5-Methoxy-N,N-dimethyltryptamine for the treatment of postpartum depression

Abstract

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof is used to treat patients suffering from postpartum depression (PPD), where 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

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 pharma- ceutically acceptable salt thereof. The present invention also makes it possible to treat PPD in nursing mothers without substantially interrupting lactation. [Background technology]

[0002] Over 50% of women may experience a short-term period of depressed or tearful mood after giving birth, however a subset of women may develop PPD (a debilitating mood disorder occurring during pregnancy or within 4 weeks after delivery).

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

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

[0005] Over 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 may 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 crucial.

[0007] Despite this obvious need, treatment options are quite limited.Most commonly, known treatments for depression are associated with limited treatment 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 drugs, lactating women are recommended to stop breastfeeding during the period of taking the drug and for a portion of the period afterwards, because the drug is excreted in milk and may put 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 either discontinue breastfeeding or discontinue / interrupt treatment.

[0010] Currently, PPD is primarily treated through psychotherapy or pharmacotherapy. National Institute for Health and Care Excellence (NICE) guidelines recommend that a higher threshold for pharmacological intervention be discussed with the patient prior to the initiation of 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, in the United States, brexanolone (Zulresso) has received FDA approval, making it the first pharmacological therapy specifically indicated for PPD. Brexanolone is a positive allosteric modulator of the GABAa receptor and is administered via a 60-hour infusion. The efficacy of brexanolone has been shown in two Phase 3 trials, one of which showed a significant reduction in Hamilton Rating Scale for Depression (HAM-D) scores 30 days after the start of the infusion, and the other failed to show efficacy beyond 7 days. However, brexanolone requires hospitalization for the 60-hour infusion and is associated with significant side effects.

[0012] A further notable fact is that patients are required to discontinue breastfeeding during brexanolone infusions, and as a result of that 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 treatment of PPD, in particular a treatment that effectively addresses depression and not only provides a rapid clinical response, but also avoids interference with the patient's daily activities, in particular with the care of the infant(s).This treatment should improve maternal function.Furthermore, there is a need for a treatment of PPD that does not require substantial interruption of breastfeeding.

[0014] In recent years, there has been great interest in hallucinogens for the treatment of psychiatric disorders, but 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, and also due to specific concerns that administration of hallucinogens may not be appropriate for breastfeeding mothers.

[0015] Hallucinogens, such as psychedelics, are chemical compounds, some naturally occurring and some synthetic, that are defined by their ability to induce sensory distortions, such as altered hearing and vision, as well as mood and cognitive distortions, in humans after consumption. The term hallucinogen encompasses a fairly broad group of psychotropic molecules with different mechanisms of action. It has been suggested that several psychiatric disorders are in principle amenable to treatment by psychotropic molecules, such as psychedelics.

[0016] However, no psychedelic drugs have been approved by any regulatory agency, and indeed the 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). WO2020 / 169850 reports on tests in healthy volunteers and clinical trials in patients suffering from treatment-resistant depression (TRD), a type 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 a treatment which is more effective (i.e. a) a higher proportion of patients experiencing a clinical response, b) a higher mean clinical response, c) an earlier onset of clinical response, and / or d) a more durable clinical response) than the aforementioned treatments.

[0019] A further object of the present invention is to provide improved psychotropic therapy compounds and dosage regimens for said treatments that have a better safety profile and / or are better tolerated than the aforementioned treatments. Another object of the present invention is to provide improved psychotropic therapy compounds and dosage regimens for said treatments that are more convenient than the aforementioned treatments. Another object of the present invention is to provide improved psychotropic therapy compounds and dosage regimens for said treatments that are associated with higher patient compliance rates (including higher treatment initiation rates) than previously described treatments. Yet a 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 therapy.

[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 the 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 pharma- ceutically 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 makes it possible to treat PPD in nursing mothers without substantially interrupting breastfeeding.

[0024] In a further aspect, the invention relates to the treatment of nursing mothers diagnosed with a psychiatric disorder.

[0025] In the context of the present invention, 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, is administered via intravenous, intramuscular, or subcutaneous administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] definition As used in the context of the present invention, unless otherwise noted, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharma- ceutically 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 (trifluoromethanesulfonic acid). A preferred example is the hydrobromide salt. The appropriate weight amount of the salt to be administered may be calculated from the weight amount of the free base, assuming that an equimolar amount is used.

[0027] 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 herself to be suffering from the disorder.

[0028] The patient may suffer from treatment-resistant disease.As used herein, "treatment-resistant" means that the patient does not have adequate improvement after at least two adequate treatment courses.In particular, the patient does not have sufficient improvement after at least two adequate treatment courses, and at least one of these two courses is drug therapy.For example, the patient does not have adequate improvement after at least two adequate drug therapy courses.

[0029] 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 suicidal tendencies. In general, it is not enough for a patient to consider himself or herself to be suffering from suicidal ideation. In some circumstances, a patient experiencing suicidal ideation is considered to be at imminent risk of or to have "the intention to commit suicide".

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

[0031] As used in the context of the present invention, unless otherwise noted, the term "therapeutically effective amount" is intended to mean the amount of an active compound or pharmaceutical ingredient that elicits 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.

[0032] "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), and further includes, but is not limited to, endpoints 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). Further relevant scales for assessing clinical outcome include the Clinician Administered Dissociative State Scale (CADSS), Brief Psychological Rating Scale (BPRS), and the Columbia Suicide Severity Rating Scale (C-SSRS).

[0033] Maternal functioning can be assessed using the Barkin Index of Maternal Functioning (BIMF).

[0034] Individual items of the scales presented, and subcombinations of individual items, may be used to assess specific disease aspects.

[0035] When evaluating clinical response at an earlier time point (e.g., 2 hours) after drug administration based on endpoints generated over a longer recall period (e.g., typically 7 days for 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.

[0036] The considerations outlined apply to early time points since, on the one hand, the influence of the patient's pre-treatment state on any scores recorded after treatment needs to be kept as low as possible in order to assess the clinical response, whereas, on the other hand, sleep items cannot be assessed later than 2 hours after drug administration.

[0037] At a later time point, e.g., day 1 or later, all items of the relevant scale for assessing clinical response can usually be assessed using an adapted recall period, if necessary, so there is no need to progress any pretreatment scores, e.g., if BIMF is assessed on day 7, a 7-day recall period is used (instead of the standard 2-week recall period).

[0038] As used in the context of the present invention, unless otherwise noted, the term "administration" (or "application") is intended to mean the introduction of a given amount of an active compound or pharmaceutical ingredient into a patient by any route. Preferably, the active compound is administered intravenously, intramuscularly, or subcutaneously.

[0039] As used in the context of the present invention, unless otherwise noted, the terms "dose" and "administration" and "dosage" refer to the amount of an active compound or pharmaceutical ingredient administered to a patient in an individual administration. The term "dosage regimen" (or "dosing regimen") is intended to mean a defined sequence of one or more individual administrations.

[0040] Postpartum depression Postpartum depression (PPD) is a complex combination of physical, emotional, and behavioral changes that occur in some women after childbirth. PPD is also known as major depressive disorder with perinatal onset. 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 4 weeks of delivery.

[0041] The patients treated according to the present invention are preferably women who have been diagnosed with PPD and are more than 4 weeks postpartum. Furthermore, the patients are preferably ≦9 months postpartum.

[0042] 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.

[0043] 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, & Åsberg,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 is more sensitive to changes brought about by antidepressants and other forms of treatment. A higher MADRS score indicates a more severe depression. The items considered are outward sadness, verbal sadness, inner tension, decreased sleep, decreased appetite, difficulty concentrating, fatigue, loss of emotion, pessimistic thoughts, and suicidal thoughts, and each item is given a score of 0 to 6. The total score ranges from 0 to 60.

[0044] The patient may have 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 contemplated that the patient may have 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] In addition to the above, we consider that PPD impairs maternal function, especially during the first year after birth, which is a crucial period for both mother and child. In most cases, the mother is the primary caregiver and therefore shoulders the majority of the tasks associated with caring for the infant.

[0049] Maternal functioning includes aspects of maternal competence related to communication with the infant(s) and maternal self-care.

[0050] Maternal functioning, including the emotional aspects of motherhood, is also important for child development. Indeed, the quality of mother-infant communication during the postnatal years influences infant development. High levels of maternal functioning are likely to correlate with positive infant development outcomes. Similarly, dysfunction in the postnatal period may impede optimal infant development.

[0051] The Barkin Index of Maternal Functioning (BIMF) is designed to measure functioning in the year after childbirth. 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.

[0052] The BIMF identifies the main areas of functioning for mothers during the postpartum period as self-care, care of the infant, mother-child communication, maternal emotional well-being, social support, control, and adjustment.

[0053] A BIMF score of 95 or less is considered herein to represent a mild impairment of maternal function, a score of 80 or less is considered herein to represent a impairment of maternal function, and a score of 65 or less is considered herein to represent a severe impairment of maternal function. The present invention particularly allows for the 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.

[0054] Activator The above discussion indicates that PPD is characterized by several aspects that represent a significant disease burden and merit appropriate treatment. Thus, treatment is required, particularly with pharmacological intervention, not only to improve the overall disease score, but also to improve specific aspects of the disease.

[0055] The inventors reasoned that carefully selected hallucinogens might lead to improved treatment of important aspects of PPD and might lead to overall improvement of the disease and maternal functioning.

[0056] The inventors further believed that in the case of treatment of nursing mothers suffering from PPD, carefully selected hallucinogens may allow for the continuation of breastfeeding without substantial interruption.

[0057] One group of hallucinogens involves compounds that bind to the 5-hydroxytryptamine (5-HT) receptors, also called serotonin receptors (seven families, 5-HT1 to 5-HT7, with several subtypes, are described). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic drugs are often referred to as "psychedelics", emphasizing their predominant ability to induce qualitatively altered states of consciousness, such as hypersensitivity, trance, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or near-death experiences, while only minimally exerting other effects, such as sedation, narcosis, or hyperstimulation.

[0058] Chemically, serotonergic psychedelics are either phenylalkylamines or indolamines, and the indolamine class is divided into two subsets, the ergolines and the tryptamines, the latter derived from tryptamine.

[0059] Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors, particularly 5-HT1A, 5-HT2A, and 5-HT2C, and their activity can also be modulated by interactions with other targets such as monoamine transporters and trace amine-associated receptors.

[0060] Recently published clinical trials using serotonergic hallucinogenic drugs such as LSD, psilocybin, and DMT (using Shamanic Blue Ayahuasca, which contains DMT) in certain psychiatric disorders suggest that these compounds may offer alternatives to currently available treatments for certain psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, which may preclude their clinical use.

[0061] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who suffered a manic attack after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication that resolved, but was followed by a typical manic episode of psychotic severity in about 3 weeks. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4):1-3) reported on a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP, and Jose M Smith, JM, 2015. Switch to mania after ayahuasca consumption in a man with bipolar disorder: a case report. International Journal of Bipolar Disorders (2015) 3:4) reported a switch to mania after consumption of ayahuasca, a DMT-containing mixture, in a man with bipolar disorder.

[0062] Further case reports can be found in Brown, T., Shao, W., Ayub, S., Chong, D., and 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.

[0063] The inventors have considered that in order to avoid induction of mania or hypomania, or at least to reduce the risk of induction of mania or hypomania, the compound administered needs to be appropriately selected and is preferably administered in a specific dosing regimen.

[0064] The present inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic of particular interest for therapeutic use. 5-MeO-DMT has a distinct pharmacological profile that differs from other psychedelic compounds.

[0065] 5-MeO-DMT is a potent, fast-acting natural serotonin (5-HT) agonist that acts at both the 5-HT1A and 5-HT2A receptors, with greater affinity for the 5-HT1A receptor subtype compared to other classical psychedelics.

[0066] The inhibition constants (K) are further detailed in the Examples section below for psilocin (the dephosphorylated form of psilocybin formed after uptake of psilocybin), DMT, and 5-MeO-DMT. i The inhibition constants (K values) of psilocin, DMT, and 5-MeO-DMT at the 5-HT1A receptor located in the hippocampus of postmortem human brain are 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, whereas psilocin and DMT exhibit intermediate affinity. The inhibition constants (K values) of psilocin, DMT, and 5-MeO-DMT are 48, 38, and 1.80 nM at the 5-HT1A receptor located in the hippocampus of postmortem human brain. iThe 5-HT2A receptors located in the frontal cortex of postmortem human brains have 5-HT2A affinity values ​​of 37, 117, and 122 nM, respectively. Thus, psilocin exhibits moderate / strong affinity for the 5-HT2A receptor, whereas DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0067] Compared with other psychotropic compounds mentioned above, 5-MeO-DMT shows enhanced affinity to 5-HT1A receptors and acts as a strong agonist. In the case of psilocin and DMT, the contribution of 5-HT2A binding is increased compared with 5-MeO-DMT, and the latter shows the largest affinity difference for 5-HT1A compared with 5-HT2A among the three compounds. Therefore, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT compared with 5-HT2A binding for the other two compounds.

[0068] It has been reported that 5-HT1A agonism reduces impulsivity and aggression, whereas 5-HT2A agonism can increase these same traits in the short term.Furthermore, the dopamine system has been implicated in contributing to mania, and increased dopamine drive has been associated with mania.LSD, psilocybin, and DMT all show increased affinity for various dopamine receptors compared to 5-MeO-DMT.

[0069] Compared to other psychedelics such as LSD, psilocybin or DMT, 5-MeO-DMT can preferably be administered to patients using the dosing schemes described herein without significant risk of inducing mania or hypomania in patients suffering from psychiatric or nervous system disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder and bipolar disorders (BD), such as bipolar I disorder and bipolar II disorder; psychiatric disorders such as schizophrenia; or personality disorders such as schizotypal personality disorder. Patients suffering from such psychiatric or nervous system disorders treated according to the present invention do not experience treatment-emerged mania or hypomania.

[0070] It should also be noted that reports of treatment-emerged mania or hypomania associated with psychoactive substance use seem to indicate that large amounts of the respective compound (e.g., DMT / ayahuasca, psilocybin, LSD) were used.

