5-methoxy-n, n-dimethyltryptamine for treatment of postpartum depression

Abstract

5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof is used for treating a patient suffering from postpartum depression (PPD), and the 5-MeO-DMT is administered via the intravenous, intramuscular or subcutaneous route.

Description

Technical Field

[0001] The present invention relates 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 pharmaceutically acceptable salt thereof. The present invention also allows for the treatment of PPD in breastfeeding mothers without the need for almost complete interruption of breastfeeding. Background Art

[0002] More than 50% of women may experience a brief period of low mood or tearfulness after childbirth. However, a subset of women may develop PPD, a debilitating mood disorder that develops during pregnancy or within 4 weeks after childbirth.

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

[0004] Research shows that PPD can have a range of negative effects on the affected mother, her baby, and her family. For example, women with PPD may have thoughts about harming themselves or their children, and they are at increased risk for suicide. PPD may further lead to disrupted interactions between mother and child, as exemplified by higher rates of disengagement behaviors and lower rates of visual and vocal communication between mother and child. Evidence also suggests a link between PPD and child development, as shown by the fact that children of those with PPD are at greater risk for impaired cognitive development.

[0005] More than 20% of women diagnosed with PPD remain depressed after 12 months of follow-up, and 13% of women still have PPD 2 years after diagnosis. In addition, there is evidence that 40% of women will relapse, and untreated cases of PPD may lead to repeated episodes of depression.

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

[0007] Despite this clear need, treatment options are limited. Known treatments for depression in general have limited success rates, especially for patients with more than mild symptoms of the disorder. In the case of PPD, a complicating factor is that patients often breastfeed. For many medications, breastfeeding women are advised not to breastfeed while taking the medication and for a period of time thereafter because the drug may be excreted in breast milk, putting the nursing infant at risk.

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

[0009] Therefore, breastfeeding patients with PPD may be faced with a situation in which they must decide whether to stop breastfeeding or discontinue / forgo treatment.

[0010] Currently, PPD is mainly treated with psychological therapy or pharmacotherapy. National Institute for Health and Care Excellence (NICE) guidelines recommend that a higher threshold for pharmacological intervention should be discussed with patients before starting treatment. Such treatments may include antidepressants such as selective serotonin reuptake inhibitors (SSRIs), some of which are not contraindicated during breastfeeding.

[0011] Recently in the United States, brexanolone (Zulresso) received FDA approval, becoming the first pharmacological therapy specifically for PPD. Brexanolide is a positive allosteric modulator of the GABAa receptor that is administered via a 60-hour infusion. The efficacy of brexanolone has been demonstrated in two Phase 3 trials—one of which showed a significant reduction in Hamilton Depression Rating Scale (HAM-D) scores 30 days after the start of the infusion, while the other trial did not show efficacy after 7 days. However, brexanolone requires hospitalization for the 60-hour infusion and is associated with severe side effects.

[0012] Another fact worth noting is that patients must stop breastfeeding while receiving brexanolone infusion, and after the drug was approved, some insurance companies required patients who planned to receive the treatment to adhere to this standard as well.

[0013] In this context, there is a need for improved treatments for PPD that are not only effective in treating depression and produce a rapid clinical response, but also avoid interfering with the patient's daily activities, especially the care of the infant. The treatment should improve maternal function. In addition, there is a need for a treatment for PPD that does not require almost complete interruption of breastfeeding.

[0014] Despite recent interest in the use of hallucinogens to treat psychiatric disorders, they have not been used to treat PPD to date. This is due to a general lack of clinical data to draw conclusions about the clinical utility of hallucinogens in PPD and because of concerns that their administration may be inappropriate for breastfeeding mothers.

[0015] Hallucinogens (including psychedelics) are chemical compounds, some naturally occurring and some synthetic, which, when taken by a person, are capable of causing sensory distortions, such as changes in hearing and vision, as well as distortions of mood and cognition. The term hallucinogen covers a fairly broad group of psychoactive molecules with different modes of action. Some mental disorders are in principle considered amenable to treatment with psychoactive molecules such as psychedelics.

[0016] However, no psychedelic drug has yet been approved by any regulatory agency. In fact, clinical experience with such molecules is still quite limited.

[0017] One compound that has been studied in clinical trials is 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). WO 2020 / 169850 reports on tests on healthy volunteers and clinical trials involving patients with treatment-resistant depression (TRD), a form of major depressive disorder. Patients with PPD were not included in the trials.

[0018] In this context, it is an object of the present invention in particular to provide a therapy that is more effective than previously described therapies (i.e., a) a greater percentage of patients experience a clinical response, b) a greater mean clinical response, c) a clinical response occurs earlier, and / or d) a clinical response is more durable).

[0019] It is a further object of the present invention to provide compounds for improved psychoactive therapy and dosing regimens for said therapy, said therapy having better safety and / or better tolerability than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapy and dosing regimens for said therapy, said therapy being more convenient than previously described therapies. It is another object of the present invention to provide compounds for improved psychoactive therapy and dosing regimens for said therapy, said therapy being associated with higher patient compliance rates (including higher treatment initiation rates) than previously described therapies. It is a still further object of the present invention to identify specific disease aspects and subgroups of specific disease aspects that may benefit from such improved psychoactive therapies.

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

[0021] It is another object of the present invention to provide a treatment for lactating mothers diagnosed with PPD or other psychiatric disorders that allows them to continue breastfeeding without significant interruption due to treatment. Summary of the invention

[0022] The present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, which is used for treating postpartum depression (PPD). The treatment can not only improve depressive symptoms, but also improve maternal function.

[0023] The present invention also allows for treatment of PPD in breastfeeding mothers without requiring near-total interruption of breastfeeding.

[0024] In another aspect, the invention relates to treating a breastfeeding mother diagnosed with a psychiatric disorder.

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

[0026] definition

[0027] As used in the context of the present invention, unless otherwise indicated, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used. Such salts are particularly acid addition salts, wherein the acid may be selected from, for example, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and trifluoromethanesulfonic acid. A preferred example is the hydrobromide salt. The appropriate weight of the salt to be administered may be calculated based on the weight of the free base, assuming the use of equimolar amounts.

[0028] As used in the context of the present invention, a "patient" to be treated is a woman diagnosed with postpartum depression (PPD) according to established medical criteria. The diagnosis will be made by a physician or psychologist. It is not enough that the human subject herself believes that she suffers from the disorder.

[0029] The patient may suffer from a treatment-resistant disease. As used herein, "treatment resistance" means that the patient has not adequately improved after at least two adequate courses of treatment. In particular, the patient has not adequately improved after at least two adequate courses of treatment, wherein at least one of the two courses is drug therapy; for example, the patient has not adequately improved after at least two adequate courses of drug therapy.

[0030] As used in the context of the present invention, "suicidal ideation" means thinking about, considering, or planning to commit suicide. A doctor or psychologist will diagnose a patient for the presence of suicidal ideation using established protocols and methods for diagnosing suicidality. Generally, it is not enough for a patient to believe that they suffer from suicidal ideation. In some cases, a patient with suicidal ideation will be at risk for imminent suicide, or will be considered to have "suicidal intent."

[0031] As used in the context of the present invention, unless otherwise indicated, the terms "treating" and "treatment" shall include the management and care of a patient for the purpose of combating a disease, illness or disorder, and includes the administration of the compounds and methods according to the present invention to alleviate the signs and / or symptoms of the disease or to eliminate the disease, illness or disorder.

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

[0033] "Clinical response" includes, but is not limited to, improvements on rating scales such as the Clinical Global Impression-Severity Scale (CGI-S), the Patient Global Impression-Severity Scale (PGI-S), the Clinical Global Impression-Improvement Scale (CGI-I), or the Patient Global Impression-Improvement Scale (PGI-I), and also includes, but is not limited to, endpoints such as the Montgomery-Asberg Depression Rating Scale (MADRS), the 17-item Hamilton Depression Rating Scale (HAM-D), or the Edinburgh Postpartum Depression Scale (EPDS). Further related scales for assessing clinical outcomes include the Clinician-Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Columbia Suicide Severity Rating Scale (C-SSRS).

