5-MeO-DMT for use in the treatment of postnatal 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).

Description

[Technical field]

[0001] The present invention is directed to an improved method for treating 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 pharma- ceutically acceptable salt thereof. The present invention also allows for the treatment of PPD in breastfeeding mothers without substantially interrupting breastfeeding. [Background technology]

[0002] Over 50% of women may experience a short-lived low mood or tearfulness after giving birth, however a subset of women may develop PPD (debilitating mood disorder) during pregnancy or within four 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 negative consequences for the affected mother, her infant(s), and her family. For example, a woman with PPD may contemplate self-harming or harming her child and is at high risk for suicide. PPD can also lead to breakdowns in the interaction between mother and child, as indicated, for example, by higher rates of disinterested behavior and lower rates of visual and vocal communication between mother and child. Evidence also suggests an association between PPD and child development, as exemplified by the fact that children of patients with PPD are at higher risk for impaired cognitive development.

[0005] More than 20% of women diagnosed with PPD remain depressed after 12 months of follow-up, and 13% continue to suffer from PPD two years after diagnosis. Furthermore, evidence suggests that 40% of women will relapse, and that depressive episodes may return if PPD is untreated.

[0006] It is therefore clear that the affliction 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. In general, known medications for depression have only limited success in treating patients, especially those whose disease symptoms are not merely mild. In the case of PPD, a compounding factor is that patients often intend to breastfeed. For many medications, lactating women are advised to stop breastfeeding while taking the medication and for a period afterwards, since the medication may be excreted in milk and may put nursing children at risk.

[0008] Moreover, studies have shown that breastfeeding mothers may be reluctant to initiate pharmacological treatment due to a variety of concerns.

[0009] As a result, breastfeeding women with PPD may be faced with the decision of whether to discontinue breastfeeding or to discontinue / withhold treatment.

[0010] Currently, PPD is primarily treated with psychotherapy or pharmacotherapy. National Institute for Health and Care Excellence (NICE) guidelines recommend that the high threshold for pharmacological interventions be discussed with the patient prior to initiating treatment. Such medications may consist of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), some of which are not contraindicated during breastfeeding.

[0011] More recently, brexanolone (Zulresso) received FDA approval in the United States, thus making it the first pharmacotherapy indicated for PPD. Brexanolone is a positive allosteric modulator of the GABAa receptor, 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, while the other failed to show efficacy beyond 7 days. However, brexanolone requires hospitalization for the 60-hour infusion and produces significant side effects.

[0012] It is also worth noting that patients are required to discontinue breastfeeding during the infusion of brexanolone, and as a result of the approval of brexanolone, some insurance companies are now requiring patients scheduled for the procedure to adhere to this standard.

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

[0014] Although there has been considerable recent interest in hallucinogens in the treatment of psychiatric disorders, so far no hallucinogens have been used to treat PPD, due to the general lack of relevant clinical data from which conclusions could be drawn about their clinical usefulness in PPD, but also due to the specific concern that administration of hallucinogens may not be appropriate for breastfeeding mothers.

[0015] Hallucinogens, including hallucinogens, are chemical compounds, some of natural origin and some synthetic, which are defined by their ability to induce perceptual distortions (such as altered hearing and vision) as well as mood and cognitive distortions in humans after ingestion. The term hallucinogen encompasses a fairly broad group of psychoactive molecules with different modes of action. It has been suggested that several psychiatric disorders could in principle be amenable to treatment by psychoactive molecules such as hallucinogens.

[0016] However, psychedelic drugs have not 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). WO 2020 / 169850 reports clinical trials on patients suffering from treatment-resistant depression (TRD) (i.e., a form of major depressive disorder) along with studies in healthy subjects. 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 therapy which is more effective (i.e., a) has a greater percentage of patients experiencing a clinical response, b) has a greater mean clinical response, c) has a more rapid onset of clinical response, and / or d) has a more durable clinical response) than the previously described therapies.

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

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

[0021] It is a further object of the present invention to provide a treatment for a breastfeeding mother who has been diagnosed with PPD or another psychiatric disorder, which will enable the mother to continue breastfeeding without significant interference from 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). The therapeutic agent not only improves depressive symptoms but also improves the maternal role.

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

[0024] definition As used in the context of the present invention, unless otherwise specified, the term "5-MeO-DMT" refers to 5-MeO-DMT free base. It is considered 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. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered may be calculated from the weight of the free base, assuming that an equimolar amount is used.

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

[0026] The patient may suffer from a treatment-resistant disease.As used herein, "treatment-resistant" means that the patient does not show sufficient improvement after at least two appropriate treatment courses.In particular, the patient does not show sufficient improvement after at least two appropriate treatment courses, where at least one of the two courses is drug therapy.For example, the patient does not show sufficient improvement after at least two appropriate drug therapy courses.

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

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

[0029] As used in the context of the present invention, and unless otherwise indicated, the term "therapeutically effective amount" is intended to mean that amount of an active compound or pharmaceutical ingredient that elicits the biological or clinical response in humans that is desired by a researcher, physician or other clinician, which biological or clinical response in humans includes alleviation of the signs and / or symptoms of the disease, condition or disorder being treated.

[0030] "Clinical response" includes, but is not limited to, improvements on rating scales such as Clinical Global Impression-Severity (CGI-S), Patient Global Impression-Severity (PGI-S), Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I), and also includes improvements on endpoints such as, but not limited to, 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 Clinical Diagnostic Dissociative Scale (CADSS), Brief Psychotic Symptom Rating Scale (BPRS) and the Columbia Suicide Severity Rating Scale (C-SSRS).

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

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

[0033] If clinical response is assessed at an earlier time point after drug administration (e.g., 2 hours) based on endpoints that have been developed with a longer recall period (e.g., typically 7 days for the MADRS), such endpoints can be reasonably modified (e.g., the recall period for the MADRS is changed to 2 hours and sleep items recorded at baseline before drug administration are carried forward).

[0034] At early time points the considerations outlined apply, on the one hand because the influence of the patient's condition before treatment on any scores recorded after treatment to assess the clinical response should be kept as low as possible, and on the other hand because sleep items cannot be assessed 2 hours after administration of the drug.

[0035] At later time points (e.g., day 1 or later), all items on the relevant scales for assessing clinical response can usually be assessed, with recall periods adapted as necessary so that any pretreatment scores do not need to be carried forward. For example, if BIMF is assessed on day 7, a 7-day recall period would be used (instead of the standard 2-week recall period).

[0036] As used in the context of the present invention, unless otherwise specified, the term "administration" (or "application") is intended to mean the introduction of a possible amount of an active compound or pharmaceutical ingredient into a patient by any route. Preferably, the active compound is administered by nasal inhalation, by buccal administration or by sublingual administration.

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

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

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

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

[0041] Postpartum depression Postpartum depression (PPD) is a complex mix of physical, emotional, and behavioral changes that occur in some women after giving birth. PPD is also known as major depressive disorder that occurs around the time of delivery. According to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), PPD is diagnosed when symptoms of major depressive disorder (MDD) begin during pregnancy or within 4 weeks after delivery.

[0042] Patients treated according to the present invention are preferably women who have been diagnosed with PPD and are >4 weeks postpartum. More preferably, the patient will be <9 months postpartum.

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

[0044] The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, SA, & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p. 382). It was designed as an adjunct to the Hamilton Depression Rating Scale (HAM-D) to make it more sensitive to changes brought about by antidepressants and other forms of medication. 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, inhibitions, inability to feel, pessimistic thoughts, and suicidal thoughts, and each item is given a score of 0 to 6. The total score ranges from 0 to 60.

[0045] Patients may have moderate or severe PPD if they score 20 or above on the Montgomery-Asberg Depression Rating Scale (MADRS) or 16 or above on the Hamilton Depression Rating Scale (HAM-D). Patients may have severe PPD if they score 35 or above on the Montgomery-Asberg Depression Rating Scale (MADRS) or 27 or above on the Hamilton Depression Rating Scale (HAM-D). Patients may be diagnosed with treatment-resistant PPD.

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

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

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

[0049] In addition to the above, the inventors believe that PPD threatens the maternal role, especially during the first year after birth, which is a critical period for both mother and baby, as in most cases the mother is the primary caregiver and therefore responsible for the majority of the tasks related to the care of the infant.

[0050] The maternal role includes aspects of the mother's self-care as well as her competence regarding interactions with the infant(s).

[0051] The maternal role, including the emotional aspects of motherhood, is also important for the development of the child. Indeed, the quality of mother-infant interactions during the first year after birth influences infant development. High levels of maternal role performance may correlate with positive infant developmental outcomes. Similarly, role failure during the postpartum period may impede optimal infant development.

[0052] The Barkin Index of Maternal Functioning (BIMF) was designed to measure role functioning during the first year after childbirth. The BIMF is a 20-item self-report measure of role functioning. Each item is assigned a score from 0 to 6, resulting in a maximum total score of 120. Higher scores indicate better maternal role performance.

[0053] The BIMF identifies the main role areas of the mother in the postnatal period as self-care, care of the infant, mother-infant interaction, maternal psychological well-being, social support, control, and adaptation.

[0054] A BIMF score of 95 or less is considered herein as a slight impairment of the maternal role, a score of 80 or less is considered herein as a severe impairment of the maternal role, and a score of 65 or less is considered herein as a severe impairment of the maternal role. The invention makes it possible in particular to improve the maternal role in patients with a pre-treatment score of 80 or less, and even in patients with a score of 65 or less.

[0055] Active Agent The above discussion indicates that PPD is characterized by several aspects, and as such, poses a significant disease burden and is amenable to appropriate treatment. Thus, not only is there a need for treatment (particularly treatment by pharmacological intervention) to improve overall disease scores, but there is also a need for treatment to improve specific aspects of the disease.

[0056] The inventors reasoned that carefully selected hallucinogens might improve the treatment of important aspects of PPD, improving the illness and maternal role overall.

[0057] Furthermore, the inventors believed that when treating breastfeeding mothers suffering from PPD, a carefully selected hallucinogen may enable breastfeeding to continue substantially uninterrupted.

[0058] One group of hallucinogens includes compounds that bind to 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 called "hallucinogens" and highlight their primary ability to induce qualitatively altered states of consciousness (e.g., euphoria, trance states, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences), but with minimal other effects such as sedation, narcosis, or hyperstimulation.

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

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

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

[0062] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11):1508-9) reported on a patient who had a manic episode after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication that then disappeared, but a typical manic episode of psychotic magnitude continued for 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 self-reported manic episode after ingesting 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 ayahuasca consumption in a man with bipolar disorder.

[0063] Further case reports can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N,N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0064] 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 must be appropriately selected and is preferably administered in a specific dosing regimen.

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

[0066] 5-MeO-DMT is a potent, fast-acting, naturally occurring 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 hallucinogens.

[0067] As described in further detail in the Examples section below, the inhibition constants (K ) of psilocin (the dephosphorylated form of psilocybin that is formed after psilocybin uptake), DMT, and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of postmortem human brains were i The inhibition constants (K values) of psilocin, DMT and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of postmortem human brains are 48, 38 and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity, whereas psilocin and DMT exhibit intermediate affinity, for the 5-HT1A receptor. iThe affinity (p < 0.05) for the 5-HT2A receptor is 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.

[0068] Compared to the other psychoactive compounds mentioned above, 5-MeO-DMT has an increased affinity for the 5-HT1A receptor and acts as a strong agonist. As for psilocin and DMT, the contribution to 5-HT2A binding is increased compared to 5-MeO-DMT, and the latter of the three compounds has the largest difference between its affinity for 5-HT2A and 5-HT1A. Thus, 5-HT1A binding plays a much larger role in the overall effect of 5-MeO-DMT compared to the other two compounds.