[0071] Our approach of sequential titration of 5-MeO-DMT significantly reduces the risk of overdosing with its attendant potential adverse events.

[0072] Furthermore, induction of isolated hypomanic events by antidepressants has been reported in patients with treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007):233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of hypomania induction.

[0073] 5-MeO-DMT can induce peak experiences (i.e. experiences characterized by a shift in emotional perspective described as a "loss of self"), often leading to an overwhelming feeling of "oneness with the universe" more rapidly than other hallucinogens, and 5-MeO-DMT has a short duration of acute hallucinogenic effects (e.g. 5-30 minutes after intravenous injection vs. several hours for oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which may be explained by specific changes in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0074] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and shows high affinity for this receptor. The present inventors have demonstrated that 5-MeO-DMT is a 5-HT7 receptor agonist and shows high affinity for this receptor.3 H]LSD, and serotonin were used to estimate nonspecific binding, and K i was determined to be 2.3 nM.

[0075] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor, at which it acts as an agonist and exhibits high (nanomolar) binding affinity.

[0076] 5-HT7 receptors have a role in neurogenesis, synaptogenesis and dendritic spine formation, among others, they are associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[0077] 5-HT7 receptors are specifically expressed in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and cerebellum.

[0078] 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, especially those involving sleep disorders. Resting-state functional connectivity analysis in patients suffering from sleep disorders revealed modulation of functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0079] The expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the function of this receptor in regulating the sleep / wake cycle. The inventors believe that this makes it possible to treat patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0080] 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 with its "resetting" of functional network connectivity and neuroplasticity effects, contributes to the efficacy of 5-MeO-DMT in treating patients suffering from sleep disorders.

[0081] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as well as to the 5-HT1A receptor, as two mediators of the effects of 5-MeO-DMT, including the "resetting" of the functional connectivity of the network and the neuroplasticity effects, allows it to exert a beneficial effect even in patients suffering from other symptoms or conditions, such as cognitive impairment, anxiety, psychomotor developmental retardation, pessimistic thinking or social / emotional withdrawal, which is supported by the clinical results demonstrated in the studies referred to herein.

[0082] Another characteristic of 5-MeO-DMT is its short half-life.

[0083] 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.

[0084] The present inventors have investigated the pharmacokinetic properties of 5-MeO-DMT and found that inhaled 5-MeO-DMT was rapidly absorbed and distributed, with maximum concentrations and pharmacological effects observed during and shortly after administration.

[0085] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that plasma concentrations drop very rapidly. Already 10 minutes after administration, concentrations are below 10% of Cmax, after 2 hours they are below 1% of Cmax, and after 3 hours 5-MeO-DMT is no longer detectable in plasma. This is true over the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation is observed with repeated dosing within the 1-4 hour time frame. Titrating the dose as disclosed herein does not result in accumulation and therefore does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after dosing.

[0086] The inventors further confirmed that 5-MeO-DMT offers various properties that make it an attractive treatment for PPD. In contrast to SSRIs, 5-MeO-DMT is a fast-acting agent (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 function. Furthermore, 5-MeO-DMT is administered during a one-day treatment session, with optional and infrequent re-administration, which distinguishes it from SSRIs that require a chronic daily dosing regimen with low compliance, as well as from brexanolone that requires long-term infusions and hospitalization.

[0087] Thus, the present invention also addresses compliance and patient convenience.

[0088] Furthermore, the present inventors have determined that treatment of PPD with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, allows for continuation of breastfeeding with only a short interruption for treatment.

[0089] In accordance with the present invention, isotopic variants of 5-MeO-DMT and pharma- ceutically acceptable salts thereof may also be used. When referring to the use of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0090] These variants are in particular deuterated forms of 5-MeO-DMT and pharma- ceutically acceptable salts of such forms.

[0091] The deuterated form of 5-MeO-DMT is one that has a higher deuterium content than would be expected based on the natural abundance of this isotope.

[0092] Deuterated forms of 5-MeO-DMT are particularly those in which deuterium is introduced at one or more defined hydrogen positions.

[0093] 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-(trideuterimethoxy)-1H-indol-3-yl]ethanamine.

[0094] Further examples include forms of 5-MeO-DMT in which deuterium is introduced at one or more hydrogen positions of the N-linked methyl group. Yet further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It should be noted that combinations of the above substitution patterns are also contemplated.

[0095] Methods for preparing these compounds are known in the art.

[0096] 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, pharma- ceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, as well as mixtures of salts of deuterated 5-MeO-DMT and salts of non-deuterated 5-MeO-DMT may also be used.

[0097] Further in accordance with the present invention, deuterated 5-MeO-DMT and salts of deuterated 5-MeO-DMT are used in molar amounts equimolar to the amounts of the corresponding non-deuterated forms.

[0098] According to the present invention, prodrugs of 5-MeO-DMT and pharma- ceutically acceptable salts of such prodrugs may also be used. 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 pharma- ceutically acceptable salt thereof, this may be replaced by a 5-MeO-DMT prodrug or a salt thereof.

[0099] In suitable prodrugs, the hydrogen at position 1 of the indole moiety is replaced with an organic moiety that can be cleaved off after administration.

[0100] An example of a suitable organic moiety is -C(O)OR 1 , -C(O)R 2 , -CH(R 3 ) OR 4 , -C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , -CH(R 3 )OC(O)OR 4 And each 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.

[0101] A preferred example of an 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.

[0102] Prodrugs, especially those of the above structure, can also be used in the form of pharma- ceutically acceptable salts.

[0103] Specific examples of prodrugs are 5-MeO-DMT carboxy-isopropylvalinate, preferably in salt form, especially as the ditrifluoroacetate salt (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).

[0104] Methods for preparing the prodrugs discussed herein are known in the art.

[0105] According to the present invention, the T of the metabolite 5-MeO-DMT was measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg. max The value is preferably 1 hour or less, more preferably 0.7 hours or less, especially 0.5 hours or less.

[0106] 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.

[0107] 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 the scores assessing the severity of depression, but also improves maternal functioning, as will be discussed in more detail below.

[0108] To further support the clinical application of 5-MeO-DMT in patients suffering from PPD, the inventors evaluated clinical data regarding the use of 5-MeO-DMT in patients treated for psychiatric reasons and noted certain improvements in disease aspects also commonly seen in patients with PPD. The inventors noted in particular improvements in various symptoms and combinations of symptoms that the inventors determined were also associated with maternal functioning.

[0109] The data stem is derived from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD, see also the Examples section below. Although the completed trial did not include patients suffering from PPD, the inventors have determined that certain clinical findings made in this trial are relevant to devising a treatment for PPD, as discussed in detail below.

[0110] In this clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. In the context of the present invention, of interest are the group that received a single dose of 12 mg and the group that received an intraday individualized dosing schedule (IDR), which allowed multiple ascending doses (6 mg, 12 mg and 18 mg) during the day, driven by the intensity of the patient-reported hallucinatory experience.

[0111] Data collected included assessment of treated patients against several background scales, including the Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the study was to demonstrate treatment efficacy through improvement in overall MADRS scores, we focused on the items that make up the various scales, noting that some of the sub-core items are particularly relevant to PPD patients and relate to maternal functioning.

[0112] 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 the treatment of PPD patients and for improving maternal function in those patients.

[0113] 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.

[0114] Thus, treatment according to the invention reduces or eliminates (or ameliorates or eliminates) aspects of the disease.

[0115] When the aspect is rated on the MADRS scale, there is an improvement (remission) of at least 1 point, or the patient is in complete remission (elimination) following treatment (ie, the respective aspect has a score of 0).

[0116] When the aspect is rated on the BPRS scale, there is an improvement (relief) of at least 1 point or the patient is in complete remission (elimination) following treatment (ie, each aspect has a score of 1).

[0117] Clinical response may also be reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means a reduction in the CGI-S score of at least one grade. Preferably, a reduction in the CGI-S score of at least two grades and / or a score of 0. Particularly preferred is a reduction in the CGI-S score of at least three grades and / or a score of 0.

[0118] The inventors further believe that improvements observed in certain MADRS items translate into improvements in aspects of maternal functioning.

[0119] Particularly relevant MADRS items are discussed in more detail below.

[0120] The MADRS item "inner tension" describes a heightened mental tension towards either vague discomfort, anxiety, inner turmoil, panic, fear or distress, which is graded according to intensity, frequency, duration and the degree of stability desired.

[0121] If the patient is calm and has only momentary inner tension, a score of 0 is assigned. If there is occasional anxiety and vague discomfort, a score of 2 is assigned. If there is continuous inner tension or intermittent panic that the patient can master with some difficulty, the score is 4. If there is constant fear or distress and overwhelming panic, the score is 6.

[0122] The inventors determined that elevated scores on the MADRS item "inner strain" adversely affect both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "inner strain" impair mother-infant communication and maternal psychological well-being as assessed by the BIMF.

[0123] Conversely, improvements on this MADRS item would translate to improvements in maternal functioning, particularly in the BIMF domain of functioning, mother-child communication and / or maternal mental well-being.

[0124] In the above study involving TRD patients, in the study group receiving the individualized dosing regimen, the aggregate score for the MADRS item "internal tension" across all eight patients was 26 at baseline. After two hours, it had fallen to 11, which corresponds to a 15-point or 58% improvement. One day after treatment, it had fallen to 6, which corresponds to a 20-point or 77% improvement. Seven days after treatment, the score had fallen to 12, which corresponds to a 14-point or 54% improvement.

[0125] In the 12 mg group, the total score for the MADRS item "internal tension" was 13 at baseline across all four patients. After 2 hours, it had decreased to 2, which corresponds to an 11-point or 85% improvement. One day after treatment, it had decreased to 3, which corresponds to a 10-point or 77% improvement. Seven days after treatment, the score had decreased to 5, which corresponds to an 8-point or 62% improvement.

[0126] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of inner tension.

[0127] Improvement in inner tension is reflected by an improvement in the inner tension score on the MADRS item at least about 2 hours; on the 1st day, e.g., about 24 hours; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0128] 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 pharma- ceutical acceptable salt thereof.

[0129] 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 pharmacologic acceptable salt thereof.

[0130] Improvement in inner tension, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0131] The improvement in inner tension, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutically acceptable salt thereof.

[0132] 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, which is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0133] As inner strain also influences other aspects of PPD, we conclude that the observed improvement in the "inner strain" item on the MADRS will further contribute to an overall improvement in maternal functioning.

[0134] The MADRS item "Fatigue" describes difficulty initiating or slowness in initiating and performing daily activities.

[0135] A score of 0 means little difficulty initiating and no weakness. A score of 2 is assigned if the patient has difficulty initiating activities. A score of 4 means difficulty initiating simple daily activities with continued effort. A score of 6 is assigned if the patient is unable to do anything without assistance and is completely exhausted.

[0136] The inventors have determined that elevated scores on the MADRS item "fatigue" adversely affect both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "fatigue" impair infant care, self-care, emotional well-being, control and regulation.

[0137] Conversely, improvement on this MADRS item would translate to improved maternal functioning, particularly in the BIMF functional domains of infant care, self-care, emotional well-being, control, and / or regulation.

[0138] In the study group receiving the individualized dosing plan, the aggregate score for the MADRS item "Fatigue" across all eight patients was 27 at baseline. After two hours, the score had decreased to 10, corresponding to a 17-point or 63% improvement. One day after treatment, the score had decreased to 5, corresponding to a 22-point or 81% improvement. Seven days after treatment, the score had decreased to 3, corresponding to a 24-point or 89% improvement.

[0139] In the 12 mg group, the MADRS "fatigue" score, aggregated across all four patients, had a baseline of 16. After 2 hours, the score had decreased to 10, corresponding to a 6 point or 38% improvement. On the first post-treatment day, the score had decreased to 0, corresponding to a 16 point or 100% improvement. On the seventh post-treatment day, the score had decreased to 3, corresponding to a 13 point or 81% improvement.

[0140] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of fatigue.

[0141] Improvement in fatigue is reflected by an improvement in the MADRS item fatigue score 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 pharma- ceutically acceptable salt thereof.

[0142] Improvement in fatigue, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0143] 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 pharmacologic acceptable salt thereof.

[0144] Improvement in fatigue, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0145] The improvement in fatigue, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0146] The inventors further conclude that the reduction or elimination of fatigue 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 the first day, e.g., about 24 hours; on the seventh day; on the 14th day; and / or on the 28th day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Since fatigue also impacts other aspects of PPD, the inventors conclude that the observed improvement in the "fatigue" item on the MADRS will further contribute to an overall improvement in maternal functioning.

[0147] The MADRS item "loss of affect" refers to the subjective experience of decreased interest in one's surroundings or activities that normally give pleasure. A decreased ability to respond emotionally to situations or people.

[0148] A score of 0 indicates normal interest in surroundings and other people, a score of 2 indicates a diminished ability to indulge in normal interests. A score of 4 is assigned in the case 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 lack of emotion toward close relatives and friends.

[0149] 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 communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "Loss of Emotions" impair mother-infant communication and emotional well-being.

[0150] Conversely, improvements on this MADRS item would translate to improvements in maternal functioning, particularly in mother-child communication and / or emotional well-being in the BIMF functional domain.

[0151] In the study group receiving the individualized dosing plan, the combined MADRS item "loss of affect" score across all eight patients had a baseline of 36. After two hours, the score had decreased to 12, which corresponds to a 24-point or 67% improvement. One day after treatment, the score had decreased to 2, which corresponds to a 34-point or 94% improvement. Seven days after treatment, the score had decreased to 6, which corresponds to a 30-point or 83% improvement.

[0152] In the 12 mg group, the MADRS item "loss of affect" score aggregated across all 4 patients had a baseline of 16. After 2 hours, the score had decreased to 9, which corresponds to a 7-point or 44% improvement. On the 1st day after treatment, the score had decreased to 1, which corresponds to a 15-point or 94% improvement. On the 7th day after treatment, the score had decreased to 1, which corresponds to a 15-point or 94% improvement.

[0153] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of emotional loss.

[0154] 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 pharma- ceutically acceptable salt thereof.

[0155] Improvement in extinguishing affect, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0156] 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 pharmacologic acceptable salt thereof.