[0034] Maternal functioning can be assessed using the Barkin Index of Maternal Functioning (BIMF).

[0035] Individual items of the scales shown as well as subcombinations of individual items can be used to assess specific disease aspects.

[0036] When clinical response is assessed at an early time point after drug administration (e.g., 2 hours), reasonable modifications to this endpoint can be made based on endpoints developed for longer recall periods (e.g., typically 7 days for MADRS) (e.g., changing the MADRS recall period to 2 hours and carrying forward sleep items recorded at baseline before drug administration).

[0037] The considerations outlined apply to early time points because, on the one hand, for the purpose of assessing clinical response, the influence of the patient's status before treatment on any score recorded after treatment should be as low as possible, while on the other hand, sleep items cannot be assessed 2 hours after drug administration.

[0038] At later time points, such as on day 1 or later, all items of the relevant scales used to assess clinical response can usually be assessed using an appropriate recall period (if necessary) so that no pre-treatment scores need to be carried forward. For example, if the BIMF is assessed on day 7, a recall period of seven days would be used (rather than the standard recall period of 2 weeks).

[0039] As used in the context of the present invention, unless otherwise indicated, the term "administering" (or "application") shall mean introducing an amount (which may be a predetermined amount) of an active compound or pharmaceutical ingredient into a patient's body via any route. Preferably, the active compound is administered by intravenous administration, intramuscular administration or subcutaneous administration.

[0040] As used in the context of the present invention, unless otherwise indicated, the terms "dose" and "dosage" and "dosage amount" shall mean the amount of active compound or pharmaceutical ingredient administered to a patient in a single administration. The term "dosage regimen" (or "dosage regimen") shall mean a defined order of one or more separate administrations.

[0041] Postpartum depression

[0042] Postpartum depression (PPD) is a complex of physical, emotional, and behavioral changes that some women experience after giving birth. PPD is also known as perinatal-onset major depressive disorder. According to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th edition) criteria, PPD is diagnosed when symptoms of major depressive disorder (MDD) occur during pregnancy or within four weeks after giving birth.

[0043] The patient treated according to the present invention is preferably a female diagnosed with PPD and is >4 weeks postpartum. In addition, the patient is preferably ≤9 months postpartum.

[0044] The depressive aspects of PPD can be assessed using the HAM-D or MADRS scores. The Edinburgh Postnatal Depression Scale (EPDS) can also be used.

[0045] The Montgomery-Asberg Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, S.A., & 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) and is more sensitive to changes brought about by antidepressants and other forms of treatment. Higher MADRS scores indicate more severe depression. The items considered are obvious sadness; reported sadness; inner tension; decreased sleep; decreased appetite; difficulty concentrating; laziness; sensory loss; pessimistic thoughts; and suicidal thoughts, and each item is scored from 0 to 6 points. The total score ranges from 0 to 60.

[0046] The patient may suffer from moderate or severe PPD, which is indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or higher. It is further contemplated that the patient may suffer from severe PPD, which is indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 27 or higher. The patient may be diagnosed with a treatment-resistant form of PPD.

[0047] Patients treated according to the present invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher.

[0048] Furthermore, patients treated according to the present invention may have a MADRS score of 28 or higher or a HAM-D score of 22 or higher.

[0049] Furthermore, patients treated according to the present invention may have a MADRS score of 35 or higher or a HAM-D score of 25 or higher.

[0050] In addition to the above, the inventors believe that PPD impairs maternal function. In particular, the first year after childbirth is a critical window for both mother and child. In most cases, the mother is the primary caregiver and is therefore responsible for most tasks related to infant care.

[0051] Maternal functioning includes aspects of maternal competence related to interaction with the infant and maternal self-care.

[0052] Maternal functioning, including the emotional aspects of motherhood, is also important for the child’s development. In fact, the quality of mother-child interactions in the first year after birth can influence infant development. High levels of maternal functioning may be associated with positive infant developmental outcomes. Likewise, impaired functioning in the postpartum period may impede optimal infant development.

[0053] The Barkin Index of Maternal Function (BIMF) is designed to measure function within one year after childbirth. The BIMF is a 20-item self-report function measurement. Each item is scored from 0 to 6, making the maximum total score 120 points. The higher the score, the better the assessment of maternal function.

[0054] BIMF identifies key areas of maternal functioning during the postpartum period as: self-care, infant care, mother-child interaction, maternal psychological well-being, social support, management, and regulation.

[0055] BIMF scores of 95 or less are considered herein to represent mild impairment of maternal function, scores of 80 or less are considered herein to represent impaired maternal function, and scores of 65 or less are considered herein to represent severely impaired maternal function. The present invention can particularly improve maternal function in patients with a pre-treatment score of 80 or less and in patients with a pre-treatment score of 65 or less.

[0056] Active Agent

[0057] The above discussion shows that PPD is characterized by a significant disease burden of its own and several aspects that require appropriate treatment. Therefore, treatment is needed not only to improve the overall disease score, especially through pharmacological intervention, but also to improve specific aspects of the disease.

[0058] The inventors believe that carefully selected hallucinogens may lead to treatments that improve important aspects of PPD and may result in overall improvements in the disorder and maternal functioning.

[0059] The inventors further contemplate that, in the treatment of lactating mothers with PPD, carefully selected hallucinogens may allow for continued breastfeeding without near-total interruption.

[0060] A group of hallucinogens consists of compounds that bind to 5-hydroxytryptamine (5-HT) receptors, also known as serotonin receptors (seven families with several subtypes are described, 5-HT1 to 5-HT7). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonergic agents are often called "psychedelics", which emphasizes their primary ability to induce qualitative changes in states of consciousness, such as euphoria, trance, time and space, spiritual experiences, loss of self-boundaries, or even near-death experiences, while other effects, such as sedation, anesthesia, or overstimulation, are minimal.

[0061] Chemically, serotonergic psychedelics are either phenylalkylamines or indoleamines, of which the indoleamines are divided into two subsets, the ergoline and the tryptamines, the latter of which are derived from tryptamine.

[0062] Various serotonergic psychedelics have different binding affinities and activation potencies for various serotonin receptors (particularly 5-HT1A, 5-HT2A, and 5-HT2C), and their activities may also be modulated through interactions with other targets such as monoamine transporters and trace amine-associated receptors.

[0063] Recently published studies using serotonergic psychedelics such as LSD, psilocybin, and DMT (using the shamanic medicine ayahuasca containing DMT) in certain psychiatric disorders suggest that these compounds may offer an alternative approach to currently available treatments for some psychiatric disorders. However, there are reports that these compounds may induce mania in patients suffering from depressive symptoms, and this may hamper their clinical use.

[0064] For example, Lake et al. (Lake, CR, Stirba, AL, Kinneman, REJr, Carlson, B., Holloway, HC, 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11): 1508-9) reported a patient who experienced a manic episode after taking LSD or an LSD analog. The patient experienced symptoms of acute LSD intoxication, which were relieved, but a typical psychotic manic episode occurred about 3 weeks later. Hendin and Penn (Hendin, HM, Penn, AD, 2021. An episode of mania following self-reported ingestion of psilocybin mushrooms in a woman previously not diagnosed with bipolar disorder: A case report. Bipolar Disorders 23(4): 1-3) reported a manic episode after self-reported ingestion of psilocybin mushrooms. Szmulewicz et al. (Szmulewicz, AG, Valerio, MP and Jose 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 man with bipolar disorder who switched to mania after consuming ayahuasca, a beverage containing DMT.

[0065] Another case report can be found in Brown, T., Shao, W., Ayub, S., Chong, D., & Cornelius, C. (2017). A Physician's attempt to self-medicate bipolar depression with N, N-dimethyltryptamine (DMT). Journal of Psychoactive Drugs, 49(4), 294-296.

[0066] The inventors believe that in order to avoid inducing mania or hypomania, or at least reduce the risk of inducing mania or hypomania, the administered compound must be appropriately selected and preferably administered according to a specific dosing regimen.

[0067] The inventors have identified 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) as a psychedelic of particular interest for use in therapy. 5-MeO-DMT has unique pharmacological properties that are distinct from other psychedelic compounds.

