5-Methoxy-N,N-dimethyltryptamine in the treatment of postnatal depression

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof is used in the treatment of patients suffering from postpartum depression (PPD).

Description

[Technical Field]

[0001] The present invention relates to an improved method for the treatment of postpartum depression (PPD), comprising administering to a patient in need thereof a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a therapeutically effective amount of a pharmaceutically acceptable salt thereof. The present invention also makes it possible to treat PPD in nursing mothers without substantially interrupting lactation. [Background technology]

[0002] More than 50% of women may experience short-term low mood or tearfulness after giving birth, but some may develop PPD, a debilitating mood disorder that occurs during pregnancy or within four weeks after giving birth.

[0003] Epidemiological studies estimate the prevalence of PPD to be approximately 15%.

[0004] Research has demonstrated that PPD has a wide range of negative consequences for affected mothers, their infant(s), and their families. For example, women with PPD may develop thoughts of self-harming or harming their child, placing them at increased risk for suicide. PPD can also lead to disrupted communication between mother and child, exemplified by high rates of withdrawal behaviors and decreased visual and vocal communication between mother and child. Evidence also suggests a link between PPD and child development, as indicated by the increased risk of cognitive developmental disorders in children of patients with PPD.

[0005] More than 20% of women diagnosed with PPD remain depressed after 12 months of follow-up, and 13% continue to suffer from PPD two years after diagnosis. Furthermore, there is evidence to suggest that 40% of women will relapse, and that untreated cases of PPD can lead to repeated bouts of depression.

[0006] It is therefore clear that the burden of PPD is significant from multiple perspectives and that successful detection and treatment of PPD is of paramount importance.

[0007] Despite this obvious need, treatment options are quite limited. Quite generally, known treatments for depression are associated with limited success rates, especially in patients who do not only suffer from mild symptoms of the disease. In the case of PPD, an aggravating factor is that patients are often breastfeeding. For many medications, lactating women are advised to discontinue breastfeeding during the period of taking the medication and for a period thereafter, as the medication is excreted in milk, potentially putting nursing children at risk.

[0008] Furthermore, studies have shown that nursing mothers may be reluctant to begin drug therapy due to a variety of concerns.

[0009] As a result, breastfeeding PPD patients may be faced with the decision to discontinue breastfeeding or to discontinue / interrupt treatment.

[0010] Currently, PPD is primarily treated through psychotherapy or pharmacotherapy. National Institute for Health and Care Excellence (NICE) guidelines recommend discussing with patients the higher threshold for pharmacological intervention before initiating treatment. Such treatment may consist of antidepressants such as selective serotonin reuptake inhibitors (SSRIs), some of which are not contraindicated during breastfeeding.

[0011] More recently, brexanolone (Zulresso) received FDA approval in the United States, making it the first pharmacological therapy specifically indicated for PPD. Brexanolone is a positive allosteric modulator of GABAa receptors and is administered via a 60-hour infusion. The efficacy of brexanolone has been demonstrated in two phase 3 trials. One trial demonstrated a significant reduction in Hamilton Rating Scale for Depression (HAM-D) scores 30 days after the start of the infusion, while the other failed to demonstrate efficacy beyond 7 days. However, brexanolone requires hospitalization for the 60-hour infusion and is associated with significant side effects.

[0012] Of further note is the fact that patients are required to discontinue breastfeeding during brexanolone infusion, and as a result of this approval, some insurance companies are now requiring patients planning the procedure to maintain this standard.

[0013] Against this background, there is a need for improved treatments for PPD, particularly those that effectively address depression and provide a rapid clinical response, but also avoid interference with the patient's daily activities, particularly with regard to caring for the infant(s). This treatment should improve maternal function. Furthermore, there is a need for treatments for PPD that do not require substantial interruption of breastfeeding.

[0014] Although there has been much interest in hallucinogens in recent years for the treatment of psychiatric disorders, this has not yet translated into the treatment of PPD. This is due to a general lack of relevant clinical data that would allow conclusions to be drawn about the clinical usefulness of hallucinogens in PPD, as well as specific concerns that administration of hallucinogens may not be appropriate for nursing mothers.

[0015] Hallucinogens, including hallucinogens, are compounds, some of which are natural and some of which are synthetic, that are defined by their ability to induce sensory distortions, such as changes in hearing and vision, as well as mood and cognitive distortions in humans after ingestion. The term hallucinogen encompasses a fairly broad group of psychotropic molecules with different mechanisms of action. It has been suggested that some psychiatric disorders could, in principle, be treated with psychotropic molecules such as hallucinogens.

[0016] However, hallucinogens have not been approved by any regulatory agency, and indeed clinical experience with such molecules remains quite limited.

[0017] One compound already being investigated in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO 2020 / 169850 reports testing in healthy volunteers and further clinical trials in patients suffering from treatment-resistant depression (TRD), a form of major depressive disorder. Patients suffering from PPD were not included in the study.

[0018] 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.

[0019] It is a further object of the present invention to provide compounds and dosage regimens for improving psychotropic therapy that have a better safety profile and / or are better tolerated than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens that are more convenient than previously described therapies. Another object of the present invention is to provide improved psychoactive therapeutic compounds and dosage regimens that are associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. A still further object of the present invention is to identify specific disease states and specific subgroups of disease states that would benefit from such improved psychotropic therapies.

[0020] A still further object of the present invention is to improve maternal function in patients suffering from PPD. It is also an object of the present invention to improve maternal function in nursing mothers diagnosed with a psychiatric disorder.

[0021] It is a further object of the present invention to provide a treatment for nursing mothers diagnosed with PPD or another psychiatric disorder that allows for continuation of breastfeeding without significant interruption due to the treatment. Summary of the Invention

[0022] The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of postpartum depression (PPD), which treatment improves not only depressive symptoms but also maternal function.

[0023] The present invention also allows for the treatment of PPD in breastfeeding mothers without substantially interrupting breastfeeding. DETAILED DESCRIPTION OF THE INVENTION

[0024] definition As used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, and the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid, and triflic acid. A preferred example is the hydrobromide salt. The appropriate weight amount of the salt to be administered can be calculated from the weight amount of the free base, assuming that an equimolar amount is used.

[0025] As used in the context of the present invention, the "patient" to be treated is a woman who has been diagnosed with postpartum depression (PPD) according to established medical criteria. The diagnosis is made by a doctor or psychologist. It is not enough for the human subject to consider themselves as suffering from the disorder.

[0026] Patient may suffer from treatment-resistant disease.As used herein, " treatment-resistant " means that after at least two appropriate treatment courses, patient does not show adequate improvement.Particularly, patient does not show sufficient improvement after at least two appropriate treatment courses, and at least one of these two courses is drug therapy.For example, patient does not show adequate improvement after at least two appropriate drug therapy courses.

[0027] As used in the context of the present invention, "suicidal ideation" refers to thinking about, considering, or planning suicide. The presence of suicidal ideation in a patient is diagnosed by a doctor or psychologist using established protocols and methods for diagnosing suicidality. Generally, it is not enough for a patient to believe that they are suffering from suicidal ideation. In some situations, a patient experiencing suicidal ideation is considered to be at imminent risk of committing suicide or to have an "intent to commit suicide."

[0028] As used in the context of the present invention, unless otherwise stated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, condition, or disorder.

[0029] 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 in humans the biological or clinical response that is sought by a researcher, physician or other clinician, including alleviation of the signs and / or symptoms of the disease, condition, or disorder being treated.

[0030] "Clinical response" includes, but is not limited to, improvements in rating scales, such as the Clinical Global Impression-Severity Scale (CGI-S), Patient Global Impression-Severity Scale (PGI-S), Clinical Global Impression-Improvement Scale (CGI-I), or Patient Global Impression-Improvement Scale (PGI-I). Furthermore, "clinical response" includes, but is not limited to, assessment items, such as the Montgomery-Asberg Depression Rating Scale (MADRS), the 17-item Hamilton Depression Rating Scale (HAM-D), or the Edinburgh Postnatal Depression Scale (EPDS). Additional relevant scales for assessing clinical outcomes include the Clinician-Administered Dissociative State Scale (CADSS), the Brief Psychological Rating Scale (BPRS), and the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0031] Maternal functioning can be assessed using the Barkin Index of Maternal Functioning (BIMF).

[0032] Individual items of the scales presented, and subcombinations of individual items, may be used to assess specific disease aspects.

[0033] When assessing clinical response at an earlier time point (e.g., 2 hours) after drug administration based on endpoints developed over a longer recall period (e.g., typically 7 days for the MADRS), rational modifications of such endpoints (e.g., changing the MADRS recall period to 2 hours and advancing sleep items recorded at baseline before drug administration) may be applied.

[0034] 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 these outlined considerations apply to earlier time points.

[0035] At later time points, e.g., Day 1 and beyond, 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).

[0036] As used in the context of the present invention, unless otherwise noted, the term "administration" (or "application") shall mean the introduction of an active compound or pharmaceutical ingredient, which may be a predetermined amount, into a patient by any route. Preferably, the active compound is administered by inhalation, nasally, bucally, or sublingually.

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

[0038] As used herein, "aerosol" refers to a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and extremely small suspended solids and / or liquid particles. The term "degradation products" refers to compounds resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation. Such reactions include, but are not limited to, oxidation. When a percentage of "degradation products" is described in the context of the present invention, it refers to the amount of 5-MeO-DMT degradation products present in a sample divided by the amount of 5-MeO-DMT + 5-MeO-DMT degradation products present in the sample, multiplied by 100%, i.e., (the sum of the amounts of all 5-MeO-DMT degradation products present in the sample) / ((the amount of 5-MeO-DMT present in the sample) + (the sum of the amounts of all 5-MeO-DMT degradation products present in the sample)) × 100%. As used herein, the term "impurities" refers to undesirable compounds that contaminate a sample of 5-MeO-DMT (or a pharmaceutically acceptable salt thereof). The impurities may be contained in the starting material prior to aerosol formation or may be decomposition products.

[0039] The term "purity" refers to 100% minus the percentage of all 5-MeO-DMT degradation products present and all other impurities present, i.e., 100% - (the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) / (the amount of 5-MeO-DMT present + the sum of the amounts of all 5-MeO-DMT degradation products present + the sum of the amounts of all other impurities present) x 100%.

[0040] The term "mass median aerodynamic diameter" (MMAD) refers to the calculated diameter where 50% of the particles present in the aerosol are larger and 50% are smaller. The term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle generation rate" refers to the mass of aerosolized 5-MeO-DMT per unit time of aerosolization.

[0041] Postpartum depression Postpartum depression (PPD) is a complex combination of physical, emotional, and behavioral changes that occur in some women after giving birth. PPD is also known as perinatal-onset major depressive disorder. According to the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition) criteria, PPD is diagnosed when symptoms of major depressive disorder (MDD) begin during pregnancy or within four weeks of delivery.

[0042] Patients treated according to the present invention are preferably women diagnosed with PPD who are more than four weeks postpartum. Furthermore, patients are preferably between nine and nine months postpartum.

[0043] The depressive aspects of PPD can be assessed by the HAM-D or MADRS scores. The Edinburgh Postnatal Depression Scale (EPDS) can also be used.

[0044] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, SA, & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry, 134, p. 382). It was designed as an adjunct to the Hamilton Rating Scale for Depression (HAM-D), which may be more sensitive to changes brought about by antidepressants and other forms of treatment. Higher MADRS scores indicate more severe depression. The items considered are outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 to 6. The overall score ranges from 0 to 60.

[0045] The patient may suffer from moderate or severe PPD 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 16 or greater. It is further considered that the patient may suffer from severe PPD 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 27 or greater. The patient may be diagnosed with a treatment-resistant form of PPD.

[0046] Patients treated according to the present invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or greater.

[0047] Additionally, patients treated according to the present invention may have a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0048] Additionally, patients treated according to the present invention may have a MADRS score of 35 or greater or a HAM-D score of 25 or greater.

[0049] In addition to the above, the inventors consider that PPD impairs maternal function, especially during the first year after birth, which is a crucial period for both mother and child, with the mother being the primary caregiver in most cases and thus shouldering the majority of the work associated with childcare tasks.

[0050] Maternal functioning includes maternal competence in relation to interaction with the child(ren) and aspects of maternal self-care.

[0051] Maternal functioning (including the mother's emotional state) is also important for child development. Indeed, the quality of mother-infant interactions during the first year of life influences the child's development. High levels of maternal functioning are likely to correlate with favorable developmental outcomes for the child. Similarly, dysfunction in the postnatal period may prevent optimal development of the child.

[0052] 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.

[0053] 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.

[0054] 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 who had a score of 80 or less before treatment, and even in patients who had a score of 65 or less.

[0055] activator The above discussion indicates that PPD is characterized by several aspects that represent a significant disease burden and merit appropriate treatment. Thus, treatment, particularly by pharmacological intervention, is necessary not only to improve overall disease scores but also to improve specific aspects of the disease.

[0056] The inventors believed that carefully selected hallucinogens may lead to improved treatment of important aspects of PPD and may lead to overall improvement in the disease and maternal functioning.

[0057] The inventors further believed that in the case of treatment of nursing mothers suffering from PPD, carefully selected hallucinogens may allow continuation of breastfeeding without substantial interruption.

[0058] One group of hallucinogens involves compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families, 5-HT1 through 5-HT7, with several subtypes, are described). Examples include lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "hallucinogens," highlighting their remarkable ability to induce qualitatively altered states of consciousness (such as euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences) while minimizing other effects (such as sedation, narcosis, or hyperstimulation).

[0059] Chemically, serotonergic hallucinogens are either phenylalkylamines or indoleamines (the indoleamines are divided into two subsets, ergolines and tryptamines), the latter being derived from tryptamine.

[0060] Various serotonergic hallucinogens have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activity may also be modulated by interactions with other targets, such as monoamine transporters and minor amine-associated receptors.

[0061] Recently published clinical trials using serotonergic hallucinogens such as LSD, psilocybin, and DMT (using shamanic ayahuasca preparations containing DMT) for certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms, which may hinder their clinical use.

[0062] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, RE Jr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who experienced a manic episode after ingesting LSD or an LSD analog. The patient experienced acute symptoms of LSD intoxication that subsequently resolved, but a typical manic episode of psychotic proportions followed approximately three weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a manic episode after ingesting psilocybin mushrooms (self-reported). Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after ayahuasca (a DMT-containing preparation) consumption in a man with bipolar disorder.

[0063] A further case report is described in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A physician's attempt to self-medicate bipolar depression with N,N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0064] 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.

[0065] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a particularly interesting hallucinogen for therapeutic use. 5-MeO-DMT has a distinct pharmacological profile that differs from that of other hallucinogenic compounds.

[0066] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype compared to other classic hallucinogens.

[0067] As further detailed in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brain were measured. i The inhibitory constants (K values) of psilocin, DMT, and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Therefore, 5-MeO-DMT exhibits high affinity, while psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe α-MeO-DMT and β-MeO-DMT binding affinity for the 5-HT2A receptor are 37, 117, and 122 nM, respectively.

[0068] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor and acts as a potent agonist. In the case of psilocin and DMT, the contribution of 5-HT2A binding is increased compared to 5-MeO-DMT, with the latter showing the largest difference in affinity for 5-HT1A compared to 5-HT2A among the three compounds. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT than 5-HT2A binding for the other two compounds.

[0069] 5-HT1A receptor agonism has been reported to reduce impulsivity and aggression, while 5-HT2A receptor agonism may short-term increase these same traits. Furthermore, the dopamine system has been implicated in the pathogenesis of mania, with increased dopamine activity leading to mania. LSD, psilocybin, and DMT all have increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0070] Compared to other hallucinogens, such as LSD, psilocybin, or DMT, 5-MeO-DMT, preferably using the administration schemes described herein, can be administered to patients without significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), e.g., bipolar I disorder and bipolar II disorder, psychotic disorders, e.g., schizophrenia, or personality disorders, e.g., schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders, when treated according to the present invention, do not experience treatment-emergent mania or hypomania.

[0071] It should also be noted that reports of treatment-emergent mania or hypomania associated with psychoactive substance use appear to indicate heavy use of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD).

[0072] Our approach of sequentially titrating 5-MeO-DMT significantly reduces the risk of administering excessive doses that may be accompanied by adverse events.

[0073] Furthermore, antidepressant-induced hypomania has been reported in patients suffering from treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. “Antidepressant-induced hypomania in treatment-resistant depression.” Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0074] 5-MeO-DMT can induce a peak experience (i.e., an experience characterized by an emotional perspective shift described as "loss of self") that often leads to an overwhelming sense of "oneness with the universe" more rapidly than other hallucinogens. 5-MeO-DMT also exhibits a short duration of acute hallucinogenic effects (e.g., 5-30 minutes after inhalation, compared with several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile that may be explained by specific changes in resting-state network (RSN) activity under 5-MeO-DMT treatment.

[0075] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. We have demonstrated that 5-MeO-DMT binds to recombinant human 5-HT7 receptors as a radioligand.3 Nonspecific binding was estimated using [H]LSD and serotonin, and the Ki was determined to be 2.3 nM.

