectable in plasma. This applies across the entire dose range examined (6 mg, 12 mg, 18 mg). No accumulation is observed with repeated dosing within the 1-4 hour time frame. The titration disclosed herein does not result in accumulation and thus in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0721] Possible metabolites of 5-MeO-DMT in humans were identified and the potential relevance of such metabolites was evaluated. In an in vitro metabolic identification study in human hepatocytes, 5-MeO-DMT free base was incubated at 10 μM for up to 120 minutes. The identified compounds and their relative proportions are shown in Table 1 below. [Table 2]

[0722] Note that subsequent assays repeatedly failed to detect the presence of 5-methoxytryptophol but reproducibly demonstrated the presence of 5-MIAA as the major metabolite, which is therefore unlikely to play a significant role in vivo.

[0723] The metabolites listed in the table above are formed via three different pathways.

[0724] The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed via oxidative deamination, which involves enzymatic removal and oxidation of the N-methyl group to form acetaldehyde: [ka]

[0725] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0726] The secondary amines, primary amines, and aldehydes were not identified, indicating that they were not present in high concentrations at any time.

[0727] This aldehyde intermediate metabolite undergoes two separate biotransformations in human hepatocytes: it is either oxidized to 5-methoxyindoleacetic acid or reduced to 5-methoxyindole-3-ethanol. [ka]

[0728] Both resulting metabolites are endogenous substances and are produced in the human body, for example, during the synthesis and metabolism of melatonin and serotonin (see, for example, Biochemistry of the Pineal. Chapter 3. in Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3. in Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).

[0729] Because the primary pathway for the metabolism of 5-MeO-DMT rapidly leads to metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the oxidative deamination of 5-MeO-DMT does not involve metabolites that require restrictions regarding lactation.

[0730] Furthermore, as detailed in the Examples section, incubation of human hepatocytes with 5-methoxytryptophol demonstrated high turnover, with the compound being completely eliminated within 24 hours. At a test concentration of 1 μM, the in vitro intrinsic clearance of 5-methoxytryptophol was 16.2 μl / min / million cells (half-life of 142 minutes).

[0731] Thus, the plasma concentration of 5-methoxytryptophol rapidly decreases to the point where it no longer occurs and reaches endogenous levels.

[0732] 5-MIAA is a weak acid and exists in plasma in an ionized form, making it unlikely that this compound will pass into breast milk.

[0733] Incubation of human hepatocytes with 5-MIAA showed low turnover, with 75-82% of 5-MIAA remaining after 72 hours. 5-MIAA is thought to be the final metabolic product of 5-MeO-DMT.

[0734] 5-MIAA exhibits relatively low plasma binding of approximately 50% (mean fraction unbound (Fu), see Examples section). It remains in circulation, subject to renal clearance. With a typical glomerular filtration rate of 90-120 ml / min, this means that all traces of 5-MIAA are removed from the circulation via urinary excretion in approximately 1-2 hours (depending on the patient's size and taking into account the increased blood volume that occurs during pregnancy).

[0735] As a result, the plasma concentration of 5-MIAA also declines rapidly.

[0736] Combined with the rapid clearance of 5-MeO-DMT (<1 hour), this supports the view that the administered treatment and all associated metabolites were cleared from the circulation in approximately 2 hours.

[0737] A further metabolite identified, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The formed metabolite is then subjected to glucuronidation catalyzed by UGT: [ka]

[0738] As part of the pharmacokinetic studies, it was determined that bufotenin was barely detectable in human serum. In any case, it was not detectable 15 minutes after administration of 5-MeO-DMT.

[0739] Bufotenin glucuronide cannot bind to the receptor and exerts no effect. Furthermore, its concentration is so low that it was not detected in the hepatocyte assay. Bufotenin glucuronide is further converted to 5-hydroxyindoleacetic acid: [ka]

[0740] 5-Hydroxyindoleacetic acid is an endogenous substance, occurring, for example, in the metabolism of melatonin and serotonin (references given above).

[0741] The O-demethylation pathway of 5-MeO-DMT leads to the major metabolite, bufotenine, which is rapidly cleared from plasma and further metabolizes compounds present only in very low concentrations, ultimately leading to metabolites that are also part of endogenous metabolic pathways. The inventors have confirmed that the O-demethylation of 5-MeO-DMT does not involve metabolites that require restrictions regarding breastfeeding.