[0068] 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist that acts at both 5-HT1A and 5-HT2A receptors, with a higher affinity for the 5-HT1A receptor subtype than other classic psychedelics.

[0069] As further detailed in the Examples section below, the inhibition constants (K) for psilocin (the dephosphorylated form of psilocybin formed following ingestion of psilocybin), DMT, and 5-MeO-DMT at the 5-HT1A receptor located in the hippocampus of postmortem human brains are shown in Table 1. i The inhibitory constants (K values) of psilocybin dephosphate, DMT, and 5-MeO-DMT at the 5-HT2A receptor in the frontal cortex of postmortem human brains were 48, 38, and 1.80 nM, respectively. Thus, 5-MeO-DMT exhibits high affinity for the 5-HT1A receptor, while dephosphopsilin and DMT exhibit moderate affinity. i values) were 37, 117, and 122 nM, respectively. Thus, dephosphorylated psilocybin exhibits moderate / strong affinity for the 5-HT2A receptor, whereas DMT and 5-MeO-DMT exhibit relatively weak affinity.

[0070] Relative to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for the 5-HT1A receptor, where 5-MeO-DMT acts as a potent agonist. Relative to 5-MeO-DMT, the contribution of 5-HT2A binding is increased in the case of dephosphorylated psilocybin and DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A relative to 5-HT2A among the three compounds. Thus, 5-HT1A binding relative to 5-HT2A binding plays a much larger role in the overall effects of 5-MeO-DMT than the other two compounds.

[0071] 5-HT1A agonists reportedly reduce impulsivity and aggression, while 5-HT2A agonists cause short-term increases in these same traits. Additionally, the dopamine system has been implicated in causing mania, with increases in dopamine drive being associated with mania. LSD, psilocybin, and DMT exhibit increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

[0072] Compared to other psychedelics (such as LSD, psilocybin, or DMT), 5-MeO-DMT can be preferably administered to patients using a dosing regimen as described herein without producing a significant risk of inducing mania or hypomania in patients suffering from psychiatric or neurological disorders, including disorders characterized by depressive episodes, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar disorder type I and bipolar disorder type II; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. Patients suffering from such psychiatric or neurological disorders and treated according to the present invention do not experience treatment-induced mania or hypomania.

[0073] It is also noteworthy that reports of treatment-induced mania or hypomania associated with psychoactive substance use appear to indicate use of a large number of the corresponding compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0074] The inventors' sequential up-titration method of 5-MeO-DMT significantly reduces the risk of overdose and the likelihood of attendant adverse events.

[0075] Further, antidepressants have been reported to induce isolated hypomanic episodes in patients with treatment-resistant depression (TRD) (Bader, Cynthia D. and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of induction of hypomania.

[0076] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective described as "loss of self," typically ending in an overwhelming sense of "oneness with the universe") more quickly than other psychedelics and has a shorter duration of acute psychedelic effects (5 to 30 minutes after intravenous injection, compared to, for example, several hours with oral psilocybin and oral LSD). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific alterations in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0077] In addition, 5-MeO-DMT is a 5-HT7 receptor agonist with high affinity for the receptor. The inventors used recombinant human 5-HT7 receptor, [ 3 H]LSD and serotonin to estimate nonspecific binding and determine K i It is 2.3nM.

[0078] Thus, in addition to the 5-HT1A and 5-HT2A receptors discussed above, 5-MeO-DMT also interacts with the 5-HT7 receptor. 5-MeO-DMT acts as an agonist at this receptor and exhibits high (nanomolar) binding affinity.

[0079] The 5-HT7 receptor plays a role in neurogenesis, synaptogenesis and dendritic spine formation. It is associated with central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception, among others.

[0080] 5-HT7 receptors are expressed particularly in Purkinje neurons of the spinal cord, raphe nuclei, thalamus, hypothalamus (including the suprachiasmatic nucleus), hippocampus, prefrontal cortex, striatal complex, amygdala, and cerebellum.

[0081] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination leads to disease states, particularly those involving sleep disturbances. In patients with sleep disturbances, resting-state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0082] The expression of 5-HT7 receptors in the suprachiasmatic nucleus corresponds to the role of said receptors in regulating the sleep / wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disorders by 5-MeO-DMT acting on the receptors.

[0083] The inventors believe that the combination of 5-MeO-DMT and the 5-HT7 receptor (as a mediator of the pharmacological effects of 5-MeO-DMT) involves a "resetting" of the functional connectivity of the network and a neuroplasticity effect, which contributes to the beneficial effects of 5-MeO-DMT in the treatment of patients suffering from sleep disorders.

[0084] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7 receptor and the 5-HT1A receptor (two mediators through which 5-MeO-DMT acts) involves a "resetting" of the functional connectivity of the network and neuroplasticity effects, allowing for beneficial effects in patients suffering from other symptoms or disorders such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or social / emotional withdrawal. This is supported by the clinical results shown in the studies cited herein.

[0085] Another characteristic of 5-MeO-DMT is its short half-life.

[0086] 5-MeO-DMT is primarily inactivated through a monoamine oxidase A-mediated deamination pathway and is O-demethylated by cytochrome P450 2D6 (CYP2D6) enzymes.

[0087] The inventors studied the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

[0088] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0089] The inventors have further determined that 5-MeO-DMT has multiple characteristics that make it an attractive treatment for PPD. Compared to SSRIs, 5-MeO-DMT is a rapid-acting agent (in the 5-MeO-DMT-TRD trial, 5 of 8 TRD patients achieved remission within 2 hours of dosing, 8 patients achieved remission on day 1, and 7 patients maintained remission on day 7). Treatment of PPD patients with 5-MeO-DMT can rapidly improve not only depressive symptoms, but also maternal functioning. In addition, 5-MeO-DMT is administered during a single day of treatment, optionally with infrequent repeated dosing, thus distinguishing it from SSRIs (which require a long-term daily dosing regimen with low compliance) and brexanolide (which requires long-term infusions and hospitalization).

[0090] Thus, the present invention also addresses compliance and patient convenience issues.

[0091] Furthermore, the inventors have determined that treatment of PPD with 5-MeO-DMT or a pharmaceutically acceptable salt thereof allows for continued breastfeeding with only brief interruptions to treatment.

[0092] According to the present invention, isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof may also be used.When referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of isotopic variants is also contemplated.

[0093] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0094] A deuterated form of 5-MeO-DMT is one that contains more deuterium than would be expected based on the natural abundance of this isotope.

[0095] The deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

[0096] 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-dimethylethylamine, 1,1-dideuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, 1,1,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethylamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1H-indol-3-yl]ethylamine.

[0097] Further examples include forms of 5-MeO-DMT in which deuterium has been introduced at one or more hydrogen positions of the N-bound methyl group. Still further examples include forms of 5-MeO-DMT in which one or more deuterium atoms replace hydrogen atoms of the indole ring system. It is also worth noting that combinations of the above substitution patterns are also contemplated.

[0098] Methods for the preparation of these compounds are known in the art.

[0099] Mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of salts of deuterated 5-MeO-DMT and non-deuterated 5-MeO-DMT may also be used in accordance with the present invention.

[0100] Furthermore, according to the present invention, the amount of deuterated 5-MeO-DMT and deuterated 5-MeO-DMT salts used is equimolar to the amount of the corresponding non-deuterated form.

[0101] According to the present invention, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs may also be used. Such prodrugs of 5-MeO-DMT may be converted to 5-MeO-DMT by metabolism. Therefore, when referring to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the 5-MeO-DMT prodrug or a salt thereof may be used instead.

[0102] In a suitable prodrug, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

[0103] An example of a suitable organic moiety is C(O)OR 1 、-C(O)R 2 、-CH(R 3 )OR 4 、-C(O)OCH(R 3 )OC(O)R 4 、-C(O)OCH(R 3 )OC(O)OR 4、-CH(R 3 )C(O)R 4 、-CH(R 3 )OC(O)R 4 、-CH(R 3 )OC(O)OR 4 , where R 1 , R 2 , R 3 and R 4 Each of is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently substituted or unsubstituted.