[0076] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor, where it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0077] 5-HT7 receptors have roles in neurogenesis, synaptogenesis and dendritic spine formation, and are involved in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0078] 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.

[0079] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination can lead to disease states, particularly those involving sleep disorders. Resting-state functional connectivity analysis in patients with sleep disorders revealed modulation of functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0080] Expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to its function in regulating the sleep / wake cycle, and the inventors believe this may allow treatment of patients suffering from sleep disorders with 5-MeO-DMT, which acts on the receptor.

[0081] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as one mediator of the pharmacological effects of 5-MeO-DMT, including "resetting" the functional connectivity of networks and neuroplasticity effects, contributes to the beneficial effects of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0082] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 and 5-HT1A receptors, as two mediators of its effects, including "resetting" functional network connectivity and neuroplasticity effects, may also enable it to exert beneficial effects in patients suffering from other symptoms or conditions, such as cognitive impairment, anxiety, psychomotor retardation, negative thinking, or social / emotional withdrawal, as supported by the clinical results demonstrated in the studies referred to herein.

[0083] Another characteristic of 5-MeO-DMT is its short half-life.

[0084] 5-MeO-DMT is primarily inactivated by the monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0085] We investigated the pharmacokinetic properties of 5-MeO-DMT and found rapid absorption and distribution of inhaled 5-MeO-DMT, with peak concentrations and pharmacological effects observed during and immediately after administration.

[0086] Analysis of the pharmacokinetic profile of 5-MeO-DMT after inhalation shows that plasma concentrations decline very rapidly. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. The titration described herein does not result in accumulation and thus does not result in high plasma concentrations, for example, at 10 minutes, 2 hours, or 3 hours after administration.

[0087] 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 rapid improvement in maternal functioning. Furthermore, 5-MeO-DMT is administered during a single treatment session with optional, irregular re-administration, which distinguishes it from SSRIs, which require chronic daily dosing regimens with low compliance, and from brexanolone, which requires long-term infusions and hospitalization.

[0088] Thus, the present invention also addresses compliance and patient convenience.

[0089] 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.

[0090] Isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used in accordance with the present invention. When reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0091] Such variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0092] The deuterated form of 5-MeO-DMT is one in which the deuterium content is higher than expected based on the natural abundance of this isotope.

[0093] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced at one or more defined hydrogen positions.

[0094] 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.

[0095] Further examples include forms of 5-MeO-DMT in which deuterium has been introduced into one or more hydrogen positions of the N-linked methyl group. Yet another example includes forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms on the indole ring system. Note that combinations of the above substitution patterns are also contemplated.

[0096] Methods for preparing these compounds are known in the art.

[0097] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated 5-MeO-DMT with salts of non-deuterated 5-MeO-DMT may also be used.

[0098] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0099] Prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used in accordance with the present invention. Such prodrugs of 5-MeO-DMT may be metabolically converted to 5-MeO-DMT. Thus, when reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the reference can be substituted for a 5-MeO-DMT prodrug or a salt thereof.

[0100] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be separated after administration.

[0101] Examples of suitable organic moieties include -C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 There is R 1 , R 2 , R 3 and R 4is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, and each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0102] A preferred example of the organic moiety is —CH(R 3 )OC(O)R 4 and -C(O)OR 1 and R 1 , R 3 and R 4 is defined as above.

[0103] Prodrugs (particularly those of the above structure) may also be used in the form of pharmaceutically acceptable salts.

[0104] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, specifically ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0105] Methods for preparing the prodrugs discussed herein are known in the art.

[0106] According to the present invention, the T of the metabolite 5-MeO-DMT measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg was max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0107] 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.

[0108] Treatment mode As already indicated above, the present invention is capable of treating patients suffering from PPD, which treatment not only results in a reduction in scores assessing the severity of depression, but also improves maternal functioning, as discussed in more detail below.

[0109] To further support the clinical application of 5-MeO-DMT in patients with PPD, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric reasons and noted specific improvements in disease aspects commonly seen in patients with PPD. The inventors noted, in particular, improvements in various symptoms and symptom combinations that the inventors determined were also related to maternal function.

[0110] The data stem is from a recently completed clinical trial examining the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below. Although the completed trial did not include patients with PPD, the inventors have determined that certain clinical findings made in this trial are relevant to devising treatments for PPD, as discussed in detail below.

[0111] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest were a group receiving a single 12 mg dose and a group receiving an intra-day individualized dosing regimen (IDR) allowing for multiple ascending doses (6 mg, 12 mg, and 18 mg) within the same day, as determined by the intensity of the patient-reported hallucinatory experience.

[0112] 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 effects through improvement in overall MADRS scores, we focused on the items that make up the various scales, noting that some of the subcore items are particularly relevant to patients with PPD and related to maternal functioning.

[0113] Multiple patients within the recruited cohort showed significant improvement in one or more of these subscore items, supporting our findings that 5-MeO-DMT is a suitable compound for treating PPD patients and for improving maternal function in these patients.

[0114] The specific subscore items for each scale are described in further detail below. We conclude that the effectiveness of treating one or more of these symptoms significantly improves the overall outcome for PPD patients treated with 5-MeO-DMT.

[0115] Thus, treatment according to the present invention reduces or eliminates (or ameliorates or eliminates) aspects of the disease.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] The inventors further believe that improvements observed on certain MADRS items translate into improvements in aspects of maternal functioning.

[0120] Particularly relevant MADRS items are discussed in more detail below.

[0121] The MADRS item "Inner tension" describes vague feelings of discomfort, irritability, inner confusion, and mental tension (ranging from panic, fear, or distress) that are rated according to intensity, frequency, duration, and the degree of relief sought.

[0122] A score of 0 is assigned if the patient is calm and experiences only fleeting inner tension. A score of 2 is assigned if there is occasional agitation and unexplained discomfort. A score of 4 is assigned if there is continuous inner tension or intermittent panic that the patient manages to overcome with some difficulty. A score of 6 is assigned if there is intense fear or anguish and insurmountable panic.

[0123] 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.

[0124] Conversely, improvement on these MADRS items leads to improvement in maternal functioning, particularly in the functional domains of the BIMF, mother-infant interaction and / or maternal psychological well-being.

[0125] In the study mentioned above involving patients with TRD, in the study group receiving the individualized dosing regimen, the aggregate score for the "internal tension" item on the MADRS across all eight patients was 26 at baseline. After two hours, the score decreased to 11, corresponding to a 15-point or 58% improvement. One day after treatment, the score decreased to 6, corresponding to a 20-point or 77% improvement. Seven days after treatment, the score decreased to 12, corresponding to a 14-point or 54% improvement.

[0126] Aggregate scores for the MADRS "internal tension" item across all four patients in the 12 mg group showed a baseline of 13. After two hours, the score had decreased to 2, corresponding to an 11-point or 85% improvement. On post-treatment day 1, the score had decreased to 3, corresponding to a 10-point or 77% improvement. On post-treatment day 7, the score had decreased to 5, corresponding to an 8-point or 62% improvement.

[0127] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of inner tension.

[0128] The improvement in inner tension is reflected by an improvement in the inner tension score on the MADRS item at least about 2 hours; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0129] Improvement in inner tension, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0130] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0131] 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.

[0132] The improvement in inner tension, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0133] The inventors further conclude that the reduction or elimination of internal tension achieved by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the MADRS total score but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed 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.

[0134] Because internal strain also influences other aspects of PPD, we conclude that the observed improvement in the "internal strain" item on the MADRS may further contribute to an overall improvement in maternal functioning.

[0135] The MADRS item "Fatigue" describes difficulty in starting or slowness in initiating and performing daily activities.

[0136] A score of 0 means that there is little difficulty in getting started and no slowness. A score of 2 is assigned if the patient has difficulty initiating activities. A score of 4 means that simple, everyday activities are difficult to initiate and require effort to perform. A score of 6 is assigned if the patient is completely exhausted and unable to do anything without assistance.

[0137] The inventors determined that elevated scores on the MADRS item "fatigue" negatively impact both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "restraint" impair parenting, self-care, emotional well-being, control, and adjustment.

[0138] 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.

[0139] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inhibition" across all eight patients was 27 at baseline. After two hours, it decreased to 10, which corresponds to a 17-point or 63% improvement. One day after treatment, it decreased to 5, which corresponds to a 22-point or 81% improvement. Seven days after treatment, it decreased to 3, which corresponds to a 24-point or 89% improvement.

[0140] In the 12 mg group, the aggregate score for the "inhibition" item on the MADRS across all four patients was 16 at baseline. After two hours, it decreased to 10, which corresponds to a 6-point or 38% improvement. On day 1 after treatment, it decreased to 0, which corresponds to a 16-point or 100% improvement. On day 7 after treatment, the score decreased to 3, which corresponds to a 13-point or 81% improvement.

[0141] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of fatigue.

[0142] The improvement in fatigue is reflected by at least an improvement in the fatigue score on 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.

[0143] 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.

[0144] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0145] Improvement in fatigue, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0146] The improvement in fatigue, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0147] The inventors further conclude that the reduction or elimination of fatigue achieved by treating PPD patients leads not only to a reduction in the MADRS total score, but also to improved maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within approximately 2 hours, and an increase in the BIMF score is also observed on day 1, e.g., approximately 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. Because fatigue also impacts other aspects of PPD, the inventors conclude that the observed improvement in the "Fatigue" item on the MADRS may further contribute to an overall improvement in maternal functioning.

[0148] The MADRS item "Apathy" describes the subjective experience of decreased interest in one's surroundings or activities that normally give pleasure. The ability to respond with appropriate emotion to situations or people is reduced.

[0149] A score of 0 indicates normal interest in surroundings and other people, a score of 2 indicates a diminished ability to enjoy things that one would normally be interested in. 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 emotionally numb experience, loss of emotions of anger, sadness, or joy, and a complete or painful absence of emotion toward close relatives and friends.

[0150] The inventors have determined that elevated scores on the MADRS item "Loss of Emotions" negatively impact both aspects of maternal functioning (maternal competence related to communication with infant(s) and maternal self-care). Elevated scores on the MADRS item "Loss of Emotions" impair mother-infant communication and emotional well-being.

[0151] Conversely, improvement on this MADRS item would translate to improved maternal functioning, particularly in the BIMF domain of functioning, mother-child communication and / or emotional well-being.

[0152] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Inability to Have Emotions" across all eight patients was 36 at baseline. After two hours, it decreased to 12, which corresponds to a 24-point or 67% improvement. One day after treatment, it decreased to 2, which corresponds to a 34-point or 94% improvement. Seven days after treatment, the score decreased to 6, which corresponds to a 30-point or 83% improvement.

[0153] Aggregating the score for the MADRS item "Inability to Have Emotions" across all four patients in the 12 mg group showed a baseline of 16. After two hours, it had decreased to 9, which corresponds to a 7-point or 44% improvement. On day 1 after treatment, it had decreased to 1, which corresponds to a 15-point or 94% improvement. On day 7 after treatment, the score had decreased to 1, which corresponds to a 15-point or 94% improvement.

[0154] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of emotional loss.

[0155] The improvement in loss of affect is reflected by an improvement in the loss of affect score on the MADRS item at least about 2 hours; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0156] Improvement in affective disorders, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores, occurs within about 2 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0157] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0158] Improvement in inability to feel, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0159] The improvement in emotional extinction, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0160] Furthermore, the inventors conclude that the reduction or elimination of emotional incapacity following treatment of PPD patients not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is rapid, i.e., within approximately 2 hours after the last administration of 5-MeO-DMT or its pharmaceutically acceptable salt, and increases in the BIMF score are also observed on days 7, 14, and / or 28. 13 Because emotional incapacity impacts other aspects of PPD, the inventors conclude that the improvement observed in the MADRS item "emotional incapacity" further contributes to an overall improvement in maternal functioning.

[0161] The MADRS item "Difficulty concentrating" describes difficulty organizing thoughts, leading to a lack of concentration that is so severe it interferes with normal functioning.

[0162] A score of 0 is given if the patient has no difficulty concentrating. A score of 2 is given if there is occasional difficulty in organizing thoughts. A score of 4 is assigned if there is difficulty concentrating or sustaining thoughts, resulting in a reduced ability to read or carry on a conversation. A score of 6 is given if the patient is unable to read or speak without great difficulty.

[0163] 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.

[0164] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly the BIMF functional domains of parenting and / or management.

[0165] 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, the score decreased to 11, corresponding to a 19-point or 63% improvement. One day after treatment, the score decreased to 1, corresponding to a 29-point or 97% improvement. Seven days after treatment, the score decreased to 9, corresponding to a 21-point or 70% improvement.

[0166] The combined MADRS "Difficulty concentrating" score across all four patients in the 12 mg group had a baseline of 16. After two hours, the score had decreased to 7, corresponding to a 9-point or 56% improvement. On day 1 after treatment, the score had decreased to 2, corresponding to a 14-point or 88% improvement. On day 7 after treatment, the score had decreased to 3, corresponding to a 13-point or 81% improvement.

[0167] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of concentration difficulties.

[0168] The improvement in difficulty concentrating is reflected by an improvement in the difficulty concentrating score on the MADRS item at least about 2 hours; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0169] 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.

[0170] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0171] Improvement in concentration difficulties, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0172] The improvement in concentration difficulties, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0173] The inventors further conclude that reducing or eliminating concentration difficulties by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the MADRS total score but also by an increase in the BIMF score, which is achieved rapidly, i.e., within approximately 2 hours, and an increase in the BIMF score is also observed on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0174] Because difficulty concentrating also impacts other aspects of PPD, we conclude that the improvement observed in the "difficulty concentrating" item of the MADRS may further contribute to an overall improvement in maternal functioning.

[0175] The MADRS item "negative thinking" refers to thoughts of guilt, inferiority, self-blame, guilt, regret, and doom and gloom.

[0176] 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.

[0177] The inventors have determined that elevated scores on the MADRS item "pessimistic thinking" negatively impact both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "pessimistic thinking" impair emotional well-being, social support, and control.

[0178] Conversely, improvement on this MADRS item would translate to improved emotional well-being, social support, and / or control in maternal functioning, particularly in the BIMF domain of functioning.

[0179] 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.

[0180] 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 decreased to 8, which corresponds to an 8-point or 50% improvement. On the first day after treatment, it decreased to 7, which corresponds to a 9-point or 56% improvement. On the seventh day after treatment, the score decreased to 8, which corresponds to an 8-point or 50% improvement.

[0181] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of negative thinking.

[0182] Improvement in negative thinking is reflected by an improvement in the negative thinking score on the MADRS item at least about 2 hours; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0183] 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.

[0184] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0185] Improvement in negative thinking, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0186] The improvement in negative thinking, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0187] The inventors further conclude that reducing or eliminating negative thinking by treating PPD patients leads not only to a reduction in the MADRS total score, but also to improved maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed 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.

[0188] Because pessimistic thinking also influences other aspects of PPD, we conclude that the observed improvement in the "pessimistic thinking" item on the MADRS may further contribute to an overall improvement in maternal functioning.

[0189] The MADRS item "Decreased Sleep" describes the experience of decreased sleep duration or depth compared to the subject's own normal pattern when well.

[0190] A score of 0 is assigned if the subject is able to sleep normally. A score of 2 reflects mild difficulty falling asleep or mildly reduced, light, or intermittent sleep. A score of 4 means at least 2 hours of reduced or interrupted sleep. A score of 6 means less than 2 or 3 hours of sleep.

[0191] The inventors have determined that elevated scores on the MADRS item "Decreased Sleep" negatively impact both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "Decreased Sleep" impair self-care, emotional well-being, and control.

[0192] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly in the BIMF functional domains of self-care, emotional well-being, and / or control.

[0193] 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 of treatment (the earliest time point to assess the treatment's impact on sleep), the score had decreased to 12, representing a 13-point or 52% improvement. By day 7 of treatment, the score had decreased to 9, representing a 16-point or 64% improvement.

[0194] The combined MADRS "Decreased Sleep" score across all four patients in the 12 mg group had a baseline of 12. After one day of treatment, the score decreased to 10, corresponding to a 2-point or 17% improvement. After seven days of treatment, the score decreased to 6, corresponding to a 6-point or 50% improvement.

[0195] The inventors conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of sleep loss.

[0196] Reduction or elimination of sleep decrement is reflected by at least an improvement in the MADRS sleep decrement item score 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.

[0197] 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.

[0198] Improvement in sleep reduction, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof.

[0199] The improvement in sleep reduction, as reflected by a decrease in CGI-S score or by a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days; particularly at least 14 days; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0200] The inventors further conclude that reducing or eliminating sleep loss by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the MADRS total score, but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 24 hours, and an increase in the BIMF score is also observed 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.

[0201] Because sleep reduction also impacts other aspects of PPD, we conclude that the observed improvement in the "sleep reduction" item on the MADRS may further contribute to an overall improvement in maternal functioning.

[0202] A further aspect of PPD that can be treated by administration of 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to a PPD patient to reduce or eliminate suicidal ideation in that patient.

[0203] In the clinical trials mentioned above involving the administration of 5-MeO-DMT, the MADRS item "suicidal thoughts" was assessed, among other things.