[0742] The third metabolic pathway involves N-oxidation: [ka]

[0743] In silico modeling of the resulting metabolites, 5-MeO-DMT-N-oxide was deemed non-genotoxic, in accordance with the negative in vitro genotoxicity evaluation of the parent molecule. As confirmed by observations in rats, this compound is water-soluble and readily excreted rapidly (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). The metabolic pathway of 5-MeO-DMT involving N-oxidation plays only a minor role, resulting in a low proportion of rapidly excreted metabolites with no apparent toxicity. We have confirmed that N-oxidation of 5-MeO-DMT does not result in any metabolites that require breastfeeding restrictions.

[0744] Based on the above, the inventors have determined that breastfeeding can be resumed immediately after treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0745] Therefore, if the patient is a nursing mother, it is recommended that nursing be discontinued until 48 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and in particular, it is recommended that nursing be discontinued until 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0746] Preferably, breastfeeding need not be interrupted for more than 6 hours, more preferably for more than 3 hours, and most preferably for more than 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0747] This short interruption and the corresponding possibility of resuming breastfeeding soon after treatment contribute to the success of the treatment, in particular to maternal function and fulfillment and the development of the child(ren).

[0748] Treating mental or nervous system conditions Disorders characterized by depressive episodes There are several disorders that are characterized by depressive episodes.

[0749] A depressive episode is a period of depressed mood and / or loss of pleasure in most activities.

[0750] For example, according to the DSM-V, a major depressive episode is characterized by the presence of five or more symptoms during the same two-week period and represents a change from past functioning, with at least one of these symptoms being either (1) depressed mood or (2) loss of interest or pleasure.

[0751] Patients suffering from a disorder characterized by depressive episodes may have a treatment-resistant form of the disorder.

[0752] Disorders characterized by depressive episodes include one or more of the following: sleep disturbance, cognitive dysfunction, anxiety, psychomotor slowing, social / emotional withdrawal, and negative thinking.

[0753] Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0754] In patients with disorders characterized by depressive episodes, altered functional connectivity is observed within and / or between several brain regions involved in cognitive processes involved in processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal.

[0755] Treating a patient suffering from a disorder characterized by depressive episodes, including treatment-resistant forms of the disorder, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the disorder characterized by depressive episodes.

[0756] Improvement in the disorder characterized by depressive episodes, as reflected by a reduction in CGI-S score, is observed at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0757] The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the disorder characterized by depressive episodes, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0758] Improvement in the disorder characterized by a depressive episode, as reflected by a reduction in the MADRS score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0759] The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in the MADRS score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in the MADRS score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0760] Improvement in the disorder characterized by depressive episodes, as reflected by a reduction in the HAM-D score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0761] The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in the HAM-D score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the patient's disorder characterized by depressive episodes, as reflected by a reduction in the HAM-D score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0762] Improvement in maternal functioning in patients with a disorder characterized by depressive episodes is reflected by an improvement in at least the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0763] The improvement in maternal functioning in patients with a disorder characterized by depressive episodes, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal functioning, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0764] Major depressive disorder (MDD) is a mood disorder that causes persistent feelings of sadness and loss of interest. It affects a person's emotions, thoughts, and behaviors and can lead to a variety of emotional and physical problems.

[0765] The patient may have moderate or severe MDD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 17 or greater. Additionally, the patient may have severe major depressive disorder as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or greater or a Hamilton Depression Rating Scale (HAM-D) score of 25 or greater.

[0766] Patients with MDD may have a treatment-resistant form (TRD) of the disorder.

[0767] MDD is accompanied by one or more of the following symptoms: sleep disturbance, cognitive dysfunction, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

[0768] Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0769] In patients with MDD, abnormal functional connectivity and dysregulation are observed within and / or between multiple resting-state networks, including the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0770] Treating patients suffering from the disorder, including treatment-resistant forms of MDD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of the MDD.

[0771] Improvement in MDD, as reflected by a decrease in CGI-S score, is observed at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0772] Improvement in MDD in a patient, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in MDD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0773] Improvement in MDD, as reflected by a reduction in the MADRS score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0774] Improvement in MDD in a patient, as reflected by a reduction in the MADRS score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement in MDD, as reflected by a reduction in the MADRS score, persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0775] Improvement in MDD, as reflected by a decrease in HAM-D score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0776] Improvement in MDD in a patient, as reflected by a reduction in the HAM-D score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in MDD, as reflected by a reduction in the HAM-D score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0777] Improvement in maternal function in patients with MDD is reflected by an improvement in at least the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0778] The improvement in maternal function in patients with MDD, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0779] Persistent depressive disorder Persistent depressive disorder, also known as dysthymia, is a chronic form of depression. It is diagnosed when a person has a depressed mood for most of the day for at least two years, with each symptom-free interval lasting less than two months.