[0104] A preferred example of an organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , where R 1 , R 3 and R 4 As defined above.

[0105] Prodrugs, especially prodrugs of the above structure, can also be used in the form of pharmaceutically acceptable salts.

[0106] Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0107] Methods for preparing prodrugs as discussed herein are known in the art.

[0108] According to the present invention, the T of the metabolite 5-MeO-DMT measured after oral administration of the prodrug at 10 mg / kg in male Sprague-Dawley (SD) rats max The value is preferably 1 hour or less, more preferably 0.7 hour or less, particularly 0.5 hour or less.

[0109] Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

[0110] Treatment

[0111] As described above, the present invention can treat patients suffering from PPD. Such treatment can not only reduce the scores assessing the severity of depression, but also improve maternal functioning, as discussed in detail below.

[0112] To further support the clinical utility of 5-MeO-DMT in patients suffering from PPD, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients being treated for psychiatric disorders and noted particular improvements in aspects of the disorder that are also commonly observed in patients with PPD. The inventors particularly noted improvements in various symptoms and combinations of symptoms, which the inventors determined were also associated with maternal functioning.

[0113] This data is derived from a recently completed clinical trial investigating the use of 5-MeO-DMT to treat patients diagnosed with treatment-resistant depression (TRD; see also the Examples section below). Although the completed trial did not involve patients suffering from PPD, as discussed in detail below, the inventors determined that certain clinical observations made in the trial were relevant to designing treatments for PPD.

[0114] In clinical trials, 5-MeO-DMT was administered via inhalation (as described in more detail in the Examples section below). Patients were assigned to different groups. Of interest in the context of the present invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed multiple dose increases (6 mg, 12 mg, and 18 mg) throughout the day, depending on the intensity of the psychedelic experience reported by the patient.

[0115] The data collected included assessments of the treated patients on several scales, including the Montgomery Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). Although the focus of the trial was to demonstrate treatment efficacy through improvements in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noticed that several sub-core items were particularly relevant to PPD patients and were related to maternal functioning.

[0116] Multiple patients in the recruited cohort demonstrated significant improvements in one or more of these subscores, confirming the inventors' findings that 5-MeO-DMT is a suitable compound for treating patients with PPD and improving maternal functioning in these patients.

[0117] The specific sub-score items for each scale are described in more detail below. The inventors conclude that efficacy in treating one or more of these symptoms will result in a significant improvement in the overall outcome for PPD patients treated with 5-MeO-DMT.

[0118] Thus, treatment according to the invention reduces or eliminates (or improves or eliminates) some aspect of the disease.

[0119] If the aspect is assessed according to the MADRS scale, there is at least one point improvement (reduction) or the patient is completely relieved (eliminated) after treatment, i.e. the corresponding aspect score is 0.

[0120] If the aspect is assessed according to the BPRS scale, there is at least one point improvement (reduction) or the patient is completely relieved (eliminated) after treatment, that is, the corresponding aspect score is 1.

[0121] The clinical response can also be reflected by a reduction in the Clinical Global Impression-Severity (CGI-S) score. According to the present invention, a reduction in the CGI-S score means that the CGI-S is reduced by at least 1 point. Preferably, the CGI-S is reduced by at least 2 points and / or to 0 points. Particularly preferably, the CGI-S is reduced by at least 3 points and / or to 0 points.

[0122] The inventors further believe that the improvements observed in certain MADRS items will translate into improvements in maternal functioning.

[0123] Particularly relevant MADRS items are discussed in more detail below.

[0124] The MADRS item "Inner Tension" represents feelings of undefined discomfort, irritability, inner confusion, mental tension escalating into panic, fear, or distress. It is rated in terms of intensity, frequency, duration, and degree of reassurance required.

[0125] If the patient is calm and has only brief bouts of nervousness, the score is 0. If there are occasional feelings of irritability and vague discomfort, the score is 2. If there is constant nervousness or intermittent panic that the patient has difficulty controlling, the score is 4. If there is constant fear or distress and overwhelming panic, the score is 6.

[0126] The inventors have determined that an increase in the score of the MADRS item "internal tension" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infants and maternal self-care). As assessed by BIMF, an increase in the score of the MADRS item "internal tension" impairs mother-child interaction and maternal psychological health.

[0127] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF domains of mother-child interaction and / or maternal psychological well-being.

[0128] In the above trial involving patients with TRD, the total score for the MADRS item “Inner Tension” for all 8 patients in the study group receiving the individualized dosing regimen was 26 at baseline. After 2 hours, the score dropped to 11, which corresponds to an improvement of 15 points or 58%. On day J after treatment, the score dropped to 6, which corresponds to an improvement of 20 points or 77%. On day 7 after treatment, the score dropped to 12, which corresponds to an improvement of 14 points or 54%.

[0129] In the 12 mg group, the total score for the MADRS item "internal tension" was 13 at baseline for all 4 patients. After 2 hours, the score dropped to 2, which corresponds to an improvement of 11 points or 85%. On the first day after treatment, the score dropped to 3, which corresponds to an improvement of 10 points or 77%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 8 points or 62%.

[0130] The inventors concluded that 5-MeO-DMT could be used to treat PPD patients to achieve a reduction or elimination of internal tension.

[0131] The improvement in inner tension is reflected in at least an improvement in the score of the MADRS item inner tension at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0132] Improvements in internal tension, as reflected by reductions in Clinical Global Impression-Severity (CGI-S) scores, occurred no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0133] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0134] Improvement in internal tension (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0135] The improvement in inner tension (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0136] The inventors also concluded that the reduction or elimination of inner tension achieved by treating PPD patients not only leads to a decrease in the total MADRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0137] As intrapersonal tension may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "internal tension" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0138] The MADRS item “sluggishness” indicates difficulty starting or slowness in initiating and performing daily activities.

[0139] A score of 0 means almost no difficulty in getting started and no slowness. If the patient has trouble starting an activity, the score is 2. A score of 4 means difficulty starting simple daily activities that require effort. If the patient is completely lazy and cannot do anything without help, the score is 6.

[0140] The inventors have determined that an increase in the score of the MADRS item "lazy" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score of the MADRS item "lazy" impairs infant care, self-care, psychological health, management and regulation.

[0141] Conversely, improvements on this MADRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of infant care, self-care, psychological well-being, management, and / or regulation.

[0142] In the study group that received the individualized dosing regimen, the total score for the MADRS item "slouching" for all eight patients was 27 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 17 points or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 22 points or 81%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 24 points or 89%.

[0143] In the 12 mg group, the total score of the MADRS item "slouching" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 10, which corresponds to an improvement of 6 points or 38%. On the first day after treatment, the score dropped to 0, which corresponds to an improvement of 16 points or 100%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

[0144] The inventors concluded that 5-MeO-DMT could be used to treat PPD patients to achieve a reduction or elimination of sluggishness.

[0145] The improvement in laziness is reflected at least in an improvement in the score of the MADRS item laziness at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0146] Improvement in laziness, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0147] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0148] An improvement in laziness (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0149] The improvement in laziness (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0150] The inventors also concluded that the reduction or elimination of laziness achieved by treating PPD patients not only results in a reduction in the total score of MADRS, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day. Since laziness can also affect other aspects of PPD, the inventors concluded that the observed improvement in the "laziness" item of the MADRS will also contribute to the overall improvement in maternal function.

[0151] The MADRS item "anesthesia" represents the subjective experience of reduced interest in one's surroundings or in activities that normally provide pleasure. A reduced ability to respond to situations or people with appropriate emotion.

[0152] A score of 0 indicates normal interest in one's surroundings and other people, and a score of 2 indicates a reduced ability to enjoy everyday interests. A score of 4 is considered a loss of interest in one's surroundings and a loss of affection for friends and acquaintances. A score of 6 reflects emotional paralysis, the inability to feel anger, sadness, or pleasure, and a complete and even painful loss of affection for friends and family.

[0153] The inventors have determined that an increase in the score of the MADRS item "sensory loss" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score of the MADRS item "sensory loss" impairs mother-child interaction and psychological health.

[0154] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functioning domains mother-child interaction and / or psychological well-being.