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

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

[0071] It should also be noted that reports of treatment-emergent 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.

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

[0073] Furthermore, antidepressants have been reported to induce isolated hypomanic events 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.

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

[0075] Furthermore, 5-MeO-DMT is a 5-HT7 receptor agonist and exhibits high affinity for the receptor. 3H]LSD, and serotonin were used to estimate nonspecific binding, and K i was determined to be 2.3 nM.

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

[0077] 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.

[0078] 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.

[0079] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination can lead to disease states, 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.

[0080] The expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to its function in regulating the sleep / wake cycle, and the inventors believe that this makes it possible to treat patients suffering from sleep disorders with 5-MeO-DMT, which acts on this receptor.

[0081] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7 receptor, as one mediator of the pharmacological effects of 5-MeO-DMT 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.

[0082] 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, negative thinking or social / emotional withdrawal, which is supported by the clinical results demonstrated in the studies referred to herein.

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

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

[0085] 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.

[0086] 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 was observed with repeated dosing within a 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.

[0087] The inventors further found that 5-MeO-DMT exhibits various properties that make it attractive as a treatment for PPD. In contrast to SSRIs, 5-MeO-DMT is a fast-acting drug (in the 5-MeO-DMT-TRD study, 5 / 8 patients with TRD achieved remission within 2 hours of administration, 8 / 8 patients achieved remission on day 1, and 7 / 8 patients maintained their remission on day 7). The use of 5-MeO-DMT to treat PPD patients may not only rapidly improve depressive symptoms, but also rapidly improve maternal role. Furthermore, 5-MeO-DMT is administered in a single treatment session (with rare optional re-administration). This makes 5-MeO-DMT different from SSRIs, which require a long daily dosing schedule associated with low compliance, and brexanolone, which requires long infusions and hospitalization.

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

[0089] Furthermore, the present inventors have found that treating PPD with 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof, allows breastfeeding to be continued with only a short interruption for treatment.

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

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

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

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

[0094] Examples of deuterated forms of 5-MeO-DMT include, but are not limited to, 1-deuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethanamine.

[0095] Further examples include 5-MeO-DMT forms in which deuterium is introduced into one or more hydrogen positions of the N-linked methyl group.Even more examples include 5-MeO-DMT forms 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.

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

[0097] In accordance with the present invention, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, 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.

[0098] 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.

[0099] 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, the reference may be substituted with a 5-MeO-DMT prodrug or a salt thereof.

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

[0101] 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.

[0102] 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.

[0103] The prodrugs (particularly those of the above structure) may also be used in the form of pharma- ceutically acceptable salts.

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

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

[0106] 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.

[0107] Further in accordance with the present invention, prodrugs of 5-MeO-DMT and salts of prodrugs of 5-MeO-DMT are used in amounts equimolar to the amounts of the corresponding non-prodrug forms.

[0108] Treatment mode As already indicated above, the present invention makes it possible to treat patients suffering from PPD, which not only reduces the scores assessing the severity of depression, but also improves the maternal role, as will be explained in more detail below.

[0109] 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 disorders and noted certain improvements in disease aspects also commonly seen in patients with PPD. In particular, the inventors noted improvements in various symptoms and combinations of symptoms that the inventors determined were also related to the maternal role.

[0110] The data are from a recently completed clinical trial investigating the use of 5-MeO-DMT in the treatment of patients diagnosed with treatment-resistant depression (TRD, see also the Examples section below. Although the completed trial did not include patients with PPD, as described in more detail below, the inventors have determined that certain clinical findings from the trial are relevant to the design of a therapeutic agent for PPD.

[0111] In the clinical trial, 5-MeO-DMT was administered by inhalation (described in more detail in the Examples section below). Patients were assigned to different groups. Of interest in the context of the present invention are those that received a single dose of 12 mg and those that received an intraday individualized dosing schedule (IDR), which allows for multiple ascending doses (6 mg, 12 mg and 18 mg) over the course of a day driven by the intensity of the patient-reported hallucinatory experience.

[0112] 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, the inventors focused on the items that make up the various scales and found that some sub-score items were particularly relevant to PPD patients and related to the maternal role.

[0113] Multiple patients within the pooled cohort showed significant improvement in one or more of these subscores, confirming our findings that 5-MeO-DMT is a suitable compound for treating PPD patients and improving their maternal role.

[0114] The specific subscore items for each scale are identified in more detail below. The inventors conclude that efficacy in treating one or more of these symptoms would significantly improve overall outcome in PPD patients treated with 5-MeO-DMT.

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

[0116] 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).

[0117] 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).

[0118] Clinical response may also be reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a decrease in the CGI-S score means a decrease in the CGI-S score of at least one grade. Preferably, a decrease in the CGI-S score of at least two grades and / or a score of 0. Particularly preferred is a decrease in the CGI-S score of at least three grades and / or a score of 0.

[0119] Furthermore, the inventors believe that improvements observed on specific MADRS items represent improvements in aspects of the maternal role.

[0120] MADRS items of particular relevance are described in more detail below.

[0121] The "inner tension" item of the MADRS refers to mental tension ranging from vague discomfort, irritability, inner confusion, to panic, fear, or distress, and is rated according to its intensity, frequency, duration, and need for reassurance.

[0122] If the patient is calm and there is only momentary inner tension, a score of 0 is assigned. If there is occasional irritability and vague discomfort, a score of 2 is assigned. If there is a constant inner tension or intermittent panic that the patient may have some difficulty overcoming, the score is 4. If there is intense fear or anguish and insurmountable panic, the score is 6.

[0123] The inventors determined that increased scores on the "internal strain" item of the MADRS negatively impact both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). Increased scores on the "internal strain" item of the MADRS impair the mother-infant interaction as well as the maternal psychological well-being as assessed by the BIMF.

[0124] Conversely, improvement on these MADRS items would translate to improvements in maternal role (particularly the BIMF role domains of mother-child interaction and / or maternal psychological well-being).

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

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

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

[0128] Improvement in inner tension is reflected by at least an improvement in the MADRS inner tension item score 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.

[0129] Improvement in inner tension, 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.

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

[0131] 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 by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0132] 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, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0133] The inventors further conclude that the reduction or elimination of inner tension achieved by treating PPD patients not only leads to a decrease in the MADRS total score, but also leads to an improvement in the maternal role as reflected by an increase in the BIMF score. This improvement will be achieved rapidly (i.e., within about 2 hours), and the increase in the BIMF score will also be seen on the 1st day (e.g., about 24 hours), 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

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

[0135] The "inhibition" item on the MADRS refers to difficulty initiating or slowness in initiating and carrying out daily activities.

[0136] A score of 0 means that the patient has almost no difficulty in starting anything and no slowness. If the patient has difficulty initiating activities, a score of 2 is assigned. A score of 4 means that simple activities that the patient normally does are difficult to start and require effort to perform. If the patient is completely inhibited and unable to do anything without assistance, a score of 6 is assigned.

[0137] The inventors have determined that increased scores on the MADRS "restraint" items negatively impact both aspects of the maternal role (the mother's capacity for interaction with the infant(s) as well as the mother's self-care). Increased scores on the MADRS "restraint" items impair infant care, self-care, psychological well-being, control and adjustment.

[0138] Conversely, improvement on this MADRS item would translate to improvement in the maternal role (particularly the BIMF role domains of infant care, self-care, psychological well-being, management and / or adaptation).

[0139] The combined MADRS "inhibition" item score across all eight patients in the study group receiving the individualized dosing regimen had a baseline of 27. 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.

[0140] The combined MADRS "inhibition" item scores across all four patients in the 12 mg group had a baseline of 16. After 2 hours, the score had decreased to 10, corresponding to a 6 point or 38% improvement. On the 1st day after treatment, the score had decreased to 0, corresponding to a 16 point or 100% improvement. On the 7th day after treatment, the score had decreased to 3, corresponding to a 13 point or 81% improvement.

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

[0142] Improved inhibition is reflected by at least an improvement in the MADRS inhibition item score 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.

[0143] Improvement in inhibition, 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.

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

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

[0146] Improved inhibition, 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 scores, 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.

[0147] The inventors further conclude that the reduction or elimination of inhibition achieved by treating a PPD patient will not only lead to a decrease in the MADRS total score, but also to an improvement in maternal role as reflected by an increase in the BIMF score. This improvement will be achieved rapidly (i.e., within about 2 hours), with increases in the BIMF score also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Because inhibition also impacts other aspects of PPD, the inventors conclude that the improvement observed in the "Inhibition" item of the MADRS will further contribute to an overall improvement in maternal role.

[0148] The "inability to feel emotions" item on the MADRS reflects awareness of a diminished interest in the environment or in activities that are usually pleasurable. There is a diminished ability to respond emotionally to situations or people in the environment.

[0149] A score of 0 indicates a normal interest in surroundings and other people, while a score of 2 indicates a diminished ability to enjoy things that one would normally be interested in. A score of 4 is assigned if there is a loss of interest in surroundings and a loss of emotion toward friends and acquaintances. A score of 6 reflects an experience of emotional numbness, an inability to feel anger, deep sadness, or joy, and a complete or distressing inability to care for close relatives and friends.

[0150] The inventors have determined that increased scores on the "unable to have feelings" item of the MADRS negatively impact both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). Increased scores on the "unable to have feelings" item of the MADRS impair mother-infant interaction and psychological well-being.

[0151] Conversely, improvement on these MADRS items would translate to improvements in maternal role (particularly the BIMF role domains of mother-child interaction and / or psychological well-being).

[0152] The combined MADRS "Inability to Have Emotions" item score across all eight patients in the study group receiving the individualized dosing plan had a baseline of 36. After two hours, the score had decreased to 12, corresponding to a 24-point or 67% improvement. One day after treatment, the score had decreased to 2, corresponding to a 34-point or 94% improvement. Seven days after treatment, the score had decreased to 6, corresponding to a 30-point or 83% improvement.

[0153] MADRS "Inability to Have Emotions" item scores compiled across all 4 patients in the 12 mg group had a baseline of 16. After 2 hours, the score had decreased to 9, corresponding to a 7 point or 44% improvement. On the 1st day after treatment, the score had decreased to 1, corresponding to a 15 point or 94% improvement. On the 7th day after treatment, the score had decreased to 1, corresponding to a 15 point or 94% improvement.

[0154] The inventors conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of the inability to have emotions.

[0155] Improvement in inability to have emotions is reflected by at least an improvement in the MADRS inability to have emotions item score on 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.

[0156] Improvement in inability to feel, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) score, occurs by approximately 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

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

[0158] Improvement in inability to feel, 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.

[0159] The improvement in inability to feel, 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, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0160] The inventors further conclude that the reduction or elimination of inability to have emotions by treating a PPD patient will not only result in a decrease in the MADRS total score, but will also result in an improvement in the maternal role as reflected by an increase in the BIMF score. This improvement will be achieved rapidly (i.e., within about 2 hours), with increases in the BIMF score also observed on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof. Because inability to have emotions affects other aspects of PPD, the inventors conclude that the improvement observed in the "inability to have emotions" item of the MADRS will further contribute to an overall improvement in the maternal role.

[0161] The "Difficulty concentrating" item on the MADRS indicates difficulty organizing one's thoughts and, more generally, a lack of ability to concentrate.

[0162] If the patient can concentrate without strain, the score is 0. If the patient occasionally has difficulty collecting their thoughts, the score is 2. If the patient has difficulty concentrating or sustaining thoughts, which impairs their ability to read or carry on a conversation, a score of 4 is assigned. If the patient has great difficulty reading or carrying on a conversation, the score is 6.