[0157] Improvement in loss of affect, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0158] The improvement in extinguishing affect, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0159] The inventors further conclude that the reduction or elimination of loss of emotion by treating PPD patients leads not only to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. 13. Because loss of sensation also impacts other aspects of PPD, the inventors conclude that the observed improvement in the "loss of emotion" item on the MADRS further contributes to an overall improvement in maternal functioning.

[0160] The MADRS item "Difficulty concentrating" refers to difficulty gathering thoughts due to lack of concentration.

[0161] If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty gathering thoughts, the score is 2. If there is difficulty concentrating and sustaining thoughts, thereby impairing the ability to read or speak, a score of 4 is assigned. If the patient is unable to read or speak without great difficulty, the score is 6.

[0162] The inventors have determined that elevated scores on the MADRS item "Difficulty concentrating" adversely affect both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "Difficulty concentrating" impair the care and management of the infant.

[0163] Conversely, improvement on this MADRS item would translate to improved maternal functioning, particularly in the BIMF domain of functioning, care and / or management of the infant.

[0164] In the study group receiving the individualized dosing plan, the combined MADRS item "Difficulty concentrating" score across all eight patients had a baseline of 30. After two hours, the score had decreased to 11, which corresponds to a 19-point or 63% improvement. One day after treatment, the score had decreased to 1, which corresponds to a 29-point or 97% improvement. Seven days after treatment, the score had decreased to 9, which corresponds to a 21-point or 70% improvement.

[0165] In the 12 mg group, the MADRS total score for "Difficulty concentrating" across all four patients was 16 at baseline. After 2 hours, the score had decreased to 7, corresponding to a 9-point or 56% improvement. After 1 day of treatment, the score had decreased to 2, corresponding to a 14-point or 88% improvement. After 7 days of treatment, the score had decreased to 3, corresponding to a 13-point or 81% improvement.

[0166] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of concentration difficulties.

[0167] Improvement in difficulty concentrating is reflected by an improvement in the difficulty concentrating score on the MADRS item at least about 2 hours; on the 1st day, e.g., about 24 hours; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0168] Improvement in concentration difficulties, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0169] 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 pharmacologic acceptable salt thereof.

[0170] Improvement in concentration difficulties, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0171] The improvement in concentration difficulties, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0172] The inventors further conclude that reduction or elimination of 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 about 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 pharma- ceutically acceptable salt thereof.

[0173] 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.

[0174] The MADRS item "negative thinking" refers to thoughts of guilt, inferiority, self-blame, sinfulness, regret, and catastrophizing.

[0175] If there are no pessimistic thoughts, a score of 0 is assigned. If there are fluctuating thoughts of failure, self-blame, or self-depreciation, the score is 2. A score of 6 is assigned if there are persistent self-blame or clear but understandable thoughts of guilt or guilt, and the patient is increasingly pessimistic about the future. If there are delusions of ruin, remorse, or irredeemable guilt, and irrational, unwavering self-blame, a score of 6 is assigned.

[0176] 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.

[0177] Conversely, improvements 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.

[0178] In the study group receiving the individualized dosing plan, the aggregated MADRS score for "pessimistic thinking" across all eight patients had a baseline of 28. After two hours, the score had decreased to 7, which corresponds to a 21-point or 75% improvement. One day after treatment, the score had decreased to 4, which corresponds to a 24-point or 86% improvement. Seven days after treatment, the score had decreased to 3, which corresponds to a 25-point or 89% improvement.

[0179] In the 12 mg group, the MADRS "pessimistic thinking" item score across all 4 patients was combined at baseline 16. After 2 hours, the score had decreased to 8, which corresponds to an 8-point or 50% improvement. On the 1st day after treatment, the score had decreased to 7, which corresponds to a 9-point or 56% improvement. On the 7th day after treatment, the score had decreased to 8, which corresponds to an 8-point or 50% improvement.

[0180] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of negative thinking.

[0181] 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 pharma- ceutically acceptable salt thereof.

[0182] Improvement in negative thinking, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0183] 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 pharmacologic acceptable salt thereof.

[0184] Improvement in negative thinking, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0185] The improvement in negative thinking, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0186] The inventors further conclude that reduction or elimination of negative thinking 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 about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the 14th day; and / or on the 28th day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0187] Because negative thinking influences other aspects of PPD, we conclude that the observed improvement in the "negative thinking" item on the MADRS may further contribute to an overall improvement in maternal functioning.

[0188] The MADRS item "reduced sleep" refers to the experience of a decrease in duration or depth of sleep compared to the subject's own healthy normal pattern.

[0189] If the subject is sleeping normally, a score of 0 is assigned. A score of 2 reflects slight difficulty in falling asleep or slight reduction, light sleep, or intermittent sleep. A score of 4 means sleep is reduced or interrupted by at least 2 hours. A score of 6 means less than 2 or 3 hours of sleep.

[0190] The inventors have determined that elevated scores on the MADRS item "reduced sleep" adversely affect both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "reduced sleep" impair self-care, emotional well-being and control.

[0191] Conversely, improvement on this MADRS item would translate to improved maternal functioning, particularly in the BIMF domains of functioning: self-care, emotional well-being, and / or management.

[0192] In the study group receiving the individualized dosing plan, the aggregated score for the MADRS item "Decreased Sleep" across all eight patients had a baseline of 25. By day 1 after treatment, the earliest time point for assessing the treatment's effect on sleep, it had fallen to 12, corresponding to a 13-point or 52% improvement. By day 7 after treatment, the score had fallen to 9, corresponding to a 16-point or 64% improvement.

[0193] In the 12 mg group, the MADRS item "Decreased Sleep" score aggregated across all 4 patients had a baseline of 12. One day after treatment, the score decreased to 10, corresponding to a 2 point or 17% improvement. Seven days after treatment, the score decreased to 6, corresponding to a 6 point or 50% improvement.

[0194] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of sleep loss.

[0195] Reduction or elimination of sleep reduction may be reflected by an improvement in the score on the sleep reduction item of the MADRS at least on the 1st day, e.g., about 24 hours; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0196] Improvement in sleep reduction, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0197] Improvement in sleep reduction, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 24 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0198] The improvement in sleep reduction, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0199] The inventors further conclude that reduction or elimination of 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, which 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 pharma- ceutically acceptable salt thereof.

[0200] 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.

[0201] 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 PPD patients to reduce or eliminate suicidal ideation in PPD patients.

[0202] In the above mentioned clinical trials involving administration of 5-MeO-DMT, the MADRS item "suicidal thoughts" was assessed, among other things.

[0203] "Suicidal thoughts" refers to feelings that there is no point in living and that one would be happy to die naturally at any time, suicidal thoughts, and / or preparations for suicide. A suicide attempt, in itself, should not affect the rating of this MADRS item.

[0204] A score of 0 means that the patient is enjoying life. A score of 2 is assigned if the PPD patient is bored with life and / or has only fleeting suicidal thoughts. A score of 4 means that the patient often has suicidal thoughts, such as thinking that death would be better, 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 for suicide and / or is actively preparing.

[0205] This MADRS scale item is of particular relevance to suicidal ideation.

[0206] The inventors have determined that elevated scores on the MADRS item "suicidal thoughts" adversely affect both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the MADRS item "suicidal thoughts" impair self-care, emotional well-being and control.

[0207] Conversely, improvement on this MADRS item would translate to improved maternal functioning, particularly in the BIMF domains of functioning: self-care, emotional well-being, and / or management.

[0208] In the study group receiving the individualized dosing plan, the combined MADRS item "suicidal thoughts" score across all eight patients had a baseline of 11. After two hours, the score had decreased to 3, which corresponds to an 8-point or 73% improvement. One day after treatment, the score had decreased to 1, which corresponds to a 10-point or 91% improvement. Seven days after treatment, the score had decreased to 3, which corresponds to an 8-point or 73% improvement.

[0209] In the 12 mg group, the MADRS item "suicidal thoughts" total score was 8 at baseline across all four patients. After 2 hours, the score had decreased to 3, corresponding to a 5-point or 63% improvement. On the first post-treatment day, the score had decreased to 5, corresponding to a 3-point or 38% improvement. On the seventh post-treatment day, the score had decreased to 7, corresponding to a 1-point or 13% improvement.

[0210] Thus, the score for the scale item specifically related to suicidal ideation, "suicidal thoughts," improves significantly, at least in patients on the individualized dosing regimen. We conclude that 5-MeO-DMT can be used to treat suicidal ideation in PPD patients.

[0211] Thus, in accordance with the present invention, treating a PPD patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.

[0212] Reduction or elimination of suicidal ideation may be reflected by an improvement in the MADRS Suicidal Thoughts item score at least about 2 hours, on the 1st day, e.g., about 24 hours; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0213] If the patient is suffering from suicidal ideation, improvement in suicidal ideation is reflected by a reduction in Clinical Global Impression-Severity (CGI-S) scores at about 2 hours, on the 1st day, e.g., about 24 hours; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0214] Improvement in suicidal ideation, 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 pharma- ceutically acceptable salt thereof.

[0215] Alternatively, the reduction in Clinical Global Impression-Severity (CGI-S) score occurs on the first day, for example, about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0216] Improvement in suicidal ideation, as assessed by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0217] Improvement in suicidal ideation, as assessed by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0218] The inventors further conclude that reduction or elimination of suicidal thoughts 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, which is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the 14th day; and / or on the 28th day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0219] Because suicidal thoughts impact other aspects of PPD, we conclude that the observed improvement in the "suicidal thoughts" item on the MADRS may further contribute to an overall improvement in maternal functioning.

[0220] The BPRS item "emotional withdrawal" relates to the patient's impaired ability to become emotionally involved in the interview situation. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. A lack of emotional engagement is indicated by an occasional failure to respond, appearing distracted at times, or smiling awkwardly, but most of the time engages spontaneously with the interviewer. 3 - Mild. Lack of emotional engagement is indicated by a noticeable inability to respond, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4 - Moderate. Emotional contact is absent for the majority of the interview as the subject is aloof, unable to make eye contact, does not seem to care if the interviewer is listening, or may be preoccupied with psychotic content. 5 - Moderately severe. Same as '4', but emotional contact is absent for the majority of the interview. 6 - Severe. Actively avoids emotional involvement. Often unresponsive or responds with yes / no (not solely due to paranoia). Responds with minimal consequences. 7 - Very severe. Consistently avoids emotional involvement. No response or yes / no responses (not solely due to paranoia). May leave meetings midway through or not respond at all.

[0221] The inventors determined that elevated scores on the BPRS item "emotional withdrawal" adversely affect both aspects of maternal functioning (maternal competence related to communication with the infant(s) and maternal self-care). Elevated scores on the BPRS item "emotional withdrawal" impair psychological well-being, mother-infant communication, and social support.

[0222] Conversely, improvement on this BPRS item would translate to improved maternal functioning, particularly in the BIMF functional domains of psychological well-being, mother-child communication and / or social support.

[0223] In the study group that received the individualized dosing plan, the aggregate score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score had decreased to 8, which corresponds to a 5-point or 38% improvement. On the 1st day after treatment, the score had decreased to 8, which corresponds to a 5-point or 38% improvement. On the 7th day after treatment, the score had decreased to 8, which corresponds to a 5-point or 38% improvement.

[0224] In the 12 mg group, the BPRS item "emotional withdrawal" total score was 13 at baseline. After 3 hours, the score decreased to 11, corresponding to a 2-point or 15% improvement. After 1 day of treatment, the score decreased to 8, corresponding to a 5-point or 38% improvement. After 7 days of treatment, the score decreased to 6, corresponding to a 7-point or 54% improvement.

[0225] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of emotional withdrawal.

[0226] 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, 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 pharma- ceutically acceptable salt thereof.

[0227] Improvement in emotional withdrawal, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0228] 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 pharmacologic acceptable salt thereof.

[0229] Improvement in emotional withdrawal, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0230] The improvement in emotional withdrawal, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0231] The inventors further conclude that reduction or elimination of emotional withdrawal by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the BPRS total score, but also by an increase in the BIMF score, which is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the 14th day; and / or on the 28th day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0232] Since emotional withdrawal also influences other aspects of PPD, we conclude that the observed improvement in the "emotional withdrawal" item on the BPRS further contributes to an overall improvement in maternal functioning.

[0233] The BPRS "blunted affect" item concerns 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 displays appropriate facial and vocal expression within normal limits. 3-Mild. Overall range of emotions is reduced, inhibited, or reserved, and spontaneous appropriate emotional responses are not frequent. Slightly monotone tone of voice. 4 - Moderate. The range of affect is significantly reduced; the patient does not show emotion or smile, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Expressions or gestures usually are followed by a return to flat affect. 5 - Moderately severe. Emotional range is severely reduced, the patient shows no emotion, smiles or responds minimally to distressing topics, gestures very little, facial expression rarely changes, and the tone of voice is monotone most of the time. 6-Severe. Little range or expression of emotion. Speech and gestures are mechanical most of the time. Facial expressions are unchanged. Voice is monotone most of the time. 7- Extremely severe. Virtually no emotional range or expression, stiff movements, monotonous tone of voice all the time.

[0234] The inventors have determined that elevated scores on the BPRS item "affective blunting" adversely affect both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the BPRS item "affective blunting" impair emotional well-being and mother-infant communication.

[0235] Conversely, improvement on this BPRS item would translate to improved maternal functioning, particularly in the BIMF domain of functioning, psychological well-being and / or mother-child communication.

[0236] The total score for the BPRS item "blunted affect" was 15 at baseline. After 3 hours, the score decreased to 11, which corresponds to a 4-point or 27% improvement. After 1 day of treatment, the score decreased to 8, which corresponds to a 7-point or 47% improvement. After 7 days of treatment, the score decreased to 8, which corresponds to a 7-point or 47% improvement.

[0237] In the 12 mg group, the BPRS item "blunted affect" total score was 11 at baseline. After 3 hours, the score decreased to 8, which corresponds to a 3-point or 27% improvement. After 1 day of treatment, the score decreased to 6, which corresponds to a 5-point or 45% improvement. After 7 days of treatment, the score decreased to 5, which corresponds to a 6-point or 55% improvement.

[0238] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of affective blunting.