[0204] "Suicidal thoughts" refers to feelings of no meaning in life, of being ready to die naturally at any time, thoughts of suicide, and / or preparations for suicide. Suicide attempts themselves should not influence the rating of this MADRS item.

[0205] A score of 0 means the patient is enjoying life. A score of 2 is assigned if the PPD patient is tired of life and has fleeting suicidal thoughts. A score of 4 means the patient feels they would be better off dead, suicidal thoughts are common, and suicide is considered a possible solution, but the patient has no specific plan or intent. A score of 6 is assigned if the patient has a clear plan to attempt suicide and / or is actively preparing.

[0206] This MADRS scale item is particularly relevant to suicidal ideation.

[0207] The inventors have determined that elevated scores on the MADRS item "suicidal thoughts" negatively impact both aspects of maternal functioning (maternal competence in interacting with infant(s) and maternal self-care). Elevated scores on the MADRS item "suicidal thoughts" impair self-care, emotional well-being, and control.

[0208] Conversely, improvement on this MADRS item would translate to improvement in maternal functioning, particularly in the BIMF functional domains of self-care, emotional well-being, and / or control.

[0209] In the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "Suicidal Thoughts" across all eight patients was 11 at baseline. After two hours, the score had fallen to 3, which corresponds to an 8-point or 73% improvement. One day after treatment, it had fallen to 1, which corresponds to a 10-point or 91% improvement. Seven days after treatment, the score had fallen to 3, which corresponds to an 8-point or 73% improvement.

[0210] Aggregating scores on the MADRS "suicidal thoughts" item across all four patients in the 12 mg group showed a baseline of 8. After two hours, the score had decreased to 3, corresponding to a 5-point or 63% improvement. On the first day after treatment, it had decreased to 5, corresponding to a 3-point or 38% improvement. On the seventh day after treatment, the score had decreased to 7, corresponding to a 1-point or 13% improvement.

[0211] Thus, scores for the scale item "suicidal thoughts," which is particularly related to suicidal ideation, are significantly improved, at least in patients on the individualized dosing regimen. We conclude that 5-MeO-DMT can be used to treat suicidal ideation in patients with PPD.

[0212] Thus, in accordance with the present invention, treating a PPD patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.

[0213] The reduction or elimination of suicidal ideation is reflected by at least an improvement in the scores for the suicidal thoughts on the MADRS item at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0214] If the patient is suffering from suicidal ideation, improvement in suicidal ideation is reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] The improvement in suicidal ideation, as assessed by a reduction in CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0219] The inventors further conclude that reducing or eliminating suicidal thoughts by treating PPD patients 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, and an increase in the BIMF score is also observed 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.

[0220] Because suicidal thoughts influence other aspects of PPD, we conclude that the improvement observed in the MADRS item "suicidal thoughts" further contributes to a general improvement in maternal functioning.

[0221] The BPRS item "Emotional Withdrawal" relates to a deficit in the patient's ability to engage emotionally in interview situations. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. Lack of affective engagement is indicated by an occasional failure to return feedback, appearing distracted at times, or smiling awkwardly, but the individual spontaneously engages with the interviewer most of the time. 3- Mild. Lack of emotional engagement is indicated by a noticeable inability to return feedback, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4- Moderate. Emotional contact is absent for most of the interview because the subject does not respond in detail, is unable to make eye contact, does not seem to care whether the interviewer is listening, or may be distracted by psychotic tendencies. 5- Moderately severe. Similar to '4', but emotional contact is absent for the majority of the interview. 6- Severe. Actively avoids emotional involvement. Often does not respond or gives yes / no responses (not solely due to paranoia). Responds with very little emotion. 7- Most severe. Consistently avoids emotional involvement. Does not respond or gives yes / no responses (not solely due to paranoia). May walk out during the interview or not respond at all.

[0222] 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 infant(s) and maternal self-care). An increased score on the BPRS item "emotional withdrawal" impairs emotional well-being, mother-infant interaction, and social support.

[0223] 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.

[0224] 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, the score decreased to 8, which corresponds to a 5-point or 38% improvement. On the 1st day after treatment, the score decreased to 8, which corresponds to a 5-point or 38% improvement. On the 7th day after treatment, the score decreased to 8, which corresponds to a 5-point or 38% improvement.

[0225] In the 12 mg group, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score decreased to 11, corresponding to a 2-point or 15% improvement. On post-treatment day 1, the score decreased to 8, corresponding to a 5-point or 38% improvement. On post-treatment day 7, the score decreased to 6, corresponding to a 7-point or 54% improvement.

[0226] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of emotional withdrawal.

[0227] The reduction or elimination of emotional withdrawal is reflected by at least an improvement in the score on the emotional withdrawal item of the BPRS at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0228] Improvement in emotional withdrawal, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0229] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0230] 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.

[0231] The improvement in emotional withdrawal, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0232] The inventors further conclude that reducing or eliminating emotional withdrawal by treating PPD patients not only leads to a decrease in BPRS total score, but also to an improvement in maternal role as reflected by an increase in BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in BIMF score is also observed 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.

[0233] Because emotional withdrawal influences other aspects of PPD, we conclude that the improvement observed in the "emotional withdrawal" item of the BPRS may further contribute to an overall improvement in the maternal role.

[0234] The BPRS item "affective blunting" relates to a restricted range of emotional expression in face, voice, and body language, as well as a marked indifference or flatness, even when discussing distressing topics. Possible scores are: 1- No emotional blunting. 2- Very mild. Emotional range is somewhat subdued or reserved, but facial expressions and tone of voice are within the normal range and appropriate. 3- Mild. Overall range of emotions is reduced, inhibited, or reserved, and spontaneous and appropriate emotional responses are rare. Voice tone is slightly monotonous. 4- Moderate. The range of emotions is significantly reduced; the patient does not show emotion or smile, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Expressions of emotion or gestures usually return to a flat emotional state. 5- Moderately severe. The range of emotions is extremely reduced, the patient does not show emotion or smile, or responds minimally to distressing topics, gestures very little, and facial expressions rarely change. The tone of voice is often monotonous. 6- Severe. Little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression is constant. Tone of voice is monotonous most of the time. 7- Most severe. Virtually no emotional range or expression, stiff movements, monotonous tone of voice throughout the entire time.

[0235] 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.

[0236] 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.

[0237] 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. On day 1 after treatment, it decreased to 8, which corresponds to a 7-point or 47% improvement. On day 7 after treatment, the score decreased to 8, which corresponds to a 7-point or 47% improvement.

[0238] 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. On the first day after treatment, it decreased to 6, which corresponds to a 5-point or 45% improvement. On the seventh day after treatment, the score decreased to 5, which corresponds to a 6-point or 55% improvement.

[0239] We conclude that by using 5-MeO-DMT to treat patients with PPD, a reduction or elimination of affective blunting can be achieved.

[0240] The reduction or elimination of blunted affect is reflected by at least an improvement in the score on the blunted affect component of the BPRS at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0241] 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.

[0242] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0243] 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.

[0244] The improvement in affective blunting, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0245] The inventors further conclude that the reduction or elimination of blunted affect by treating PPD patients results in improved maternal functioning, as reflected not only by a decrease in the BPRS total score, but also by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on day 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.

[0246] Because blunted affect also impacts other aspects of PPD, we conclude that the improvement observed in the BPRS item "blunted affect" further contributes to a general improvement in maternal functioning.

[0247] The BPRS item "Guilt" concerns excessive concern or regret about past actions. Possible scores are: 1- No guilt. 2 - Very mild. Preoccupied with disappointing someone or failing at something, but not distracted. Can easily shift thoughts to other things. 3 - Mild. Somewhat preoccupied with disappointment or failure. Tends to express guilt to others. 4 - Moderate. Disproportionate preoccupation with guilt, having done something wrong, or having hurt others by 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. Delusional guilt or irrational self-blame that is largely unrelated to the situation. Moderately distracted. 7 - Most severe. Delusions of guilt or irrational self-blame that are highly unrelated to the situation. Subject is highly preoccupied with feelings of guilt and likely to disclose or act on the delusion.

[0248] 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 infant(s) and maternal self-care). An increased score on the BPRS item "guilt" impairs self-care, mother-infant interaction, emotional well-being, and control.

[0249] 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.

[0250] 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 decreased to 14, which corresponds to a 20-point or 59% improvement. One day after treatment, it decreased to 11, which corresponds to a 23-point or 68% improvement. Seven days after treatment, it decreased to 10, which corresponds to a 24-point or 71% improvement.

[0251] 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 decreased to 9, which corresponds to a 9-point or 50% improvement. On day 1 after treatment, it decreased to 5, which corresponds to a 13-point or 72% improvement. On day 7 after treatment, the score decreased to 5, which corresponds to a 13-point or 72% improvement.

[0252] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of guilt.

[0253] The reduction or elimination of guilt is reflected by an improvement in the score on the guilt item of the BPRS at least about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0254] 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.

[0255] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0256] 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.

[0257] The improvement in guilt, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0258] The inventors further conclude that treating PPD patients with reduced or eliminated guilt not only leads to a decrease in the BPRS total score, but also to an improvement in maternal role as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on day 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.

[0259] Because guilt influences other aspects of PPD, we conclude that the improvement observed in the "guilt" item of the BPRS may further contribute to an overall improvement in the maternal role.

[0260] The "Anxiety" item of the BPRS relates to reported apprehension, tension, fear, panic, or worry. Possible scores are: 1- No anxiety. 2 - Very mild. Reports discomfort due to worry that occurs more frequently than most healthy people or occasional worry. 3 - Mild. Frequent anxiety, but able to quickly redirect attention elsewhere. 4 - Moderate. Worried most of the time and unable to easily focus on other things, but does not impair functioning, or occasional autonomic anxiety, but does not impair functioning. 5 - Moderately severe. There are frequent but not daily periods of autonomic anxiety, or some areas of functioning are impaired by anxiety or worry. 6 - Severe. Autonomic anxiety occurs daily but not all day long, or many areas of functioning are impaired by anxiety or constant worry. 7 - Severe. Involuntary anxiety lasts all day or most areas of functioning are disrupted by anxiety or persistent worry.

[0261] 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.

[0262] 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.

[0263] 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 decreased to 19, corresponding to an 18-point or 49% improvement. One day after treatment, the score decreased to 16, corresponding to a 21-point or 57% improvement. Seven days after treatment, the score decreased to 17, corresponding to a 20-point or 54% improvement.

[0264] In the 12 mg group, the aggregate score for the BPRS item "anxiety" across all four patients was 25 at baseline. After 3 hours, the score decreased to 11, corresponding to a 14-point or 56% improvement. On day 1 after treatment, the score decreased to 6, corresponding to a 19-point or 76% improvement. On day 7 after treatment, the score decreased to 6, corresponding to a 19-point or 76% improvement.

[0265] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of anxiety.

[0266] The reduction or elimination of anxiety is reflected by an improvement in the score on the anxiety item of the BPRS at least about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0267] Improvement in anxiety, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0268] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0269] 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.

[0270] The improvement in anxiety, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0271] The inventors further conclude that the reduction or elimination of anxiety by treating PPD patients not only leads to a decrease in the BPRS total score, but also to an improvement in maternal role as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on day 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.

[0272] Because anxiety influences other aspects of PPD, we conclude that the improvement observed in the "anxiety" item of the BPRS may further contribute to an overall improvement in the maternal role.

[0273] The "tension" item of the BPRS relates to observable physical and motor symptoms of tension, "nervousness," and excitement. Possible scores are:

[0274] 1- No tension.

[0275] 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.

[0276] 3 - Mild. Same as "2", but signs of tension are more frequent or exaggerated.

[0277] 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.

[0278] 5 - Moderately severe. Frequent exertional strain accompanied by one or more symptoms often occurs simultaneously. Rarely, strain symptoms may be absent.

[0279] 6 - Severe. Same as 5, but with persistent signs of tension.

[0280] 7 - Most severe. Multiple motor symptoms are present in succession, e.g., continuous walking and rubbing of hands.

[0281] 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.

[0282] 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.

[0283] 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, the score had fallen to 11, which corresponds to a 5-point or 31% improvement. On the first day after treatment, it had fallen to 11, which corresponds to a 5-point or 31% improvement. On the seventh day after treatment, the score had fallen to 10, which corresponds to a 6-point or 38% improvement.

[0284] In the 12 mg group, the aggregate score for the BPRS item "tension" across all four patients was 14 at baseline. After 3 hours, the score had decreased to 9, which corresponds to a 5-point or 36% improvement. On the first day after treatment, it had decreased to 6, which corresponds to an 8-point or 57% improvement. On the seventh day after treatment, the score had decreased to 6, which corresponds to an 8-point or 57% improvement.

[0285] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of tension.

[0286] The reduction or elimination of tension is reflected by at least an improvement in the score on the tension item of the BPRS at about 2 hours, 1 day (e.g., about 24 hours), 7 days, 14 days, and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0287] 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.

[0288] Additionally or alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0289] Improvement in tone, as reflected by a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score of at least "much improved," preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0290] The improvement in tone, as reflected by a decrease in the CGI-S score or by a score of at least "much improved" on the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0291] The inventors further conclude that the reduction or elimination of tension by treating PPD patients not only leads to a decrease in the BPRS total score, but also to an improvement in maternal role as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on day 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.

[0292] Because strain also influences other aspects of PPD, we conclude that the improvement observed in the "strain" item of the BPRS may further contribute to an overall improvement in the maternal role.

[0293] Improvement in one or more aspects of PPD also leads to an overall improvement. Preferably, treatment results in remission.

[0294] 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.

[0295] Further alternatively, or in addition, remission of depressive symptoms may be reflected by a HAM-D score of 7 or less, achieved by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, achieved on day 1, e.g., about 24 hours; day 7; day 14, and / or day 28.

[0296] From the above, it follows that treatment of PPD patients with 5-MeO-DMT or a pharmaceutically acceptable salt thereof leads not only 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.

[0297] 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%.

[0298] 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%.

[0299] 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%.

[0300] 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%.

[0301] 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%.

[0302] 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%.

[0303] 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%.

[0304] 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.

[0305] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0306] Breastfeeding As used herein, the term "lactation" refers to the process of feeding human breast milk to a child. Breastfeeding includes feeding milk directly from the breast, as well as pre-expressing breast milk and then bottle-feeding the breast milk to a child.

[0307] As noted above, for many medications, breastfeeding patients may be faced with the decision to discontinue breastfeeding or discontinue / withdraw from treatment.

[0308] If a decision is made to discontinue breastfeeding in order to undergo treatment, this decision negatively impacts maternal functioning, particularly impairing the functional domains of mother-child interaction and psychological well-being.

[0309] The present invention also addresses the need for treatment of psychiatric or nervous system disorders in nursing mothers without substantially interrupting breastfeeding.

[0310] According to the present invention, breastfeeding can be resumed immediately after treatment.

[0311] The present inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT in an effort to determine at what point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, breast-feeding could be initiated without exposing the infant to any associated risks.

[0312] Additionally, breast milk was collected from lactating patients treated for PPD with 5-MeO-DMT. As described in more detail in the Examples section, lactating patients suffering from PPD were administered a 6 mg dose of 5-MeO-DMT, followed one hour later by an additional 12 mg dose of 5-MeO-DMT.

[0313] After the final dose of 5-MeO-DMT, breast milk samples, as well as serum and urine samples, were analyzed at several time points to confirm the presence of 5-MeO-DMT, bufotenin (the major metabolite of 5-MeO-DMT), and 5-MIAA (the final metabolite of 5-MeO-DMT).

[0314] For the administered compound, 5-MeO-DMT itself, absorption and distribution are rapid, with maximum concentrations and pharmacological effects observed during administration, eg, by inhalation, and shortly after ingestion.

[0315] Plasma protein binding is low (13-23%).

[0316] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows a very rapid decline in plasma concentrations. Ten minutes after administration, concentrations are already below 10% of Cmax, two hours after administration are below 1% of Cmax, and after three hours, 5-MeO-DMT is no longer detectable in plasma. This holds true across the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed with repeated dosing within a 1-4 hour time frame. The titration disclosed herein does not result in accumulation, and therefore does not result in high plasma concentrations of 5-MeO-DMT, for example, at 10 minutes, 2 hours, or 3 hours after administration.

[0317] The rapid decline in plasma concentrations results in only a short period of time during which 5-MeO-DMT can enter breast milk, resulting in 5-MeO-DMT only being present in breast milk for a short period of time.

[0318] The patient data obtained confirmed that 5-MeO-DMT concentrations in breast milk declined rapidly (see Example 12). No 5-MeO-DMT was detected in measurements taken after 24 hours.

[0319] When determining the potential effects of maternal drug administration on breastfed infants, it is standard practice to calculate the relative infant dose (RID) (Bennett, PN, and LJ Notarianni. "Risk from drugs in breast milk: an analysis by relative dose." Br J Clin Pharmacol 42.5 (1996): P673-4). The RID is the dose to which the infant is exposed through breast milk ingestion (μg / kg / day) divided by the dose received by the mother (μg / kg / day).