[0163] The inventors determined that an increase in the MADRS "Difficulty concentrating" item score adversely affects both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). An increase in the MADRS "Difficulty concentrating" item score impairs the care and management of the infant.

[0164] Conversely, improvement on this MADRS item would translate to improvement in maternal role (particularly the BIMF role domain of caring for and / or managing the infant).

[0165] The combined MADRS "Difficulty concentrating" item score across all eight patients in the study group receiving the individualized dosing plan had a baseline of 30. After two hours, the score had decreased to 11, corresponding to a 19-point or 63% improvement. One day after treatment, the score had decreased to 1, corresponding to a 29-point or 97% improvement. Seven days after treatment, the score had decreased to 9, corresponding to a 21-point or 70% improvement.

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

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

[0168] Improvement in difficulty concentrating is reflected by an improvement in the MADRS difficulty concentrating item 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.

[0169] 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.

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

[0171] 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.

[0172] 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 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.

[0173] The inventors further conclude that reduction or elimination of concentration difficulties by treating PPD patients not only leads to a decrease in the MADRS total score, but also leads to an improvement in the maternal role as reflected by an increase in the BIMF score, which is achieved rapidly (i.e., within about 2 hours) and is also seen on days 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0174] Because concentration difficulties influence other aspects of PPD, we conclude that the improvement observed in the "concentration difficulties" item of the MADRS may further contribute to an overall improvement in the maternal role.

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

[0176] 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 irreparable guilt, and irrational, unwavering self-blame, a score of 6 is assigned.

[0177] The inventors have determined that increasing scores on the "pessimistic thinking" item of the MADRS negatively impact both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). Increased scores on the "pessimistic thinking" item of the MADRS impair psychological well-being, social support and control.

[0178] Conversely, improvement on this MADRS item would translate to improvement in the maternal role (particularly the BIMF role domains psychological well-being, social support and / or control).

[0179] The combined MADRS "pessimistic thinking" item score across all eight patients in the study group receiving the individualized dosing plan had a baseline of 28. After two hours, the score had decreased to 7, corresponding to a 21-point or 75% improvement. One day after treatment, the score had decreased to 4, corresponding to a 24-point or 86% improvement. Seven days after treatment, the score had decreased to 3, corresponding to a 25-point or 89% improvement.

[0180] MADRS "pessimistic thinking" item scores across all four patients in the 12 mg group were compiled at baseline of 16. After 2 hours, the score had decreased to 8, corresponding to an 8-point or 50% improvement. On the first day after treatment, the score had decreased to 7, corresponding to a 9-point or 56% improvement. On the seventh day after treatment, the score had decreased to 8, corresponding to an 8-point or 50% improvement.

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

[0182] Improvement in negative thinking is reflected by at least an improvement in the MADRS negative thinking item score 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.

[0183] 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.

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

[0185] 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.

[0186] 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 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.

[0187] The inventors further conclude that the reduction or elimination of negative thinking by treating PPD patients not only leads to a decrease in the MADRS total score, but also leads to an improvement in the maternal role as reflected by an increase in the BIMF score. This improvement will be achieved rapidly (i.e., within about 2 hours), and the increase in the BIMF score will also be seen on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

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

[0189] The "decreased sleep" item on the MADRS refers to the experience of decreased duration or depth of sleep compared with an individual's normal pattern when healthy.

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

[0191] The inventors have determined that increasing scores on the MADRS "reduced sleep" item negatively impact both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). Increasing scores on the MADRS "reduced sleep" item impair self-care, psychological well-being and control.

[0192] Conversely, improvement on this MADRS item would translate to improvement in the maternal role (particularly the BIMF role domains of self-care, psychological well-being and / or management).

[0193] The combined MADRS "Decreased Sleep" item score across all eight patients in the study arm receiving the individualized dosing plan had a baseline of 25. By the first day of treatment (the earliest time point to assess the treatment's effect on sleep), the score had decreased to 12, corresponding to a 13-point or 52% improvement. By the seventh day of treatment, the score had decreased to 9, corresponding to a 16-point or 64% improvement.

[0194] MADRS "Decreased Sleep" item scores across all 4 patients in the 12 mg group were compiled from 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.

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

[0196] Reduction or elimination of sleep reduction is reflected by at least an improvement in the MADRS sleep reduction item score on the 1st day (e.g., about 24 hours), 7th day, 14th day, and / or 28th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0197] 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.

[0198] 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.

[0199] 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 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.

[0200] The inventors further conclude that the reduction or elimination of sleep loss by treating PPD patients not only leads to a decrease in the MADRS total score, but also leads to an improvement in maternal role as reflected by an increase in the BIMF score, which is achieved rapidly (i.e., within about 24 hours), with increases in the BIMF score also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0201] Because sleep reduction influences other aspects of PPD, we conclude that the improvements observed in the "reduced sleep" item of the MADRS may further contribute to an overall improvement in the maternal role.

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

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

[0204] "Suicidal thoughts" refers to feelings that there is no point in life and that one would be happy to die naturally at any time, suicidal thoughts, and / or preparations for suicide. Suicide attempts themselves should not influence the rating of this MADRS item.

[0205] 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 to attempt suicide and / or is actively preparing to commit suicide.

[0206] This MADRS scale item is of particular relevance to suicidal ideation.

[0207] The inventors have determined that increasing scores on the MADRS "suicidal thoughts" item negatively impact both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). Increasing scores on the MADRS "suicidal thoughts" item impair self-care, psychological well-being and control.

[0208] Conversely, improvement on this MADRS item would translate to improvement in the maternal role (particularly the BIMF role domains of self-care, psychological well-being and / or management).

[0209] The combined MADRS "suicidal thoughts" item score across all eight patients in the study group receiving the individualized dosing plan 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.

[0210] MADRS "suicidal thoughts" item scores across all four patients in the 12 mg group were compiled at baseline as 8. After 2 hours, the score had decreased to 3, corresponding to a 5 point or 63% improvement. On the 1st day after treatment, the score had decreased to 5, corresponding to a 3 point or 38% improvement. On the 7th day after treatment, the score had decreased to 7, corresponding to a 1 point or 13% improvement.

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

[0212] Thus, in accordance with the present invention, by treating a PPD patient suffering from suicidal ideation, the suicidal ideation is reduced or eliminated.

[0213] Reduction or elimination of suicidal ideation is reflected by at least an improvement in the MADRS Suicidal Thoughts item score 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.

[0214] 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 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.

[0215] 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.

[0216] 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 pharma- ceutically acceptable salt thereof.

[0217] 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.

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

[0219] The inventors further conclude that reduction or elimination of suicidal thoughts by treating a PPD patient not only leads to a decrease in the MADRS total score, but also leads to an improvement in the maternal role as reflected by an increase in the BIMF score, which is achieved rapidly (i.e., within about 2 hours), with increases in the BIMF score also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0220] Because suicidal thoughts influence other aspects of PPD, we conclude that the improvement observed in the "suicidal thoughts" item of the MADRS may further contribute to an overall improvement in the maternal role.

[0221] The BPRS item "emotional withdrawal" concerns the patient's lack of ability to relate emotionally in the interview situation. Possible scores are: 1- No emotional withdrawal. 2 - Very mild. Lack of emotional engagement is indicated by an occasional failure to return feedback, appearing distracted at times, or smiling awkwardly, but engages spontaneously with the interviewer most of the time. 3 - Mild. Lack of emotional engagement is indicated by a noticeable inability to provide feedback, appearing distracted, or lacking warmth, but is responsive to the interviewer when prodded. 4 - Moderate. Emotional contact is absent for much of the interview because the person is short-sighted, does not make eye contact, does not seem to care if the interviewer is listening, or may be preoccupied with psychotic content. 5 - Moderately severe. As in "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 due to paranoia alone). Responds with very little emotion. 7- Most severe. Consistently avoids emotional involvement. Does not respond or gives yes / no responses (not solely due to paranoia). May leave during interview or not respond at all.

[0222] The inventors determined that increasing scores on the BPRS "emotional withdrawal" item negatively impact both aspects of the maternal role (maternal capacity for interaction with the infant(s) as well as maternal self-care). Increasing scores on the BPRS "emotional withdrawal" item are associated with impaired psychological well-being, mother-infant interaction and social support.

[0223] Conversely, improvement on this BPRS item would translate to improvements in the maternal role (particularly the BIMF role domains of psychological well-being, mother-child interaction and / or social support).

[0224] The BPRS "emotional withdrawal" item scores for the study group receiving the individualized dosing plan were compiled with a baseline of 13. 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.

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

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

[0227] Reduction or elimination of emotional withdrawal is reflected by at least an improvement in the BPRS emotional withdrawal item score 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.

[0228] 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.

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

[0230] Improvement in emotional withdrawal, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) score, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0231] 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 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.

[0232] The inventors further conclude that the reduction or elimination of emotional withdrawal by treating PPD patients not only leads to a decrease in BPRS total score, but also leads to an improvement in the maternal role as reflected by an increase in BIMF score. This improvement will be achieved rapidly (i.e., within about 2 hours), with increases in BIMF score also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

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

[0234] The BPRS "flattened affect" item concerns not only a restricted range of emotional expression in face, voice, and body language, but also a marked indifference or flatness even when discussing distressing topics. Possible scores are: 1- There is no flattening of emotions. 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. Voice tone is somewhat monotonous. 4 - Moderate. The range of affect is significantly reduced, the patient does not show emotion, smiles, or rarely responds to distressing topics. The tone of voice is monotonous or spontaneous movements are significantly reduced. Usually, any expression or gesture is followed by a return to flat affect. 5 - Moderately severe. Emotional range is severely reduced, the patient does not show emotion or smile or responds minimally to distressing topics, gestures are few, 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- Most severe. Virtually no range or expression of emotion, stiff movements, monotonous tone of voice all the time.

[0235] The inventors have determined that an increase in the BPRS "flattened affect" item score negatively impacts both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). An increase in the BPRS "flattened affect" item score impairs psychological well-being and mother-infant interaction.

[0236] Conversely, improvement on this BPRS item would translate to improvements in the maternal role (particularly the BIMF role domains of psychological well-being and / or mother-child interaction).

[0237] The BPRS "flat affect" item score was tabulated with a baseline of 15. After 3 hours, the score had decreased to 11, which corresponds to a 4-point or 27% improvement. After 1 day of treatment, the score had decreased to 8, which corresponds to a 7-point or 47% improvement. After 7 days of treatment, the score had decreased to 8, which corresponds to a 7-point or 47% improvement.

[0238] The BPRS "flat affect" item score for the 12 mg group was tabulated with a baseline of 11. After 3 hours, the score had decreased to 8, corresponding to a 3 point or 27% improvement. On the 1st post-treatment day, the score had decreased to 6, corresponding to a 5 point or 45% improvement. On the 7th post-treatment day, the score had decreased to 5, corresponding to a 6 point or 55% improvement.

[0239] We conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of affective flattening.

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

[0241] Improved emotional flattening, 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.

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

[0243] Improved emotional flattening, as reflected by a score of at least "much improved" on the Clinical Global Impression-Improvement (CGI-I) or Patient Global Impression-Improvement (PGI-I) scores, preferably occurs by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0244] The improvement in emotional flattening, 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, and more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0245] The inventors further conclude that the reduction or elimination of flat affect by treating PPD patients not only leads to a decrease in BPRS total score, but also leads to an improvement in the maternal role as reflected by an increase in BIMF score. This improvement will be achieved rapidly (i.e., within about 2 hours), and the increase in BIMF score will also be seen on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0246] Because flat affect influences other aspects of PPD, we conclude that the improvements observed in the "flat affect" item of the BPRS may further contribute to an overall improvement in the maternal role.