[0239] The reduction or elimination of blunted affect is reflected by at least an improvement in the score on the blunted affect item of the BPRS 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 pharma- ceutically acceptable salt thereof.

[0240] Improvement in blunted affect, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0241] 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 pharmacologic acceptable salt thereof.

[0242] Improvement in blunted affect, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0243] Improvement in blunted affect, as reflected by a reduction in the CGI-S score or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0244] The inventors further conclude that reduction or elimination of emotional blunting by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the BPRS total score, but also by an increase in the BIMF score, which is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0245] Because blunted affect also impacts other aspects of PPD, we conclude that the observed improvement in the 'blunted affect' item on the BPRS may further contribute to an overall improvement in maternal functioning.

[0246] The BPRS item "Guilt" relates to 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 switch thoughts to other things. 3 - Mild. Preoccupied and somewhat preoccupied with disappointing someone or failing at something. Tends to convey guilt to others. 4 - Moderate. Disproportionately preoccupied with feelings of guilt, having done something wrong, or having hurt others by something they have done or failed to do, but can quickly shift their attention elsewhere. 5 - Moderately severe. Preoccupied with feelings of guilt, disappointment or failure; able to focus on other things but only with great effort. Not delusional. 6 - Severe. Delusional feelings of guilt or irrational self-blame that is not particularly relevant to the situation. Moderately distracted. 7 - Very severe. Delusional feelings of guilt or irrational self-blame that is grossly out of proportion to the circumstances. Subject is highly preoccupied with feelings of guilt and likely to disclose to others or act on the delusion.

[0247] The inventors determined that elevated scores on the BPRS item "guilt" adversely impact both aspects of maternal functioning (maternal competence related to communication with the infant(s) and maternal self-care). Elevated scores on the BPRS item "guilt" impair self-care, mother-infant communication, emotional well-being and control.

[0248] Conversely, improvement on this BPRS item would translate to improved maternal functioning, particularly in the BIMF functional domains of self-care, mother-child communication, emotional well-being and / or control.

[0249] In the study group receiving the individualized dosing plan, the aggregated BPRS item "guilt" score across all eight patients had a baseline of 34. After three hours, the score had decreased to 14, corresponding to a 20-point or 59% improvement. One day after treatment, the score had decreased to 11, corresponding to a 23-point or 68% improvement. Seven days after treatment, the score had decreased to 10, corresponding to a 24-point or 71% improvement.

[0250] In the 12 mg group, the BPRS "guilt" total score was 18 across all four patients at baseline. After 3 hours, the score decreased to 9, corresponding to a 9-point or 50% improvement. After 1 day of treatment, the score decreased to 5, corresponding to a 13-point or 72% improvement. After 7 days of treatment, the score decreased to 5, corresponding to a 13-point or 72% improvement.

[0251] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of guilt.

[0252] 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, 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 pharma- ceutically acceptable salt thereof.

[0253] Improvement in guilt, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0254] 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 pharmacologic acceptable salt thereof.

[0255] Improvement in guilt, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0256] The improvement in guilt, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0257] The inventors further conclude that reduction or elimination of guilt by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the BPRS total score, but also by an increase in the BIMF score, which is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0258] Because guilt also influences other aspects of PPD, we conclude that the observed improvement in the "guilt" item on the BPRS will further contribute to an overall improvement in maternal functioning.

[0259] 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 worrying. 3 - Mild. Worries a lot, but can quickly shift attention elsewhere. 4 - Moderate. Worried most of the time and unable to easily focus on other things but does not interfere with functioning, or has occasional autonomic anxiety but does not interfere with functioning. 5 - Moderately severe. Frequent (but not daily) periods of anxiety with autonomic involvement or some areas of functioning impaired by worry or anxiety. 6 - Severe. Paraautonomic anxiety is present every day but not all day or many areas of functioning are impaired by anxiety or constant worry. 7-Very severe. Paraautonomic anxiety is present consistently throughout the day or most areas of functioning are impaired by anxiety or constant worry.

[0260] The inventors determined that elevated scores on the BPRS item "anxiety" adversely affect both aspects of maternal functioning (maternal competence related to communicating with the infant(s) and maternal self-care). Elevated scores on the BPRS item "anxiety" impair emotional well-being, social support and control.

[0261] Conversely, improvement on this BPRS item would translate to improved emotional well-being, social support and / or control in maternal functioning, particularly in the BIMF domain of functioning.

[0262] In the study group receiving the individualized dosing plan, the BPRS "anxiety" item score aggregated across all eight patients had a baseline of 37. After three hours, the score had decreased to 19, which corresponds to an 18-point or 49% improvement. One day after treatment, the score had decreased to 16, which corresponds to a 21-point or 57% improvement. Seven days after treatment, the score had decreased to 17, which corresponds to a 20-point or 54% improvement.

[0263] In the 12 mg group, the BPRS "anxiety" item score across all four patients was combined, with a baseline of 25. After 3 hours, the score had decreased to 11, corresponding to a 14-point or 56% improvement. After 1 day of treatment, the score had decreased to 6, corresponding to a 19-point or 76% improvement. After 7 days of treatment, the score had decreased to 6, corresponding to a 19-point or 76% improvement.

[0264] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of anxiety.

[0265] 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, 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 pharma- ceutically acceptable salt thereof.

[0266] Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0267] 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 pharmacologic acceptable salt thereof.

[0268] Improvement in anxiety, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0269] Improvement in anxiety, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I or PGI-I score, preferably persists for at least 6 days, particularly at least 14 days, and more preferably at least 28 days after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0270] The inventors further conclude that reducing or eliminating anxiety by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the BPRS total score, but also by an increase in the BIMF score, which is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the 14th day; and / or on the 28th day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0271] Because anxiety also influences other aspects of PPD, we conclude that the observed improvement in the "anxiety" item on the BPRS will further contribute to an overall improvement in maternal functioning.

[0272] The BPRS item "tension" relates to observable physical and motor symptoms of tension, "nervousness," and agitation. Possible scores are: 1- No tension. 2 - Very mild. More restless than most people, but within normal limits. Some temporary signs of tension, such as picking fingernails, rocking feet, scratching the scalp several times, or tapping fingers. 3 - Mild. Same as "2" but with more frequent or exaggerated signs of tension. 4-Moderate. Many and frequent signs of motor tension, one or more signs may occur simultaneously, e.g., shaking the legs while rubbing the hands. Signs of tension may be absent. 5 - Moderately severe. Many and frequent signs of motor tension, often with one or more signs occurring simultaneously. Signs of tension may rarely be absent. 6 - Severe. Same as "5", but the signs of tension are persistent. 7-Very severe. Multiple motor symptoms of tension are continually present (e.g., constant pacing and rubbing of the hands).

[0273] The inventors determined that elevated scores on the BPRS item "strain" adversely affect both aspects of maternal functioning (maternal competence related to communication with the infant(s) and maternal self-care). Elevated scores on the BPRS item "strain" impair mother-infant communication and emotional well-being.

[0274] Conversely, improvement on this BPRS item would translate to improved maternal functioning, particularly in the BIMF domain of functioning, mother-child communication and / or emotional well-being.

[0275] In the study group receiving the individualized dosing plan, the aggregated score for the BPRS "tension" item across all eight patients had a baseline of 16. After three hours, the score had decreased to 11, which corresponds to a 5-point or 31% improvement. On the first day after treatment, the score had decreased to 11, which corresponds to a 5-point or 31% improvement. On the seventh day after treatment, the score had decreased to 10, which corresponds to a 6-point or 38% improvement.

[0276] In the 12 mg group, the BPRS "tension" item score aggregated across all 4 patients had a baseline of 14. After 3 hours, the score had decreased to 9, which corresponds to a 5 point or 36% improvement. On the 1st post-treatment day, the score had decreased to 6, which corresponds to an 8 point or 57% improvement. On the 7th post-treatment day, the score had decreased to 6, which corresponds to an 8 point or 57% improvement.

[0277] We conclude that 5-MeO-DMT may be used to treat patients with PPD to achieve a reduction or elimination of tension.

[0278] The reduction or elimination of tension is reflected by an improvement in the score on the tension item of the BPRS 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 pharma- ceutically acceptable salt thereof.

[0279] Improvement in 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 pharma- ceutical acceptable salt thereof.

[0280] 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 pharmacologic acceptable salt thereof.

[0281] Improvement in tension, as reflected by a score of at least "much improved" on a Clinical Global Impression-Improvement (CGI-I) score or a Patient Global Impression-Improvement (PGI-I) score, preferably occurs within about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0282] The improvement in tension, as reflected by a reduction in the CGI-S score, or by a score of at least "much improved" in the CGI-I score 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 pharma- ceutical acceptable salt thereof.

[0283] The inventors further conclude that reduction or elimination of tension by treating PPD patients leads to improved maternal functioning, as reflected not only by a reduction in the BPRS total score, but also by an increase in the BIMF score, which is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the first day, e.g., about 24 hours; on the seventh day; on the fourteenth day; and / or on the twenty-eighth day, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0284] Because strain also influences other aspects of PPD, we conclude that the observed improvement in the "strain" item on the BPRS will further contribute to an overall improvement in maternal functioning.

[0285] Improvement in one or more aspects of PPD also leads to an overall improvement. Preferably, the treatment results in remission.

[0286] Remission of depressive symptoms may be reflected by a MADRS score of 10 or less, occurring by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, occurring on day 1, e.g., about 24 hours; day 7; day 14, and / or day 28.

[0287] 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 pharma- ceutically acceptable salt thereof, achieved on day 1, e.g., about 24 hours; day 7; day 14, and / or day 28.

[0288] From the above, it follows that treatment of PPD patients with 5-MeO-DMT or a pharma- ceutically 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.

[0289] Improvement of maternal function includes improvement of the functional domain of self-care. For example, improvement of fatigue and / or sleep loss in MADRS items leads to increase in BIMF scale score reflecting self-care. The improvement of the cumulative score of BIMF scale items reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0290] Improvement in maternal functioning includes improvement in the functional domain of infant care. For example, improvement in fatigue and / or difficulty concentrating items of the MADRS item leads to an increase in the BIMF scale score reflecting infant care. The improvement in the cumulative score of the BIMF scale item reflecting self-care is preferably at least 15%, more preferably at least 25%.

[0291] The improvement of maternal function includes the improvement of the functional domain of mother-child communication. For example, the improvement of MADRS items of emotional elimination and inner tension leads to an increase in the BIMF scale score reflecting mother-child communication. The improvement of the cumulative score of the BIMF scale items reflecting mother-child communication is preferably at least 5%, more preferably at least 15%.

[0292] The improvement of maternal function includes the improvement of the functional domain of mental well-being.For example, the improvement of MADRS items of fatigue, pessimistic thinking, loss of emotion, inner tension and / or decreased sleep leads to the increase of BIMF scale score reflecting mental well-being.The improvement of the cumulative score of BIMF scale items reflecting mental well-being is preferably at least 25%, more preferably at least 35%.

[0293] The improvement of maternal function includes the improvement of the functional domain of social support.For example, the improvement of the pessimistic thinking of MADRS item leads to the increase of the BIMF scale score reflecting social support.The improvement of the cumulative score of the BIMF scale item reflecting social support is preferably at least 10%, more preferably at least 20%.

[0294] Improvement in maternal functioning includes improvement in the functional domain of management. For example, improvement in the MADRS items of fatigue, pessimistic thinking and / or difficulty concentrating leads to an increase in the BIMF scale score reflecting management. The improvement in the cumulative score of the BIMF scale items reflecting management is preferably at least 20%, more preferably at least 30%.

[0295] Improvement in maternal functioning includes improvement in the functional domain of regulation. For example, improvement in the MADRS item fatigue leads to an increase in the BIMF scale score reflecting regulation. The improvement in the cumulative score of the BIMF scale items reflecting regulation is preferably at least 5%, more preferably at least 15%.

[0296] Improved maternal functioning is associated with one or more, particularly two or more, functional domains on the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child communication, maternal emotional well-being, social support, and control and regulation.

[0297] The BIMF total score is improved by 10% or more, preferably 20% or more.

[0298] Breastfeeding As noted above, with regard to many medications, breastfeeding PPD patients may be faced with the decision to either discontinue breastfeeding or discontinue / interrupt treatment.

[0299] If a decision is made to discontinue breastfeeding in order to undergo treatment, this decision has a negative impact on maternal functioning, particularly impairing the functional areas of mother-child communication and emotional well-being.

[0300] The present invention also addresses the need to treat PPD in nursing mothers without substantially interrupting breastfeeding.

[0301] According to the present invention, breast-feeding can be resumed immediately after treatment.

[0302] The inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT as part of an effort to determine when breast-feeding can occur after administration of 5-MeO-DMT or a pharma- ceutical acceptable salt without exposing the nursing infant to associated risks.

[0303] Absorption and distribution of inhaled 5-MeO-DMT is rapid, with peak concentrations and pharmacological effects observed during and shortly after administration.

[0304] Plasma protein binding is low (13-23%).

[0305] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that plasma concentrations drop very rapidly. Already 10 minutes after administration, concentrations are below 10% of Cmax, after 2 hours they are below 1% of Cmax, and after 3 hours 5-MeO-DMT is no longer detectable in plasma. This is true over the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation is observed with repeated dosing within the 1-4 hour time frame. Titrating the dose as disclosed herein does not result in accumulation and therefore does not result in high plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after dosing.

[0306] The possible metabolic products of 5-MeO-DMT in humans were identified to evaluate the potential relevance of such metabolites. In an in vitro metabolic identification study in human hepatocytes, 5-MeO-DMT free base was incubated at 10 μM for up to 120 minutes. The compounds identified and their relative ratios are shown in Table 1 below. [Table 1]

[0307] Note that subsequent assays repeatedly failed to detect the presence of 5-methoxytryptophol but reproducibly demonstrated the presence of 5-MIAA as the major metabolite, and thus 5-methoxytryptophol is unlikely to play a significant role in vivo.

[0308] The metabolites listed in the table above are formed via three different pathways.

[0309] The two most important metabolic products, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed via oxidative deamination, which involves the enzymatic removal and oxidation of the N-methyl group to form acetaldehyde: [ka]

[0310] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0311] Secondary amines, primary amines, and aldehydes were not identified, indicating that they are not always present in significant concentrations.