[0155] In the study group that received the individualized dosing regimen, the total score for the MADRS item "loss of sensation" for all eight patients was 36 at baseline. After 2 hours, the score dropped to 12, which corresponds to an improvement of 24 points or 67%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 34 points or 94%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 30 points or 83%.

[0156] In the 12 mg group, the total score for the MADRS item "loss of sensation" for all 4 patients was 16 at baseline. After 2 hours, the score dropped to 9, which corresponds to an improvement of 7 points or 44%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%. On the seventh day after treatment, the score dropped to 1, which corresponds to an improvement of 15 points or 94%.

[0157] The inventors concluded that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of sensory loss.

[0158] The improvement in anesthesia is reflected in at least an improvement in the score for the MADRS item anesthesia at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0159] Improvement in anesthesia, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0160] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0161] Improvement in anesthesia (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0162] The improvement in sensory loss (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0163] The inventors also concluded that reducing or eliminating sensory loss by treating PPD patients not only results in a decrease in the total MADRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed at 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. 13 Since sensory loss can also affect other aspects of PPD, the inventors concluded that the observed improvement in the "sensory loss" item of the MADRS will also contribute to the overall improvement in maternal function.

[0164] The MADRS item “difficulty concentrating” indicates difficulty focusing thoughts, resulting in an inability to concentrate.

[0165] If the patient has no difficulty concentrating, the score is 0. If there is occasional difficulty collecting one's thoughts, the score is 2. If the difficulty concentrating and maintaining thoughts leads to reduced ability to read or hold a conversation, the score is 4. If the patient cannot read or hold a conversation easily, the score is 6.

[0166] The inventors have determined that increased scores on the MADRS item "Difficulty Concentrating" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the MADRS item "Difficulty Concentrating" impair infant care and management.

[0167] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domain infant care and / or management.

[0168] In the study group that received the individualized dosing regimen, the total score for the MADRS item "Difficulty concentrating" was 30 at baseline for all eight patients. After 2 hours, the score dropped to 11, which corresponds to an improvement of 19 points or 63%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 29 points or 97%. On the seventh day after treatment, the score dropped to 9, which corresponds to an improvement of 21 points or 70%.

[0169] In the 12 mg group, the total score for the MADRS item "difficulty concentrating" was 16 at baseline for all 4 patients. After 2 hours, the score dropped to 7, which corresponds to an improvement of 9 points or 56%. On the first day after treatment, the score dropped to 2, which corresponds to an improvement of 14 points or 88%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 13 points or 81%.

[0170] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to reduce or eliminate difficulty concentrating.

[0171] The improvement in difficulty concentrating is reflected in at least an improvement in the score for the MADRS item difficulty concentrating at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0172] Improvement in difficulty concentrating, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0173] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0174] Improvement in difficulty concentrating (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0175] The improvement in difficulty concentrating (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0176] The inventors also concluded that reducing or eliminating difficulty concentrating by treating PPD patients not only results in a decrease in the total MADRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed at 7 days; 14 days; and / or 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0177] As difficulty concentrating may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "difficulty concentrating" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0178] The MADRS item “negative thoughts” represents thoughts of guilt, inferiority, self-blame, sin, regret, and destructiveness.

[0179] If there are no pessimistic thoughts, the score is 0. If there are fluctuating thoughts of failure, self-blame, or self-deprecation, the score is 2. The score refers to persistent self-accusations, or clear but still justified thoughts of guilt or sin, and the patient's increasing pessimism about the future. If there are delusions of annihilation, remorse, or irreparable guilt, and absurd and unshakable self-accusations, the score is 6.

[0180] The inventors have determined that increased scores on the MADRS item "pessimistic thoughts" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the MADRS item "pessimistic thoughts" impair psychological health, social support and management.

[0181] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being, social support, and / or management.

[0182] In the study group that received the individualized dosing regimen, the total score for the MADRS item "pessimistic thoughts" for all eight patients was 28 at baseline. After 2 hours, the score dropped to 7, which corresponds to an improvement of 21 points or 75%. On the first day after treatment, the score dropped to 4, which corresponds to an improvement of 24 points or 86%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 25 points or 89%.

[0183] In the 12 mg group, the total score for the MADRS item "pessimistic thoughts" was 16 at baseline for all 4 patients. After 2 hours, the score dropped to 8, which corresponds to an improvement of 8 points or 50%. On the first day after treatment, the score dropped to 7, which corresponds to an improvement of 9 points or 56%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 8 points or 50%.

[0184] The inventors concluded that 5-MeO-DMT could be used to treat PPD patients to achieve a reduction or elimination of pessimistic thoughts.

[0185] The improvement in pessimistic thoughts is reflected in at least an improvement in the score of the MADRS item pessimistic thoughts at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0186] Improvement in pessimistic thoughts, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurred no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0187] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0188] Improvement in pessimistic thoughts (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0189] The improvement in pessimistic thoughts (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0190] The inventors also concluded that reducing or eliminating pessimistic thoughts by treating PPD patients not only leads to a decrease in the total MADRS score, but also leads to an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0191] As negative thoughts may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "negative thoughts" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0192] The MADRS item "Sleep reduction" represents the experience of a decrease in sleep duration or depth compared to the subject's normal pattern when healthy.

[0193] When the subject sleeps normally, the score is 0. A score of 2 reflects mild difficulty falling asleep or slightly reduced, shallow or intermittent sleep. A score of 4 means reduced or interrupted sleep of at least two hours. A score of 6 means less than two or three hours of sleep.

[0194] The inventors have determined that an increase in the score for the MADRS item "Sleep reduction" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). An increase in the score for the MADRS item "Sleep reduction" impairs self-care, psychological health and management.

[0195] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychological well-being, and / or management.

[0196] In the study group that received the individualized dosing regimen, the total score for the MADRS item "reduced sleep" was 25 at baseline for all eight patients. On day 1 after treatment, the earliest time point at which the effect of treatment on sleep was assessed, the score decreased to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score decreased to 9, which corresponds to an improvement of 16 points or 64%.

[0197] In the 12 mg group, the total score of the MADRS item "reduced sleep" for all 4 patients was 12 at baseline. On day 1 after treatment, the score dropped to 10, which corresponds to an improvement of 2 points or 17%. On day 7 after treatment, the score dropped to 6, which corresponds to an improvement of 6 points or 50%.

[0198] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve reduction or elimination of sleep loss.

[0199] Reduction or elimination of sleep loss is reflected in at least an improvement in the score for the MADRS item sleep loss on day 1, e.g., about 24 hours; day 7; day 14; and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0200] Improvement in sleep loss, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0201] Improvement in sleep loss (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0202] The improvement in sleep loss (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0203] The inventors also concluded that reducing or eliminating sleep loss by treating PPD patients not only results in a decrease in the total MADRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 24 hours, and an increase in the BIMF score will be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0204] As sleep reduction may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "sleep reduction" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0205] Another aspect of PPD that can be treated by administering 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to a PPD patient to reduce or eliminate the patient's suicidal ideation.

[0206] In the above-mentioned clinical studies involving 5-MeO-DMT administration, the MADRS item “suicidal thoughts” was assessed.

[0207] "Suicidal ideation" represents a feeling that life is not worth living and that a natural death is desirable, suicidal thoughts, and / or preparations for suicide. Suicide attempts themselves should not affect the rating of this MADRS item.

[0208] A score of 0 means that the patient enjoys life. If the patient with PPD feels tired of life and / or has only brief suicidal thoughts, the score is 2. A score of 4 means that the patient feels that death would be better, suicidal thoughts are common and suicide is seen as a possible solution, but the patient has no specific plan or intention. A score of 6 means that the patient has a clear suicide plan and / or is actively preparing for it.

[0209] This MADRS scale item is particularly relevant to suicidal ideation.

[0210] The inventors have determined that increased scores on the MADRS item "suicidal thoughts" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the MADRS item "suicidal thoughts" impair self-care, psychological health and management.

[0211] Conversely, improvements on this MADRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, psychological well-being, and / or management.