[0247] The BPRS "guilt" item concerns excessive preoccupation with or remorse for past actions. Possible scores are: 1- No guilt. 2 - Very mild. Preoccupied with disappointing someone or failing at something, but not distracted. Can easily shift attention to other things. 3 - Mild. Somewhat preoccupied with disappointing someone or failing at something. Tends to express 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 they are able to quickly shift their attention elsewhere. 5 - Moderately severe. Feelings of guilt, preoccupation with disappointing someone or failing at something, can focus attention elsewhere but only with great effort. Not delusional. 6 - Severe. Delusional guilt or irrational self-blame that is grossly out of proportion to the circumstances. Moderately distracted. 7 - Severe. Delusional feelings of guilt or irrational self-blame that are grossly out of proportion to the circumstances. The person is so preoccupied with the feelings of guilt that they may disclose to others or act on the delusion.

[0248] The inventors determined that increasing scores on the BPRS "guilt" item negatively impact both aspects of the maternal role (the maternal competence regarding interactions with the infant(s) as well as the maternal self-care). Increasing scores on the BPRS "guilt" item impair self-care, mother-infant interaction, psychological well-being and control.

[0249] Conversely, improvement on this BPRS item would translate to improvement in the maternal role (particularly the BIMF role areas self-care, mother-infant interaction, psychological well-being and / or management).

[0250] The BPRS "guilt" item score was compiled across all eight patients in the study group receiving the individualized dosing plan, with 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.

[0251] The BPRS "guilt" item scores across all four patients in the 12 mg group were compiled from a baseline of 18. After 3 hours, the score had decreased to 9, corresponding to a 9 point or 50% improvement. On the first day after treatment, the score had decreased to 5, corresponding to a 13 point or 72% improvement. On the seventh day after treatment, the score had decreased to 5, corresponding to a 13 point or 72% improvement.

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

[0253] Reduction or elimination of guilt is reflected by an improvement in the BPRS guilt item scores 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.

[0254] 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.

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

[0256] 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.

[0257] 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 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.

[0258] The inventors further conclude that reducing or eliminating guilt by treating a PPD patient not only leads to a decrease in the BPRS total score, but also leads to an improvement in the maternal role as reflected by an increase in the BIMF score, which is achieved rapidly (i.e., within about 2 hours), with increases in the BIMF score also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

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

[0260] The "anxiety" item of the BPRS relates to reported apprehension, tension, fear, panic or worry. Possible scores are: 1- No anxiety. 2 - Very mild. Reports some discomfort due to more or less frequent worries than is normal for most healthy people. 3 - Mild. Worries frequently but can immediately 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. There are frequent but not daily periods of autonomic anxiety or some areas of functioning are impaired by anxiety or worry. 6 - Severe. Autonomic anxiety is present every day but not all day or many areas of functioning are impaired by anxiety or constant worry. 7- Severe. Autonomic anxiety is present consistently throughout the day or most areas of functioning are impaired by anxiety or constant worry.

[0261] The inventors determined that increased scores on the BPRS "anxiety" item negatively impact both aspects of the maternal role (the maternal competence regarding interactions with the infant(s) as well as the maternal self-care). Increased scores on the BPRS "anxiety" item impair psychological well-being, social support and control.

[0262] Conversely, improvement on this BPRS item would translate to improvement in the maternal role (particularly the BIMF role domains psychological well-being, social support and / or control).

[0263] Aggregated BPRS "anxiety" item scores across all eight patients in the study group receiving the individualized dosing plan had a baseline of 37. After three hours, the score had decreased to 19, corresponding to an 18-point or 49% improvement. One day after treatment, the score had decreased to 16, corresponding to a 21-point or 57% improvement. Seven days after treatment, the score had decreased to 17, corresponding to a 20-point or 54% improvement.

[0264] The BPRS "anxiety" item score was compiled across all four patients in the 12 mg group, 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.

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

[0266] Reduction or elimination of anxiety is reflected by an improvement in the BPRS anxiety item scores 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.

[0267] 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.

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

[0269] 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.

[0270] 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.

[0271] The inventors further conclude that the reduction or elimination of anxiety by treating a PPD patient not only leads to a decrease in the BPRS total score, but also leads to an improvement in the maternal role as reflected by an increase in the BIMF score, which is achieved rapidly (i.e., within about 2 hours), and the increase in the BIMF score is also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

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

[0273] The "tension" item of the BPRS relates to observable physical and motor symptoms of tension, "nervousness," and excitement. Possible scores are: 1- No tension. 2 - Very mild. More restless than most, but within normal limits. There are some transient signs of tension, such as picking at fingernails, shuffling feet, and repeated scratching or tapping of the scalp. 3 - Mild. As in "2", but symptoms of tension are more frequent or worse. 4 - Moderate. Motor signs of tightness are numerous and frequent, sometimes with one or more signs occurring simultaneously (e.g., constant foot swaying while kneading hands). There are periods when signs of tightness are absent. 5 - Moderately severe. Signs of motor tension are numerous and frequent, often with one or more signs occurring simultaneously. There are still rare periods when signs of tension are absent. 6 - Severe. As in "5", but signs of tension persist. 7 - Most severe. Multiple signs of motor tightness are present and persistent, e.g., constant pacing and rubbing of hands.

[0274] The inventors determined that an increase in the score on the "strain" item of the BPRS negatively impacts both aspects of the maternal role (the maternal capacity for interaction with the infant(s) as well as the maternal self-care). An increase in the score on the "strain" item of the BPRS impairs mother-infant interaction and psychological well-being.

[0275] Conversely, improvement on this BPRS item would translate to improvements in maternal role (particularly the BIMF role domains of mother-child interaction and / or psychological well-being).

[0276] Aggregated BPRS "tension" item scores across all eight patients in the study group receiving the individualized dosing plan had a baseline of 16. After three hours, the score had decreased to 11, corresponding to a 5 point or 31% improvement. One day after treatment, the score had decreased to 11, corresponding to a 5 point or 31% improvement. Seven days after treatment, the score had decreased to 10, corresponding to a 6 point or 38% improvement.

[0277] Aggregated BPRS "tension" item scores across all four patients in the 12 mg group had a baseline of 14. After 3 hours, the score had decreased to 9, corresponding to a 5 point or 36% improvement. On the 1st day after treatment, the score had decreased to 6, corresponding to an 8 point or 57% improvement. On the 7th day after treatment, the score had decreased to 6, corresponding to an 8 point or 57% improvement.

[0278] The inventors conclude that 5-MeO-DMT can be used to treat patients with PPD to achieve a reduction or elimination of tension.

[0279] Reduction or elimination of tension is reflected by an improvement in the BPRS tension item 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.

[0280] Improvement in tension, 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.

[0281] 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.

[0282] 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 by about 2 hours after the last administration of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0283] 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 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.

[0284] The inventors further conclude that the reduction or elimination of tension by treating a PPD patient not only leads to a decrease in the BPRS total score, but also leads to an improvement in the maternal role as reflected by an increase in the BIMF score, which is achieved rapidly (i.e., within about 2 hours), and the increase in the BIMF score is also observed on days 1 (e.g., about 24 hours), 7, 14, and / or 28 after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0285] Because strain also influences other aspects of PPD, we conclude that the improvement observed in the "strain" item of the BPRS may further contribute to an overall improvement in the maternal role.

[0286] Improvement in one or more aspects of PPD also leads to an overall improvement. Preferably, treatment leads to remission.

[0287] 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.

[0288] 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.

[0289] From the above, it can be seen that treating PPD patients with 5-MeO-DMT or a pharma- ceutically acceptable salt thereof not only reduces MADRS scores, particularly including subscores, as detailed above, but also leads to improvements in the BIMF scale domains. The reduction in MADRS scores, as well as improvements in maternal role, are confirmed by clinical data, as discussed in the Examples section below.

[0290] Improvements in maternal role include improvements in the role domain of self-care. For example, improvements in MADRS items of inhibition and / or sleep reduction lead to an increase in the BIMF scale score reflecting self-care. The improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0291] The improvement of the maternal role includes an improvement in the role domain of caring for the infant. For example, an improvement in the MADRS items of inhibition and / or difficulty in concentrating leads to an increase in the BIMF scale score reflecting caring for the infant. The improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 15%, more preferably at least 25%.

[0292] The improvement of the maternal role includes the improvement in the role domain of the mother-child interaction. For example, the improvement in the MADRS items of emotionlessness and inner tension leads to an increase in the BIMF scale score reflecting the mother-child interaction. The improvement of the cumulative score of the BIMF scale items reflecting the mother-child interaction is preferably at least 5%, more preferably at least 15%.

[0293] The improvement of the maternal role includes the improvement in the role domain of psychological well-being. For example, the improvement in the MADRS items inhibition, pessimistic thinking, inability to have emotions, inner tension and / or sleep reduction leads to an increase in the BIMF scale score reflecting psychological well-being. The improvement of the cumulative score of the BIMF scale items reflecting psychological well-being is preferably at least 25%, more preferably at least 35%.

[0294] The improvement of maternal role includes improvement in the role domain of social support.For example, improvement in MADRS item pessimistic thinking leads to increase in BIMF scale score reflecting social support.Improvement of the cumulative score of BIMF scale item reflecting social support is preferably at least 10%, more preferably at least 20%.

[0295] Improvements in the maternal role include improvements in the role domain of control. For example, improvements in the MADRS items inhibition, pessimistic thinking, and / or difficulty concentrating lead to an increase in the BIMF scale score reflecting control. The improvement in the cumulative score of the BIMF scale items reflecting control is preferably at least 20%, more preferably at least 30%.

[0296] Improvements in maternal role include improvements in the role domain of adaptation. For example, an improvement in the MADRS item of inhibition leads to an increase in the BIMF scale score reflecting adaptation. The improvement in the cumulative score of the BIMF scale items reflecting adaptation is preferably at least 5%, more preferably at least 15%.

[0297] Improvement in maternal role relates to one or more, particularly two or more, role domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, care of the infant, mother-infant interaction, maternal psychological well-being, social support, control, and adjustment.

[0298] The BIMF total score improves by 10% or more, preferably 20% or more.

[0299] Breastfeeding As indicated above, with respect to many medications, breastfeeding PPD patients may be faced with the situation of having to decide whether to discontinue breastfeeding or to discontinue / withhold treatment.

[0300] If a decision is made to discontinue breastfeeding in order to undergo treatment, this will adversely affect the maternal role, particularly compromising the role areas of mother-child interaction and psychological well-being.

[0301] The present invention also addresses the need to treat PPD in breastfeeding mothers without substantially interrupting breastfeeding.

[0302] According to the present invention, breastfeeding can be resumed immediately after the procedure.

[0303] The present inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT in an attempt to determine at what point after administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, breast-feeding can be permitted without exposing the infant to any associated risks.

[0304] Absorption and distribution of inhaled 5-MeO-DMT was rapid, with maximum concentrations and pharmacological effects occurring during and shortly after administration.

[0305] Plasma protein binding is low (13-23%).

[0306] 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 was observed with repeated dosing within a 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.

[0307] The possible metabolites of 5-MeO-DMT in humans were identified and the potential relevance of such metabolites was evaluated. In an in vitro metabolic identification study with 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]

[0308] It should be noted 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 may not play any significant role in vivo.

[0309] The metabolites listed in the table above are formed via three different pathways.