[0780] During a depression, two or more of the following must be present: 1. Hopelessness, 2. Low energy or fatigue, 3. Low self-esteem, 4. Decreased (insomnia) or increased (hypersomnia) sleep, 5. Loss of appetite or overeating, 6. Difficulty making decisions or poor concentration.

[0781] Patients with persistent depressive disorder may have a treatment-resistant form of the disorder.

[0782] Persistent depressive disorder is accompanied by one or more of the following: sleep disturbance, cognitive dysfunction, anxiety, psychomotor slowing, social / emotional withdrawal, and negative thinking.

[0783] Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0784] In patients with persistent depressive disorder, altered functional connectivity is observed within and / or between several brain regions involved in cognitive processes involving processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal. Functional connectivity abnormalities are observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity differs significantly from that observed in healthy controls.

[0785] Treating 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.

[0786] Improvement in persistent depressive disorder, as reflected by a decrease in CGI-S score, is observed at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0787] The improvement in the patient's persistent depressive disorder, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the persistent depressive disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0788] Improvement in persistent depressive disorder, as reflected by a reduction in MADRS score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0789] The improvement in the patient's persistent depressive disorder, as reflected by a reduction in the MADRS score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0790] Improvement in persistent depressive disorder, as reflected by a reduction in HAM-D score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0791] The improvement in the patient's persistent depressive disorder, as reflected by a reduction in the HAM-D score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in the persistent depressive disorder, as reflected by a reduction in the HAM-D score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0792] Improvement in maternal functioning in patients with persistent depressive disorder is reflected by an improvement in at least the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0793] The improvement in maternal functioning in patients with persistent depressive disorder, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal functioning, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0794] Seasonal affective disorder Seasonal affective disorder is a mood disorder with a seasonal pattern; symptoms often begin in the fall and subside in the spring. Many people experience sadness, hopelessness, loss of interest in activities, fatigue, and social withdrawal.

[0795] Patients with seasonal affective disorder may have a treatment-resistant form of the disorder.

[0796] Seasonal affective disorder is associated with one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor slowing, social / emotional withdrawal, and negative thinking.

[0797] Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D).

[0798] In patients with seasonal affective disorder, altered functional connectivity is observed within and / or between several brain regions involved in cognitive processes involving processing, regulation, emotional memory, rumination, impaired concentration, and physiological arousal. Functional connectivity abnormalities are observed within and / or between the DMN, salience network, executive control network, and limbic network. Functional connectivity is significantly different from that observed in healthy controls.

[0799] Treating 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 the seasonal affective disorder.

[0800] Improvement in seasonal affective disorder, as reflected by a decrease in CGI-S score, is observed at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0801] The improvement in seasonal affective disorder in a patient, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in seasonal affective disorder, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0802] Improvement in seasonal affective disorder, as reflected by a reduction in the MADRS score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0803] The improvement in seasonal affective disorder in a patient, as reflected by a reduction in the MADRS score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement in seasonal affective disorder, as reflected by a reduction in the MADRS score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0804] Improvement in seasonal affective disorder, as reflected by a decrease in the HAM-D score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

[0806] Improvement in maternal function in patients with seasonal affective disorder is reflected by an improvement in at least the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0807] The improvement in maternal function in patients with seasonal affective disorder, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The improvement in maternal function, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0808] Bipolar disorder Bipolar disorder (BD) is a mental health condition characterized by extreme mood swings, including low mood (major depressive episodes) and high mood (manic or hypomanic episodes). BD is a relapsing, chronic illness that affects more than 1% of the world's population, regardless of ethnic origin or socioeconomic status.

[0809] Patients with BD may have a treatment-resistant form of the disorder.

[0810] BD is classified as bipolar I disorder if there is at least one manic episode, with or without depressive episodes. BD is classified as bipolar II disorder if there is at least one hypomanic episode (but no full-blown manic episode) and one major depressive episode. If these symptoms are due to medication or medical problems, it is not diagnosed as bipolar disorder.

[0811] Patients with BD, whether diagnosed with bipolar II disorder or bipolar I disorder, particularly have a current major depressive episode.