[0312] The aldehyde intermediate metabolite undergoes two separate biotransformations in human hepatocytes: it is either oxidized to 5-methoxyindoleacetic acid or reduced to 5-methoxyindole-3-ethanol. [ka]

[0313] Both resulting metabolites are endogenous substances and are formed in the human body, for example, during the synthesis and metabolism of melatonin and serotonin (see, for example, Biochemistry of the Pineal. Chapter 3. In Melatin 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).

[0314] Because the primary pathway for metabolism of 5-MeO-DMT rapidly leads to metabolites that are also part of the endogenous metabolic pathway, the inventors determined that oxidative deamination of 5-MeO-DMT does not involve metabolites that require restrictions regarding lactation.

[0315] Furthermore, as described in detail in the Examples section, incubation of 5-methoxytryptophol with human hepatocytes showed a high turnover rate, with the compound being completely cleared by 24 hours. At a test concentration of 1 μM, the in vitro endogenous clearance of 5-methoxytryptophol was 16.2 μl / min / million cells (half-life 142 minutes).

[0316] Thus, the plasma concentration of 5-methoxytryptophol declines rapidly to endogenous levels, if it is formed at all.

[0317] 5-MIAA is a weak acid and is present in plasma in an ionized form, reducing the ability of the compound to pass into breast milk.

[0318] Incubation of 5-MIAA with human hepatocytes shows low metabolic turnover, with remaining 5-MIAA concentrations of 75-82% after 72 h. 5-MIAA is thought to be the final metabolic product of 5-MeO-DMT.

[0319] 5-MIAA exhibits relatively low plasma binding of approximately 50% (mean fraction unbound (Fu), see Examples section). It remains in the circulation undergoing renal clearance. With a standard glomerular filtration rate of 90-120 ml / min, this means that in approximately 1-2 hours (depending on the patient's size and taking into account the increased blood volume that occurs during pregnancy) all traces of 5-MIAA are cleared from the circulation for urinary excretion.

[0320] As a result, the plasma concentration of 5-MIAA also declines rapidly.

[0321] Combined with the rapid clearance of 5-MeO-DMT (<1 hour), this supports the notion that the administered therapy and all associated metabolites were cleared from the circulation in approximately 2 hours.

[0322] A further metabolite identified, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The formed metabolite is then subjected to glucuronidation catalyzed by UGTs: [ka]

[0323] As part of the pharmacokinetic studies, it was determined that bufotenine was barely detectable in human serum; in all cases, it was undetectable 15 minutes after administration of 5-MeO-DMT.

[0324] Bufotenin glucuronide is unable to bind to the receptor and exerts no effect. Moreover, its concentration is so low that it was not detected in the hepatocyte assay. Bufotenin glucuronide is further converted to 5-hydroxyindoleacetic acid: [ka]

[0325] 5-Hydroxyindoleacetic acid is an endogenous substance, occurring, for example, in the metabolism of melatonin and serotonin (see above).

[0326] Because the O-demethylation pathway of 5-MeO-DMT leads to the major metabolite bufotenine, which is rapidly cleared from plasma, and further metabolism leads to compounds that are only present in very low concentrations, and ultimately to metabolites that are also part of endogenous metabolic pathways, the inventors have determined that the O-demethylation of 5-MeO-DMT does not involve metabolites that require restrictions with respect to lactation.

[0327] The third metabolic pathway involves N-oxidation: [ka]

[0328] In silico modeling of the metabolites formed, 5-MeO-DMT-N-oxide was deemed non-genotoxic, consistent with the negative in vitro genotoxicity assessment of the parent molecule. As confirmed by observations in rats, the compound is water soluble and rapidly excreted (Sitaram, BR., Lockett, L., Blackman, GL, McLeod, 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 pathway of 5-MeO-DMT metabolism involving N-oxidation plays only a minor role, leading to a low proportion of rapidly excreted metabolites with no apparent toxicity, the inventors determined that the N-oxidation of 5-MeO-DMT does not involve metabolites that require restrictions regarding lactation.

[0329] Based on the above, the inventors have determined that breast-feeding can be resumed immediately following treatment with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0330] Therefore, if the patient is a nursing mother, the patient is advised to discontinue breast-feeding until 48 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and in particular, the patient is advised to discontinue breast-feeding until 24 hours after the last administration of 5-MeO-DMT or a pharma-ceutically acceptable salt thereof.

[0331] Preferably, breastfeeding should be discontinued for no more than 6 hours, more preferably no more than 3 hours, and most preferably no more than 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0332] This short interruption, and the corresponding possibility of resuming breastfeeding immediately after the procedure, contributes to the success of the procedure and in particular to the functioning and health of the mother and the development of the infant(s).

[0333] Mode of administration The therapeutically effective amount of 5-MeO-DMT is administered intravenously, intramuscularly or subcutaneously. Administration via these routes can ensure a rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., by intravenous injection.

[0334] 5-MeO-DMT may be used as a pharma- ceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration by injection, examples of excipients and vehicles for such formulations are known in the art.

[0335] Dosage regimen The present invention also provides dose ranges, specific doses, as well as administration regimens (administration schemes) and suitable routes of administration.

[0336] The present invention is based in part on the inventors' conclusion that the occurrence of a hallucinogenic climax experience in the acute phase following administration of 5-MeO-DMT causally facilitates, or at least as a surrogate behavioral marker of an underlying unknown therapeutic mechanism, the therapeutic effect of 5-MeO-DMT in patients suffering from PPD, in particular one or more of the aspects defined above.

[0337] The result is a superior therapeutic profile that achieves the peak experience more rapidly, in a greater percentage of patients, and with greater reproducibility within each individual patient compared to previously tested hallucinogens, dosing regimens, and routes of administration.

[0338] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., no attenuation or disappearance of the hallucinogenic effect after re-administration) as the basis for enabling a dosing regimen with frequent re-administration (e.g., more than once a day or daily) designed to increase the incidence of peak experiences and thereby increase the therapeutic effect. 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 point), induction of mania or hypomania, or a less meaningful hallucinogenic experience with little or no memory of the altered state (so-called "whiteout"). Furthermore, by starting with a low dose, patients generally become accustomed to the hallucinogenic experience and are prepared for the more intense symptoms that occur with a higher dose, thereby affecting the experience in a positive way. Additionally, the possibility of initiating treatment at lower doses may increase patient acceptance of the therapeutic approach and improve overall compliance rates at the patient population level.

[0339] Frequent re-administration of serotonergic hallucinogens, intended to increase the rate of peak experiences and modulate the reproducibility of peak experiences, as well as to improve therapeutic efficacy, reduce side effects, and increase compliance, may not be possible with other psychedelics due to the delayed onset and long duration of the hallucinogenic effects, and the rapid development of tolerance (i.e., the hallucinogenic effects diminish or disappear after re-administration), which may last for several days.

[0340] 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.

[0341] In preferred amounts, the dose of 5-MeO-DMT administered to a patient as defined herein diagnosed with postpartum depression, including treatment-resistant forms of the disorder, including those associated with suicidal ideation, is in the range of about 1 mg to about 10 mg, or any amount within that range, administered in the form of a formulation for administration based on a pharma- ceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, which weight amount can be calculated from the stated weight amount of 5-MeO-DMT free base, assuming that an equimolar amount is used. Useful specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. It should be noted that when a range is given herein, such as "about 1 mg to about 10 mg," the inventors contemplate all discrete values ​​within that range, some of which are specifically mentioned, but not all of which are mentioned (simply for brevity).

[0342] In a preferred embodiment, the improved method using a therapeutically effective amount of 5-MeO-DMT for the treatment of patients as defined herein diagnosed with postpartum depression, including treatment-resistant forms of the disorder, including those associated with suicidal ideation, includes the occurrence of a clinical response by about 2 hours after administration of 5-MeO-DMT.

[0343] In a preferred embodiment, an improved method using a therapeutically effective amount of 5-MeO-DMT for the treatment of a patient as defined herein diagnosed with postpartum depression, including treatment-resistant forms of the disorder, including those associated with suicidal ideation, comprises sustaining a clinical response, including a clinical response that occurs by about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0344] In a preferred embodiment, the improved method with a therapeutically effective amount of 5-MeO-DMT for the treatment of patients as defined herein diagnosed with postpartum depression, including treatment-resistant forms of the disorder, including those associated with suicidal ideation, comprises the administration of more than a single dose of 5-MeO-DMT.

[0345] In a 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 2-7 doses, the interval between each dose within each treatment block being greater than or equal to about 1 hour and less than or equal to about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block being greater than or equal to about 6 days.

[0346] 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, 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.

[0347] 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 1-3 doses, with the interval between each dose within each treatment block being about 1-4 hours, preferably 1-2 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.

[0348] In one embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0349] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0350] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until it reaches 10 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0351] For embodiments in which the dosage is increased with each subsequent administration, the dosage of the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dosage of the previous administration. For example, if the dosage of the first administration is 1 mg and the dosage increment is 3 mg, the dosage of the second administration will be 4 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage for the third administration is 7 mg.

[0352] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg for the first administration, and then increased to a dosage selected from about 4 mg to about 6 mg for the second administration and from about 7 mg to about 9 mg for the third administration, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects. Specific amounts that are effective for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0353] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg for the first administration, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration and from about 2.5 mg to about 3.5 mg for the third administration, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects. Specific amounts that are effective for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0354] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of a first treatment block, and then increased for each subsequent administration within the first treatment block until it reaches 10 mg or all administrations within that treatment block are administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if a patient experienced a hallucinogenic high experience at a dose of 8 mg, and therefore the highest dosage in the first treatment block was 8 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 8 mg.

[0355] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg for the first administration of the first treatment block, then increased to a dosage selected from about 4 mg to about 6 mg for the second administration of the first treatment block and to a dosage selected from about 7 mg to about 9 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts that are effective for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0356] In a particularly preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 0.5 mg to about 1.5 mg for the first administration of the first treatment block, and then increased to a dosage selected from about 1.5 mg to about 2.5 mg for the second administration of the first treatment block and to a dosage selected from about 2.5 mg to about 3.5 mg for the third administration of the first treatment block, unless the patient has yet to experience a hallucinogenic high within that treatment block or the managing physician has determined that further dose increases are inappropriate based on observed side effects, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Specific amounts that are effective for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0357] It is understood that pharma- ceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens, and that the appropriate weight of the salt to be administered may be calculated from the weight of the free base listed, assuming that an equimolar amount is used.

[0358] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0359] The occurrence of a "hallucinatory peak experience" in a patient can be identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0360] The occurrence of a "hallucinatory peak experience" in a patient can also be identified by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0361] In accordance with the present invention, the occurrence of a "hallucinatory peak experience" in a patient is preferably identified by achieving a score of at least 75 on the Peak Experience Scale (PES) Total Score (also referred to as the Peak Psychedelic Experience Questionnaire (PPEQ)), which is the average of the patient's responses, on a scale of 0 to 100, to the following three questions: 1. How intense was the experience? 2. How out of control was it? 3. How profound (i.e., meaningful) was the experience?

[0362] Further aspects of the invention 1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharma- ceutically acceptable salt thereof, for use in the treatment of a patient suffering from postpartum depression (PPD), wherein said 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, is administered via an intravenous, intramuscular or subcutaneous route.

[0363] 2. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 1, wherein said 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.

[0364] 3. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 2, wherein said patient has a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0365] 4. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 2, wherein said patient has a MADRS score of 35 or greater or a HAM-D score of 27 or greater.

[0366] 5. 5-MeO-DMT or a pharma- ceutically 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.

[0367] 6. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 5, wherein said patient further suffers from suicidal thoughts.

[0368] 7. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 6, wherein said patient further suffers from a slightly impaired reduced maternal function.

[0369] 8. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 7, wherein said patient has a Birkin Index of Maternal Functioning (BIMF) score of 95 or less, such as 80 or less, in particular 65 or less.

[0370] 9. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 8, wherein said 5-MeO-DMT or salt thereof is administered at a dose or dosing regimen that causes said patient to experience a hallucinogenic high experience.

[0371] 10. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use according to any one of aspects 1 to 9, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharma-ceutical acceptable salt is administered instead of 5-MeO-DMT.

[0372] 11. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1-9, wherein a dosage of about 2 mg, or about 5 mg, or about 8 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0373] 12. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1-9, wherein a dosage of about 1 mg, or about 2 mg, or about 3 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0374] 13. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered in 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.

[0375] 14. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 1-10 or 13, wherein the 5-MeO-DMT is administered at a dosage of about 1 mg to about 3 mg for a first administration, then increased to a dosage of about 4 mg to about 6 mg for a second administration unless the patient has yet to experience a hallucinatory climax experience, and then increased to a dosage of about 7 mg to about 9 mg for a third administration unless the patient has yet to experience a hallucinatory climax experience, or an equimolar amount of the pharma-ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0376] 15. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 14, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0377] 16. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use according to aspect 1-10, or 13, wherein the 5-MeO-DMT is administered at a dosage of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dosage of about 1.5 mg to about 2.5 mg for a second administration, unless the patient has yet experienced a hallucinogenic climax experience, and then increased to a dosage of about 2.5 mg to about 3.5 mg for a third administration, unless the patient has yet experienced a hallucinogenic climax experience, or an equimolar amount of the pharma-ceutical acceptable salt is administered instead of 5-MeO-DMT.

[0378] 17. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 16, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0379] 18. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 13 to 17, wherein the interval between two administrations is at least 1 hour and at most 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.

[0380] 19. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 9 to 18, wherein the onset of a hallucinogenic peak experience is identified by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible 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.

[0381] 20. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 19, wherein the onset of a hallucinogenic climax experience is identified by achieving a Peak Experience Scale (PES) Total Score of at least 75.

[0382] 21. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 20, wherein said 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered via intravenous injection.

[0383] 22. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiments 1 to 21, 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 pharma- ceutically acceptable salt thereof.

[0384] 23. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 22, wherein the clinical response, as reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score, is observed 1 day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0385] 24. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 23, 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 pharma- ceutically acceptable salt thereof.

[0386] 25. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0387] 26. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 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 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0388] 27. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiments 1 to 27, wherein the clinical response is assessed by at least a 50% improvement in said MADRS or 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 pharma- ceutically acceptable salt thereof.