[0310] The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed by oxidative deamination, which requires enzymatic removal of the N-methyl group and oxidation to form acetaldehyde. [ka]

[0311] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0312] Secondary amines, primary amines and aldehydes were not identified, indicating that they were not always present in significant concentrations.

[0313] The aldehyde intermediate metabolite undergoes two separate biotransformations in human hepatocytes and is either oxidized to 5-methoxyindoleacetic acid or reduced to 5-methoxyindole-3-ethanol. [ka]

[0314] Both resulting metabolites are endogenous substances and are formed in the human body, for example, in the synthesis and metabolism of melatonin and serotonin (see, for example, Biochemistry of the Pineal. Chapter 3 in Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3 in Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).

[0315] Because the major pathway for 5-MeO-DMT metabolism rapidly yields 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 would require restrictions regarding breastfeeding.

[0316] Furthermore, as detailed in the Examples section, incubation of 5-methoxytryptophol with human hepatocytes indicates rapid turnover with complete elimination of the compound within 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).

[0317] Thus, plasma concentrations of 5-methoxytryptophol will decline rapidly to endogenous levels, provided that any is formed at all.

[0318] 5-MIAA is a weak acid and will exist in an ionized form in plasma, making it unlikely that the compound will pass into breast milk.

[0319] When 5-MIAA was incubated with human hepatocytes, the residual 5-MIAA concentration after 72 hours was 75-82%, indicating a slow turnover. 5-MIAA is believed to be the final metabolic product of 5-MeO-DMT.

[0320] 5-MIAA exhibits a relatively low plasma binding rate of approximately 50% (mean unbound fraction (Fu), see Examples section). 5-MIAA remains in the circulation and is subject to excretion by the kidney. Given a standard glomerular filtration rate of 90-120 ml / min, this means that all traces of 5-MIAA are cleared from the circulation for urinary excretion in approximately 1-2 hours (depending on the patient's size and taking into account the increased blood volume that occurs during pregnancy).

[0321] Consequently, plasma concentrations of 5-MIAA also decline rapidly.

[0322] This, coupled with the rapid clearance of 5-MeO-DMT (<1 h), supports the notion that elimination of the administered therapeutic drug and all associated metabolites from the circulation is complete in approximately 2 h.

[0323] A further metabolite, bufotenine, was identified and is the result of O-demethylation catalyzed by CYP2D6. The metabolite formed then undergoes glucuronidation catalyzed by UGTs. [ka]

[0324] As part of pharmacokinetic studies, it has been determined that bufotenine is virtually undetectable in human serum; none is detectable 15 minutes after administration of 5-MeO-DMT.

[0325] Bufotening glucuronide cannot bind to the receptor and does not exert any effect. Moreover, its concentration is so low that it was not detected in the hepatocyte assay. Bufotening glucuronide is further converted to 5-hydroxyindoleacetic acid. [ka]

[0326] 5-Hydroxyindoleacetic acid is an endogenous substance occurring, for example, in the metabolism of melatonin and serotonin (see above references).

[0327] The O-demethylation pathway of 5-MeO-DMT leads to the primary metabolite bufotenin, which is rapidly cleared from plasma, and further metabolism leads to compounds present at very low concentrations, and ultimately to metabolites that are also part of endogenous metabolic pathways. Thus, the inventors have determined that the O-demethylation of 5-MeO-DMT is not accompanied by metabolites that would require restrictions regarding breastfeeding.

[0328] The third metabolic pathway involves N-oxidation. [ka]

[0329] In silico modeling of the metabolite formed, 5-MeO-DMT-N-oxide, appears to be non-genotoxic, in agreement with the negative in vitro genotoxicity evaluation of the parent molecule. The compound is water soluble and rapidly excreted, as confirmed by observations in rats (Sitaram, BR, Lockett, L., Blackman, GL, McLeod, WR, 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine and their N-oxides in the rat. Biochemical Pharmacology 36:2235-2231). Because the metabolic pathway of 5-MeO-DMT involving N-oxidation does not play a significant role and results in a low proportion of rapidly excreted metabolites with no apparent toxicity, the inventors have determined that the N-oxidation of 5-MeO-DMT does not involve metabolites that would require the imposition of restrictions on breastfeeding.

[0330] 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.

[0331] Thus, in instances where the patient is a breastfeeding mother, the patient is advised to discontinue breastfeeding until 48 hours after the last dose of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof, and in particular, the patient is advised to discontinue breastfeeding until 24 hours after the last dose of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0332] Preferably, breast-feeding should be interrupted 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.

[0333] 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 maternal role and the well-being and development of the infant(s).

[0334] Mode of administration The therapeutically effective amount of 5-MeO-DMT is administered by inhalation, nasal administration, buccal administration or sublingual administration. Administration via these routes can ensure a rapid onset of action. The most preferred route of administration is administration by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in one breath.

[0335] For nasal administration, 5-MeO-DMT can be used as a pure substance or in the form of a nasal administration preparation, examples of which are known in the art.For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt (preferably hydrobromide) or in the form of a pharmaceutically acceptable salt (preferably hydrobromide).Examples of suitable devices are known in the art.

[0336] Buccal or sublingual administration can also be by a pharma- ceutically acceptable salt of 5-MeO-DMT (preferably the hydrobromide salt) per se or in a formulation as is commonly known in the art (e.g., tablets, films, sprays, creams).

[0337] The administration is particularly by inhalation of an aerosol. Such an aerosol comprises (a) a pharma- ceutically acceptable gas and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof, and the aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, in particular about 2 mg / l to about 9 mg / l). The pharma- ceutical acceptable gas is preferably air.

[0338] The aerosol particles preferably contain less than 1 wt% impurities, in particular less than 0.5 wt% impurities. The aerosol particles further preferably contain less than 0.5 wt% 5-MeO-DMT decomposition products, in particular less than 0.2 wt% 5-MeO-DMT decomposition products resulting from chemical modification of 5-MeO-DMT as a result of chemical reactions during aerosol formation.

[0339] In a further preferred embodiment, the aerosol consists essentially of (a) air, and (b) aerosol particles of 5-MeO-DMT, or a pharma- ceutically acceptable salt thereof.

[0340] The aerosol particles preferably contain 5-MeO-DMT in the free base form.

[0341] The aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 μm and greater than 0.1 μm, in particular a mass median aerodynamic diameter of less than 2 μm and greater than 0.1 μm.

[0342] The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof formed on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT to generate aerosol particles. The thickness of the thin layer can be less than about 10 μm, particularly less than about 7.5 μm. The thickness of the thin layer can be in the range of about 0.1 μm to about 10 μm, particularly in the range of about 0.3 μm to about 7.5 μm.

[0343] A thin layer of 5-MeO-DMT configured on a solid support can be exposed to thermal energy via air passing over the thin layer. Alternatively, a thin layer of 5-MeO-DMT configured on a solid support can be exposed to thermal energy via the solid support.

[0344] The temperature of the air passing over the thin layer may range from about 180° C. to about 260° C. The air passing over the thin layer may in particular have a temperature of about 210° C. and may be passed over the thin layer at a flow rate of about 12 l / min for about 15 seconds.

[0345] The aerosol particles can be contained in a volume of about 3 liters or less, particularly a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. The aerosol particles are preferably delivered to the patient in a single inhalation.

[0346] 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and a pharma-ceutically acceptable salt thereof are provided in the form of an aerosol. Such an aerosol has a suitable aerosol particle mass concentration so that a therapeutically effective dose of the aerosol can be administered to a patient in a single inhalation.

[0347] The aerosol useful in the present invention can be formed using thermal energy.When using thermal energy to form aerosol of a compound, it is very difficult to predict the conditions suitable for safe, efficient and predictable aerosolization, especially when the aerosol is to be used to deliver the compound to a patient systemically via the lungs.Relevant variables in this context include a) the dose of the compound, b) the morphological state of the compound that is made aerosolizable (e.g., crystalline form, or thin layer form), c) the amount of thermal energy that the compound is exposed to (defined by temperature and duration of exposure), and d) the volume of air that is introduced to create the aerosol (defined by flow rate and duration of airflow).

[0348] The compositions and methods described herein are for the safe, efficient and predictable systemic delivery of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof to a patient via inhalation. "Safe" means that the aerosol particles should contain only small amounts of impurities and 5-MeO-DMT degradation products, "efficient" means that the dose is aerosolized, preferably nearly completely or completely, to a defined extent, that the aerosol has desirable physical properties for systemic delivery of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof via the lungs, primarily via alveolar absorption, and that the aerosol can be inhaled by a patient in a single inhalation (i.e., within one deep breath), and "predictable" means that there should be little or no variation in the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol.

[0349] A suitable aerosol can be obtained by a) providing a therapeutically effective amount of 5-MeO-DMT as a thin layer on a solid support, b) exposing the thin layer of 5-MeO-DMT to a controlled elevated temperature for a short period of time, and c) providing a controlled amount of air such that an aerosol is formed.

[0350] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can include an aerosol formed by a) exposing a thin layer of 5-MeO-DMT configured on a solid support to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% wt impurities and less than 0.5% 5-MeO-DMT degradation products, and 3) is capable of being delivered to a patient by a single inhalation.

[0351] The generation of aerosol particles characterized by an aerodynamic mass median diameter of less than 3 microns, containing less than 1% wt of impurities and less than 0.5% wt of 5-MeO-DMT degradation product drug in the aerosol volume, and capable of being delivered to a patient via a single inhalation, is achieved by defining a) the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by temperature and duration of exposure), and d) the total amount of air passed over the thin layer of 5-MeO-DMT (defined by air flow rate and duration of air flow).

[0352] Preferably, the thin layer of 5-MeO-DMT is exposed to thermal energy via air passing over the thin layer, where the air is heated. The temperature of the heated air passing over the thin layer may range from about 180° C. to about 260° C. The temperature of the air passing over the thin layer may in particular be about 210° C.

[0353] Alternatively, the thin layer of 5-MeO-DMT is exposed to thermal energy through the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated. The temperature of the heated solid support can range from about 180°C to about 420°C.

[0354] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is of high purity, being at least 99%, preferably at least 99.5% pure.

[0355] Preferably, the dosage of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT formed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Specific amounts that are effective are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Specific preferred amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0356] The solid support on which 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is provided may have a variety of shapes. Examples of such shapes include, but are not limited to, cylinders less than 1.0 mm in diameter, boxes less than 1.0 mm thick, and virtually any shape permeated with small (e.g., less than 1.0 mm in size) pores. Preferably, the solid support has a large surface area to volume ratio (e.g., greater than 100 per meter) and a large surface area to mass ratio (e.g., greater than 1 cm per gram). 2 super).

[0357] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface area to volume ratio of about 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter results in a support that retains the high surface area to mass ratio of the original sheet but has a lower surface area to volume ratio (about 400 per meter).

[0358] A number of different materials are used to construct the solid support. Such material types include, but are not limited to, metals, inorganic materials, carbon-containing materials, and polymers. Examples of material types are: aluminum, silver, gold, stainless steel, copper and tungsten, silica, glass, silicon and alumina, graphite, porous carbon, carbon yarn and carbon felt, polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are also used.

[0359] When aluminum is used as the solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (defined surface area 2 m 2 1 / g alumina (Aldrich, St. Louis, Mo.) and silicon wafers such as those used in the semiconductor industry. Carbon yarn and carbon felt are available from American Kynol, Inc., New York, NY.

[0360] Preferably, the thickness of the thin layer of 5-MeO-DMT formed on the solid support is less than about 10 μm, in particular less than about 7.5 μm. The thickness of the thin layer can be in the range of about 0.1 μm to about 10 μm, in particular in the range of 0.3 μm to 7.5 μm.