[0212] In the study group that received the individualized dosing regimen, the total score for the MADRS item "suicidal thoughts" for all eight patients was 11 at baseline. After 2 hours, the score dropped to 3, which corresponds to an improvement of 8 points or 73%. On the first day after treatment, the score dropped to 1, which corresponds to an improvement of 10 points or 91%. On the seventh day after treatment, the score dropped to 3, which corresponds to an improvement of 8 points or 73%.

[0213] In the 12 mg group, the total score for the MADRS item "suicidal thoughts" was 8 at baseline for all 4 patients. After 2 hours, the score dropped to 3, which corresponds to an improvement of 5 points or 63%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 3 points or 38%. On the seventh day after treatment, the score dropped to 7, which corresponds to an improvement of 1 point or 13%.

[0214] Thus, the score of the scale item "suicidal ideation", which is particularly relevant to suicidal ideation, was significantly improved, at least in the patients on the individualized dosing regimen. The inventors concluded that 5-MeO-DMT can be used to treat suicidal ideation in patients with PPD.

[0215] Thus, according to the present invention, treatment of a PPD patient suffering from suicidal ideation may reduce or eliminate the suicidal ideation.

[0216] Reduction or elimination of suicidal ideation is reflected at least in an improvement in the score of the MADRS item suicidal ideation at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0217] If the patient suffers from suicidal ideation, improvement in suicidal ideation is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, e.g., about 24 hours; on day 7; on day 14; and / or on day 28.

[0218] Improvement in suicidal ideation, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0219] Alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0220] Improvement in suicidal ideation (assessed as at least a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0221] The improvement in suicidal ideation (assessed as a decrease in the CGI-S score or at least as a "much improved" score in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0222] The inventors also concluded that reducing or eliminating suicidal thoughts by treating PPD patients not only results in a decrease in the total MADRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0223] As suicidal thoughts may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "suicidal thoughts" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0224] The BPRS item "emotional withdrawal" is related to the patient's deficits in expressing emotions in the interview situation. Possible scores are:

[0225] 1- No emotional withdrawal.

[0226] 2 - Very Mild. Lack of emotional engagement, as evidenced by occasional failure to respond to comments, occasional absent-mindedness or a stiff smile, but most of the time interacting spontaneously with the interviewer.

[0227] 3 - Mild. Lack of emotional engagement, as evidenced by an apparent failure to respond to comments, appearing distracted or lacking enthusiasm, but responding when approached by the interviewer.

[0228] 4 - Moderate. Emotional contact is absent during most of the interview, as the subject does not respond in detail, makes no eye contact, does not seem to care whether the interviewer is listening, or may be immersed in the psychotic material.

[0229] 5 - Moderately severe. Same as 4, but emotional contact was absent during most of the interview.

[0230] 6 - Severe. Actively avoids emotional engagement. Frequently unresponsive or yes / no responses (not just due to persecutory delusions). Or only minimally emotionally responsive.

[0231] 7 - Extreme. Consistently avoids emotional engagement. No response or yes / no answers (not just due to persecutory delusions). May walk away during the interview or not respond at all.

[0232] The inventors have determined that increased scores on the BPRS item "emotional withdrawal" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "emotional withdrawal" impair psychological health, mother-child interaction and social support.

[0233] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being, mother-child interaction, and / or social support.

[0234] In the study group that received the individualized dosing regimen, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%.

[0235] In the 12 mg group, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 2 points or 15%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 7 points or 54%.

[0236] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of emotional withdrawal.

[0237] Reduction or elimination of affective withdrawal is reflected in at least an improvement in the score of the BPRS item affective withdrawal at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0238] Improvement in affective withdrawal, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0239] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0240] Improvement in affective withdrawal (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0241] The improvement in affective withdrawal (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0242] The inventors also concluded that reducing or eliminating emotional withdrawal by treating PPD patients not only results in a decrease in the total BPRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0243] Since emotional withdrawal may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "emotional withdrawal" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0244] The BPRS item “Blunting of Emotion” involves a restricted range of emotional expressiveness in the face, voice, and gestures, as well as apparent apathy or indifference even when discussing painful topics. Possible scores are:

[0245] 1- No emotional blunting.

[0246] 2 - Very Mild. Emotional range is slightly suppressed or reserved, but facial expressions and voice intonation are appropriate and within normal range.

[0247] 3 - Mild. Overall reduced, suppressed or reserved emotional range, without many spontaneous and appropriate emotional responses. Slightly monotonous tone of voice.

[0248] 4 - Moderate. The range of emotions is markedly diminished, and except in rare cases, the patient does not show emotion, smile, or respond to distressing topics. The tone of voice or spontaneous movements is markedly reduced. Displays of emotion or gestures usually result in a return of emotion that is cold.

[0249] 5 - Moderate to severe. The range of emotions is very diminished, the patient does not show emotion, smile, or respond to painful topics, and the facial expression does not change often except for minimal, few gestures. The tone of voice is monotonous most of the time.

[0250] 6 - Severe. Very little emotional range or expression. Speech and gestures are mechanical most of the time. Facial expression does not change. Voice intonation is monotonous most of the time.

[0251] 7 - Extreme. There is little emotional range or expression, and movements are stiff. The tone of voice is monotonous at all times.

[0252] The inventors have determined that increased scores on the BPRS item "emotional blunting" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "emotional blunting" impair psychological health and mother-child interaction.

[0253] Conversely, improvements on this BPRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains psychological well-being and / or mother-child interaction.

[0254] The total score for the BPRS item "blunting" was 15 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 4 points or 27%. On the first day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%. On the seventh day after treatment, the score dropped to 8, which corresponds to an improvement of 7 points or 47%.

[0255] In the 12 mg group, the total score for the BPRS item "blunting" was 11 at baseline. After 3 hours, the score dropped to 8, which corresponds to an improvement of 3 points or 27%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 5 points or 45%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 6 points or 55%.

[0256] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of affective blunting.

[0257] Reduction or elimination of blunting is reflected in at least an improvement in the score of the BPRS item blunting at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0258] Improvement in blunted affect, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0259] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0260] Improvement in affective blunting (as reflected at least by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0261] The improvement in affective blunting (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0262] The inventors also concluded that reducing or eliminating blunting of affect by treating PPD patients not only results in a decrease in the total BPRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0263] Since blunting may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "blunting" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0264] The BPRS item “Guilt” is related to excessive concern or regret about past behavior. Possible scores are:

[0265] 1- No guilt.

[0266] 2 - Very Mild. Worries about disappointing someone or failing at something, but is not distracted. Can easily shift thoughts to other things.

[0267] 3-Mild. Worry about disappointing someone or failing at something and tends to be distracted. Tends to express guilt to others.

[0268] 4 - Moderate. Obsessively dwells on guilt, wrongdoing, or hurting others by something they did or did not do, but can easily shift their focus to other things.

[0269] 5 - Moderate to severe. Obsessing over guilt, disappointing someone, or failing at something; can shift focus to other things but only with great effort. Not delusional.

[0270] 6 - Severe. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. Moderate absent-mindedness present.

[0271] 7 - Extreme. Delusional guilt or irrational self-blame that is highly disproportionate to the circumstances. The subject is extremely preoccupied with guilt and may disclose it to others or act on the delusion.

[0272] The inventors have determined that increased scores on the BPRS item "Guilt" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "Guilt" impair self-care, mother-child interaction, psychological health, and management.

[0273] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of self-care, mother-child interaction, psychological well-being, and / or management.

[0274] In the study group that received the individualized dosing regimen, the total score for the BPRS item "guilt" was 34 at baseline for all eight patients. After 3 hours, the score dropped to 14, which corresponds to an improvement of 20 points or 59%. On the first day after treatment, the score dropped to 11, which corresponds to an improvement of 23 points or 68%. On the seventh day after treatment, the score dropped to 10, which corresponds to an improvement of 24 points or 71%.

[0275] In the 12 mg group, the total score of the BPRS item "guilt" for all 4 patients was 18 at baseline. After 3 hours, the score dropped to 9, which corresponds to an improvement of 9 points or 50%. On the first day after treatment, the score dropped to 5, which corresponds to an improvement of 13 points or 72%. On the seventh day after treatment, the score dropped to 5, which corresponds to an improvement of 13 points or 72%.