[0812] The severity of the current major depressive episode can be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS). The patient can have a total score of 19 or greater, e.g., 24 or greater, particularly 37 or greater.

[0813] Alternatively or additionally, the patient may have a Bipolar Depression Rating Scale (BDRS) total score of 19, such as 24 or greater, particularly 37 or greater.

[0814] BD is associated with one or more of the following: sleep disturbances, cognitive dysfunction, anxiety, psychomotor slowing, social / emotional withdrawal, and negative thinking.

[0815] Severity and treatment success can be assessed, for example, by the Montgomery-Asberg Depression Rating Scale (MADRS) or the Hamilton Depression Rating Scale (HAM-D), or the Bipolar Depression Rating Scale (BDRS).

[0816] The BDRS is designed to measure the severity of depressive symptoms in bipolar depression. It has been validated for clinical use by trained raters. Based on a clinical interview, BDRS items assess the severity of depressive and / or mixed symptoms experienced by the patient currently and over the past few days. In the event of a discrepancy between current and past few days' symptoms, the rating should reflect the current symptoms. The scale contains 20 questions, with a maximum possible score of 60. Higher scores indicate greater severity.

[0817] Questions address depressed mood, sleep disturbances, appetite disturbances, decreased social engagement, decreased energy and activity, decreased motivation, poor concentration and memory impairment, anxiety, anhedonia, flat affect, feelings of worthlessness, helplessness and hopelessness, suicidal thoughts, guilt, psychotic symptoms, irritability, lability, increased motor drive, increased speech, and agitation.

[0818] Each of these aspects is assessed and assigned a score of 0, 1, 2, or 3.

[0819] Patients with BD exhibit characteristic abnormal intrinsic architecture and interconnectivity of resting-state networks. Compared to healthy controls, resting-state functional magnetic resonance imaging (FMRI) has demonstrated altered functional connectivity of specific regions within and / or between the default mode network, salience network, and central executive network. Notably, altered functional connectivity within the default mode network has also been observed in patients with sleep disorders.

[0820] Treating patients suffering from the disorder, including treatment-resistant forms of BD, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof results in improvement of BD.

[0821] Improvement in BD, as reflected by a decrease in CGI-S score, is observed at about 2 hours, on day 1, e.g., about 24 hours, on day 7, on day 14, and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0822] Improvement in BD in a patient, as reflected by a reduction in CGI-S score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in BD, as reflected by a reduction in CGI-S score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0823] Improvement in BD, as reflected by a decrease in MADRS score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0824] Improvement in BD in a patient, as reflected by a reduction in the MADRS score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement in BD, as reflected by a reduction in the MADRS score, persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0825] Improvement in BD, as reflected by a decrease in HAM-D score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0826] Improvement in BD in a patient, as reflected by a reduction in HAM-D score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement in BD, as reflected by a reduction in HAM-D score, persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0827] Improvement in BD, as reflected by a decrease in BDRS score, is observed on day 1, e.g., about 24 hours, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0828] Improvement in BD in a patient, as reflected by a reduction in BDRS score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the improvement in BD, as reflected by a reduction in BDRS score, persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0829] Improvement in maternal function in patients with BD is reflected by an improvement in at least the BIMF total score on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0830] Improvement in maternal function in patients with BD, as reflected by an improvement in the BIMF total score, occurs within about 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Improvement in maternal function, as reflected by an improvement in the BIMF total score, preferably persists for at least 14 days, and more preferably for at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0831] Anxiety disorders Anxiety disorders are a type of mental health condition. Symptoms include feelings of nervousness, panic, and fear, as well as sweating and rapid heartbeat. Anxiety involves a complex cognitive, emotional, physiological, and behavioral response system associated with preparation for an anticipated event or situation that is perceived as threatening.

[0832] Anxiety disorders are also accompanied by one or more of the following: sleep disturbances, cognitive dysfunction, social / emotional withdrawal, and negative thinking.

[0833] Patients with anxiety disorders may have a treatment-resistant form of the disorder.

[0834] The severity of anxiety disorders can be assessed using the Beck Anxiety Inventory (BAI), the Hamilton Anxiety Rating Scale (HAM-A), the psychological anxiety subscale of the HAM-A (sum of items 1-6 and 14), the anxious mood item of the HAM-A (item 1), and the "anxiety" item of the Brief Psychiatric Rating Scale (BPRS).

[0835] Anxiety disorders are also associated with suicidal thoughts.