[0361] Preferably, the total amount of air passing over the thin layer of 5-MeO-DMT is defined by a flow rate between about 6 liters per minute and about 40 liters per minute, preferably between about 8 liters per minute and about 16 liters per minute, and the duration of the air flow is selected so that the total volume of the aerosol does not exceed about 3 liters, and the total volume of the aerosol is preferably between about 1 liter and 3 liters (such as between 2 liters and 3 liters). For example, at an air flow rate of about 6 liters per minute, the duration of the air flow should be less than about 30 seconds. A specific effective air flow rate and duration of the air flow is about 12 liters per minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another specific effective air flow rate and duration of the air flow is about 10 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another specific effective air flow rate and duration of the air flow is about 8 liters per minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful specific air flow rate and duration of air flow is 10 liters per minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0362] The aerosol generation rate is greater than 0.1 mg / sec.

[0363] The aerosol particle mass concentration of the aerosol is about 0.5 mg / l to about 18 mg / l (such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, particularly about 2 mg / l to about 9 mg / l).

[0364] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and more than 0.1 microns, preferably less than 2.5 microns and more than 0.1 microns, most preferably less than 2 microns and more than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1% wt impurities, preferably less than 0.5% wt impurities.

[0365] The 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt of 5-MeO-DMT decomposition products, preferably less than 0.2% wt of 5-MeO-DMT decomposition products.

[0366] A composition for delivering a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol formed by a) exposing a 12 mg dose of 5-MeO-DMT configured on a solid support as a thin layer less than 5 microns thick to a temperature of 210° C. for 15 seconds by passing heated air over the thin layer, wherein the aerosol has one or more of the following characteristics: 1) contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) contains aerosol particles characterized by less than 1% impurities and less than 0.5% wt of 5-MeO-DMT degradation products, and 3) is capable of being delivered to a patient by a single inhalation.

[0367] Those skilled in the art who are aware of the aerosol characteristics and aerosolization conditions defined in the present invention can identify suitable vaporization devices or systems that lead to the required aerosol characteristics. Examples of such suitable vaporization devices or systems include, for example, the Volcano Medic Vaporization System (Storz&Bickel, Germany, as disclosed in, for example, EP 0 933 093 B1, and EP 1 884 254 B1, and registered Community design 003387299-0001), which includes a dosing capsule with associated drip pad, and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA, as disclosed in, for example, US 7,458,374 B2, US 9,370,629 B2, and US 9,687,487 B2). The generated aerosol is collected in a balloon, from which it can be inhaled by the patient.

[0368] Dosage regimen The present invention also provides dose ranges, specific doses, as well as administration regimens (dosing schemes).

[0369] 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.

[0370] Thus, achieving a peak experience more rapidly, in a greater percentage of patients, and with greater reproducibility within an individual patient compared to previously tested hallucinogens and dosing regimens would result in a superior therapeutic profile.

[0371] 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 prospect of initiating treatment at lower doses may increase patient acceptance of the therapeutic approach and improve overall compliance at the patient population level.

[0372] 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 hallucinogens due to the delayed onset and long duration of the hallucinogenic effect, and the rapid development of tolerance (i.e., attenuation or disappearance of the hallucinogenic effect after re-administration) that may last for several days.

[0373] Patients, as defined herein, diagnosed with postpartum depression (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) are treated by administration of 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy (i.e., the patient is not receiving any other treatment for PPD or symptoms associated with PPD).

[0374] The dosage of 5-MeO-DMT administered to a patient, as defined herein, diagnosed with postpartum depression (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) ranges from about 1 mg to about 25 mg, or any amount within that range, preferably from about 2 mg to about 20 mg, and more preferably from about 4 mg to about 20 mg. Specific amounts that are effective are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. The patient may also be treated with an equimolar dose of a pharma- ceutically acceptable salt of 5-MeO-DMT (such as the hydrobromide salt). It should be noted that when a range is given herein, such as "about 1 mg to about 25 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).

[0375] In a preferred embodiment, the improved method for treating a patient, as defined herein, diagnosed with postpartum depression (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises generating a clinical response by about 2 hours after administration of 5-MeO-DMT.

[0376] In a preferred embodiment, an improved method for treating a patient as defined herein diagnosed with postpartum depression (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises sustaining a clinical response, 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.

[0377] In a preferred embodiment, an improved method for treating a patient as defined herein diagnosed with postpartum depression (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprises administering more than one dose of 5-MeO-DMT.

[0378] 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.

[0379] 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.

[0380] 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.

[0381] 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 25 mg, preferably about 2 mg to about 20 mg, and more preferably about 4 mg to about 20 mg. Specific amounts that are effective are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0382] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased with each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first.

[0383] In an even more preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increased for each subsequent administration within each treatment block until it reaches 20 mg or all administrations within that treatment block have been administered, whichever occurs first, or until the patient experiences a hallucinogenic high experience or the managing physician determines that further dose increases are inappropriate based on observed side effects.

[0384] For embodiments in which the dosage is increased with each subsequent administration, the dosage of the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, and most preferably about 6 mg to the dosage of the previous administration. For example, if the dosage of the first administration is 6 mg and the dosage increment is 6 mg, the dosage of the second administration will be 12 mg unless one of the stopping criteria mentioned above is reached. Preferably, the dosage of the third administration will be 18 mg.

[0385] In a preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increased to a dosage selected from about 8 mg to about 14 mg for the second administration and to a dosage selected from about 14 mg to about 20 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 6 mg, about 12 mg, and about 18 mg.

[0386] In a further preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of a first treatment block, and then increased for each subsequent administration within the first treatment block until it reaches 20 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 18 mg, and therefore the highest dosage in the first treatment block was 18 mg, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks would be 18 mg.

[0387] In a most preferred embodiment, the dosage of 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of the first treatment block, then increased to a dosage selected from about 8 mg to about 14 mg for the second administration of the first treatment block and to a dosage selected from about 14 mg to about 20 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 6 mg, about 12 mg, and about 18 mg.

[0388] It is understood that pharma- ceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens, and the appropriate weight of the salt to be administered may be calculated from the weight of the free base listed, assuming an equimolar amount is used.

[0389] According to the present invention, it is preferred that 5-MeO-DMT is not administered in combination with an MAO inhibitor.

[0390] The occurrence of a "hallucinatory peak experience" in a patient can be identified by achieving at least 60% of the maximum score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0391] The occurrence of a "hallucinatory peak experience" in a patient can also be identified by achieving at least 60% of the maximum 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).

[0392] 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?

[0393] 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).

[0394] 2. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 1, wherein said patient has a score of 20 or greater on the Montgomery-Asberg Depression Rating Scale (MADRS) or a score of 16 or greater on the 17-item Hamilton Depression Rating Scale (HAM-D).

[0395] 3. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiment 2, wherein said patient has a MADRS score of 28 or greater or a HAM-D score of 22 or greater.

[0396] 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.

[0397] 5. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 4, wherein the patient has been diagnosed with treatment-resistant postpartum depression.

[0398] 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.

[0399] 7. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 6, wherein the patient further has a minor, major or major maternal impairment.

[0400] 8. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 7, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 95 or less, such as 80 or less, in particular 65 or less.

[0401] 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.

[0402] 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 4 mg to about 20 mg of 5-MeO-DMT is administered, or an equimolar amount of said pharma-ceutical acceptable salt is administered instead of 5-MeO-DMT.

[0403] 11. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 1-9, wherein a dosage of about 6 mg, or about 12 mg, or about 18 mg is administered, or an equimolar amount of said pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0404] 12. 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.

[0405] 13. 5-MeO-DMT or a pharma- ceutical or pharmaceutical acceptable salt thereof for use according to aspects 1 to 12, wherein the 5-MeO-DMT is administered at a dosage of about 2 mg to about 8 mg for a first administration, then increased to a dosage of about 8 mg to about 14 mg for a second administration, unless the patient has yet to experience a hallucinatory climax experience, and then increased to a dosage of about 14 mg to about 20 mg for a third administration, unless the patient has yet to experience a hallucinatory climax experience; or an equimolar amount of the pharma-ceutical or pharmaceutical acceptable salt thereof is administered in place of 5-MeO-DMT.

[0406] 14. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 13, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharma- ceutically acceptable salt is administered instead of 5-MeO-DMT.

[0407] 15. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 12 to 14, 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.

[0408] 16. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 9 to 15, wherein the onset of a hallucinogenic peak experience is identified by achieving at least 60% of the maximum score on each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) questionnaire, or by achieving a Peak Experience Scale (PES) Total Score of at least 75.

[0409] 17. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 16, wherein the onset of a hallucinogenic climax experience is identified by achieving a Peak Experience Scale (PES) Total Score of at least 75.

[0410] 18. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 17, wherein said 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered by inhalation or by nasal, buccal or sublingual administration.

[0411] 19. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 18, wherein the 5-MeO-DMT or a pharma- ceutically acceptable salt thereof is administered in the form of an aerosol, said aerosol comprising (a) a pharma- ceutically acceptable gas, and (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharma- ceutically acceptable salt thereof, and wherein the aerosol particle mass concentration of the aerosol is from about 0.5 mg / l to about 18 mg / l, for example from about 0.5 mg / l to about 12.5 mg / l.

[0412] 20. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 19, wherein the aerosol is generated by a) exposing a thin layer of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof constituted on a solid support to thermal energy, and b) passing air over the thin layer to generate aerosol particles.

[0413] 21. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspects 18 to 20, wherein the dosage of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof to be administered to the patient is inhaled in one breath.

[0414] 22. 5-MeO-DMT for use according to any one of embodiments 18 to 21, wherein said 5-MeO-DMT is used in the form of a free base.

[0415] 23. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to embodiments 1 to 22, wherein the 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.

[0416] 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 occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0417] 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 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0418] 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 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0419] 27. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 26, 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.

[0420] 28. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 27, wherein a clinical response, as assessed by at least a 50% improvement in the MADRS score or the HAM-D score compared to the respective score prior to treatment, occurs by no later than about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0421] 29. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 28, wherein a clinical response, as assessed by an improvement of at least 75% in said MADRS score or said HAM-D score compared to the respective score prior to treatment, occurs by no later than about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0422] 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 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 by about 2 hours after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0423] 31. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 30, wherein remission of depressive symptoms as assessed by a MADRS score of 31.10 or less, or a HAM-D score of 7 or less, occurs on the first day, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0424] 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, as assessed by an improvement of at least 50% in the MADRS score or the HAM-D score compared to the respective score prior to treatment, persists for at least 6 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0425] 33. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 32, wherein the clinical response, as assessed by an improvement of at least 75% in the MADRS score or the HAM-D score compared to the respective score before treatment, is on the 7th day after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0426] 34. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 33, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, 7 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0427] 35. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 34, wherein the clinical response, as assessed by an improvement of at least 50% in the MADRS score or the HAM-D score compared to the respective score prior to treatment, persists for at least 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0428] 36. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 35, wherein the clinical response, as assessed by an improvement of at least 75% in the MADRS score or the HAM-D score compared to the respective score before treatment, is 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0429] 37. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 36, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, 14 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0430] 38. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 37, wherein the clinical response, as assessed by an improvement of at least 50% in the MADRS score or the HAM-D score compared to the respective score prior to treatment, persists for at least 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0431] 39. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of aspects 1 to 38, wherein the clinical response, as assessed by an improvement of at least 75% in the MADRS score or the HAM-D score compared to the respective score before treatment, is 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0432] 40. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of claims 1 to 39, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less, or a HAM-D score of 7 or less, 28 days after the last administration of 5-MeO-DMT or a pharma- ceutically acceptable salt thereof.