[0276] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of guilt feelings.

[0277] The reduction or elimination of guilt is reflected in at least an improvement in the score of the BPRS item Guilt at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0278] Improvement in guilt feelings, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0279] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0280] Improvement in guilt feelings (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0281] The improvement in guilt feelings (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0282] The inventors also concluded that reducing or eliminating guilt by treating PPD patients not only results in a decrease in the total BPRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0283] Since guilt also affects other aspects of PPD, the inventors conclude that the observed improvements in the "guilt" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0284] The BPRS item "Anxiety" relates to reported worry, nervousness, fear, panic, or concern. Possible scores are:

[0285] 1- No anxiety.

[0286] 2 - Very Mild. Reports some discomfort due to worrying more often than most normal people or occasionally worrying.

[0287] 3-Mild. Frequent worrying but easily able to shift attention to other things.

[0288] 4 - Moderate. Worried most of the time, unable to easily redirect attention, but functioning is not impaired; occasionally anxious with autonomic symptoms, but functioning is not impaired.

[0289] 5 - Moderate to severe. Frequent but not daily anxiety with periods of autonomic symptoms or disruption of some areas of functioning due to anxiety or worry.

[0290] 6 - Severe. Anxiety is present every day with autonomic symptoms that do not persist throughout the day, or many areas of functioning are disrupted by anxiety or persistent worry.

[0291] 7 - Extreme. Anxiety with autonomic symptoms persists throughout the day, or most areas of functioning are disrupted by anxiety or persistent worry.

[0292] The inventors have determined that increased scores on the BPRS item "Anxiety" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the infant and maternal self-care). Increased scores on the BPRS item "Anxiety" can impair psychological health, social support and management.

[0293] Conversely, improvements on this BPRS item will lead to improvements in maternal functioning, particularly in the BIMF functional domains of psychological well-being, social support, and / or management.

[0294] In the study group that received the individualized dosing regimen, the total score for the BPRS item "Anxiety" for all eight patients was 37 at baseline. After 3 hours, the score dropped to 19, which corresponds to an improvement of 18 points or 49%. On the first day after treatment, the score dropped to 16, which corresponds to an improvement of 21 points or 57%. On the seventh day after treatment, the score dropped to 17, which corresponds to an improvement of 20 points or 54%.

[0295] In the 12 mg group, the total score of the BPRS item "anxiety" for all 4 patients was 25 at baseline. After 3 hours, the score dropped to 11, which corresponds to an improvement of 14 points or 56%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 19 points or 76%.

[0296] The inventors concluded that 5-MeO-DMT could be used to treat PPD patients to achieve a reduction or elimination of anxiety.

[0297] The reduction or elimination of anxiety is reflected in at least an improvement in the score of the BPRS item anxiety at about 2 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, such as about 24 hours, after; at day 7; at day 14; and / or at day 28.

[0298] Improvement in anxiety, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0299] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0300] Improvement in anxiety (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0301] The improvement in anxiety (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0302] The inventors also concluded that reducing or eliminating anxiety by treating PPD patients not only results in a decrease in the total BPRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will be observed on the 1st day, such as about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0303] Since anxiety can also affect other aspects of PPD, the inventors conclude that the observed improvements in the "anxiety" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0304] The BPRS item "Tense" is related to observable physical and motor manifestations of nervousness, "nervousness," and agitation. Possible scores are

[0305] 1- No tension.

[0306] 2 - Very mild. More irritable than most people but within normal limits. Some brief signs of nervousness, such as picking at nails, rocking feet, excessive scratching of scalp, or finger tapping.

[0307] 3 - Mild. Same as "2", but nervous signs are more frequent or exaggerated.

[0308] 4-Moderate. Signs of motor tension are numerous and frequent, sometimes one or more signs occur simultaneously, e.g., shaking of the feet with twisting of the hands. Sometimes signs of tension are absent.

[0309] 5 - Moderate to severe. Many and frequent signs of motor strain, often with one or more signs present at the same time. Still, in rare cases, no signs of strain are present.

[0310] 6 - Severe. Same as "5", but signs of tension are persistent.

[0311] 7 - Extreme. Multiple motor signs of nervousness persist, such as constant pacing and hand twisting.

[0312] The inventors have determined that increased scores on the BPRS item "strain" have a negative impact on two aspects of maternal functioning (maternal ability related to interaction with infant and maternal self-care). Increased scores on the BPRS item "strain" impair mother-child interaction and psychological health.

[0313] Conversely, improvements on this BPRS item would lead to improvements in maternal functioning, particularly in the BIMF functional domains mother-child interaction and / or psychological well-being.

[0314] In the study group that received the individualized dosing regimen, the total score for the BPRS item "Tense" was 16 at baseline for all eight patients. After 3 hours, the score dropped to 11, which corresponds to an improvement of 5 points or 31%. On the first day after treatment, the score dropped to 11, which corresponds to an improvement of 5 points or 31%. On the seventh day after treatment, the score dropped to 10, which corresponds to an improvement of 6 points or 38%.

[0315] In the 12 mg group, the total score of the BPRS item "Tense" was J4 at baseline for all 4 patients. After 3 hours, the score dropped to 9, which corresponds to an improvement of 5 points or 36%. On the first day after treatment, the score dropped to 6, which corresponds to an improvement of 8 points or 57%. On the seventh day after treatment, the score dropped to 6, which corresponds to an improvement of 8 points or 57%.

[0316] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of tension.

[0317] The reduction or elimination of tension is reflected in at least an improvement in the score of the BPRS item tension at about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, such as about 24 hours; on day 7; on day 14; and / or on day 28.

[0318] Improvement in stress, as reflected by a decrease in Clinical Global Impression-Severity (CGI-S) scores, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0319] Additionally or alternatively, the reduction in Clinical Global Impression - Severity (CGI-S) score occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0320] Improvement in stress (at least as reflected by a score of "much improved" on the Clinical Global Impression-Improvement (CGI-I) score or the Patient Global Impression-Improvement (PGI-I) score) preferably occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0321] The improvement in tension (reflected by a decrease in the CGI-S score or at least by a score of "much improved" in the CGI-I score or the PGI-I score) preferably persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0322] The inventors also concluded that reducing or eliminating stress by treating PPD patients not only results in a decrease in the total BPRS score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement will be achieved quickly, i.e., within about 2 hours, and an increase in the BIMF score will also be observed on the 1st day, such as about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0323] Since stress may also affect other aspects of PPD, the inventors conclude that the observed improvements in the "stress" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0324] Improvement in one or more aspects of PPD will also result in overall improvement. Preferably, treatment results in remission.

[0325] Relief of depressive symptoms can be reflected by a MADRS score equal to or less than 10 and occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; occurs on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0326] Alternatively or additionally, relief from depressive symptoms may be reflected by a HAM-D score equal to or less than 7 and occurring no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; occurring on day 1, e.g., about 24 hours later; on day 7; on day 14; and / or on day 28.

[0327] As can be seen from the above, the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to treat PPD patients not only leads to a reduction in MADRS scores (especially including the sub-scores detailed above), but also improves the domains of the BIMF scale. As discussed in the Examples section below, clinical data confirms a reduction in MADRS scores and an improvement in maternal function.

[0328] The improvement of maternal function includes the improvement of self-care function domain.For example, the improvement of MADRS project laziness and / or sleep reduction can lead to the increase of BIMF scale score reflecting self-care.The improvement of the cumulative score of BIMF scale project reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0329] The improvement of maternal function includes the improvement of infant care function area.For example, the improvement of MADRS project lazy and / or difficulty concentrating can lead to the increase of BIMF scale score reflecting infant care.The improvement of the cumulative score of BIMF scale project reflecting self-care is preferably at least 15%, more preferably at least 25%.

[0330] The improvement of maternal function includes the improvement of mother-child interaction functional domain. For example, the improvement of MADRS project sensory loss and inner tension can lead to the increase of BIMF scale score reflecting mother-child interaction. The improvement of the cumulative score of BIMF scale project reflecting mother-child interaction is preferably at least 5%, more preferably at least 15%.