[0389] 28. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use according to aspects 1 to 27, wherein the clinical response is assessed by at least a 75% improvement in said MADRS or 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 pharma- ceutical acceptable salt thereof.

[0390] 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 24, wherein remission of depressive symptoms, as assessed by a MADRS score of 29.10 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 pharma- ceutically acceptable salt thereof.

[0391] 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiments 1 to 29, wherein remission of depressive symptoms, as assessed by a MADRS score of 30.10 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 pharma- ceutically acceptable salt thereof.

[0392] 31. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 30, wherein said clinical response is assessed by at least a 50% improvement in said MADRS or HAM-D score compared to the respective score before treatment, and lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0393] 32. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 31, wherein the clinical response is assessed by at least a 75% improvement in said MADRS or HAM-D score compared to the respective score before treatment, and is 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0394] 33. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 32, 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 pharma- ceutically acceptable salt thereof.

[0395] 34. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 33, wherein said clinical response is assessed by at least a 50% improvement in said MADRS or HAM-D score compared to the respective score before treatment, and lasts for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0396] 35. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 34, wherein the clinical response is assessed by at least a 75% improvement in said MADRS or HAM-D score compared to the respective score before treatment, and is 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0397] 36. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 35, 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 pharma- ceutically acceptable salt thereof.

[0398] 37. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 36, wherein said clinical response is assessed by at least a 50% improvement in said MADRS or HAM-D score compared to the respective score before treatment, and lasts for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0399] 38. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1 to 37, wherein the clinical response is assessed by at least a 75% improvement in said MADRS or HAM-D score compared to the respective score before treatment, and is 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0400] 39. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 38, 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 pharma- ceutically acceptable salt thereof.

[0401] 40. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutical acceptable salt thereof for use according to any of aspects 1 to 39, wherein the patient is a nursing mother who is advised to discontinue breastfeeding for up to 48 hours after the last dose of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0402] 41. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutical acceptable salt thereof for use according to any of aspects 1 to 39, wherein the patient is a nursing mother who is advised to discontinue breastfeeding for up to 24 hours after the last dose of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0403] 42. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutical acceptable salt thereof for use according to any of aspects 1 to 39, wherein the patient is a nursing mother who is advised to discontinue breastfeeding for up to 6 hours after the last dose of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0404] 43. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutical acceptable salt thereof for use according to any of aspects 1 to 39, wherein the patient is a nursing mother who is advised to discontinue breastfeeding for up to 3 hours after the last administration of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0405] 44. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutical acceptable salt thereof for use according to any of aspects 1 to 39, wherein the patient is a nursing mother who is advised to discontinue breastfeeding for up to 2 hours after the last dose of 5-MeO-DMT or a pharma-ceutical acceptable salt thereof.

[0406] 45. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 44, wherein said treatment improves maternal function.

[0407] 46. ​​5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 45, wherein the improvement relates to one or more, in particular two or more, functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child communication, maternal mental health, social support, control, and adjustment.

[0408] 47. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 45 or 46, wherein the BIMF score is improved by 10% or more, preferably by 20% or more. EXAMPLES

[0409] The following examples are included to aid in the understanding of the invention and are not intended, and should not be construed as, limiting the invention, as set forth in the claims which follow, in any manner.

[0410] Example 1-5 - Generation and administration of MeO-DMT aerosol Step 1: A stock solution of 5-MeO-DMT free base in 100% ethanol is prepared in a volumetric flask such that the target dose of 5-MeO-DMT free base to be administered to a volunteer or patient via inhalation is contained in a solution volume of 200 μl. A typical target dosage is 1 mg to 25 mg of 5-MeO-DMT. For example, for a target dose of 18 mg of 5-MeO-DMT, 90 mg of 5-MeO-DMT is dissolved in 100% ethanol to a final solution volume of 1 ml. An aliquot of the stock solution may then be stored in a vial until further use.

[0411] Step 2: 200 μl of the solution is transferred into a dosing capsule containing an infusion pad (Storz & Bickel, Germany) and the dosing capsule is then closed.

[0412] Step 3: The dosing capsule filled with the 5-MeO-DMT ethanol solution is transferred to the filling chamber of the first Volcano Medic Vaporizer, preheated at a temperature set at 55°C. The vaporizer airflow is then switched on for 60 seconds at a pre-set rate of approximately 12 l / min. The heated air flows through the dosing capsule, evaporating the ethanol while the target dose of 5-MeO-DMT remains within the capsule as a thin layer covering the stainless steel wire mesh. Correct preparation of the dosing 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 dose of 5-MeO-DMT.

[0413] Step 4: The prepared dose capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second Volcano Medic Vaporizer, which is preheated at a temperature set at 210°C and has the airflow turned on for at least 5 minutes and then turned off immediately before transfer. A valved inhalation balloon (Storz & Bickel, Germany) is attached to the socket of the filling chamber, the filling chamber is tightly closed, and the airflow is immediately thereafter turned on for exactly 15 seconds at a preset flow rate of about 12 1 / min and then turned off. This aerosolizes the entire dose of 5-MeO-DMT and disperses it in the approximately 3 liters of air in the inhalation balloon. It can be confirmed that the 5-MeO-DMT has been accurately aerosolized by demonstrating that the capsule's weight has returned approximately to its initial weight.

[0414] Step 5: The balloon is then removed from the filling chamber, the valve automatically closes, a mouthpiece is attached to the balloon and the aerosol is ready to be administered immediately to a volunteer or patient.

[0415] Step 6: To prepare for administration, the patient is asked to first take 1-2 deep inhalations and complete exhalations, concluding this sequence with a deep exhalation. Then, holding the mouthpiece firmly against the lips, inhale the entire volume of the inhalation balloon completely in one inhalation, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, the patient is instructed to lie down.

[0416] Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020 / 169850 A1, the contents of which are incorporated herein by reference.

[0417] 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 reduced to 7-12 °C over 30 min. Crystallization occurred after stirring at 7-12 °C for 10 min. Subsequently, after stirring at 7-12 °C for 1 h, the batch was filtered. After washing with MTBE (1 mL, 0.5 vol) at 7-12 °C, the batch was pulled dry under vacuum for 3.5 h to give 1.02 g of a pale orange solid (50% recovery). The isolated solid was analyzed for purity by HPLC as described in WO2020 / 169850A1. The purity was found to be 99.74% area.

[0418] The analysis further indicates that the levels of individual impurities were less than 0.10% area. Solvent analysis of the sample showed an MTBE level of 17 ppm.

[0419] Example 3-5—Preparation of MeO-DMT Hydrobromide 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0420] 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 a single aliquot (1 M in ethanol, 1 equivalent). The mixture was maintained at that temperature and equilibrated for 3 hours.

[0421] 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 under vacuum at 40° C. for 18 hours.

[0422] An off-white crystalline material was obtained.

[0423] The salt has a melting point of 174°C and is characterized by an X-ray diffraction pattern 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, measured using Cu Kα radiation.

[0424] Example 4 - Determination of inhibition constants of 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.

[0425] Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank: all donors had died suddenly, had no history of coma, psychiatric or neurological disorders, were under 65 years of age, and samples were obtained within 72 hours of death.

[0426] 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 cell debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was kept 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), homogenized using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. The pellet was resuspended in ice-cold membrane preparation buffer and incubated at 37°C for 10 min, followed by centrifugation at 20,500 g for 10 min. The pellet was resuspended and centrifuged a final time (20,500×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 was 50 mM Tris-HCl (pH 7.7), 4 mM CaCl 2 and 0.1% ascorbic acid. The assay buffer consisted of 50 mM Tris (pH 7.7), 4 mM CaCl 2 , 0.1% ascorbic acid and 10 μM pargyline.

[0427] For saturation binding assays, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue / tube) were incubated 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 (non-specific binding) for 30 min at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

[0428] For the displacement assay, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue / tube) were incubated 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 (non-specific binding) or 50 μl of one of the test compounds at one of 10 concentrations from 1 to 10,000 nM for 30 min at 25°C.

[0429] Membrane-bound radioactivity was harvested by filtration under vacuum through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. Filters were washed briefly with ice-cold wash buffer (wash settings 0, 9, 9) and radioactivity determined by liquid scintillation counting (1 ml Packard MV gold scintillator).

[0430] The compound concentration required to inhibit 50% of the 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.

[0431] 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 two more times to wash the tissue (20,500 × g, 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.

[0432] For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg wet weight of tissue / tube) were incubated 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 (non-specific binding) for 60 min at 25° C. Assay and wash buffer consisted of 50 mM Tris-HCl buffer pH 7.4.

[0433] For the displacement assay, 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 [3H]MDL-100,907 and either 50 μl of assay buffer (total binding) or 50 μl of 10 μM ketanserin (non-specific binding) or 50 μl of one of the test compounds at one of 10 concentrations from 1 to 10,000 nM.

[0434] Membrane-bound radioactivity was harvested and measured as above, and data analysis was also performed as above.

[0435] result In hippocampal membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K d The concentrations (p<0.01, p<0.01) of the agonists were 0.51, 0.28, and 0.52 nM, respectively.

[0436] The mean inhibition constants (K i The values ​​of the Hill slopes for all the compounds were close to 1, suggesting a one-site binding model.

[0437] In frontal cortical membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K d The concentrations of 0.11, 0.08 and 0.08 nM, respectively.

[0438] The mean inhibition constants (K i The Hill slopes for all compounds were close to 1, suggesting a one-site binding model.

[0439] The selectivity ratios of psilocin, DMT and 5-MeO-DMT for the 5-HT2A receptor versus the 5-HT1A receptor were 0.78, 3.1 and 68, respectively.

[0440] Example 5 - Clinical Trial in Patients Affected by TRD A Phase 1 / 2 clinical trial of 5-MeO-DMT administered by inhalation 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 applying an individualized dosing schedule with intrapatient escalation 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 higher doses administered only if the peak experience was not achieved with the previous dose. The primary endpoint of Part A was to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in patients with TRD. The primary endpoint of Part B was to evaluate 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 after dosing.

[0441] In Part A, 3 of 4 patients in both arms (12 mg and 18 mg) experienced at least 1 ADR, all of which were mild and resolved spontaneously. No SAEs were reported.

[0442] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS resolution 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.

[0443] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0444] 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%).

[0445] No clinically significant changes were observed in any of the safety nonclinical laboratory analyses, vital signs, psychiatric safety assessments, or cognitive function measures in either Part A or Part B.

[0446] The results are summarized in the table below. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0447] Example 6-5 - Pharmacokinetic evaluation of MeO-DMT and bufotenin To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups containing eight subjects each were formed. Subjects received a single dose of 6 mg; 12 mg or 18 mg of 5-MeO-DMT by inhalation. Blood samples were obtained at 1; 2; 4; 7; 10; 15; 20; 30; 45 min and 1; 1.5; 2; 3; 4 h after administration.

[0448] 5-MeO-DMT concentrations were determined 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.

[0449] The median Cmax values ​​obtained for the 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).

[0450] Table 4 below shows the median plasma concentration percentages of Cmax determined for the indicated time points. [Table 8]

[0451] Pharmacokinetic measurements were also performed with an escalating dosing scheme, with essentially similar results.

[0452] We also measured plasma concentrations of the 5-MeO-DMT metabolite bufotenine. In only a few samples were concentrations above the lower level of quantification (LLOQ) (25 pg / ml). After 15 min, bufotenine concentrations were always below the LLOQ.

[0453] Substantially similar observations were made when subjects who underwent a titration scheme were included.

[0454] Example 7-5-MeO-DMT Toxicity Test 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). These conditions included treatment with or without the rat liver metabolic activation system (S-9) at concentrations up to 5000 μg / plate (the maximum concentration recommended by current regulatory guidelines).

[0455] Example 8 - Binding of 5-MeO-DMT to human plasma proteins The in vitro binding of 5-MeO-DMT to plasma proteins was determined using high-throughput dialysis. Equilibrium times and non-specific binding were determined using human plasma at a nominal 5-MeO-DMT concentration of 1 μM. After 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 concentration of 5-MeO-DMT in samples from the plasma and buffer compartments was determined by LC-MS / MS. The protein binding results are presented below: [Table 9]

[0456] Example 9-5-Human Metabolism of MeO-DMT 5-MeO-DMT was incubated at nominal concentrations of 1 μM and 10 μM with human hepatocytes suspended in Leibovitz L-15 medium (1×10 6 cells / mL).

[0457] A standard stock solution of 5-MeO-DMT was prepared at 20 mM in ethanol and further diluted to a concentration of 2 mM with Leibovitz L-15 medium. For incubation with cryopreserved hepatocytes, the 2 mM stock solution was diluted to a concentration of 20 μM or 2 μM with Leibovitz L-15 medium. Aliquots (250 μL) of the 20 μM and 2 μM test article formulations were added to each hepatocyte incubation sample (250 μL) as required to give a final test article concentration in the incubation of 10 μM or 1 μM, respectively, and the incubation contained less than 1% (v / v) solvent.

[0458] Incubations were performed 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 min by the addition of ice-cold acetonitrile (0.5 mL). For 10 μM, incubations were terminated after 0, 10, 30, 60, and 120 min by the addition of ice-cold acetonitrile containing the internal standard (1 μg / mL Psilocin-d10).

[0459] 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.

[0460] Blank control incubations were performed using Leibovitz L-15 medium instead of the test substances. No cell control samples were performed using Leibovitz L-15 medium instead of hepatocytes. Aliquots of blank control samples were taken at 120 min, while control samples without cells were taken at 0, 30, and 120 for the 1 μM incubations and at 0 and 120 min for the 10 μM incubations.

[0461] All 1 μM incubations were performed in duplicate, while all 10 μM incubations were performed in singletons. All samples were stored at -80°C (nominal) prior to analysis.