[0433] 41. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 48 hours after the last dose of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0434] 42. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 24 hours after the last dose of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0435] 43. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 6 hours after the last dose of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0436] 44. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 3 hours after the last dose of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0437] 45. 5-MeO-DMT or a pharma- ceutical acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother and is advised to discontinue breastfeeding until 2 hours after the last dose of 5-MeO-DMT or a pharma- ceutical acceptable salt thereof.

[0438] 46. ​​5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 45, wherein said treatment improves maternal role.

[0439] 47. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 46, wherein the improvement relates to one or more, in particular two or more, role domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, care of the infant, mother-infant interaction, maternal psychological well-being, social support, control, and adjustment.

[0440] 48. 5-MeO-DMT or a pharma- ceutically acceptable salt thereof for use according to aspect 46 or 47, wherein the BIMF score improves by 10% or more, preferably by 20% or more. EXAMPLES

[0441] 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.

[0442] Example 1 – Generation and administration of 5-MeO-DMT aerosol Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask such that the target dose of 5-MeO-DMT free base to be administered to a subject or patient by inhalation is contained in a solution volume of 200 μl. A typical target dose of 5-MeO-DMT is 1 mg to 25 mg. For example, if the target dose of 5-MeO-DMT is 18 mg, then 90 mg of 5-MeO-DMT would be dissolved in 100% ethanol to a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until the time of use.

[0443] Step 2: 200 μl of the solution is transferred into a dosing capsule containing a drip pad (Storz & Bickel, Germany) and the dosing capsule is then closed with its lid.

[0444] 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, which has been preheated with the temperature set to 55°C. The vaporizer airflow is then turned on for 60 seconds at a pre-set flow rate of approximately 12 l / min. The heated air flows into the dosing capsule, evaporating the ethanol and leaving the target dose of 5-MeO-DMT in the capsule as a thin layer covering the stainless steel wire mesh. It can be confirmed that the dosing capsule has been accurately calibrated by demonstrating that the final weight increase of the capsule compared to the weight of the empty capsule is approximately equal to the target dose of 5-MeO-DMT.

[0445] Step 4: The prepared dosage capsule is removed from the filling chamber. The dosage capsule is then transferred to the filling chamber of a second Volcano Medic Vaporizer, which is preheated by setting the temperature at 210° C. and has the airflow turned on for at least 5 minutes and turned off immediately before transferring the capsule. A valved inhalation balloon (Storz&Bickel, Germany) is attached to the socket of the filling chamber, the filling chamber is tightly closed, and immediately thereafter the airflow is turned on for exactly 15 seconds at a preset flow rate of about 12 l / 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 weight of the capsule has returned approximately to its initial weight.

[0446] 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 to the subject or patient.

[0447] Step 6: To prepare for administration, ask the patient to first inhale deeply and exhale completely 1-2 times, concluding this sequence with a deep exhale. Then, holding the mouthpiece firmly against the lips, inhale the entire volume of the inhalation balloon completely in one inhalation, hold the breath for 10 (± 2.5) seconds, then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

[0448] 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.

[0449] 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. After stirring at 7-12° C. for 10 min, crystallization occurred. Following stirring at 7-12° C. for 1 h, the batch was filtered. After washing with MTBE (1 mL, 0.5 vol), the batch was dried under vacuum at 7-12° C. for 3.5 h to give 1.02 g (50% recovery) of a pale orange solid. The isolated solid was analyzed for purity by HPLC as described in WO 2020 / 169850 A1. The purity was found to be 99.74% area.

[0450] Analysis further indicates that the levels of individual impurities were below 0.10% area. Solvent analysis of the sample indicated an MTBE level of 17 ppm.

[0451] Example 3 – Preparation of 5-MeO-DMT hydrobromide 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0452] 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 temperature and equilibrated for 3 hours.

[0453] After 1 hour, a suspension formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried in vacuum at 40° C. for 18 hours.

[0454] An off-white crystalline material was obtained.

[0455] 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.

[0456] Example 4 – Determination of inhibition constants for central 5-HT1A and 5-HT2A receptors in postmortem human brain membrane preparations In this study, the affinity of three hallucinogenic test compounds (psilocin, DMT and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in postmortem human brain tissue from the hippocampus and frontal cortex, respectively, was determined using radioligand binding techniques.

[0457] 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.

[0458] 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 (20,500xg, 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. Membrane preparation buffer consisted of 50 mM Tris-HCl (pH 7.7), 4 mM CaCl2, and 0.1% ascorbic acid. Assay buffer consisted of 50 mM Tris (pH 7.7), 4 mM CaCl2, 0.1% ascorbic acid, and 10 μM pargyline.

[0459] For saturation binding analysis, hippocampal membranes (400 μl, equivalent to 1.25 mg wet weight tissue / tube) were diluted with 50 μl of 0.075–9.6 nM [ 3 H]8-OH-DPAT was incubated with 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.

[0460] 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 was incubated for 30 min at 25°C with 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 ranging from 1 to 10000 nM.

[0461] 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 rapidly washed with ice-cold wash buffer (wash settings 0, 9, 9) and radioactivity was measured by liquid scintillation counting (1 ml Packard MV Gold scintillator).

[0462] 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.

[0463] 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 homogenized again in 0.25 M sucrose (1:15 w / v) and centrifuged at 750 g for 10 min. The supernatants were combined, diluted with ice-cold 50 mM Tris-HCl assay buffer (pH 7.4, 1:100 w / v), homogenized using a narrow-gap glass / Teflon homogenizer (12 strokes, 800 rpm), and centrifuged at 20,500 g for 10 min. The pellet was centrifuged twice more (20,500 x g, 10 min) to wash the tissue. 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.

[0464] For saturation binding analysis, frontal cortex membranes (400 μl, equivalent to 4 mg wet weight tissue / tube) were diluted with 50 μl of 0.00625–0.8 nM [ 3 H]MDL-100,907 was incubated with either 50 μl of assay buffer or 50 μl of 10 μM ketanserin (nonspecific binding) for 60 min at 25° C. Assay buffer and wash buffer consisted of 50 mM Tris-HCl buffer (pH 7.4).

[0465] 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 ranging from 1 to 10,000 nM.

[0466] Membrane-bound radioactivity was collected and measured as above, and data analysis was also performed as above.

[0467] result In hippocampal membranes derived from postmortem human brain tissue, 3 The dissociation constant (K d The dissociation constants (K d The concentrations of 0.51, 0.28 and 0.52 nM, respectively.

[0468] The mean inhibition constants (K i The Hill slopes of all the compounds were close to 1, suggesting a one-site binding model.

[0469] 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.

[0470] The mean inhibition constants (K i The Hill slopes of all the compounds were close to 1, suggesting a one-site binding model.

[0471] 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.

[0472] 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 escalating doses 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.

[0473] In Part A, 3 of 4 patients in both arms (12 mg and 18 mg) experienced at least one ADR. All of them were mild and resolved spontaneously. No SAEs were reported.

[0474] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission at post-dose day 7, and one additional patient (25%) in the 18 mg group had a MADRS clinical response at post-dose day 7. The mean MADRS percent change from baseline at day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

[0475] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0476] 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%).

[0477] No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or cognitive function measures in either Part A or Part B.

[0478] The results are summarized in the table below. [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7]

[0479] Example 6 – Pharmacokinetic evaluation of 5-MeO-DMT and bufotenine To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups (8 subjects per group) were formed. Subjects received a single dose of 6 mg, 12 mg, or 18 mg of 5-MeO-DMT by inhalation. Blood samples were collected at 1, 2, 4, 7, 10, 15, 20, 30, and 45 minutes and at 1, 1.5, 2, 3, and 4 hours after administration.

[0480] 5-MeO-DMT concentrations were measured using LC-MS / MS. PK parameters were generated by algebraic analysis of individual concentration versus time plots. Analysis was performed using Phoenix WinNonlin 6.3 software.

[0481] The median Cmax values ​​obtained in 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).

[0482] Table 4 below shows the median plasma concentration percentages of Cmax measured at the indicated time points. [Table 8]

[0483] Pharmacokinetic measurements were also performed using a dosing scheme based on ascending dose titration, with substantially similar results.

[0484] The plasma concentration of the 5-MeO-DMT metabolite bufotenine was also measured. In only a few samples were concentrations above the lower limit of quantification (LLOQ) (25 pg / ml). From 15 min onwards, bufotenine concentrations were always below the LLOQ.

[0485] Substantially similar observations were made when subjects undergoing an escalating titration scheme were included.

[0486] Example 7 – Toxicity testing of 5-MeO-DMT 5-MeO-DMT did not induce mutations in four histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101) under conditions that included treatment with concentrations up to 5000 μg / plate (the maximum recommended concentration according to current regulatory guidelines) in the absence and presence of a rat liver metabolic activation system (S-9).

[0487] Example 8 – Binding of 5-MeO-DMT to human plasma proteins The in vitro binding of 5-MeO-DMT to plasma proteins was measured using a high-throughput dialysis method. Equilibrium time and non-specific binding were measured in human plasma at a nominal concentration of 1 μM 5-MeO-DMT. Following evaluation of the equilibrium data, plasma protein binding was investigated at nominal concentrations of 0.1, 1 and 10 μM over a dialysis time of 4 hours. 5-MeO-DMT concentrations in samples from the plasma and buffer compartments were measured by LC-MS / MS. Protein binding results are shown below: [Table 9]

[0488] Example 9 – Human metabolism of 5-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).

[0489] A standard stock solution of 5-MeO-DMT was prepared at 20 mM in ethanol and further diluted to a concentration of 2 mM in 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 in Leibovitz L-15 medium. Aliquots (250 μL) of the 20 μM and 2 μM test substance formulations were added to each hepatocyte incubation sample (250 μL) as appropriate, such that the final concentration of test substance in the incubation medium was 10 μM or 1 μM, respectively, and the incubation medium contained less than 1% (v / v) solvent.

[0490] Incubations were performed at approximately 37°C in a shaking water bath (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).

[0491] The samples were mixed by vortexing and centrifuged at approximately 13,000 rpm for 10 minutes at room temperature. After centrifugation, the protein-free supernatant was removed for analysis.

[0492] Blank control incubations were performed using Leibovitz L-15 medium instead of the test substances. Cell-free control samples were also performed using Leibovitz L-15 medium instead of hepatocytes. Aliquots of blank control samples were taken at 120 min, and cell-free control samples were taken at 0, 30, and 120 min for the 1 μM incubations and 0 and 120 min for the 10 μM incubations.

[0493] All incubations at 1 μM were performed in duplicate and all incubations at 10 μM were performed in single replicates. All samples were stored at -80°C (nominal) prior to analysis.

[0494] Appropriate chromatographic conditions were developed to retain the parent compound and obtain a suitable 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- and low-energy mass spectra (MSE). Prior to sample analysis, 100 μL aliquots of each sample were evaporated to near dryness at room temperature under a steady stream of nitrogen and then reconstituted with 50 μL of mobile phase A (0.1% formic acid in water). Each sample (0, 30 and 120 min, 10 μM) was analyzed using accurate mass LC-MS to measure 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 incubation samples at 10 μM were not analyzed and were stored at -80°C (nominal).

[0495] The data were examined for the presence of metabolites by comparison with standards of the test substances for retention time and based on the accurate mass of potential metabolites using screening software (UNIFI version 1.9.4) and user-defined search parameters. To support a candidate metabolite, the measured accurate mass of the peak detected in the sample used for structure elucidation to confirm the molecular formula had to be within 5 ppm of the theoretical mass.