[0320] Estimates of daily breast milk intake and frequency of breastfeeding, as well as measured breast milk concentrations, can be used to determine infant exposure.

[0321] For example, a published estimate of daily breast milk intake as a function of infant weight is 150 ml / kg / day. To model exposure, a 5 kg infant is assumed to be breastfed three times over a 24-hour period, with 250 ml of breast milk per feeding. 5-MeO-DMT concentrations are assumed to be 2167.0 pg / ml (measured at hour 1) in the first feeding, 560.6 pg / ml (measured at hour 2.5) in the second feeding, and 42.1 pg / ml (measured at hour 8.5) in the third feeding. Based on this, the infant's total exposure (daily infant dose, DID) would be 692425 pg 5-MeO-DMT / day (0.000692425 mg / day), which corresponds to 0.000138485 mg / kg / day.

[0322] For maternal 5-MeO-DMT exposure, the total dose is 18 mg (6 mg as the first dose and 12 mg as the second dose according to the applicable titration scheme).

[0323] Also, because the amount actually delivered to the patient may be less than the prescribed dose, the RID calculation is performed assuming that the actual delivered amount is only 50% of the prescribed dose to avoid any possibility of underestimating the infant's exposure.

[0324] Assuming a typical maternal weight of 60 kg, the resulting RIDs are 0.092% (based on a maternal exposure of 9 mg) to 0.046% (based on a maternal exposure of 18 mg).

[0325] The threshold for recognition of "low risk" RID is 10%. From the calculations, it is clear that the 5-MeO-DMT RID is well below this threshold.

[0326] Furthermore, it should be noted that the 0.046% to 0.092% range is a conservative estimate. It assumes that 5-MeO-DMT concentrations remain constant between feedings (even though actual concentrations decline rapidly), ignoring the fact that with more than three feedings per day likely occurring and each feeding being smaller, infants are exposed to decreasing 5-MeO-DMT concentrations over time.

[0327] Furthermore, the estimate assumes that breast milk is not expressed or discarded.

[0328] Therefore, the actual RID will be less than the estimated value.

[0329] Possible metabolites of 5-MeO-DMT in humans were identified and the potential relevance of such metabolites was evaluated. In an in vitro metabolic characterization study in human hepatocytes, 5-MeO-DMT free base was incubated at 10 μM for up to 120 minutes. The identified compounds and their relative proportions are shown in Table 1 below. [Table 1] Of note, subsequent assays repeatedly failed to detect the presence of 5-methoxytryptophol, but reproducibly demonstrated the presence of 5-MIAA as the major metabolite, which likely plays no significant role in vivo.

[0330] The metabolites listed in the table above are formed via three different pathways.

[0331] The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed via oxidative deamination, which involves enzymatic removal and oxidation of the N-methyl group to form acetaldehyde: [ka] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0332] The secondary amines, primary amines, and aldehydes were not identified, indicating that they were not present in high concentrations at any time.

[0333] This aldehyde intermediate metabolite undergoes two separate biotransformations in human hepatocytes: it is either oxidized to 5-methoxyindoleacetic acid (5-MIAA) or reduced to 5-methoxyindole-3-ethanol. [ka] Both resulting metabolites are endogenous substances and are formed in the human body (e.g., during the synthesis and metabolism of melatonin and serotonin) (see, e.g., Biochemistry of the Pineal. Chapter 3. in Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3. in Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).

[0334] Because the primary pathway for the metabolism of 5-MeO-DMT rapidly leads to metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the oxidative deamination of 5-MeO-DMT does not involve metabolites that require restrictions regarding breastfeeding.

[0335] Furthermore, as detailed in the Examples section, incubation of 5-methoxytryptophol with human hepatocytes showed high turnover, with the compound being completely eliminated within 24 hours. At a test concentration of 1 μM, the in vitro intrinsic clearance of 5-methoxytryptophol was 16.2 μl / min / million cells (half-life of 142 minutes).

[0336] Thus, plasma concentrations of 5-methoxytryptophol, if formed at all, decline rapidly to reach endogenous levels.

[0337] 5-MIAA has been identified as the major human metabolite.

[0338] Incubation of 5-MIAA with human hepatocytes showed low turnover, with 75-82% of 5-MIAA remaining after 72 hours. 5-MIAA is thought to be the final metabolic product of 5-MeO-DMT.

[0339] 5-MIAA exhibits a relatively low plasma binding rate (mean unbound fraction (Fu)) of approximately 50% (see Examples section), yet it remains in the circulation subject to renal clearance.

[0340] If we ignore the endogenous production of 5-MIAA and assume that 5-MIAA is formed instantaneously from 5-MeO-DMT after administration of a single dose of the compound, a standard glomerular filtration rate of 90–120 ml / min suggests that 5-MIAA would be cleared from the circulation due to urinary excretion in approximately 1–2 h.

[0341] For example, the urinary concentration of 5-MIAA measured after 2.5 hours was 12,980,501 pg / ml (approximately 12.98 mg / l), indicating that most of the formed 5-MIAA was rapidly excreted.

[0342] As a result, plasma concentrations of 5-MIAA decline rapidly.

[0343] To more accurately estimate changes in plasma concentrations of 5-MIAA, several factors must be considered, including the patient's size and the increased blood volume that occurs during pregnancy. It is understood that there is interindividual variability in the glomerular filtration rate and the rate of metabolism of 5-MeO-DMT.

[0344] Furthermore, although the formation of 5-MIAA is rapid, pharmacokinetic data from healthy volunteers and even PPD patients indicate that small amounts of 5-MeO-DMT (equivalent to less than 10% of Cmax) may still be present after approximately 1 hour, resulting in the actual formation of 5-MIAA over a period of time following administration of 5-MeO-DMT.

[0345] Furthermore, when more than one dose of 5-MeO-DMT is administered, there is no accumulation of 5-MeO-DMT if the doses are spaced at least about one hour apart, although there is still measurable amounts of 5-MIAA in the serum after 2.5 hours, indicating some accumulation of this metabolite if subjects take doses one hour apart.

[0346] 5-MIAA is a weak acid and exists in plasma in an ionized form, reducing the tendency of the compound to pass into breast milk.

[0347] Nevertheless, it can be assumed that some 5-MIAA enters breast milk, especially during the limited period when plasma concentrations of 5-MIAA are relatively high.

[0348] Further information on the concentration-time profile is obtained from the measured breast milk concentrations of 5-MIAA as outlined in Example 12. These data can be used to calculate an estimate of the infant's exposure to 5-MIAA.

[0349] The 5-MIAA concentration is assumed to be 13945.2 pg / ml (measured at 1 hour) in the first 250 ml lactation, 13240.9 pg / ml (measured at 2.5 hours) in the second lactation, and 359.4 pg / ml (measured at 8.5 hours) in the third lactation. Based on this, the total exposure to the infant (DID) would be 0.00688638 mg 5-MIAA / day, which corresponds to 0.00137728 mg / kg / day.

[0350] Of note, 5-MIAA concentrations in breast milk at 24 hours are nearly 400-fold lower than at 1 hour, so there is no relevant exposure after 1 day.

[0351] Maternal exposure to 5-MIAA can be estimated based on the amount of 5-MeO-DMT administered and the proportion of 5-MeO-DMT converted to 5-MIAA.

[0352] In the metabolism experiment described above, the mixture contains approximately 60% 5-MIAA after 2 hours. Because metabolism is not complete, the actual percentage of 5-MeO-DMT converted to 5-MIAA will be higher. It can be assumed that more than 60%, and up to nearly 100%, of 5-MeO-DMT is converted to 5-MIAA as a final metabolic product, which is then excreted.

[0353] Considering the molecular weights (218.29 g / mol for 5-MeO-DMT and 205.21 g / mol for 5-MIAA), a total 18 mg 5-MeO-DMT dose would yield 10.15 mg 5-MIAA (60% conversion) to 16.92 mg 5-MIAA (100% conversion). Assuming only 9 mg of 5-MeO-DMT is delivered, as above, 5.08 mg 5-MIAA (60% conversion) to 8.46 mg 5-MIAA (100% conversion) would be formed.

[0354] Therefore, maternal exposure ranges from 0.085 mg / kg / day to 0.282 mg / kg / day, yielding estimated RID values ​​of 0.49% to 1.62%.

[0355] As shown, the accepted threshold for a "low risk" RID is 10%, and it is clear from the calculations, which represent conservative estimates, that the 5-MIAA RID is significantly below this threshold.

[0356] Moreover, the risk profile of 5-MIAA is low considering not only its subthreshold daily RID values ​​but also the fact that this compound is formed endogenously as a metabolite of certain natural tryptophan derivatives (e.g., serotonin).

[0357] Finally, levels of bufotenin, the major metabolite of 5-MeO-DMT, were assessed in urine, serum, and breast milk as described in Example 12. Notably, bufotenin was not detected in serum or breast milk at any time point, and was only detected in urine at the 2.5 hour time point (32.3 pg / ml). This data further demonstrates that bufotenin does not increase the risk profile of 5-MeO-DMT.

[0358] The above calculations are based on a titration regimen including doses of 6 mg and 12 mg of 5-MeO-DMT, and the conclusions reached are valid for single doses up to 12 mg, which would result in lower exposure to 5-MeO-DMT and its metabolites.

[0359] Extrapolating to higher doses and assuming a linear relationship between dose increment and increasing breast milk concentration, and therefore infant exposure, leads to the conclusion that the RID of 5-MeO-DMT, and also of 5-MIAA, is still significantly below 10% for lactating mothers treated with higher doses of 5-MeO-DMT, e.g., 18 mg or 25 mg as a single dose or as the final dose in an ascending dose scheme.

[0360] This is true even when taking into account the storage effect of 5-MIAA in breast milk.

[0361] Linear extrapolation is justified based on the observed linear pharmacokinetic profile of 5-MeO-DMT.

[0362] Finally, when considering risks to infants, daily dosing should be considered, as in chronic treatment regimes, because this eliminates the need to consider cumulative exposure of the infant over time.

[0363] A further identified metabolite, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The formed metabolite then undergoes glucuronidation catalyzed by UGTs. [ka] As part of pharmacokinetic studies, we determined that bufotenin was barely detectable in human serum. In any case, it was not detectable 15 minutes after administration of 5-MeO-DMT. Small amounts were detected in urine 2.5 hours later (Example 12).

[0364] Bufotenin glucuronide cannot bind to the receptor and exerts no effect. Furthermore, its concentration is so low that it was not detected in the hepatocyte assay. Bufotenin glucuronide is further converted to 5-hydroxyindoleacetic acid: [ka] 5-Hydroxyindoleacetic acid is an endogenous substance, occurring, for example, in the metabolism of melatonin and serotonin (references given above).

[0365] The O-demethylation pathway of 5-MeO-DMT plays a minor role and leads to the major metabolite, bufotenin, which is rapidly removed from plasma and further metabolized to compounds present only in very low concentrations, ultimately leading to metabolites that are also part of endogenous metabolic pathways. The present inventors have determined that O-demethylation of 5-MeO-DMT does not involve metabolites that require restrictions regarding breastfeeding.

[0366] The third metabolic pathway involves N-oxidation: [ka] In silico modeling of the metabolites formed, 5-MeO-DMT-N-oxide was determined to be nongenotoxic, consistent with the negative in vitro genotoxicity assessment of the parent molecule. This compound is water-soluble and subject to rapid excretion, as confirmed by observations in rats (Sitaram, B.R., Lockett, L., Blackman, G.L., McLeod, W.R., 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine, and their N-oxides in the rat. Biochemical Pharmacology 36: 2235-2231). Because the metabolic pathway of 5-MeO-DMT involving N-oxidation plays a minor role and results in a low proportion of rapidly excreted metabolites without apparent toxicity, we determined that N-oxidation of 5-MeO-DMT does not involve metabolites that require restrictions regarding lactation.

[0367] 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.

[0368] It is safe for nursing patients to simply temporarily discontinue breastfeeding. Typically, breastfeeding is not normally permitted during the actual treatment, i.e., during administration of 5-MeO-DMT or its pharmaceutically acceptable salts, and for the duration of the subsequent hallucinogenic experience. However, once the immediate effects of administration have ceased, nursing patients may safely resume breastfeeding.

[0369] Early resumption of breastfeeding represents a significant benefit to the breastfeeding patient, their health, and the health of their infant.

[0370] The mother undergoing treatment may be advised, for example, to temporarily discontinue breastfeeding for a certain period of time or until a particular event occurs.

[0371] Cessation of breastfeeding means that the baby cannot be breastfed, or even expressed breast milk if breastfeeding is not recommended, although previously collected breast milk can be bottle-fed. The crucial point is when the breast milk is expressed (not when the child is fed).

[0372] Breastfeeding can be resumed for the indicated period or immediately after the event.

[0373] For example, mothers are encouraged to temporarily discontinue breastfeeding only for the duration of the actual procedure (e.g., until the Clinical Assessment of Readiness for Discharge (CADR) indicates readiness for discharge).

[0374] A Clinical Assessment of Readiness for Discharge (CADR) is performed to determine if there are any clinical barriers that would prevent the patient from returning home.

[0375] Readiness for discharge according to CADR requires that the following be observed: all adverse events have resolved or, if not resolved, do not prevent discharge; the patient is fully oriented; the patient has no hallucinations or perceptual distortions; the patient is alert (promptly responds to name-calling in a normal tone, and has a modified observer alertness / sedation rating of 5); vital signs have not changed clinically significantly compared to baseline; and in the treating physician's opinion, the patient is ready for discharge.

[0376] CADR may be administered approximately 1 hour after the last dose. Alternatively, a qualified professional may perform an independent discharge readiness assessment based on relevant factors such as the patient's vital signs and / or alertness / sedation.

[0377] Patients may be advised not to resume breastfeeding before 6 hours after discharge from the hospital or the last dose, whichever is later, preferably 3 hours after discharge from the hospital or the last dose, whichever is later, more preferably 2 hours after discharge from the hospital or the last dose, whichever is later, and especially 1 hour after discharge from the hospital or the last dose, whichever is later.

[0378] It is also possible to wait longer before resuming breastfeeding (eg, until the concentration of 5-MeO-DMT and / or its metabolites in breast milk samples falls below a certain threshold).

[0379] For example, breastfeeding may be temporarily discontinued until the 5-MeO-DMT concentration in breast milk samples falls to less than 2000 pg / ml, 500 pg / ml, or 75 pg / ml, and / or the 5-MIAA concentration in breast milk falls to less than 14000 pg / ml, 2000 pg / ml, or 75 pg / ml.

[0380] Alternatively, breast milk may be pumped until the concentration of 5-MeO-DMT and / or 5-MIAA falls below the indicated level and then discarded.

[0381] Furthermore, breastfeeding may be temporarily discontinued for a certain period of time, based on, for example, clinical experience regarding the concentration of 5-MeO-DMT and / or its metabolites in breast milk. In one example, a patient is advised to discontinue breastfeeding until 48 hours after receiving the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Patients are advised to discontinue breastfeeding preferably until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and more preferably until 12 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Even more preferably, breastfeeding needs to be discontinued for only 6 hours, even more preferably for only 3 hours, particularly for only 2 hours, and most preferably for only 1 hour after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0382] This short interruption, and the corresponding possibility of resuming breastfeeding immediately after the procedure, contributes to the success of the procedure, in particular to maternal function and health and the development of the infant(s).

[0383] To avoid any associated risks to the infant, it is desirable to keep the concentrations of 5-MeO-DMT and / or 5-MIAA in breast milk as low as possible. As long as the concentrations of 5-MeO-DMT and / or 5-MIAA in breast milk exceed a predetermined threshold, any associated risks to the infant can be avoided by discarding any expressed breast milk or by resuming breastfeeding only when the 5-MeO-DMT and / or 5-MIAA concentrations in breast milk fall below the predetermined threshold. In a preferred embodiment, the threshold for 5-MeO-DMT in breast milk is as low as possible. In a further preferred embodiment, the threshold for 5-MIAA in breast milk is as low as possible. In a most preferred embodiment, the threshold for both 5-MeO-DMT and 5-MIAA in breast milk is as low as possible.

[0384] Various preferred threshold values ​​for 5-MeO-DMT and / or 5-MIAA in expressed breast milk are provided below. [Table 2]

[0385] Delivered Infant Dose (DID) for 5-MeO-DMT and / or 5-MIAA The delivered infant dose (DID) for 5-MeO-DMT and / or 5-MIAA should be kept as low as possible. In a preferred embodiment, the DID for 5-MeO-DMT is kept as low as possible. In a more preferred embodiment, the DID for 5-MIAA is kept as low as possible. In a most preferred embodiment, the DID for both 5-MeO-DMT and 5-MIAA is kept as low as possible.

[0386] The relevant DIDs for 5-MeO-DMT and / or 5-MIAA of the present invention are as follows: [Table 3] Achieving the DID requires adaptation of breastfeeding, which can be an appropriate time for resumption of breastfeeding, an appropriate number of breastfeeds during the first 24 hours after resumption of breastfeeding, an appropriate period of pumping and discarding breast milk, or a combination of these measures.