[0462] Appropriate chromatographic conditions were developed to retain the parent compound and obtain an appropriate chromatographic response. The 0, 30, and 120 min incubation samples generated after incubation with 5-MeO-DMT at 10 μM were analyzed using reversed-phase LC-MS analysis to generate high-energy and low-energy mass spectra (MSE). Prior to sample analysis, a 100 μL aliquot of each sample was evaporated to near dryness under a steady stream of nitrogen at room temperature and then reconstituted with 50 μL of mobile phase A (0.1% formic acid in water). Each sample (0 min, 30 min, 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 determine the profile of metabolites formed. Appropriate blank and control samples were also analyzed. The 10 and 60 min 10 μM incubation samples were not analyzed and were stored at -80°C (nominal).

[0463] Data were screened for the presence of metabolites by comparison of retention times with test substance reference standards and based on the accurate mass of potential metabolites using screening software (UNIFI version 1.9.4) and user-defined search parameters. To confirm a suspected metabolite, the measured accurate mass of the peak detected in the sample used for structural elucidation must be within 5 ppm of the theoretical mass to confirm the molecular formula.

[0464] The results obtained are summarized in Table 1 above.

[0465] 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 Hμrel co-culture assays with human hepatocytes (Hμrel HumanPool™, primary hepatic co-culture model from Visikol Inc.).

[0466] Incubations were performed using initial concentrations of 1 μM and 10 μM, with sampling at 0, 1, 2, 4, 8, 24, 48, and 72 hours (h). Samples were analyzed using UPLC / QE-orbitrap-MS.

[0467] The remaining LC / MS peak areas detected for the test compounds after each incubation time point with the Hμrel co-culture assay compared to the corresponding 0 min incubation sample are shown in the table below. The assay control diazepam results (elimination half-life) showed that the enzyme activity was within normal levels.

[0468] [Table 10] [Table 11]

[0469] A low metabolic turnover was observed for 5-MIAA, with the amount remaining after a 72-h period being 75-82% in the presence of hepatocytes, whereas no loss was observed in the stromal cell control.

[0470] High metabolic turnover was observed for 5-methoxytryptophol, with complete disappearance by 24 h in the presence of hepatocytes and none in the stromal cell control.

[0471] With human hepatocytes and a test concentration of 1 μM, an in vitro endogenous clearance of 0.15 μl / min / million cells (half-life 15,400 min) was obtained for 5-MIAA, while the corresponding value for 5-methoxytryptophol was 16.2 μl / min / million cells (half-life 142 min).

[0472] The predicted hepatic extraction rates were 2% for 5-MIAA and 67% for 5-methoxytryptophol.

[0473] Example 11-5 - Plasma binding of 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 12]

[0474] Example 12 - Clinical trial of 5-MeO-DMT administered by inhalation to patients with postpartum depression The single-arm, open-label clinical trial will enroll 15 adult female patients with a clinical diagnosis of postpartum depression (PPD).

[0475] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0476] More specifically, patients will receive up to three doses of 5-MeO-DMT on day 0 (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. Failure to achieve a peak experience (total score ≥ 75) after 6 mg administration; 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 outside the normal range but not considered clinically significant by the investigator. 3. Similarly, the third dose (18 mg) is administered only if: a. No peak experience (total score ≥ 75) was achieved after administration of 12 mg; 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 outside the normal range but not considered clinically significant by the investigator.

[0477] Patients will be assessed post-injection for hallucinatory peak experiences (based on a patient-rated visual analog scale, the PE scale), sedation, and other endpoints. Follow-up visits will be scheduled 1 and 7 days after the date of injecting.

[0478] 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) of 18.5 to 35 kg / m at screening 2 (inclusive). 3. Meets the study criteria for PPD as assessed by a study psychiatrist or registered psychologist: A diagnosis of major depressive disorder without psychotic features as confirmed by the Mini-Institutional Mental Health Interview (MINI) with perinatal onset occurring after conception and up to the first 4 weeks after delivery. b. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 28 at screening and pre-dose on Day 0. 6. Must have discontinued breastfeeding at the time of screening, or if still lactating or actively breastfeeding at screening, agree to temporarily discontinue breastfeeding from just before study drug administration on Day 0 through 24 hours after the last dose, expressing and discarding all breast milk as needed during that 24 hour period, but which must incorporate expression / discarding at 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding. 4. Must agree to complete abstinence (complete avoidance of heterosexual intercourse) or use a highly effective (failure rate <1%) medically acceptable method of contraception for 30 days prior to and 90 days after 5-MeO-DMT administration. Patients must have a negative pregnancy test at screening and the day prior to testing (day -1). 5. Willing to postpone initiation of other antidepressant or anxiety medication until after the end of the study on Day 7 and agree to keep any psychotherapy unchanged during the study.

[0479] Candidate patients who meet any of the following major exclusion criteria will be excluded from participating in the study: 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past bipolar disorder, manic or hypomanic episodes, 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 comorbid psychiatric illness that would cause the investigator to determine that the patient is unsuitable 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, in the judgment of a clinical psychiatrist or registered 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. Taking an antidepressant within 14 days or 5 half-lives (whichever is longer) prior to treatment (exception: within the past 5 weeks for fluoxetine). 5.Having taken any other drug with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Previously experienced significant adverse reactions to hallucinogenic or hallucinogenic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) as determined by the investigator. 7. Have a known allergy or hypersensitivity or any other contraindication to 5-MeO-DMT. 8. Any current or past clinically significant medical condition that would cause the investigator to determine that the patient is unsuitable for the study (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of pregnancy-induced hypertension during pregnancy or after delivery (e.g., gestational hypertension, preeclampsia, superimposed preeclampsia), uncontrolled diabetes mellitus, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head trauma with loss of consciousness)). 9. The patient is receiving any medication or other substance that would cause the investigator to determine that the patient is unsuitable for the study. 10. Has clinically significant abnormalities in physical exam, vital signs, ECG, or clinical laboratory parameters that would cause the study physician to consider the patient unsuitable for the study. 11. Patients who have a positive pregnancy test at screening or the day before the study (day -1) are pregnant or intend to become pregnant during the study and up to 90 days after 5-MeO-DMT administration. 12. Patients with a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0480] The primary objective of this 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 of 5-MeO-DMT in adult female patients with PPD.

[0481] 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.

[0482] The exploratory objective is to determine the amount of 5-MeO-DMT and metabolites (bufotenin and 5-methoxyindole-3-acetic acid (5-MIAA)) in breast milk, blood and urine by LC / MS / MS measurement 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).

[0483] The primary endpoint of this study was the antidepressant effect of 5-MeO-DMT as measured by the change from baseline in the MADRS assessed at day 7.

[0484] Secondary endpoints include the antidepressant effects of 5-MeO-DMT, as assessed by: The antidepressant effects of 5-MeO-DMT are assessed by: 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 dose of study drug on Day 0 and on Day 1, The proportion of responders (≥ 50% reduction from baseline in MADRS total score) 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Change from baseline in the Clinical Global Impression-Severity scale (CGI-S) 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 testing (day -1), 1 hour after the last study medication dose, at discharge, in the evening on day 0, and on days 1 and 7; • 5-MeO-DMT and bufotenine exposure in blood obtained the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, and on days 1 and 7; Safety and tolerability of 5-MeO-DMT assessed by: o Reporting of treatment-emergent adverse events (TEAEs); Clinically significant changes from baseline in ECG, vital signs, non-clinical safety tests, and peak expiratory flow measurements. o Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after administration of each study drug) and as part of the discharge assessment on Day 0; Change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS), assessed on day 0 and as part of the discharge evaluation on days 1 and 7; Change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed on day 0 and as part of the discharge evaluation on days 1 and 7; o Change from baseline in C-SSRS assessed on day 0 and as part of the discharge assessment on days 1 and 7; Change from baseline in the YMRS assessed on day 0 and as part of the discharge assessment on days 1 and 7; • The PsE experienced by the patient, reported 30–60 minutes after each dose, at the time when the PsE subsided; PsE assessment using the Peak Experience (PE) scale to assess the achievement of Peak Experiences (PE scale total score ≥ 75); Challenging Experience Questionnaire (CEQ), Mystical Experience Questionnaire (MEQ-30); • Duration of PsE, defined as the time from administration of study drug to the point at which PsE subsided (as scored by the study physician and patient) (ending 30–60 min after each administration).

[0485] So far, one patient with postpartum depression diagnosed by a psychiatrist has been enrolled in 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 up to the first 4 weeks after delivery. The patient was diagnosed with postpartum depression after the delivery of 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.

[0486] result Except for a transient, clinically non-relevant increase in heart rate and blood pressure immediately following administration of 5-MeO-DMT, no other significant changes in vital parameters occurred. Evaluation of the ECG (3 hours after administration) and safety non-clinical laboratory tests (7 days), CADSS (3 hours, 1 day, and 7 days) were unremarkable. The few adverse events reported (crampy left abdominal pain and headache, both on day 0) were mild, short in duration, and resolved spontaneously by the end of the study.

[0487] 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. A PES score of 85.7 was achieved at this dose, ≥75, indicating that the patient experienced a hallucinatory peak experience and completed the IDR.

[0488] Importantly, 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 this improvement was maintained 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 13-1] [Table 13-2]

[0489] In particular, significant improvements were observed on several MADRS items, which are outlined in Table 9. Patients' baseline scores reflected the absence of symptoms on some items (loss of appetite, difficulty concentrating, suicidal thoughts), whereas scores reflecting severe symptoms (e.g., decreased sleep, inner tension) showed marked improvement.

[0490] Similarly, improvements were seen in several BPRS items, including hypochondriasis, anxiety, emotional withdrawal, guilt and tension.

[0491] Furthermore, improvement in maternal function was evidenced by 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).

[0492] Several functional domains of maternal functioning were also assessed, as defined by Barkin et al. The improvements in each functional domain are outlined in more detail in Table 11.

[0493] Here, significant improvements in self-care, mental well-being and management were achieved, with improvement rates ranging from 18% (management) to 44% (self-care). These improvements strengthen the relationship between improvement in depressive items assessed by the MADRS and improvement in maternal functioning.

[0494] Note that the patients' scores were already relatively high before treatment: in some functional areas the scores were at or near the maximum (see Table 11), so the extent of improvement with therapy was limited. [Table 14-1] [Table 14-2] [Table 15]

[0495] Summary and Conclusion A. An individualized dosing regimen of 6 mg 5-MeO-DMT followed by 12 mg 5-MeO-DMT administered by inhalation was well tolerated and induced surprising and highly significant clinical responses in patients formally diagnosed with postpartum depression. B. This clinical response occurs rapidly, within 2 hours of 5-MeO-DMT administration. Such rapid onset is rare and not seen with traditional classes of antidepressants, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRls), and serotonin-norepinephrine reuptake inhibitors (SNRls), which generally take 4-6 weeks to be effective. C. Patients experienced clinical remission within 2 hours of 5-MeO-DMT administration according to the IDR, which is vastly superior to any other approved treatment for postpartum depression and to all hallucinogens tested to date. D. Significant clinical responses were sustained over a 7-day follow-up period, although 5-MeO-DMT was only administered once and is no longer effectively present in the body during this time frame (see pharmacokinetic data in Example 6 above). This observation supports the excellent clinical profile of 5-MeO-DMT and allows for convenient dosing intervals. E. In addition to the antidepressant effects, 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. F. In addition to the antidepressant effect, endpoints assessing maternal functioning, such as self-care, emotional well-being and control, as assessed using the BIMF, were positively affected, supporting the additional benefit of 5-MeO-DMT for patients suffering from PPD, as well as the improvement of core depressive symptoms.

[0496] 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 pharmacotherapies for postpartum depression and all hallucinogens tested to date.

[0497] Combined with the short duration of acute hallucinogenic effects and a favorable safety profile, these data indicate that the present invention solves the technical problem of providing improved psychotropic therapy in patients with postpartum depression.

[0498] Example 13 - Clinical trial of 5-MeO-DMT administered by intravenous injection to patients with postpartum depression - a prophetic example The clinical trial will involve adult female patients who have been clinically diagnosed with postpartum depression (PPD).

[0499] Patients receive a daily individualized 5-MeO-DMT dosing regimen via intravenous injection. 5-MeO-DMT is provided in the form of its hydrobromide salt and a formulation for intravenous injection. It is understood that the dosages of 5-MeO-DMT referred to below relate to the weight amount of the free base, and dosages of the hydrobromide salt of 5-MeO-DMT can be calculated assuming that equimolar amounts are used.

[0500] More specifically, patients will receive up to three doses of 5-MeO-DMT on day 0 (2 mg, 5 mg, and 8 mg). 1. All patients will receive an initial dose of 2 mg of 5-MeO-DMT. 2. The second dose (5 mg) is administered only if: a. Failure to achieve a peak experience (total score ≥ 75) after 2 mg administration; and b. If the 2 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 outside the normal range but not considered clinically significant by the investigator. 3. Similarly, the third dose (8 mg) is administered only if: a. Failure to achieve a peak experience (total score ≥ 75) after administration of 5 mg; and b. If the 5 mg dose is deemed safe and well tolerated by the investigator, 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 outside the normal range but not considered clinically significant by the investigator.

[0501] Patients will be assessed post-injection for hallucinatory peak experiences (based on a patient-rated visual analog scale, the PE scale), sedation, and other endpoints. Follow-up visits will be scheduled 1 and 7 days after the date of injecting.

[0502] 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) of 18.5 to 35 kg / m at screening 2 (inclusive). 3. Meets the study criteria for PPD as assessed by a study psychiatrist or registered psychologist: A diagnosis of major depressive disorder without psychotic features as confirmed by the Mini-Institutional Mental Health Interview (MINI) with perinatal onset occurring after conception and up to the first 4 weeks after delivery. b. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 28 at screening and pre-dose on Day 0. 6. Must have discontinued breastfeeding at the time of screening, or if still lactating or actively breastfeeding at screening, agree to temporarily discontinue breastfeeding from just before study drug administration on Day 0 through 24 hours after the last dose, expressing and discarding all breast milk as needed during that 24 hour period, but which must incorporate expression / discarding at 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding. 4. Must agree to complete abstinence (complete avoidance of heterosexual intercourse) or use a highly effective (failure rate <1%) medically acceptable method of contraception for 30 days prior to and 90 days after 5-MeO-DMT administration. Patients must have a negative pregnancy test at screening and the day prior to testing (day -1). 5. Willing to postpone initiation of other antidepressant or anxiety medication until after the end of the study on Day 7 and agree to keep any psychotherapy unchanged during the study.