[0836] Suicidal ideation can be assessed using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0837] Anxiety disorders are examined by functional magnetic resonance imaging. Generally, all anxiety disorders show abnormalities in the default mode network (DMN). Additional networks affected by these disorders are the salience network (SN) and the sensorimotor network (SMN). The resting balance within and / or between these networks relative to the DMN, for example, the SMN and SN, may be abnormal in various anxiety disorders.

[0838] Treating patients suffering from anxiety disorders, including treatment-resistant forms of such disorders, with 5-MeO-DMT or a pharmaceutically acceptable salt thereof reduces or eliminates anxiety.

[0839] The reduction or elimination of anxiety in a patient suffering from an anxiety disorder is observed about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0840] In a patient suffering from an anxiety disorder, the reduction or elimination of anxiety occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the reduction or elimination of anxiety persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0841] A clinical response in patients with anxiety disorders, including treatment-resistant forms thereof, is reflected by at least a 50% reduction in the HAM-A score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, compared to the respective pre-treatment score.

[0842] A clinical response reflected by at least a 50% reduction in the HAM-A score compared to the respective pre-treatment score in patients with anxiety disorders, including treatment-resistant forms of the disorder, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. A clinical response reflected by at least a 50% reduction in the HAM-A score in patients with anxiety disorders, including treatment-resistant forms of the disorder, persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0843] Remission of anxiety in patients with anxiety disorders, including treatment-resistant forms of such disorders, is reflected by a HAM-A score of 7 or less at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0844] Relief of anxiety, as reflected by a HAM-A score of 7 or less in patients with anxiety disorders, including treatment-resistant forms of anxiety disorders, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Relief of anxiety, as reflected by a HAM-A score of 7 or less in patients with anxiety disorders, including treatment-resistant forms of anxiety disorders, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0845] In patients suffering from anxiety disorders, including treatment-resistant forms of anxiety disorders, a reduction or elimination of anxiety, as reflected by a decrease in the score on the Mental Anxiety subscale of the HAM-A (sum of items 1-6 and 14), is observed at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, at 1 day, e.g., about 24 hours, 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0846] In patients with anxiety disorders, including treatment-resistant forms, the reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. The reduction or elimination of anxiety, as reflected by a reduction in the score on the HAM-A Psychic Anxiety subscale (sum of items 1-6 and 14), persists preferably for at least 6 days, particularly at least 14 days, and more preferably at least 28 days, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0847] In patients suffering from an anxiety disorder, including a treatment-resistant form of the disorder, a reduction or elimination of anxiety, as...

Claims

1. A pharmaceutical composition comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for the treatment of mental or neurological disorders in lactating mothers, wherein the 5-MeO-DMT is administered intravenously, intramuscularly, or subcutaneously.

2. The pharmaceutical composition according to claim 1, wherein the mental or nervous system disorder is accompanied by one or more symptoms selected from sleep disorders, cognitive impairment, anxiety, psychomotor retardation, social / emotional withdrawal, and negative thinking.

3. The pharmaceutical composition according to claim 1, wherein the patient has a treatment-resistant form of the aforementioned disorder.

4. The pharmaceutical composition according to claim 3, wherein the improvement of the disorder, reflected by a decrease in the CGI-S score, is observed about 2 hours, day 1, for example, about 24 hours, day 7, day 14, and / or day 28 after the last administration of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 3, wherein the improvement of the disorder, as reflected by the decrease in the CGI-S score, occurs within approximately two hours after the last administration of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 3, wherein the improvement of the disorder, as reflected by the reduction in the CGI-S score, lasts for at least 6 days, in particular at least 14 days, and more preferably at least 28 days, after the last administration of the 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 1, wherein the patient further has slightly impaired, impaired, or severely impaired maternal function.

8. The pharmaceutical composition according to claim 7, wherein the patient has a Birkin Index (BIMF) score of 95 or less for maternal function, for example, 80 or less, and particularly 65 or less.

9. The pharmaceutical composition according to claim 1, wherein maternal function is improved by the aforementioned treatment.

10. The pharmaceutical composition according to claim 1, wherein the improvement relates to one or more, particularly two or more, functional domains of maternal function selected from self-management, childcare, mother-child interaction, maternal mental well-being, social support, management, and adaptation, according to the Birkin Index (BIMF).

11. The pharmaceutical composition according to claim 8, wherein the BIMF score is improved by 10% or more, preferably by 20% or more.

12. The pharmaceutical composition according to claim 1, administered in a dose or dosage regimen that causes the patient to experience a supreme psychedelic experience.