[0387] Relative Infant Dose (RID) for 5-MeO-DMT and / or 5-MIAA The relative infant dose (RID) for 5-MeO-DMT and / or 5-MIAA should be as low as possible. In a preferred embodiment, the RID for 5-MeO-DMT is kept as low as possible. In a more preferred embodiment, the RID for 5-MIAA is kept as low as possible. In a most preferred embodiment, the RID for both 5-MeO-DMT and 5-MIAA is kept as low as possible.

[0388] The relevant RIDs for 5-MeO-DMT and / or 5-MIAA of the present invention are as follows: [Table 4] Achieving the RID requires adaptation of breastfeeding, which can be an appropriate time for resumption of breastfeeding, an appropriate number of breastfeeds during the first 24 hours after resumption of breastfeeding, an appropriate period of pumping and discarding breast milk, or a combination of these measures.

[0389] Delivered Infant Dose (DID) and Relative Infant Dose (RID) Combinations for 5-MeO-DMT and / or 5-MIAA It has been explained that the DID and RID for 5-MeO-DMT and / or 5-MIAA are related aspects of the present invention. While each individual aspect is related as such, in a preferred embodiment of the present invention, both aspects of the DID for 5-MeO-DMT and / or 5-MIAA and the RID for 5-MeO-DMT and / or 5-MIAA should be considered in combination. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0390] In one embodiment, a DID for 5-MeO-DMT and a RID for 5-MeO-DMT are combined. In a preferred embodiment, the DID and RID for 5-MeO-DMT are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0391] In a further embodiment, a DID for 5-MIAA and a RID for 5-MIAA are combined. In a preferred embodiment, the DID and RID for 5-MIAA are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0392] In a further embodiment, a DID for 5-MeO-DMT and a RID for 5-MIAA are combined. In a preferred embodiment, the DID for 5-MeO-DMT and the RID for 5-MIAA are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0393] In a further embodiment, a RID for 5-MeO-DMT and a DID for 5-MIAA are combined. In a preferred embodiment, the RID for 5-MeO-DMT and the DID for 5-MIAA are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0394] In a more preferred embodiment, the DIDs for 5-MeO-DMT and 5-MIAA, and the RIDs for 5-MeO-DMT and 5-MIAA, are combined. In a preferred embodiment, the DIDs for 5-MeO-DMT and 5-MIAA, and the RIDs for 5-MeO-DMT and 5-MIAA, are kept as low as possible. Related DIDs and related RIDs that can be combined are provided in the present invention.

[0395] Mode of administration A therapeutically effective amount of 5-MeO-DMT is administered by inhalation, nasal administration, buccal administration, or sublingual administration. Administration via these routes can ensure a rapid onset of action. The most preferred administration route is inhalation. Preferably, a therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

[0396] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration formulation, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably hydrobromide) or in the form of a formulation of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0397] Buccal or sublingual administration may also rely on a pharmaceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in the form of a formulation (e.g., tablet, film, spray, cream) as commonly known in the art.

[0398] Administration is typically via inhalation of an aerosol. Such aerosols contain (a) a pharmaceutically acceptable gas; and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, with the aerosol having an aerosol particle mass density of about 0.5 mg / L to about 18 mg / L, such as about 0.5 mg / L to about 12.5 mg / L, preferably about 1.3 mg / L to about 10 mg / L, and particularly about 2 mg / L to about 9 mg / L. The pharmaceutically acceptable gas is preferably air.

[0399] The aerosol particles preferably contain less than 1 wt.% impurities, particularly less than 0.5 wt.% impurities, and further preferably contain less than 0.5 wt.% 5-MeO-DMT degradation products, particularly less than 0.2 wt.% 5-MeO-DMT degradation products resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0400] In a further preferred embodiment, the aerosol consists essentially of (a) air, and (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0401] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0402] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular a mass median aerodynamic diameter of less than 2 μm and greater than 0.1 μm.

[0403] The aerosol may be formed by: a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof formed on a solid support to thermal energy; and b) passing air over the thin layer of 5-MeO-DMT to produce aerosol particles. The thickness of the thin layer may be less than about 10 μm, particularly less than about 7.5 μm. The thickness may range from about 0.1 μm to about 10 μm, particularly from about 0.3 μm to about 7.5 μm.

[0404] A thin layer of 5-MeO-DMT formed on a solid support may be exposed to thermal energy via air passing over the layer, or alternatively, a thin layer of 5-MeO-DMT formed on a solid support may be exposed to thermal energy via the solid support.

[0405] The temperature of the air passing over the thin layer may range from about 180° C. to about 260° C. The air passing over the thin layer may in particular have a temperature of about 210° C. and may be passed over the thin layer at a rate of about 12 1 / min for about 15 seconds.

[0406] The aerosol particles can be contained in a volume of about 3 liters or less, particularly about 1 to about 3 liters, for example, about 2 to about 3 liters. The aerosol particles are preferably delivered to the patient in a single inhalation.

[0407] The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. The 5-MeO-DMT and a pharmaceutically acceptable salt thereof are provided in the form of an aerosol. Such an aerosol has a suitable aerosol particle mass concentration so that a therapeutically effective dose of the aerosol can be administered to a patient in a single inhalation.

[0408] Aerosols useful in the present invention can be formed using thermal energy. When using thermal energy to form an aerosol of a compound, it is very difficult to predict the conditions suitable for safe, efficient, and predictable aerosolization, especially when the aerosol is to be used to systemically deliver the compound to a patient via the lungs. Relevant variables in this context include: a) the dose of the compound; b) the morphological state of the compound used for aerosolization (e.g., crystalline form or thin layer form); c) the amount of thermal energy to which the compound is exposed (defined by temperature and exposure duration); and d) the volume of air introduced to create the aerosol (defined by flow rate and duration of airflow).

[0409] The compositions and methods described herein are for the safe, efficient, and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient via inhalation. "Safe" means that the aerosol particles should contain only small amounts of impurities and 5-MeO-DMT degradation products; "efficient" means that the dose is aerosolized, preferably nearly completely or completely, to a defined extent; the aerosol has desirable physical properties for systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof via the lungs, primarily via alveolar absorption; and the aerosol can be inhaled by a patient in a single inhalation (i.e., in a single deep breath); and "predictable" means that there should be little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0410] A suitable aerosol can be obtained by a) providing a therapeutically effective amount of 5-MeO-DMT as a thin layer on a solid support, b) briefly exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature, and c) providing a controlled amount of air so that an aerosol is formed.

[0411] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a thin layer of 5-MeO-DMT formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% wt impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) is capable of being delivered to a patient by a single inhalation.

[0412] The generation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, which contain less than 1% by weight of impurities and less than 0.5% by weight of 5-MeO-DMT drug degradation products by aerosol volume and which can be delivered to a patient by a single inhalation, is achieved by specifying a) the dose of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by the temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by the air flow rate and duration of the air flow).

[0413] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, whereby the air is heated. The temperature of the heated air passing over the thin layer can range from about 180°C to about 260°C. The temperature of the air passing over the thin layer can be, in particular, about 210°C.

[0414] Alternatively, the thin layer of 5-MeO-DMT can be exposed to thermal energy through the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The temperature of the heated solid support can range from about 180°C to about 420°C.

[0415] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is highly pure, having a purity of at least 99%, preferably at least 99.5%.

[0416] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT formed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Effective specific amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0417] The solid support on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided can have a variety of shapes. Examples of such shapes include, but are not limited to, a cylinder less than 1.0 mm in diameter, a box less than 1.0 mm thick, and virtually any shape permeated with small (e.g., less than 1.0 mm in size) pores. Preferably, the solid support has a large surface-to-volume ratio (e.g., greater than 100 per meter) and a large surface-to-mass ratio (e.g., greater than 1 cm per gram). 2 (more than)

[0418] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet 0.25 mm thick has a surface area to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder 1 cm in diameter results in a support that retains the high surface area to mass ratio of the original sheet but has a lower surface area to volume ratio (about 400 per meter).

[0419] Several different materials are used to construct solid supports. Such material types include, but are not limited to, metals, inorganic materials, carbonaceous materials, and polymers. The following are examples of material types: aluminum, silver, gold, stainless steel, copper and tungsten, silica, glass, silicon and alumina, graphite, porous carbon, carbon yarn and carbon felt, polytetrafluoroethylene, and polyethylene glycol. Combinations of materials and coated variants of materials are also used.

[0420] When aluminum is used as the solid support, aluminum foil is a suitable material. Examples of silica, alumina, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (defined surface area 2 m), and 21 / g (>1000 psi) alumina (Aldrich, St. Louis, Mo.) and silicon wafers such as those used in the semiconductor industry. Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0421] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, particularly less than about 7.5 μm, and may range from about 0.1 μm to about 10 μm, particularly from 0.3 μm to 7.5 μm.

[0422] Preferably, the total volume of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of about 6 liters per minute to about 40 liters per minute, preferably about 8 liters per minute to about 16 liters per minute, and the duration of the airflow is selected so that the total volume of aerosol does not exceed about 3 liters, preferably about 1 liter to 3 liters (e.g., 2 liters to 3 liters). For example, at an airflow rate of about 6 liters per minute, the duration of the airflow should be less than about 30 seconds. A specific effective airflow rate and duration is about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another specific effective airflow rate and duration is about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another specific effective airflow rate and duration is about 8 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful specific air flow rate and duration of air flow is 10 liters per minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0423] The aerosol generation rate is greater than 0.1 mg / sec.

[0424] The aerosol has an aerosol particle mass density of from about 0.5 mg / l to about 18 mg / l, for example from about 0.5 mg / l to about 12.5 mg / l, preferably from about 1.3 mg / l to about 10 mg / l, and especially from about 2 mg / l to about 9 mg / l.

[0425] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and greater than 0.1 microns, preferably less than 2.5 microns and greater than 0.1 microns, and most preferably less than 2 microns and greater than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% wt impurities, preferably less than 0.5% wt impurities.

[0426] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt of 5-MeO-DMT degradation products, preferably less than 0.2% wt of 5-MeO-DMT degradation products.

[0427] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a 12 mg dose of 5-MeO-DMT, organized on a solid support as a thin layer less than 5 microns thick, to a temperature of 210°C for 15 seconds by passing heated air over the thin layer, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns; 2) contains aerosol particles characterized by less than 1% impurities and less than 0.5% wt 5-MeO-DMT degradation products; and 3) is capable of being delivered to a patient by a single inhalation.

[0428] Those skilled in the art, aware of the aerosol characteristics and aerosolization conditions defined in the present invention, can identify suitable vaporization devices or systems that produce the required aerosol characteristics. Examples of such suitable vaporization devices or systems include, for example, the Volcano Medic Vaporization System (Storz & Bickel, Germany; e.g., EP 0 933 093 B1, EP 1 884 254 B1, and registered Community design 0033872990001) with an associated dosage capsule with a drip pad, and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA; e.g., U.S. Pat. No. 7,458,374 B2, U.S. Pat. No. 9,370,629 B2, and U.S. Pat. No. 9,687,487 B2). The generated aerosol may be collected in a balloon and inhaled by the patient from the balloon.

[0429] Dosage regimen The present invention also provides dose ranges, specific doses, as well as administration regimens (administration schemes).

[0430] The present invention is based in part on the inventors' conclusion that the occurrence of an acute hallucinogenic peak experience following administration of 5-MeO-DMT may causally facilitate, or at least serve as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from PPD, particularly one or more of the aspects defined above.

[0431] Thus, achieving the peak experience more quickly, in a greater proportion of patients, and with greater reproducibility within individual patients compared to previously tested hallucinogens and dosing regimens would result in a superior therapeutic profile.

[0432] Furthermore, the present invention relies on the short duration of action of 5-MeO-DMT and the associated lack of tolerance (i.e., no reduction or disappearance of the hallucinogenic effect after re-administration) as the basis for a dosing regimen with frequent re-administration (e.g., more than once daily or daily), which is designed to increase the incidence of peak experiences and thereby enhance therapeutic benefit. Such repeated administration within a short period of time also allows for intra-individual dose optimization, thereby reducing the risk of overdosing, which may otherwise result in physical side effects (e.g., serotonin syndrome), negative psychological reactions (e.g., flashbacks of the experience at a later time), the induction of mania or hypomania, or a less meaningful hallucinogenic experience with little or no memory of the altered state (so-called "whiteout"). Furthermore, starting with a low dose generally allows patients to become accustomed to the hallucinogenic experience and prepare them for the more intense symptoms that occur at higher doses, thereby positively influencing the experience at that higher dose. Additionally, the prospect of initiating treatment at lower doses will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0433] Frequent re-administration of serotonergic hallucinogens to improve the rate and reproducibility of peak experiences, as well as to enhance therapeutic efficacy, reduce side effects, and improve compliance rates, may not be possible with other hallucinogens due to the slow onset and long duration of hallucinogen effects, and the rapid onset of tolerance (i.e., reduced or absent hallucinogen effects after re-administration), which may last for several days.

[0434] Patients diagnosed with postpartum depression, as defined herein, including treatment-resistant forms of the disorder, including those associated with suicidal ideation, are treated by administration of 5-MeO-DMT. In a preferred embodiment, the 5-MeO-DMT is administered as monotherapy, i.e., the patient is not receiving any other treatment for PPD or symptoms associated with PPD.

[0435] The dosage of 5-MeO-DMT administered to patients diagnosed with postpartum depression, as defined herein (including treatment-resistant forms of this disorder, including those associated with suicidal ideation), ranges from about 1 mg to about 25 mg, or any amount within that range, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg, and most preferably from about 4 mg to about 12 mg. Useful specific amounts include, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, e.g., the hydrobromide salt. It should be noted that when a range, such as "about 1 mg to about 25 mg," is provided herein, the inventors contemplate all discrete values ​​within that range, some of which are specifically mentioned, but not all of which are mentioned (solely for brevity).

[0436] In a preferred embodiment, the improved method for treating a patient, as defined herein, diagnosed with postpartum depression (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises producing a clinical response by about 2 hours after administration of 5-MeO-DMT.

[0437] In a preferred embodiment, an improved method for treating a patient, as defined herein, diagnosed with postpartum depression (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, comprising a clinical response that occurs by about 2 hours after administration of 5-MeO-DMT, for at least about 6 days after the last administration of 5-MeO-DMT, preferably for at least about 14 days after the last administration of 5-MeO-DMT, and more preferably for at least about 28 days after the last administration of 5-MeO-DMT.

[0438] In a preferred embodiment, the improved method for treating a patient, as defined herein, diagnosed with postpartum depression (including treatment-resistant forms of the disorder, including those of the disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises administering more than a single dose of 5-MeO-DMT.

[0439] In one preferred embodiment, this more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with the interval between each administration within each treatment block being at least about 1 hour and not more than about 24 hours, and with the interval between the end of one treatment block and the start of the next treatment block being at least about 6 days.

[0440] In an even more preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, with the interval between each dose within each treatment block being about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0441] In a most preferred embodiment, the more than one dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 doses, with the interval between each dose within each treatment block being about 1 to 4 hours, preferably 1 to 2 hours, and with the interval between the end of one treatment block and the start of the next treatment block being about 6 days or more.

[0442] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and treatment block is constant for that individual patient and is selected from about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg, and most preferably about 4 mg to about 12 mg. Specific useful amounts are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0443] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0444] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a peak hallucinatory experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0445] For embodiments in which the dose is increased with each subsequent administration, the dose of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg, to the dose of the previous administration. For example, if the dose of the first administration is 6 mg and the dose increment is 6 mg, the dose of the second administration will be 12 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dose of the third administration will be 18 mg.

[0446] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first dose, and then increased to a dose selected from about 8 mg to about 14 mg for the second dose and to a dose selected from about 14 mg to about 20 mg for the third dose, unless the patient has already experienced a peak hallucinatory experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects. Specific effective amounts for the first, second, and third doses are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0447] In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first dose in a first treatment block, and then increased for each subsequent dose in the first treatment block until it reaches 20 mg or all doses in that treatment block are administered, whichever occurs first, or until the patient experiences a peak hallucinatory experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dose in that first treatment block being used as the dose for all subsequent treatment blocks and doses within those subsequent treatment blocks. For example, if a patient experiences a peak hallucinatory experience at a dose of 18 mg, and therefore the highest dose in the first treatment block is 18 mg, then the dose for all subsequent treatment blocks and doses within those subsequent treatment blocks will be 18 mg.

[0448] In a most preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of a first treatment block, and then increased to a dose selected from about 8 mg to about 14 mg for the second administration of the first treatment block and to a dose selected from about 14 mg to about 20 mg for the third administration of the first treatment block, unless the patient has already experienced a peak hallucinatory experience within that treatment block or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dose in that first treatment block being used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific effective amounts for the first, second, and third administrations in the first treatment block are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0449] It will be understood that pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens, and the appropriate weight of the salt to be administered may be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0450] According to the present invention, it is preferred that 5-MeO-DMT is not administered in conjunction with an MAO inhibitor.

[0451] The occurrence of a "peak hallucinatory experience" in a patient can be confirmed by achieving at least 60% of the maximum possible score on each of the four subscales (mysticism, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experiences Questionnaire (MEQ30) (reviewed in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0452] The occurrence of a "peak hallucinatory experience" in a patient can be confirmed by achieving at least 60% of the maximum possible score on the oceanic-unbounded (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (reviewed in Roseman L et al., Front Pharmacol. 2018;8:974).