[0496] The results obtained are summarized in Table 1 above.

[0497] 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 examined in a Hμrel co-culture assay with human hepatocytes (Hμrel HumanPool™, a primary hepatocyte co-culture model from Visikol Inc.).

[0498] Incubations were performed at initial concentrations of 1 and 10 μM and samples were taken at 0, 1, 2, 4, 8, 24, 48, and 72 hours (h) Samples were analyzed using UPLC / QE-orbitrap-MS.

[0499] Residual LC / MS peak areas of test compounds detected after each incubation time point in the Hμrel co-culture assay are shown in the table below, relative to the corresponding 0 min incubation sample. Assay control diazepam results (elimination half-life) indicated enzyme activity was within normal values. [Table 10] [Table 11]

[0500] The turnover of 5-MIAA was slow, with 75-82% remaining after 72 hours in the presence of hepatocytes, whereas no disappearance was observed in the interstitial cell control.

[0501] Rapid turnover of 5-methoxytryptophol was observed, being completely cleared within 24 h in the presence of hepatocytes but not in the interstitial cell control.

[0502] With human hepatocytes and a test concentration of 1 μM, 5-MIAA gave an in vitro intrinsic clearance of 0.15 μl / min / million cells (half-life 15 400 min), whereas the corresponding value for 5-methoxytryptophol was 16.2 μl / min / million cells (half-life 142 min).

[0503] The predicted hepatic extraction rates were 2% for 5-MIAA and 67% for 5-methoxytryptophol.

[0504] Example 11 –Plasma binding of 5-MIAA Binding to human plasma proteins was measured and the unbound fraction (fu) of triplicates is reported as well as the mean unbound fraction, standard deviation and mean % recovery (Table 8). [Table 12]

[0505] Example 12 – Clinical trial of inhaled 5-MeO-DMT in 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).

[0506] Patients will receive a daily individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0507] More specifically, on day 0, patients will receive up to three doses of 5-MeO-DMT: 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. 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) were determined by the investigator to be within normal ranges or outside the normal ranges but not clinically significant. 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) were determined by the investigator to be within normal ranges or outside the normal ranges but not clinically significant.

[0508] 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.

[0509] All patients considered for participation in a clinical trial must meet the following criteria: 1. Females aged 18-45 years (inclusive) at the time of screening. 2. Body mass index (BMI) at screening: 18.5-35 kg / m 2 The range is inclusive. 3. Meets the PPD testing criteria as assessed by a testing psychiatrist or licensed psychologist: a. Diagnosis of major depressive disorder without psychotic features as confirmed by the Mini-Institute for Mental Illnesses (MINI) with perinatal onset occurring during pregnancy or later and within 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 total abstinence (abstain completely from heterosexual intercourse) or use a medically accepted method of contraception that is highly effective (failure rate <1%) 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 before the study (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.

[0510] Potential patients meeting 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, has a current or past diagnosis of 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 as determined by a study psychiatrist or licensed psychologist based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS). 4. Receiving antidepressant therapy within 14 days or 5 half-lives (whichever is longer) prior to dosing (exception: within the past 5 weeks for fluoxetine). 5. Having received any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives (whichever is longer) prior to dosing. 6. Have previously experienced a significant adverse reaction to hallucinogenic or hallucinogenic drugs (e.g., psilocybin, Psilocybe mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) as determined by the investigator. Known allergy or hypersensitivity to 7.5-MeO-DMT or any other contraindication. 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 pregnancy-induced hypertension during pregnancy or the postnatal period (e.g., gestational hypertension, preeclampsia-eclampsia, aggravated 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 investigator to consider the patient unsuitable for the study. 11. Patients who have a positive pregnancy test at screening or the day prior to the study (day -1) are pregnant or plan 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.

[0511] The primary objective of the study was to determine the onset and 7-day durability of antidepressant effect of daily individualized dosing regimens of 6 mg, 12 mg, and 18 mg 5-MeO-DMT in adult female patients with PPD.

[0512] 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.

[0513] 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).

[0514] The primary endpoint of the study was the antidepressant effect of 5-MeO-DMT as measured by the percentage change from baseline in the MADRS at day 7.

[0515] Secondary endpoints included the antidepressant effects of 5-MeO-DMT assessed by: The antidepressant effects of 5-MeO-DMT were evaluated 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. o Percent change from baseline in MADRS assessed 2 hours after the last dose of study drug on Day 0 and on Day 1; o 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; o Percent change from baseline in Clinical Global Impression-Severity (CGI-S) score 2 hours after the last dose of study drug on Day 0, and on Days 1 and 7; - Effects on maternal behavior as assessed by percentage change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores; Exposure to 5-MeO-DMT and bufotenin in breast milk obtained the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, in the evening of day 0, and on days 1 and 7. - 5-MeO-DMT and bufotenin exposure in blood obtained the day before the study (day -1), 1 hour after the last dose of study drug, at discharge, on days 1 and 7; Safety and tolerability of 5-MeO-DMT were assessed by: o reporting of treatment-emergent adverse events (TEAEs); Clinically significant percent change from baseline in ECG, vital signs, safety laboratory 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; o Percent change from baseline in the Clinical Diagnostic Dissociative Scale (CADSS) assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; Percent change from baseline in the Brief Psychiatric Rating Scale (BPRS), assessed as part of the discharge assessment on Day 0, and on Days 1 and 7; o Percent change from baseline in C-SSRS assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; o Percent change from baseline in YMRS assessed as part of the discharge assessment on Day 0 and on Days 1 and 7; The PsE experienced by the patient, reported 30-60 minutes after each dose, when the PsE subsided; o PsE assessment using the Peak Experience (PE) scale to assess the achievement of Peak Experiences (PE scale total score ≥ 75); oChallenging Experience Questionnaire (CEQ), oMystical Experience Questionnaire (MEQ-30), • Duration of PsE (ending 30–60 min after each administration), defined as the time from administration of study drug to the point at which PsE subsided (as scored by the investigator and the patient).

[0516] 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, with perinatal onset occurring after conception and within the first 4 weeks after delivery, as confirmed by the Mini-Instrumental Mental Health Interview (MINI) (v7.0.2). The patient was diagnosed with postpartum depression after the birth 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.

[0517] result Apart from a transient, clinically non-relevant increase in heart rate and blood pressure immediately following administration of 5-MeO-DMT, no other notable changes occurred in vital parameters. ECG (3 hours after administration) and safety laboratory analyses (day 7) and CADSS (3 hours, days 1 and 7) were also unremarkable. The few adverse events reported (crampy left abdominal pain and headache, both on day 0) were mild, short-lived, and resolved spontaneously by the end of the study.

[0518] 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.

[0519] 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]

[0520] In particular, significant improvements were noted 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 significant improvements were noted on items with scores reflecting severe symptoms (e.g., decreased sleep, inner tension).

[0521] Similarly, improvements were seen in several BPRS items, including hypochondriasis, anxiety, emotional withdrawal, guilt and tension.

[0522] In addition, as outlined in Table 10, improvements in maternal role were evidenced by improvements in the BIMF scores recorded on day 7, with the total score improving from 92 to 105 (out of a maximum of 120), a 14% improvement.

[0523] Several role domains of the maternal role were also assessed, as defined by Barkin et al. Improvement in each role domain is outlined in more detail in Table 11.

[0524] In this respect, notable improvements were achieved in self-care, psychological well-being and management, with improvement percentages ranging from 18% (management) to 44% (self-care). These improvements reinforce the relationship between improvement in depression items assessed by the MADRS and improvement in the maternal role.

[0525] Note that this patient already had relatively high scores before treatment: in several role domains, scores were at or near maximum (see Table 11), so there was limited room for improvement with treatment. [Table 14-1] [Table 14-2] [Table 15]

[0526] Summary and Conclusion A. An individualized dosing regimen of 6 mg inhaled 5-MeO-DMT followed by 12 mg inhaled 5-MeO-DMT was well tolerated and induced surprising and highly significant clinical responses in patients formally diagnosed with postpartum depression.

[0527] B. Clinical response occurs rapidly, within 2 hours of 5-MeO-DMT administration. Such rapid onset is unusual and not seen with traditional classes of antidepressants (including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and others), which generally take 4-6 weeks to demonstrate efficacy.

[0528] With C.IDR, patients experienced clinical remission within 2 hours of 5-MeO-DMT administration, which is far superior to any other approved treatment for postpartum depression and to all hallucinogens tested to date.

[0529] D. Significant clinical responses were sustained over a 7-day follow-up period. However, 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.

[0530] 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.

[0531] F. In addition to the antidepressant effect, maternal role endpoints assessed using BIMF (e.g. self-care, psychological well-being and control) were also positively affected, supporting the idea that the benefits of 5-MeO-DMT for patients with PPD extend beyond improving the core depression symptom.

[0532] 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.

[0533] Together with the short duration of acute hallucinogenic effects and a good safety profile, these data indicate that the present invention solves the technical problem of providing an improved psychoactive therapy for patients with postpartum depression.

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.

2. The pharmaceutical composition according to claim 1, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher before treatment, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or higher before 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 is also suffering from suicidal thoughts.

7. The pharmaceutical composition according to claim 1, wherein the patient further has a slight, severe, or significant defect in the maternal role, and the patient has a Barkin Index of Maternal Functioning (BIMF) score of 95 or less prior to treatment, for example, 80 or less prior to treatment, and particularly 65 or less prior to treatment.

8. The pharmaceutical composition according to claim 1, wherein a dose of approximately 4 mg to approximately 20 mg of 5-MeO-DMT is administered, or an equimolar amount of the pharmaceutically acceptable salt is administered.

9. 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.

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

11. The pharmaceutical composition according to claim 9, wherein each subsequent dose after the first dose is administered in a larger dose than the previous dose.

12. The pharmaceutical composition according to claim 9, wherein the patient receives subsequent doses unless he experiences a hallucinatory peak experience.

13. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 2 mg to approximately 8 mg for the first dose, then increased to a dose of approximately 8 mg to approximately 14 mg for the second dose, unless the patient has not yet experienced a hallucinogenic peak experience or the managing physician determines that further dose increases are inappropriate based on observed side effects, then increased to a dose of approximately 14 mg to approximately 20 mg for the third dose, or an equimolar amount of the pharmaceutically acceptable salt thereof is administered. The pharmaceutical composition according to claim 1.

14. The pharmaceutical composition according to claim 13, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, the third dose of 5-MeO-DMT is about 18 mg, or an equimolar amount of the pharmaceutically acceptable salt is administered.

15. 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.

16. The 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered to the patient in a dose or 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 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 score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving at least 60% of the maximum score on the Peak Experience Scale (PES) Total The pharmaceutical composition according to claim 1, identified by achieving at least 75 in Score.

17. The pharmaceutical composition according to claim 1, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered by inhalation, or by nasal administration, buccal administration, or sublingual administration.

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

19. The pharmaceutical composition according to claim 1, wherein a clinical response, as assessed by an improvement of at least 50% in the MADRS score 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.

20. The pharmaceutical composition according to claim 1, wherein the treatment improves the mother's role.

21. The pharmaceutical composition according to claim 20, wherein the improvements relate to one or more, particularly two or more, role areas selected from self-care, infant care, mother-child interaction, maternal psychological well-being, social support, management, and adaptation, according to the Barkin Index of Maternal Functioning (BIMF).

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

23. 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, negative thinking, anxiety, cognitive impairment, and social / emotional withdrawal.