13. The pharmaceutical composition according to claim 1, wherein a dosage of 5-MeO-DMT in an amount of approximately 1 mg to approximately 10 mg is administered, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

14. The pharmaceutical composition according to claim 1, wherein a dosage of approximately 2 mg, or approximately 5 mg, or approximately 8 mg is administered, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

15. The pharmaceutical composition according to claim 1, wherein a dosage of approximately 1 mg, approximately 2 mg, or approximately 3 mg is administered, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

16. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a salt thereof is administered in an initial dose in the first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations, each subsequent administration using a dose greater than the previous administration, unless the patient has experienced a supreme psychedelic experience.

17. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT is administered in a dose of approximately 1 mg to approximately 3 mg for the first dose, and thereafter, unless the patient has already experienced a supreme psychedelic experience, the dose is increased to approximately 4 mg to approximately 6 mg for the second dose, and thereafter, unless the patient has already experienced a supreme psychedelic experience, the dose is increased to approximately 7 mg to approximately 9 mg for the third dose, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

18. The pharmaceutical composition according to 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, the third dose of 5-MeO-DMT is about 8 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

19. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT is administered in a dose of approximately 0.5 mg to approximately 1.5 mg in the first dose, and thereafter, unless the patient has already experienced a supreme psychedelic experience, the dose is increased to approximately 1.5 mg to approximately 2.5 mg in the second dose, and thereafter, unless the patient has already experienced a supreme psychedelic experience, the dose is increased to approximately 2.5 mg to approximately 3.5 mg in the third dose, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

20. The pharmaceutical composition according to 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, the third dose of 5-MeO-DMT is about 3 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

21. The pharmaceutical composition according to claim 16, wherein the interval between the two administrations is 1 hour or more and 24 hours or less, for example, about 1 to 4 hours, preferably about 1 to 2 hours.

22. The pharmaceutical composition according to claim 12, wherein the manifestation of the aforementioned supreme psychedelic experience is confirmed by achieving at least 60% of the maximum possible score in each of the four subscales (mysticism, positive mood, transcendence of space and time, and inexpressibility) of the 30-item revised Mystical Experiences Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Oceanic Boundless (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least 75 of the total score on the Peak Experience Scale (PES).

23. The pharmaceutical composition according to claim 22, wherein the manifestation of the supreme psychedelic experience is confirmed by achieving a total score of at least 75 on the supreme experience scale (PES).

24. The pharmaceutical composition according to claim 1, administered by intravenous injection.

25. The aforementioned disorders include: disorders characterized by depressive episodes, such as major depressive disorder (MDD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar I disorder and bipolar II disorder; anxiety disorders, such as separation anxiety disorder, agoraphobia, generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder, phobias, and substance / medication-induced anxiety disorders; somatic symptom disorders; obsessive-compulsive disorder and related disorders, such as obsessive-compulsive disorder (OCD) and body dysmorphic disorder (BDD); and post-traumatic stress disorder (PTSD). The pharmaceutical composition according to claim 1, which is a pain disorder, for example, chronic pain, fibromyalgia, and migraine; a mental and behavioral disorder resulting from psychotropic substance use, for example, substance use disorder (SUD); a mental disorder, for example, schizophrenia, eating disorders, attention deficit hyperactivity disorder (ADHD); a personality disorder, for example, schizotypal personality disorder and borderline personality disorder, autism spectrum disorder, chronic fatigue syndrome, HIV, post-COVID symptoms, or a mental or neurological disorder associated with traumatic brain injury.

26. The pharmaceutical composition according to claim 1, wherein the patient suffers from a sleep disorder.

27. ​​The pharmaceutical composition according to any one of claims 1 to 26, wherein the patient is a lactating mother and is advised to discontinue breastfeeding for up to 48 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

28. The pharmaceutical composition according to any one of claims 1 to 26, wherein the patient is a lactating mother and is advised to discontinue breastfeeding for up to 24 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

29. The pharmaceutical composition according to any one of claims 1 to 26, wherein the patient is a lactating mother and is advised to discontinue breastfeeding for up to 6 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

30. The pharmaceutical composition according to any one of claims 1 to 26, wherein the patient is a lactating mother and is advised to discontinue breastfeeding for up to 3 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

31. The pharmaceutical composition according to any one of claims 1 to 26, wherein the patient is a lactating mother and is advised to discontinue breastfeeding for up to two hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.