[0453] In accordance with the present invention, the occurrence of a "peak hallucinatory experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES), also known as the Peak Hallucinatory Experience Questionnaire (PPEQ), which is the average of the patient's responses, rated from 0 to 100, to the following three questions: 1. How intense the experience was, 2. To what extent did it cause loss of control, and 3. How severe (i.e., profound and significant) was the experience?

[0454] Further aspects of the invention 1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of patients suffering from postpartum depression (PPD).

[0455] 2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 1, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or greater.

[0456] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 2, wherein the patient has a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0457] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 2, wherein the patient has a MADRS score of 35 or greater or a HAM-D score of 27 or greater.

[0458] 5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 4, wherein the patient has been diagnosed with a treatment-resistant form of postpartum depression.

[0459] 6. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to any one of aspects 1 to 5, wherein the patient further suffers from suicidal thoughts.

[0460] 7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 6, wherein the patient further suffers from slightly impaired, impaired, or severely impaired maternal function.

[0461] 8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 7, wherein the patient has a Birkin Index of Maternal Functioning (BIMF) score of 95 or less (such as 80 or less, particularly 65 or less).

[0462] 9. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to any one of aspects 1 to 8, administered at a dose or dosing regimen that causes said patient to experience a peak hallucinatory experience.

[0463] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 9, wherein a dosage of about 4 mg to about 20 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0464] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 9, wherein a dosage of about 6 mg, or about 12 mg, or about 18 mg is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0465] 12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered at a first dosage for a first administration, and the 5-MeO-DMT or salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration, unless the patient experiences a hallucinogenic high experience.

[0466] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of Aspects 1 to 12, wherein the 5-MeO-DMT is administered at a dosage of about 2 mg to about 8 mg for a first administration, then increased to a dosage of about 8 mg to about 14 mg for a second administration unless the patient has already experienced a hallucinogenic high experience, and then increased to a dosage of about 14 mg to about 20 mg for a third administration unless the patient has already experienced a hallucinogenic high experience; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0467] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 13, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0468] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 12 to 14, wherein the interval between two administrations is at least 1 hour and not more than 24 hours, such as about 1 to 4 hours, and preferably about 1 to 2 hours.

[0469] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 9 to 15, wherein the manifestation of a hallucinogenic peak experience is identified by achieving at least 60% of the maximum score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item Revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving a Peak Experience Scale (PES) Total Score of at least 75.

[0470] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 16, wherein the onset of a hallucinogenic peak experience is identified by achieving a Peak Experience Scale (PES) Total Score of at least 75.

[0471] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 17, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by inhalation or by nasal, buccal, or sublingual administration.

[0472] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 18, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas, and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of from about 0.5 mg / L to about 18 mg / L (e.g., to about 12.5 mg / L).

[0473] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 19, wherein the aerosol is generated by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer to produce aerosol particles.

[0474] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 18 to 20, wherein the dosage of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled in a single breath.

[0475] 22. 5-MeO-DMT for use according to any one of aspects 18 to 21, wherein the 5-MeO-DMT is used in the form of a free base.

[0476] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 22, wherein a clinical response, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0477] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 23, wherein the clinical response, as reflected by a reduction in the 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.

[0478] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 24, wherein the clinical response, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0479] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 25, wherein the clinical response, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0480] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 26, wherein the clinical response, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, is sustained for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0481] 28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 27, wherein a clinical response, as measured by at least a 50% improvement in the MADRS score or the HAM-D score, compared to the respective score before treatment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0482] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 28, wherein a clinical response, as measured by at least a 75% improvement in the MADRS score or the HAM-D score, compared to the respective score before treatment, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0483] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1-29, wherein remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0484] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 30, wherein remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0485] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 31, wherein the clinical response, as measured by an improvement of at least 50% in the MADRS score or the HAM-D score, compared to the respective score before treatment, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0486] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 32, wherein the clinical response, as assessed by at least a 75% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, is 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0487] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 33, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0488] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 34, wherein the clinical response, as measured by an improvement of at least 50% in the MADRS score or the HAM-D score, compared to the respective score before treatment, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0489] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 35, wherein the clinical response, as assessed by at least a 75% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, is 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0490] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 36, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0491] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 37, wherein the clinical response, as measured by an improvement of at least 50% in the MADRS score or the HAM-D score, compared to the respective score before treatment, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0492] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 38, wherein the clinical response, as assessed by at least a 75% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, is 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0493] 40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 39, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0494] 41. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in any of aspects 1-40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0495] 42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use in any of aspects 1-40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0496] 43. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in any of aspects 1-40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0497] 44. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in any of aspects 1-40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0498] 45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 40, wherein the patient is a nursing mother and is advised to discontinue nursing for up to 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0499] 46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 45, wherein said treatment improves maternal function.

[0500] 47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 46, wherein the improvement relates to one or more, in particular two or more, functional domains of the Birkin Index of Maternal Functioning (BIMF) selected from self-care, parenting, mother-infant interaction, psychological well-being of the mother, social support, management, and adaptation.

[0501] 48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 46 or 47, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

[0502] Provisions of the present invention 1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of patients suffering from postpartum depression (PPD).

[0503] 2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 1, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or greater, or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or greater.

[0504] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 2, wherein the patient has a MADRS score of 28 or more or a HAM-D score of 22 or more.

[0505] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 2, wherein the patient has a MADRS score of 35 or more or a HAM-D score of 27 or more.

[0506] 5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 4, wherein the patient has been diagnosed with treatment-resistant postpartum depression.

[0507] 6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 5, wherein the patient further suffers from suicidal thoughts.

[0508] 7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 6, wherein the patient further suffers from slightly impaired, impaired, or severely impaired maternal function.

[0509] 8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 7, wherein the patient has a Birkin Index of Maternal Function (BIMF) score of 95 or less (such as 80 or less, particularly 65 or less).

[0510] 9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 8, administered at a dose or dosing regimen that causes said patient to experience a peak hallucinatory experience.

[0511] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 9, wherein a dosage of about 4 mg to about 20 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0512] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 9, wherein a dosage of about 6 mg, or about 12 mg, or about 18 mg is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0513] 12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered at a first dosage for a first administration, and the 5-MeO-DMT or salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration unless the patient experiences a peak hallucinatory experience.

[0514] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 12, wherein the 5-MeO-DMT is administered at a dosage of about 2 mg to about 8 mg for a first administration, thereafter increased to a dosage of about 8 mg to about 14 mg for a second administration, unless the patient has already experienced a peak hallucinatory experience, and thereafter increased to a dosage of about 14 mg to about 20 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0515] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 13, wherein the first dosage of 5-MeO-DMT is about 6 mg, the second dosage of 5-MeO-DMT is about 12 mg, and the third dosage of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0516] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 12 to 14, wherein the interval between two administrations is at least 1 hour and not more than 24 hours, for example, about 1 to 4 hours, preferably about 1 to 2 hours.

[0517] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in clauses 9 to 15, wherein the manifestation of a peak hallucinatory experience is confirmed by achievement of at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and indescribability) of the 30-item Revised Mystical Experiences Questionnaire (MEQ30), or by achievement of at least 60% of the maximum possible score on the Oceanic Without Boundaries (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achievement of a total score of at least 75 on the Peak Experiences Scale (PES).

[0518] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 16, wherein said occurrence of a peak hallucinatory experience is confirmed by the achievement of a Peak Experience Scale (PES) total score of at least 75.

[0519] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 17, to be administered by inhalation or by nasal, buccal or sublingual administration.

[0520] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 18, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas, and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of from about 0.5 mg / L to about 18 mg / L (such as to about 12.5 mg / L).

[0521] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 19, wherein the aerosol is generated by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer to produce aerosol particles.

[0522] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 18 to 20, wherein the dosage of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled in a single breath.

[0523] 22. 5-MeO-DMT for use according to clauses 18 to 21, wherein the 5-MeO-DMT is used in the form of a free base.

[0524] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 22, wherein the clinical response, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0525] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 23, wherein the clinical response, as reflected by a 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.

[0526] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in clauses 1 to 24, wherein the clinical response, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0527] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in clauses 1 to 25, wherein the clinical response, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0528] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in clauses 1 to 26, wherein the clinical response, as reflected by a reduction in Clinical Global Impression-Severity (CGI-S) score, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0529] 28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 27, wherein the clinical response is assessed by at least a 50% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, and occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0530] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 28, wherein the clinical response is assessed by at least a 75% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, and occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0531] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in clauses 1 to 29, wherein remission of depressive symptoms, as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less, occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0532] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 30, wherein remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less occurs 1 day (e.g., about 24 hours) after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0533] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 31, wherein the clinical response, as assessed by an improvement of at least 50% in the MADRS score or the HAM-D score compared to the respective score before treatment, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0534] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 32, wherein a clinical response, as assessed by at least a 75% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, is present 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0535] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 33, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less, 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0536] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 34, wherein the clinical response, as assessed by an improvement of at least 50% in the MADRS score or the HAM-D score compared to the respective score before treatment, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0537] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 35, wherein a clinical response, as assessed by at least a 75% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, is present 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0538] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 36, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0539] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 37, wherein the clinical response, as assessed by an improvement of at least 50% in the MADRS score or the HAM-D score compared to the respective score before treatment, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0540] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 38, wherein a clinical response, as assessed by at least a 75% improvement in the MADRS score or the HAM-D score compared to the respective score before treatment, is present 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0541] 40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 39, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0542] 41. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of clauses 1 to 40, wherein the patient is a nursing mother and is advised to discontinue nursing for up to 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0543] 42. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of clauses 1 to 40, wherein the patient is a nursing mother and is advised to discontinue nursing for up to 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0544] 43. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of clauses 1 to 40, wherein the patient is a nursing mother and is advised to discontinue nursing for up to 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0545] 44. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of clauses 1 to 40, wherein the patient is a nursing mother and is advised to discontinue nursing for up to 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0546] 45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of clauses 1 to 40, wherein the patient is a nursing mother and is advised to discontinue nursing for up to two hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0547] 46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clauses 1 to 45, wherein said treatment improves maternal function.

[0548] 47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 46, wherein the improvement relates to one or more, in particular two or more, functional domains of the Birkin Index of Maternal Functioning (BIMF) selected from self-care, parenting, mother-infant interaction, psychological well-being of the mother, social support, management and adaptation.

[0549] 48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to clause 46 or 47, wherein the BIMF score is improved by 10% or more, preferably 20% or more. [Example]

[0550] The following examples are included to aid in the understanding of the invention and are not intended to, and should not be construed to, limit the invention, as set forth in the claims that follow, in any way.

[0551] Example 1 – 5-MeO-DMT Aerosol Generation and Administration Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask so that the target dose of 5-MeO-DMT free base to be administered to a subject or patient by inhalation is contained in a solution volume of 200 μl. Typical target doses of 5-MeO-DMT are 1 mg to 25 mg. For example, if the target dose of 5-MeO-DMT is 18 mg, then 90 mg of 5-MeO-DMT would be dissolved in 100% ethanol to make a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

[0552] Step 2: 200 μl of the solution is transferred into a dosing capsule containing a drip pad (Storz & Bickel, Germany), which is then closed with a lid.

[0553] Step 3: The dosage capsule filled with the 5-MeO-DMT ethanol solution is transferred to the filling chamber of the first Volcano Medic vaporizer, which is preheated to a temperature set at 55°C. The vaporizer's airflow is then turned on for 60 seconds at a preset flow rate of approximately 12 L / min. The heated air flows into the dosage capsule, evaporating the ethanol and leaving the target dosage of 5-MeO-DMT inside the capsule as a thin layer covering the stainless steel wire mesh. Accurate preparation of the dosage capsule can be confirmed by demonstrating that the final weight gain of the capsule compared to the weight of the empty capsule is approximately equal to the target dosage of 5-MeO-DMT.

[0554] Step 4: The prepared dose capsule was removed from the filling chamber and then transferred to the filling chamber of a second Volcano Medic vaporizer. This vaporizer was preheated with the temperature set to 210°C and the airflow on for at least 5 minutes, then turned off immediately before transfer. A valved inhalation balloon (Storz & Bickel, Germany) was attached to the socket of the filling chamber, the filling chamber was tightly closed, and immediately thereafter the airflow was turned on at a preset flow rate of approximately 12 l / min for exactly 15 seconds, then turned off. This resulted in the entire 5-MeO-DMT dose being aerosolized and distributed into the approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of 5-MeO-DMT could be confirmed by verifying that the capsule's weight had returned to approximately its initial weight.

[0555] Step 5: The balloon is then removed from the filling chamber, at which point the valve automatically closes. A mouthpiece is attached to the balloon, and the aerosol is ready to be administered immediately to the subject or patient.

[0556] Step 6: To prepare for administration, ask the patient to first take one or two deep breaths and exhale completely, concluding this sequence with a deep exhale. Then, holding the mouthpiece firmly against the lips, inhale the entire volume of the inhalation balloon completely in one breath, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

[0557] Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO2020 / 169850A1, the contents of which are incorporated herein by reference.

[0558] Example 2 Preparation of High-Purity 5-MeO-DMT 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 vol) at 35-40°C and then cooled to room temperature over 30 min. After stirring at room temperature for 50 min, no crystallization was observed, so the batch temperature was lowered to 7-12°C over 30 min. Crystallization occurred after 10 min of stirring at 7-12°C. Following stirring at 7-12°C for 1 h, the batch was filtered. After washing with MTBE (1 mL, 0.5 vol), the batch was dried under vacuum at 7-12°C for 3.5 h to give 1.02 g (50% recovery) of a pale orange solid. The isolated solid was analyzed for purity by HPLC as described in WO2020 / 169850A1. The purity was found to be 99.74% area.

[0559] The analytical results further indicate that the levels of individual impurities were less than 0.10% area. Solvent analysis of the sample indicated an MTBE level of 17 ppm.

[0560] Example 3 – Preparation of 5-MeO-DMT Hydrobromide 5-MeO-DMT HBr was prepared in 100 mg scale.

[0561] The free base of 5-MeO-DMT was mixed with isopropyl acetate (10 volumes) and the resulting 5-MeO-DMT solution was heated to 50° C. HBr was charged in one single aliquot (1 M in ethanol, 1 equivalent). The mixture was maintained at that temperature and allowed to equilibrate for 3 hours.

[0562] After 1 hour, a suspension formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried in vacuo at 40° C. for 18 hours.

[0563] An off-white crystalline material was obtained.

[0564] The salt has a melting point of 174°C and is characterized by an X-ray diffraction pattern measured using Cu Kα radiation, including peaks at 14.5°2θ±0.2°2θ, 16.7°2θ±0.2°2θ, 17.0°2θ±0.2°2θ, 20.6°2θ±0.2°2θ, 20.7°2θ±0.2°2θ, 21.4°2θ±0.2°2θ, 24.2°2θ±0.2°2θ, 24.8°2θ±0.2°2θ, 25.3°2θ±0.2°2θ, and 27.4°2θ±0.2°2θ.

[0565] Example 4 Determination of inhibition constants for central 5-HT1A and 5-HT2A receptors in postmortem human brain membrane preparations In this study, the affinity of three hallucinogenic test compounds (psilocin, DMT, and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue from the hippocampus and frontal cortex, respectively, was determined using radioligand binding techniques.

[0566] Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors died suddenly, had no history of coma, psychiatric or neurological disorders, were under 65 years of age, and had been dead for less than 72 hours.

[0567] Binding to 5-HT1A receptors in postmortem human hippocampus The hippocampi were homogenized in ice-cold 0.25 M sucrose (1:30 w / v) using a motor-driven Teflon pestle (12 strokes at 120 rpm). Myelin and cellular debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice, and the pellet was rehomogenized in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined, diluted with ice-cold membrane preparation buffer (1:100 w / v), and centrifuged at 20,500 g for 10 min using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm). The pellet was resuspended in ice-cold membrane preparation buffer, incubated at 37°C for 10 min, and then centrifuged at 20,500 g for 10 min. The pellet was resuspended and centrifuged a final time (20,500 x g, 10 min) to wash the tissue. The resulting pellet was then resuspended in ice-cold assay buffer to a tissue concentration equivalent to 3.125 mg wet weight tissue / ml. All centrifugations were performed at 4°C. The membrane preparation buffer consisted of 50 mM Tris-HCl, pH 7.7, 4 mM CaCl2, and 0.1% ascorbic acid. The assay buffer consisted of 50 mM Tris (pH 7.7), 4 mM CaCl2, 0.1% ascorbic acid, and 10 μM pargyline.

[0568] For saturation binding analysis, hippocampal membranes (400 μl, equivalent to 1.25 mg wet weight tissue / tube) were diluted with 50 μl of 0.075–9.6 nM [ 3 H]8-OH-DPAT and either 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding) for 30 min at 25° C. Wash buffer consisted of 50 mM Tris (pH 7.7).