[0503] Candidate patients who meet any of the following major exclusion criteria will be excluded from participating in the study: 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past bipolar disorder, manic or hypomanic episodes, 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 comorbid psychiatric illness that would cause the investigator to determine that the patient is unsuitable 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, in the judgment of a clinical psychiatrist or registered 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. Taking an antidepressant within 14 days or 5 half-lives (whichever is longer) prior to treatment (exception: within the past 5 weeks for fluoxetine). 5.Having taken any other drug with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Previously experienced significant adverse reactions to hallucinogenic or hallucinogenic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) as determined by the investigator. 7. Have a known allergy or hypersensitivity or any other contraindication to 5-MeO-DMT. 8. Any current or past clinically significant medical condition that would cause the investigator to determine that the patient is unsuitable for the study (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of pregnancy-induced hypertension during pregnancy or after delivery (e.g., gestational hypertension, preeclampsia, superimposed preeclampsia), uncontrolled diabetes mellitus, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head trauma with loss of consciousness)). 9. The patient is receiving any medication or other substance that would cause the investigator to determine that the patient is unsuitable for the study. 10. Has clinically significant abnormalities in physical exam, vital signs, ECG, or clinical laboratory parameters that would cause the study physician to consider the patient unsuitable for the study. 11. Patients who have a positive pregnancy test at screening or the day before the study (day -1) are pregnant or intend to become pregnant during the study and up to 90 days after 5-MeO-DMT administration. 12. Patients with a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0504] The primary objective of this study was to determine the onset and 7-day durability of antidepressant effect of daily individualized dosing regimens of 2 mg, 5 mg, and 8 mg of 5-MeO-DMT in adult female patients with PPD.

[0505] 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 2 mg, 5 mg, and 8 mg 5-MeO-DMT in adult female patients with PPD.

[0506] The exploratory objective is to determine the amount of 5-MeO-DMT and metabolites (bufotenin and 5-methoxyindole-3-acetic acid (5-MIAA)) in breast milk, blood and urine by LC / MS / MS measurement after daily IDR doses of 2 mg, 5 mg and 8 mg of 5-MeO-DMT in adult female patients with PPD (metabolite identity screening may be performed if necessary).

[0507] The primary endpoint of this study was the antidepressant effect of 5-MeO-DMT as measured by the change from baseline in the MADRS assessed at day 7.

[0508] Secondary endpoints include the antidepressant effects of 5-MeO-DMT, as assessed by: The antidepressant effects of 5-MeO-DMT are assessed by: 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 dose of study drug on Day 0 and on Day 1, The proportion of responders (≥ 50% reduction from baseline in MADRS total score) 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Change from baseline in the Clinical Global Impression-Severity scale (CGI-S) 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 testing (day -1), 1 hour after the last study medication dose, at discharge, in the evening on day 0, and on days 1 and 7; • 5-MeO-DMT and bufotenine exposure in blood obtained the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, and on days 1 and 7; Safety and tolerability of 5-MeO-DMT assessed by: o Reporting of treatment-emergent adverse events (TEAEs); Clinically significant changes from baseline in ECG, vital signs, non-clinical safety tests, and peak expiratory flow measurements; Assessment of sedation (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after each study drug dose) and as part of the Day 0 discharge assessment; Change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS) assessed as part of the discharge evaluation on days 0, 1, and 7; Change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed on day 0 and as part of the discharge evaluation on days 1 and 7; o Change from baseline in C-SSRS assessed on day 0 and as part of the discharge assessment on days 1 and 7; Change from baseline in the YMRS assessed on day 0 and as part of the discharge assessment on days 1 and 7; • The PsE experienced by the patient, reported 30–60 minutes after each dose, at the time when the PsE subsided; PsE assessment using the Peak Experience (PE) scale to assess the achievement of Peak Experiences (PE scale total score ≥ 75); Challenging Experience Questionnaire (CEQ); Mystical Experience Questionnaire (MEQ-30); • Duration of PsE, defined as the time from administration of study drug to the point at which PsE subsided (as scored by the study physician and patient) (ending 30–60 min after each administration).

[0509] Example 14 - Clinical trial of 5-MeO-DMT administered by intravenous injection to patients with postpartum depression - a prophetic example The clinical trial will involve adult female patients who have been clinically diagnosed with postpartum depression (PPD).

[0510] Patients receive a daily individualized 5-MeO-DMT dosing regimen via intravenous injection. 5-MeO-DMT is provided in the form of its hydrobromide salt and a formulation for intravenous injection. It is understood that the dosages of 5-MeO-DMT referred to below relate to the weight amount of the free base, and dosages of the hydrobromide salt of 5-MeO-DMT can be calculated assuming that equimolar amounts are used.

[0511] More specifically, patients will receive up to three doses of 5-MeO-DMT on day 0 (1 mg, 2 mg, and 3 mg). 1. All patients will receive an initial dose of 1 mg 5-MeO-DMT. 2. The second dose (2 mg) is administered only if: a. No peak experience (total score ≥ 75) was achieved after administration of 1 mg; and b. If the 1 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 outside the normal range but not considered clinically significant by the investigator. 3. Similarly, a third dose (3 mg) is administered only if: a. Failure to achieve a peak experience (total score ≥ 75) after 2 mg administration; and b. If the 2 mg dose is deemed safe and well tolerated by the investigator, 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 outside the normal range but not considered clinically significant by the investigator.

[0512] Patients will be assessed post-injection for hallucinatory peak experiences (based on a patient-rated visual analog scale, the PE scale), sedation, and other endpoints. Follow-up visits will be scheduled 1 and 7 days after the date of injecting.

[0513] 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) of 18.5 to 35 kg / m at screening 2 (inclusive). 3. Meets the study criteria for PPD as assessed by a study psychiatrist or registered psychologist: A diagnosis of major depressive disorder without psychotic features as confirmed by the Mini-Institutional Mental Health Interview (MINI) with perinatal onset occurring after conception and up to the first 4 weeks after delivery. b. Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 28 at screening and pre-dose on Day 0. 6. Must have discontinued breastfeeding at the time of screening, or if still lactating or actively breastfeeding at screening, agree to temporarily discontinue breastfeeding from just before study drug administration on Day 0 through 24 hours after the last dose, expressing and discarding all breast milk as needed during that 24 hour period, but which must incorporate expression / discarding at 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding. 4. Must agree to complete abstinence (complete avoidance of heterosexual intercourse) or use a highly effective (failure rate <1%) medically acceptable method of contraception for 30 days prior to and 90 days after 5-MeO-DMT administration. Patients must have a negative pregnancy test at screening and the day prior to testing (day -1). 5. Willing to postpone initiation of other antidepressant or anxiety medication until 7 days after the end of the study and agree to keep any psychotherapy unchanged during the study.

[0514] Candidate patients who meet any of the following major exclusion criteria will be excluded from participating in the study: 1. Based on medical history, psychiatric evaluation, and MINI assessment, current or past bipolar disorder, manic or hypomanic episodes, 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 comorbid psychiatric illness that would cause the investigator to determine that the patient is unsuitable 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, in the judgment of a clinical psychiatrist or registered 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. Taking an antidepressant within 14 days or 5 half-lives (whichever is longer) prior to treatment (exception: within the past 5 weeks for fluoxetine). 5.Having taken any other drug with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Previously experienced significant adverse reactions to hallucinogenic or hallucinogenic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) as determined by the investigator. 7. Have a known allergy or hypersensitivity or any other contraindication to 5-MeO-DMT. 8. Any current or past clinically significant medical condition that would cause the investigator to determine that the patient is unsuitable for the study (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of pregnancy-induced hypertension during pregnancy or after delivery (e.g., gestational hypertension, preeclampsia, superimposed preeclampsia), uncontrolled diabetes mellitus, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, neurodegenerative disease, meningitis, encephalitis, and head trauma with loss of consciousness)). 9. The patient is receiving any medication or other substance that would cause the investigator to determine that the patient is unsuitable for the study. 10. Has clinically significant abnormalities in physical exam, vital signs, ECG, or clinical laboratory parameters that would cause the study physician to consider the patient unsuitable for the study. 11. Patients who have a positive pregnancy test at screening or the day before the study (day -1) are pregnant or intend to become pregnant during the study and up to 90 days after 5-MeO-DMT administration. 12. Patients with a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0515] The primary objective of this study is to determine the onset and 7-day durability of antidepressant effect of daily individualized dosing regimens of 1 mg, 2 mg, and 3 mg of 5-MeO-DMT in adult, female patients (those with PPD).

[0516] 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 1 mg, 2 mg, and 3 mg 5-MeO-DMT in adult female patients with PPD.

[0517] The exploratory objective is to determine the amount of 5-MeO-DMT and metabolites (bufotenin and 5-methoxyindole-3-acetic acid (5-MIAA)) in breast milk, blood and urine by LC / MS / MS measurement after daily IDR doses of 1 mg, 2 mg and 3 mg of 5-MeO-DMT in adult female patients with PPD (metabolite identity screening may be performed if necessary).

[0518] The primary endpoint of this study was the antidepressant effect of 5-MeO-DMT as measured by the change from baseline in the MADRS assessed at day 7.

[0519] Secondary endpoints include the antidepressant effects of 5-MeO-DMT, as assessed by: The antidepressant effects of 5-MeO-DMT are assessed by: 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 dose of study drug on Day 0 and on Day 1; Proportion of responders (≥ 50% reduction from baseline in MADRS total score) 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; Change from baseline in the Clinical Global Impression-Severity scale (CGI-S) 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 testing (day -1), 1 hour after the last study medication dose, at discharge, in the evening on day 0, and on days 1 and 7; • 5-MeO-DMT and bufotenine exposure in blood obtained the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, and on days 1 and 7; Safety and tolerability of 5-MeO-DMT assessed by: o Reporting of treatment-emergent adverse events (TEAEs); Clinically significant changes from baseline in ECG, vital signs, non-clinical safety tests, and peak expiratory flow measurements. Sedation assessment (Modified Observer's Assessment of Alertness and Sedation scale [MOAA / S]) after each dose (when PsE subsided and 60 minutes after administration of each study drug) and as part of the discharge assessment on Day 0; Change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS), assessed on day 0 and as part of the discharge evaluation on days 1 and 7; Change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed on day 0 and as part of the discharge evaluation on days 1 and 7; o Change from baseline in C-SSRS assessed on day 0 and as part of the discharge assessment on days 1 and 7; Change from baseline in the YMRS assessed on day 0 and as part of the discharge assessment on days 1 and 7; • The PsE experienced by the patient, reported 30–60 minutes after each dose, at the time when the PsE subsided; PsE assessment using the Peak Experience (PE) scale to assess the achievement of Peak Experiences (PE scale total score ≥ 75); Challenging Experience Questionnaire (CEQ); Mystical Experience Questionnaire (MEQ-30); • Duration of PsE, defined as the time from administration of study drug to the point at which PsE subsided (as scored by the study physician and patient) (ending 30–60 min after each administration).

Claims

1. A pharmaceutical composition for treating postpartum depression (PPD) in a patient, comprising 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via an intravenous, intramuscular, or subcutaneous route.

2. The pharmaceutical composition according to claim 1, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher prior to treatment.

3. The pharmaceutical composition according to claim 1, wherein the patient has a MADRS score of 28 or higher or a HAM-D score of 22 or higher before treatment.

4. The pharmaceutical composition according to claim 1, wherein the patient has a MADRS score of 35 or higher or a HAM-D score of 27 or higher before treatment.

5. The pharmaceutical composition according to claim 1, wherein the postpartum depression is treatment-resistant postpartum depression.

6. The pharmaceutical composition according to claim 1, wherein the patient further suffers from suicidal thoughts.

7. The patient suffers from further slightly impaired, impaired, or severely impaired maternal function, and the patient has a Birkin Index (BIMF) score for maternal function of 95 or less prior to treatment, such as 80 or less prior to treatment, particularly 65 or less prior to treatment. The pharmaceutical composition according to claim 1.

8. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in a first dose for a first administration, and the 5-MeO-DMT or a salt thereof is administered in 0 to 6 subsequent administrations.

9. The pharmaceutical composition according to claim 8, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in 1 to 6 doses within 24 hours.

10. The pharmaceutical composition according to claim 8, wherein each subsequent dose after the first dose is administered in a larger dose than the previous dose.

11. The pharmaceutical composition according to claim 8, wherein the patient receives subsequent doses unless he experiences a hallucinatory peak experience.

12. The pharmaceutical composition according to claim 1, wherein the interval between two administrations is 1 hour or more and 24 hours or less, approximately 1 to 4 hours, preferably approximately 1 to 2 hours.

13. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered to the patient in a dose or administration regimen that causes the patient to experience a hallucinogenic peak experience, and the occurrence of the hallucinogenic peak experience is identified by achieving at least 60% of the maximum possible score on each of the 30-item revised Mystical Experience Questionnaire (MEQ30) subscales for mystical, positive mood, transcendence of time and space, and inexpressibility, or by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least 60% of the maximum possible score on the Peak Experience Scale (PES) Total The pharmaceutical composition according to claim 1, identified by achieving at least 75 in Score.

14. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by intravenous injection.

15. The pharmaceutical composition according to claim 1, wherein a clinical response, assessed by at least a 50% improvement in the MADRS or HAM-D score compared to the respective scores before treatment, is observed approximately two hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to claim 1, wherein a clinical response, assessed by at least a 50% improvement in the MADRS or HAM-D score compared to the respective scores before treatment, is observed at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 1, wherein the treatment improves maternal function.

18. The pharmaceutical composition according to claim 17, wherein the improvement relates to one or more functional areas of maternal function selected from self-care, infant care, mother-child communication, maternal mental health, social support, management, and coordination, as measured by the Birkin Index (BIMF).

19. The pharmaceutical composition according to claim 17, wherein the improvement relates to BIMF, and the total BIMF score is improved by 10% or more, preferably by 20% or more.

20. The pharmaceutical composition according to claim 1, wherein the treatment results in improvement of at least one of the following: sleep disorders, psychomotor developmental delay, pessimistic thinking, anxiety, cognitive impairment, and social / emotional withdrawal.