[0569] In the displacement assay, hippocampal membranes (400 μl, equivalent to 1.25 mg wet weight tissue / tube) were diluted with 50 μl of 0.6 nM [ 3H]8-OH-DPAT and either 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (nonspecific binding), or 50 μl of one of the test compounds at one of 10 concentrations between 1 and 10,000 nM, were incubated for 30 min at 25°C.

[0570] Membrane-bound radioactivity was recovered by filtration under vacuum through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. Filters were rapidly washed with ice-cold wash buffer (wash settings 0, 9, 9), and radioactivity was measured by liquid scintillation counting (1 ml Packard MV Gold scintillator).

[0571] The compound concentration required to inhibit 50% of specific binding (IC 50 ) and Hill Slope were calculated by using nonlinear regression. i was calculated using a one-site binding model that takes into account ligand depletion.

[0572] Binding to 5-HT2A receptors in postmortem human frontal cortex Frontal cortices were homogenized in ice-cold 0.25 M sucrose (1:30 w / v) using a motor-driven Teflon pestle (12 strokes at 120 rpm). Myelin and cellular debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice, and the pellet was rehomogenized in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined, diluted with ice-cold 50 mM Tris-HCl assay buffer (pH 7.4, 1:100 w / v), homogenized using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. The pellet was centrifuged twice more to wash the tissue (20,500 × g for 10 min). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer (pH 7.4) to a tissue concentration equivalent to 10 mg wet weight tissue / ml. All centrifugations were performed at 4°C.

[0573] For saturation binding analysis, frontal cortical membranes (400 μl, equivalent to 4 mg wet weight tissue / tube) were diluted with 50 μl of 0.00625–0.8 nM [ 3 H]MDL-100,907 and either 50 μl of assay buffer or 50 μl of 10 μM ketanserin (nonspecific binding) were incubated for 60 min at 25° C. Assay buffer and wash buffer consisted of 50 mM Tris-HCl buffer (pH 7.4).

[0574] For displacement assays, frontal cortex membranes (400 μl, equivalent to 4 mg wet weight tissue / tube) were incubated for 60 min at 25°C with 50 μl of 0.1 nM [H]MDL-100,907 and either 50 μl of assay buffer (total binding) or 50 μl of 10 μM ketanserin (nonspecific binding), or 50 μl of one of the test compounds at one of 10 concentrations between 1 and 10,000 nM.

[0575] Membrane-bound radioactivity was collected and measured as described above, and data analysis was also performed as described above.

[0576] result In hippocampal membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K values) were determined for each of the three donors. d The values ​​were 0.51, 0.28, and 0.52 nM, respectively.

[0577] The mean inhibition constants (K i The Hill slopes for all compounds were close to 1, suggesting a one-site binding model.

[0578] In frontal cortical membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K values) were determined for each of the three donors. d The values ​​were 0.11, 0.08, and 0.08 nM, respectively.

[0579] The mean inhibition constants (K i The Hill slopes for all compounds were close to 1, suggesting a one-site binding model.

[0580] The selectivity ratios of psilocin, DMT, and 5-MeO-DMT for the 5-HT2A receptor relative to the 5-HT1A receptor were 0.78, 3.1, and 68, respectively.

[0581] Example 5 – Clinical Trial in Patients with TRD A Phase 1 / 2 clinical trial of inhaled 5-MeO-DMT, as described herein, has been completed in patients with treatment-resistant major depressive disorder (TRD). The study was designed in two parts. Part A was an open-label, single-arm, single-dose Phase 1 study with two dose levels (12 mg (n=4) and 18 mg (n=4)). Part B was an open-label, single-arm Phase 2 study employing an individualized dosing regimen with intrapatient titration of 5-MeO-DMT. Patients (n=8) received at least one and up to three doses of 5-MeO-DMT daily (6 mg, 12 mg, and 18 mg), with dose escalation occurring only if the previous dose did not provide a peak experience. The primary endpoint of Part A was to assess the safety and tolerability of a single dose of 5-MeO-DMT in patients with TRD. The primary endpoint of Part B was to assess the effect on depression severity, as measured by the proportion of patients in remission (defined as a MADRS total score of 10 or less) at 7 days post-dose.

[0582] In Part A, 3 of 4 patients in both groups (12 mg and 18 mg) experienced at least 1 ADR. All were mild and resolved spontaneously. No SAEs were reported.

[0583] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission at day 7, and one additional patient (25%) in the 18 mg group had a MADRS clinical response at day 7. The mean percent change from baseline in MADRS at day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

[0584] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0585] The primary endpoint was met, with 7 of 8 patients (87.5%) achieving MADRS remission at day 7 (p<0.0001). The mean MADRS change from baseline at day 7 was 24.4 (76%).

[0586] No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or cognitive function measures in either Part A or Part B.

[0587] The results are summarized in the table below. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0588] Example 6 – Pharmacokinetic evaluation of 5-MeO-DMT and bufotenin To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups (8 subjects per group) were formed. Subjects received a single inhaled dose of 6 mg, 12 mg, or 18 mg of 5-MeO-DMT. Blood samples were collected at 1, 2, 4, 7, 10, 15, 20, 30, and 45 minutes and 1, 1.5, 2, 3, and 4 hours after administration.

[0589] 5-MeO-DMT concentrations were measured using LC-MS / MS. PK parameters were generated by algebraic analysis of individual concentration versus time plots. Analysis was performed using Phoenix WinNonlin 6.3 software.

[0590] The median Cmax values ​​obtained for these three groups were 11.85 ng / ml (6 mg group), 22.90 ng / ml (12 mg group), and 38.45 ng / ml (18 mg group).

[0591] Table 4 below shows the median plasma concentration percentages of Cmax measured at the indicated time points. [Table 11] Pharmacokinetic measurements were also performed using a dosing scheme relying on ascending doses, with substantially similar results.

[0592] We also measured plasma concentrations of bufotenin, a metabolite of 5-MeO-DMT. Only a few samples had concentrations above the lower limit of quantification (LLOQ) (25 pg / ml). After 15 min, bufotenin concentrations consistently fell below the LLOQ.

[0593] Substantially similar observations were made when subjects receiving a titration scheme were included.

[0594] Example 7 – Toxicity testing of 5-MeO-DMT 5-MeO-DMT did not induce mutations in four histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101) under conditions that included treatment with rat liver metabolic activation (S-9) at concentrations up to 5000 μg / plate (the maximum recommended concentration according to current regulatory guidelines).

[0595] Example 8 – Binding of 5-MeO-DMT to human plasma proteins The in vitro binding of 5-MeO-DMT to plasma proteins was investigated using high-throughput dialysis. Equilibration time and nonspecific binding were measured at a nominal 5-MeO-DMT concentration of 1 μM using human plasma. Following evaluation of the equilibrium data, plasma protein binding was investigated at nominal concentrations of 0.1, 1, and 10 μM using a dialysis time of 4 hours. The concentrations of 5-MeO-DMT in samples from the plasma and buffer compartments were measured by LC-MS / MS. The protein binding results are presented below: [Table 12]

[0596] Example 9 – Human metabolism of 5-MeO-DMT 5-MeO-DMT was incubated with human hepatocytes suspended in Leibovitz L-15 medium (1 x 106 cells / mL) at nominal concentrations of 1 μM and 10 μM.

[0597] A standard stock solution of 5-MeO-DMT was prepared in ethanol at 20 mM and further diluted with Leibovitz L-15 medium to a concentration of 2 mM. When culturing cryopreserved hepatocytes, the 2 mM stock solution was diluted with Leibovitz L-15 medium to adjust the concentration to 20 μM or 2 μM. Aliquots (250 μL) of the 20 μM and 2 μM test substance formulations were added to each hepatocyte incubation sample (250 μL) as appropriate, so that the final test substance concentrations in the incubation were 10 μM or 1 μM, respectively, and the incubation contained less than 1% (v / v) solvent.

[0598] Incubations were carried out in a shaking water bath at approximately 37°C (total incubation volume 0.5 mL). For 1 μM, incubations were terminated after 0, 5, 10, 20, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile (0.5 mL). For 10 μM, incubations were terminated after 0, 10, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile containing the internal standard (1 μg / mL psilocin-d10).

[0599] The samples were vortex mixed and centrifuged at approximately 13,000 rpm for 10 minutes at room temperature. After centrifugation, the protein-free supernatant was removed for analysis.

[0600] Blank control incubations were performed with Leibovitz L-15 medium instead of test substances. Cell-free control samples were performed with Leibovitz L-15 medium instead of hepatocytes. Aliquots of blank control samples were taken at 120 min, and cell-free control samples were taken at 0, 30, and 120 min for the 1 μM incubations and at 0 and 120 min for the 10 μM incubations.

[0601] All 1 μM incubations were performed in duplicate, while all 10 μM incubations were performed in singlet. All samples were stored at −80° C. (nominal) prior to analysis.

[0602] Suitable chromatographic conditions were developed to retain the parent compound and obtain a suitable chromatographic response. The 0-, 30-, and 120-minute incubation samples generated after incubation with 5-MeO-DMT at 10 μM were analyzed using reversed-phase LC-MS to generate high- and low-energy mass spectra (MSEs). Prior to sample analysis, 100 μL aliquots of each sample were evaporated to near dryness under a steady stream of nitrogen at room temperature and then reconstituted in 50 μL of mobile phase A (0.1% aqueous formic acid). Each sample (0, 30, and 120 min, 10 μM) was analyzed using accurate mass LC-MS to determine the relative levels of the parent compound at each time point and to identify the profile of metabolites formed. Appropriate blank and control samples were also analyzed. The 10- and 60-minute 10 μM incubation samples were not analyzed and were stored at -80°C (nominal).

[0603] Using screening software (UNIFI version 1.9.4) and user-defined search parameters, the data were scrutinized for the presence of metabolites by comparison of retention time with reference standards of the test substance and based on the accurate mass of the potential metabolites. Confirmation of a suspected metabolite required that the measured accurate mass of the peak detected in the sample used for structural elucidation be within 5 ppm of its theoretical mass to confirm the molecular formula.

[0604] The results obtained are summarized in Table 1 above.

[0605] Example 10 - Metabolic stability of 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol in a human hepatocyte co-culture model The metabolic stability of 5-MIAA and 5-methoxytryptophol was investigated in a Hμrel co-culture assay with human hepatocytes (Hμrel HumanPool™, a primary liver co-culture model from Visikol Inc.).

[0606] Incubations were performed using initial concentrations of 1 and 10 μM, and samples were taken at 0, 1, 2, 4, 8, 24, 48, and 72 hours (h). These samples were analyzed using UPLC / QE-orbitrap-MS.

[0607] The remaining LC / MS peak areas detected in the Hμrel co-incubation assay after each incubation time point for the test compounds are shown in the table below, compared to the corresponding 0 min incubation sample. The assay control diazepam results (elimination half-life) indicated that the enzyme activity was within normal levels. [Table 13] [Table 14] Low turnover was observed for 5-MIAA, with 75-82% of the remaining abundance after a 72-hour period in the presence of hepatocytes, whereas no loss was observed in the stromal cell control.

[0608] High turnover was observed for 5-methoxytryptophol, which was completely cleared by 24 hours in the presence of hepatocytes and not in the stromal cell control.

[0609] With human hepatocytes and a test concentration of 1 μM, an in vitro intrinsic clearance of 0.15 μl / min / million cells (half-life 15 400 min) was obtained for 5-MIAA, whereas the corresponding value for 5-methoxytryptophol was 16.2 μl / min / million cells (half-life 142 min).

[0610] The predicted hepatic extraction rates were 2% for 5-MIAA and 67% for 5-methoxytryptophol.

[0611] Example 11 – Plasma binding of 5-MIAA Binding to human plasma proteins was measured and reported are the unbound fraction (fu) of three replicates, as well as the mean unbound fraction, standard deviation, and mean % recovery (Table 8). [Table 15]

[0612] Example 12 – Clinical trial of 5-MeO-DMT administered by inhalation to patients with postpartum depression This single-arm, open-label clinical trial will involve 15 adult female patients with a clinical diagnosis of postpartum depression (PPD).

[0613] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0614] More specifically, on day 0, patients will receive 5-MeO-DMT at up to three doses: 6 mg, 12 mg, and 18 mg. 1. All patients will receive an initial dose of 6 mg of 5-MeO-DMT. 2. The second dose (12 mg) is administered only if: a. Peak experience (total score ≥ 75) was not achieved after the 6 mg dose, and b. If the 6 mg dose is deemed safe and well tolerated by the investigator, c. Any psychoactive effects (PsE) from the previous dose have subsided; and d. Pre-dose vital parameters and forced expiratory volume in 1 second (FEV1) are within normal ranges or are outside the normal range but not clinically significant, as determined by the investigator. 3. Similarly, the third dose (18 mg) is administered only if: a. Peak experience (total score ≥ 75) was not achieved after the 12 mg dose, and b. The 12 mg dose is deemed safe and well tolerated by the investigator, and c. Any PsE from the previous dose has subsided, and d. Pre-dose vital parameters and forced expiratory volume in 1 second (FEV1) are within normal ranges or are outside the normal range but not clinically significant, as determined by the investigator.

[0615] Patients will be assessed post-dose for peak hallucinatory experience (based on the patient-rated visual analog scale PE scale), sedation, and other endpoints. Follow-up visits are scheduled for days 1 and 7 after dosing.

[0616] All patients considered for participation in a clinical trial must meet the following criteria: 1. Female, aged 18-45 years (inclusive) at the time of screening. 2. Body mass index (BMI) at screening is 18.5 to 35 kg / m 2 The range is inclusive. 3. Meet the PPD testing criteria as assessed by a testing psychiatrist or licensed psychologist. a. Diagnosis of major depressive disorder without psychotic features confirmed by Mini-Institute of Mental Illness Interview (MINI), with perinatal onset occurring from pregnancy onwards and within the first 4 weeks postpartum. b. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 28 at screening and pre-dose on Day 0. 6. Either breastfeeding must be discontinued at the time of screening, or if still breastfeeding or actively breastfeeding at the time of screening, must agree to temporarily discontinue breastfeeding from immediately prior to study drug administration on Day 0 until 24 hours after the last dose, expressing and discarding all breast milk as needed during that 24-hour period, which must include expressing / discarding at 2.5 hours after the last dose and at 24 hours after the last dose before resuming breastfeeding. 4. Patients must agree to maintain complete abstinence (total avoidance of heterosexual intercourse) or use a highly effective (<1% failure rate) medically approved method of contraception for 30 days before and 90 days after taking 5-MeO-DMT. Patients must have a negative pregnancy test at screening and the day before testing (day -1). 5. Willing to postpone initiation of other antidepressant or anxiety medications until after the end of the study on Day 7 and agree to maintain any psychotherapy unchanged during the study.

[0617] Potential patients who meet any of the following major exclusion criteria will be excluded from participation in this study. 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past diagnosis of bipolar disorder, manic or hypomanic episode, psychotic disorder, major depressive disorder (MDD) or other mood disorder with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient ineligible for the study. 2. Have one or more first- or second-degree relatives currently or previously diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD). 3. At significant risk for suicide, as determined by an examining psychiatrist or licensed psychologist, based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS). 4. Have been taking an antidepressant within 14 days or 5 half-lives (whichever is longer) prior to taking this drug (exception: within the last 5 weeks for fluoxetine). 5. Received any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to taking this drug. 6. Previously experienced a significant adverse reaction to hallucinogens or hallucinogenic drugs (e.g., psilocybin, Symphysema mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline), as determined by the investigator. 7. Known allergy or hypersensitivity to 5-MeO-DMT, or any other contraindication. 8. Any current or past clinically significant condition that, in the opinion of the investigator, would make the patient ineligible for the study (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new-onset hypertensive disorder of pregnancy during pregnancy or the postnatal period (e.g., gestational hypertension, preeclampsia-eclampsia, aggravated preeclampsia), uncontrolled diabetes, severe cardiovascular disease, severe hepatic or renal failure, severe brain damage (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head injury with loss of consciousness)). 9. Taking any medication or other substance that, in the opinion of the investigator, makes the patient ineligible for the study. 10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters render the patient ineligible for the study, as determined by the investigator. 11. Patient has a positive pregnancy test at screening or the day before the test (day -1), is pregnant, or is planning to become pregnant during the study period or up to 90 days after taking 5-MeO-DMT. 12. Patients with a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0618] The primary objective of the study was to determine the onset and 7-day durability of antidepressant effect of daily individualized dosing regimens of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in adult female patients with PPD.

[0619] Secondary objectives are to determine the antidepressant and anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE), and effects on cognitive outcomes of daily individualized dosing regimens of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in adult female patients with PPD.

[0620] The exploratory objective is to determine the amount of 5-MeO-DMT and its metabolites (bufotenin and 5-methoxyindole-3-acetic acid (5-MIAA)) in breast milk, blood, and urine by LC / MS / MS after daily IDR doses of 6 mg, 12 mg, and 18 mg of 5-MeO-DMT in adult female patients with PPD (metabolite identity screening may be performed if necessary).

[0621] The primary endpoint of this study was the assessment of the antidepressant effect of 5-MeO-DMT, as measured by the change from baseline in the MADRS, assessed at day 7.

[0622] Secondary endpoints include the antidepressant effects of 5-MeO-DMT as assessed by: Antidepressant effects of 5-MeO-DMT assessed by: o The proportion of patients in remission (MADRS ≤ 10) 2 hours after the last dose of study drug on day 0, and on days 1 and 7; Change from baseline in the MADRS assessed 2 hours after the last study drug dose on Day 0 and on Day 1; o Proportion of responders (≥50% reduction from baseline in MADRS total score) at 2 hours after the last study drug dose on Day 0, and on Days 1 and 7; Change from baseline in the Clinical Global Impression-Severity (CGI-S) scale 2 hours after the last study drug dose on Day 0, and on Days 1 and 7; ·Effects on maternal behavior as assessed by change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores; 5-MeO-DMT and bufotenin exposure in breast milk obtained the day before the test (day -1), 1 hour after the last study drug dose, at discharge, in the evening of day 0, and on days 1 and 7; 5-MeO-DMT and bufotenin exposure in blood obtained the day before the test (day -1), 1 hour after the last study drug dose, at discharge, days 1 and 7; Safety and tolerability of 5-MeO-DMT as assessed by: o Reporting of treatment-emergent adverse events (TEAEs); o Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, and peak expiratory flow measurements; o Sedation assessment (Modified Observer Assessment of Awareness and Sedation Scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after each study drug dose) and as part of the discharge assessment on Day 0; o Change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS), assessed as part of the discharge assessment on day 0 and also on days 1 and 7; o Change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed as part of the discharge assessment on Day 0 and also on Days 1 and 7; o Change from baseline in the C-SSRS assessed as part of the discharge assessment on day 0 and also on days 1 and 7; o Change from baseline in the YMRS assessed as part of the discharge assessment on day 0 and also on days 1 and 7; Patients reported experiencing PsE 30-60 minutes after each dose (when the PsE had worn off): ○ PsE assessment using the Peak Experience (PE) scale to assess achievement of a Peak Experience (PE scale total score ≥ 75); ○ Difficult Experiences Questionnaire (CEQ); o Mystical Experiences Questionnaire (MEQ-30); Duration of PsE, defined as the time from taking the study drug to the time when PsE subsided (as scored by the investigator and the patient) (completed 30–60 minutes after each dose).

[0623] Patient 1 To date, one patient diagnosed with postpartum depression by a psychiatrist has been recruited into the clinical trial. The diagnosis was major depressive disorder without psychotic features, confirmed by the Mini-Instrumental Interview for Mental Illnesses (MINI) (v7.0.2), with perinatal onset occurring after pregnancy and within the first four weeks after delivery. The patient was diagnosed with postpartum depression after giving birth to her third child. The patient completed all scheduled visits. The inhalation procedure was performed appropriately by the patient and was well tolerated, with no inhalation-related adverse events.

[0624] Results - 1st patient Aside from transient, clinically irrelevant increases in heart rate and blood pressure immediately following administration of 5-MeO-DMT, no other notable changes occurred in vital parameters. ECG (3 hours after administration), safety laboratory analyses (Day 7), and assessments of the CADSS (3 hours, Days 1 and 7) were also unremarkable. The few adverse events reported (crampy left abdominal pain and headache, both on Day 0) were mild, short-lived, and resolved spontaneously by the end of the study.

[0625] Regarding the intensity of the hallucinatory experience, a PES score of 17.3 was achieved in response to exposure to the nominal 6 mg dose, indicating the need to proceed to a subsequent higher dose of 12 mg, as per the individualized dosing plan design. The PES score achieved at this dose was 85.7, above 75, indicating that this patient had experienced a peak hallucinatory experience and completed the IDR.

[0626] Importantly, this patient reported a major improvement in depressive symptoms as assessed by the MADRS at the earliest assessment time point, 2 hours after drug administration, and the effect was sustained over time (Table 9). This patient also met standard criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score ≤ 10). [Table 16-1] [Table 16-2]

[0627] In particular, significant improvements were observed on several MADRS items, which are outlined in Table 9. Patients' baseline scores on some items reflected the absence of symptoms (loss of appetite, difficulty concentrating, suicidal thoughts), whereas items with scores reflecting severe symptoms (e.g., decreased sleep, inner tension) showed significant improvement.

[0628] Similarly, improvements were observed in several BPRS items, including hypochondriasis, anxiety, emotional withdrawal, guilt, and tension.

[0629] Furthermore, improvement in maternal function was evident by the improvement in BIMF scores recorded on day 7, as outlined in Table 10, with the total score improving by 14%, from 92 to 105 (out of a possible total of 120).

[0630] Several functional domains of maternal functioning were also assessed, as defined by Barkin et al. Improvements in each functional domain are outlined in more detail in Table 11.

[0631] Here, significant improvements in self-care, emotional well-being, and control were achieved, with percentage improvements ranging from 18% (control) to 44% (self-care). These improvements strengthen the relationship between improvements in depression as assessed by the MADRS and improvements in maternal functioning.

[0632] It is noted that this patient's scores were already relatively high before treatment. In some functional domains, scores were at or near maximum (see Table 11), limiting the extent of improvement with this treatment. [Table 17-1] [Table 17-2] [Table 18]

[0633] Summary and Conclusion A. A personalized dosing regimen of 6 mg of 5-MeO-DMT followed by 12 mg of 5-MeO-DMT administered by inhalation was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

[0634] B. Clinical response occurs rapidly, within 2 hours of 5-MeO-DMT administration. Such rapid onset is unusual and not seen with traditional classes of antidepressants (including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others), which generally take 4-6 weeks to demonstrate efficacy.

[0635] C. IDR showed that patients experienced clinical remission within 2 hours of 5-MeO-DMT administration, which is far superior to any other approved treatment for postpartum depression and to all hallucinogens tested to date.

[0636] D. Although 5-MeO-DMT was administered only once and was no longer effectively present in the body during the 7-day follow-up period (see pharmacokinetic data in Example 6 above), significant clinical responses persisted over this time frame. This observation supports the favorable clinical profile of 5-MeO-DMT, allowing for convenient dosing intervals.

[0637] E. In addition to the antidepressant effect, endpoints assessing other symptoms (e.g., hypochondriasis, emotional withdrawal, anxiety, guilt, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

[0638] F. In addition to the antidepressant effect, measures assessing maternal functioning (assessed using the BIMF, such as self-care, emotional well-being, and control) were also positively affected. This supports additional benefits of 5-MeO-DMT for patients suffering from PPD beyond the improvement of core depressive symptoms.

[0639] Patient 2 A second patient diagnosed by a psychiatrist with postpartum depression was recruited for the clinical trial. The diagnosis was major depressive disorder without psychotic features, confirmed by the Mini-Instrumental Interview for Mental Illnesses (MINI) (v7.0.2), with perinatal onset occurring after conception and within the first 4 weeks after delivery. The patient completed all scheduled visits (here, day 5 instead of day 7). The inhalation procedure was performed appropriately by the patient and was well tolerated with no inhalation-related adverse events.

[0640] Results - 2nd patient Aside from a transient, clinically unrelated increase in heart rate immediately after administration of 5-MeO-DMT, no other notable changes occurred in vital parameters. Evaluations of ECG (3 hours after administration), safety laboratory analyses (hours 3 and 7), and CADSS (hours 3, 1, and 7) were unremarkable. The few adverse events reported (vomiting on day 0 and headache on day 5) were mild, short-lived, and resolved spontaneously by the end of the study.

[0641] Regarding the intensity of the hallucinatory experience, a PES score of 1 was achieved in response to exposure to the 6 mg nominal dose. This score indicated that the personalized dosing plan design required progression to the next higher dose, 12 mg, 1 hour after the first dose. The PES score achieved at this dose was 94.7, greater than 75, indicating that this patient had experienced a peak hallucinatory experience and completed the IDR.

[0642] Significantly, this patient reported a significant improvement in depressive symptoms as assessed by the MADRS at the earliest assessment time point, 2 hours after drug administration, and the effect was maintained over time (Table 12). This patient also met standard criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score ≤ 10). [Table 19-1] [Table 19-2] [Table 19-3]

[0643] Significant improvements were demonstrated on several MADRS items, which are outlined in Table 12. Although the patient's baseline score for suicidal ideation reflected low severity compared with other symptoms, significant improvements were seen on all other items with scores reflecting severe symptoms.

[0644] Similarly, improvements were observed in several BPRS items, including anxiety, emotional withdrawal, conceptual integration disorder, guilt, and tension.

[0645] Furthermore, improvement in maternal function was evident by the improvement in BIMF scores recorded on day 7, as outlined in Table 13, with the total score improving by over 40%, from 74 to 104 (out of a maximum total of 120).

[0646] Several functional domains of maternal function were also assessed as defined by Barkin et al. Improvements in each functional domain are outlined in more detail in Table 14.

[0647] Here, notable improvements were achieved in all domains except infant care (which already achieved maximum scores at baseline), with percentage improvements ranging from approximately 27% (social support) to 450% (adjustment). These improvements strengthen the relationship between improvements in depression assessed by the MADRS and improvements in maternal functioning. [Table 20-1] [Table 20-2] [Table 21]

[0648] Summary and Conclusion A. A personalized dosing regimen of 6 mg of 5-MeO-DMT followed by 12 mg of 5-MeO-DMT administered by inhalation was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

[0649] B. Clinical response occurs rapidly, within 2 hours of 5-MeO-DMT administration. Such rapid onset is unusual and not seen with traditional classes of antidepressants (including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others), which generally take 4-6 weeks to demonstrate efficacy.

[0650] C. IDR showed that patients experienced clinical remission within 2 hours of 5-MeO-DMT administration, which is far superior to any other approved treatment for postpartum depression and to all hallucinogens tested to date.

[0651] D. Although 5-MeO-DMT was administered only once and was no longer effectively present in the body during the 5-day follow-up period (see pharmacokinetic data in Example 7 above), significant clinical responses persisted over this time frame. This observation supports the favorable clinical profile of 5-MeO-DMT, allowing for convenient dosing intervals.

[0652] E. In addition to the antidepressant effect, endpoints assessing other symptoms (e.g., emotional withdrawal, anxiety, guilt, conceptual integration disorders, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

[0653] F. In addition to the antidepressant effect, measures assessing maternal functioning (assessed using the BIMF, including self-care, emotional well-being, mother-infant interaction, social support, and adaptation and control) were also positively affected. This supports additional benefits of 5-MeO-DMT for patients suffering from PPD beyond the improvement of core depressive symptoms.

[0654] final conclusion The embodiments clearly demonstrate that 5-MeO-DMT, when used in accordance with the present invention, has a significantly improved efficacy profile compared to approved pharmacological therapies for postpartum depression and all hallucinogens tested to date.

[0655] These data, combined with the short duration of acute hallucinogenic effects and a favorable safety profile, demonstrate that the present invention solves the technical problem of providing improved psychoactive therapy in patients with postpartum depression.

[0656] Additional Results – Patient 2 The second patient was breastfeeding, and as per the clinical trial protocol, breast milk samples were collected before and at multiple time points after the administration of the last dose. These samples were then analyzed by LC-MS / MS assay to detect 5-MeO-DMT, bufotenin (the primary metabolite of 5-MeO-DMT), and 5-MIAA (the final metabolite of 5-MeO-DMT). Similar analyses were also performed on the patient's serum and urine samples. The data are summarized in the table below. [Table 22-1] [Table 22-2]

[0657] The data demonstrate rapid clearance of 5-MeO-DMT from serum until the first measurement time point 1 hour after the last dose, at which point a concentration of 132.9 pg / mL was detected, and concentrations remained below the lower limit of quantitation for the assay at all subsequent time points. Furthermore, endogenous levels of 5-MIAA were confirmed in serum before dosing, with peak concentrations detected at the first measurement time point (1 hour after dosing) and returning to baseline levels within 1 day. Urine assay data show that 5-MeO-DMT was present at approximately 4-fold higher concentrations than those detected in serum at 1 hour (indicating significant excretion by this time point) and rapidly declined to undetectable levels after this time point, whereas 5-MIAA levels peaked at approximately 127-fold higher concentrations than those detected in serum at 2.5 hours and rapidly declined to endogenous levels within 7 days. Bufotenin was not detected in urine at any time point except 2.5 hours after dosing. Taken together, these data confirm the rapid metabolism and clearance of 5-MeO-DMT in vivo.

[0658] Analysis of breast milk samples showed a lack of bufotenin, but 5-MeO-DMT concentrations were 2167 pg / ml at 1 hour post-dose, which rapidly declined to levels similar to those found endogenously in serum before dosing by 8.5 hours post-dose. A similar trend was observed for 5-MIAA.

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of a patient suffering from postpartum depression (PPD), wherein the patient suffers from moderate or severe depression and from impaired or severely impaired maternal function.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from severe depression and also suffers from impaired or severely impaired maternal function.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from severe depression and also suffers from severely impaired maternal function.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the patient has a MADRS score of 20 or more.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the patient has a MADRS score of 35 or more.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient has a Birkin Index of Maternal Function (BIMF) score of 80 or less (particularly 65 or less).

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the impaired or severely impaired maternal function affects the functional domain of mother-infant interaction and / or care.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the score assigned to the functional domain of mother-infant interaction and / or care by the Birkin Index of Maternal Function (BIMF) is less than or equal to 60% of the maximum score for said functional domain.

9. 9. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 8, wherein the patient is in a state of remission of depressive symptoms on day 7.

10. 10. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 9, wherein the patient is in a state of remission of depressive symptoms on day 28.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 10, wherein maternal function is improved on day 7 compared to said function before treatment.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 11, wherein maternal function is improved on day 28 compared to said function before treatment.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 12, wherein the BIMF score is improved by at least 10%, preferably at least 20% on day 7.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 13, wherein the BIMF score improves by at least 10 points, preferably at least 20 points, in particular at least 30 points on day 7.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 14, wherein the treatment leads to an improvement in the Birkin Index of Maternal Function (BIMF) scores assigned to the functional domains of mother-infant interaction and / or management at day 7 to more than 60% of the maximum possible score for each of said functional domains, preferably more than 80% of the maximum possible score.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 15, wherein the BIMF score is improved by at least 10%, preferably at least 20% at 28 days.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 16, wherein the BIMF score is improved by at least 10 points, preferably at least 20 points, in particular at least 30 points at 28 days.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 17, wherein the treatment leads to an improvement in the Birkin Index of Maternal Functioning (BIMF) score assigned to the functional domain of mother-infant interaction and / or management at day 28 to more than 60% of the maximum possible score, preferably more than 80% of the maximum possible score.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 18, administered at a dose or dosage regimen that causes the patient to experience a peak hallucinatory experience.

20. 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 19, wherein a dosage of about 4 mg to about 20 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

21. 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 19, wherein a dosage of about 6 mg, or about 12 mg, or about 18 mg is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

22. 21. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 20, wherein the 5-MeO-DMT or a salt thereof is administered at a first dosage for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration unless the patient experiences a peak hallucinatory experience.

23. 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 22, wherein the 5-MeO-DMT is administered at a dosage of about 2 mg to about 8 mg for a first administration, thereafter increased to a dosage of about 8 mg to about 14 mg for a second administration, and thereafter increased to a dosage of about 14 mg to about 20 mg for a third administration, unless the patient has already experienced a peak hallucinatory experience, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

24. 24. The 5-MeO-DMT or pharmaceutically acceptable salt thereof for use according to claim 23, wherein the first dosage of 5-MeO-DMT is about 6 mg, the second dosage of 5-MeO-DMT is about 12 mg, and the third dosage of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 22 to 24, wherein the interval between two administrations is at least 1 hour and at most 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

26. 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 19, wherein a dosage of about 4 mg to about 12 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

27. 27. The use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof according to claim 26, wherein a dosage of about 6 mg, or about 12 mg is administered, or an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

28. 27. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 26, wherein the 5-MeO-DMT or a salt thereof is administered at a first dosage for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations, with each subsequent administration using a higher dosage than the previous administration unless the patient experiences a peak hallucinatory experience.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 28, wherein the interval between two administrations is at least 1 hour and at most 24 hours, for example, about 1 to 4 hours, preferably 1 to 2 hours.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 19 to 29, wherein the manifestation of a peak hallucinatory experience is confirmed by achievement of at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and indescribable) of the 30-item Revised Mystical Experiences Questionnaire (MEQ30), or by achievement of at least 60% of the maximum possible score on the Oceanic Without Boundaries (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achievement of a total score of at least 75 on the Peak Experiences Scale (PES).

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 30, wherein the onset of a peak hallucinatory experience is confirmed by the achievement of a Peak Experience Scale (PES) total score of at least 75.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 31, administered by inhalation or by nasal, buccal or sublingual administration.

33. 33. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 32, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas, and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of from about 0.5 mg / L to about 18 mg / L (e.g., to about 12.5 mg / L).

34. 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 33, wherein the aerosol is generated by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer to produce aerosol particles.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 32 to 34, wherein the dosage of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled in a single breath.

36. 5-MeO-DMT for use according to claims 32 to 35, wherein the 5-MeO-DMT is used in the form of a free base.

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