[0331] The improvement of maternal function includes the improvement of mental health function field.For example, the improvement of MADRS project laziness, pessimistic thoughts, sensory loss, inner tension and / or sleep reduction can lead to the increase of BIMF scale score reflecting mental health.The improvement of the cumulative score of BIMF scale project reflecting mental health is preferably at least 25%, more preferably at least 35%.

[0332] The improvement of maternal function includes the improvement of social support function domain. For example, the improvement of pessimistic thoughts of MADRS project will lead to the increase of BIMF scale score reflecting social support. The improvement of the cumulative score of BIMF scale project reflecting social support is preferably at least 10%, more preferably at least 20%.

[0333] The improvement of maternal function includes the improvement of management function area.For example, the improvement of MADRS project laziness, pessimistic thoughts and / or difficulty in concentrating attention can lead to the increase of BIMF scale score reflecting management.The improvement of the cumulative score of BIMF scale project reflecting management is preferably at least 20%, more preferably at least 30%.

[0334] The improvement of maternal function includes the improvement of the domain of regulation function. For example, the improvement of MADRS item laziness can lead to an increase in the BIMF scale score reflecting regulation. The improvement of the cumulative score of the BIMF scale items reflecting regulation is preferably at least 5%, more preferably at least 15%.

[0335] Improvement in maternal functioning relates to one or more, in particular two or more, domains of functioning selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

[0336] The BIMF total score is improved by 10% or more, preferably by 20% or more.

[0337] Breastfeeding

[0338] As noted above, for many medications, a breastfeeding patient with PPD may be faced with a situation where a decision must be made whether to discontinue breastfeeding or discontinue / abstain from treatment.

[0339] If a decision is made to stop breastfeeding in order to receive treatment, this decision will have a negative impact on maternal functioning, particularly impairing areas of functioning such as mother-child interaction and psychological well-being.

[0340] The present invention also addresses the need for treating PPD in breastfeeding mothers without nearly completely interrupting breastfeeding.

[0341] According to the present invention, breastfeeding can be resumed shortly after treatment.

[0342] The inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT to determine the time point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt that breastfeeding can be initiated without exposing the breastfed infant to any associated risks.

[0343] Absorption and distribution of inhaled 5-MeO-DMT are rapid, with maximum concentrations and pharmacological effects observed during and immediately after dosing.

[0344] The plasma protein binding rate is low (13-23%).

[0345] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation showed that plasma concentrations decreased very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; after 2 hours, concentrations were 1% or less of Cmax; and after 3 hours, 5-MeO-DMT was no longer detected in the plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration over a time range of 1 to 4 hours. Up-titration as disclosed herein does not result in accumulation and therefore does not result in higher plasma concentrations, for example, 10 minutes, 2 hours, or 3 hours after administration.

[0346] Metabolites of 5-MeO-DMT that may occur in humans were identified to assess the potential relevance of such metabolites. In an in vitro metabolic characterization study in human hepatocytes, 5-MeO-DMT free base was incubated at 10 μM for up to 120 minutes. The identified compounds and their relative proportions are shown in Table 1 below:

[0347] Table 1

[0348] Compound Relative proportion Bufotenine (5-OH-DMT) 5％ 5-MeO-DMT 7％ 5-MeO-DMT-N-oxide 1％ 5-Methoxyindole-3-ethanol (5-methoxytryptol) 25％ 5-Methoxyindoleacetic acid (5-MIAA) 61％

[0349] It is noteworthy that subsequent assays repeatedly failed to detect the presence of 5-methoxytryptol but reproducibly demonstrated the presence of 5-MIAA as the major metabolite. Therefore, 5-methoxytryptol is unlikely to play any significant role in vivo.

[0350] The metabolites listed in the table above are formed via three different pathways.

[0351] The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindole-3-ethanol, are formed by oxidative deamination. This involves enzymatic removal of the N-methyl group and oxidation to form acetaldehyde:

[0352]

[0353] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0354] No secondary amines, primary amines, or aldehydes were identified, indicating that they were not present in significant concentrations at any time.

[0355] The aldehyde intermediate metabolite undergoes two independent biotransformations in human hepatocytes. The aldehyde intermediate metabolite is either oxidized to 5-methoxyindoleacetic acid or reduced to 5-methoxyindole-3-ethanol.

[0356]

[0357] Both resulting metabolites are endogenous substances and are formed in the human body, for example, during the synthesis and metabolism of melatonin and serotonin (see, for example, Chapter 3 in Melatonin and the Mammalian Pineal Gland. Biochemistry of the Pineal. Arendt J (ed.) Chapman & Hall, 1995; Chapter 3 in Slominski R and Slominski AT. Melatonin in the Promotion of Health. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Watson RR (ed.) CRC Press 2012).

[0358] Because the major pathway of 5-MeO-DMT metabolism rapidly produces metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the oxidative deamination of 5-MeO-DMT does not involve metabolites that would require restrictions on breastfeeding.

[0359] Furthermore, as described in detail in the Examples section, incubation of 5-methoxytryptol with human hepatocytes indicated a high metabolic turnover rate, with the compound completely eliminated within 24 hours. At a test concentration of 1 μM, the in vitro intrinsic clearance of 5-methoxytryptol was 16.2 μl / min / million cells (half-life 142 minutes).

[0360] Therefore, the plasma concentration of 5-methoxytryptol (to the extent that it is formed) will drop rapidly and reach endogenous levels.

[0361] 5-MIAA is a weak acid that will be present in plasma in an ionized form, thereby reducing the possibility of the compound entering breast milk.

[0362] Incubation of 5-MIAA with human hepatocytes indicated a low metabolic turnover rate, with the remaining 5-MIAA concentration being 75-82% after 72 h. 5-MIAA is considered to be the final metabolite of 5-MeO-DMT.

[0363] 5-MIAA exhibits a relatively low plasma binding rate (mean unbound fraction (Fu); see Examples section) of about 50%. After renal clearance, 5-MIAA remains in the circulation. Given the standard glomerular filtration rate of 90-120 ml / min, this means that within approximately 1-2 hours, all traces of 5-MIAA are removed from the circulation and excreted in the urine (depending on the patient's size and taking into account the increase in blood volume that occurs during pregnancy).

[0364] Therefore, the plasma concentration of 5-MIAA will also decrease rapidly.

[0365] Together with the rapid clearance of 5-MeO-DMT (<1 hour), this supports the notion that the administered therapy and all associated metabolites are cleared from the circulation within approximately 2 hours.

[0366] Another identified metabolite, bufotoxin, is the result of O-demethylation catalyzed by CYP2D6. The resulting metabolite is then glucuronidated by UGT:

[0367]

[0368] As part of the pharmacokinetic studies, it was determined that bufotoxin was virtually undetectable in human serum. In any case, bufotoxin was undetectable 15 minutes after administration of 5-MeO-DMT.

[0369] Toad serotonin glucuronide cannot bind to the receptor and does not play any role. In addition, the concentration of toad serotonin glucuronide is so low that it cannot be detected in the hepatocyte assay. Toad serotonin glucuronide is further converted to 5-hydroxyindoleacetic acid:

[0370]

[0371] 5-Hydroxyindoleacetic acid is an endogenous substance which is present, for example, in the metabolism of melatonin and serotonin (cf. above).

[0372] Since the O-demethylation pathway of 5-MeO-DMT produces the major metabolite bufotoxin, which is rapidly cleared from plasma and further metabolism produces compounds that are only present at very low concentrations and ultimately produce metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the O-demethylation of 5-MeO-DMT does not involve metabolites that require restrictions on breastfeeding.

[0373] The third metabolic pathway involves N-oxidation:

[0374]

[0375] In computer simulations of the metabolites formed, 5-MeO-DMT-N-oxide was found to be non-genotoxic, which is consistent with the negative in vitro genotoxicity assessment of the parent molecule. As confirmed by observations in rats, the compound is soluble in water and rapidly excreted (Sitaram, BR, Lockett, L., Blackman, GL, McLeod, WR, 1987. Urinary excretion of 5-methoxy-N, N-dimethyltryptamine, N, N-dimethyltryptamine and their N-oxides in the rat. Biochemical Pharmacology 36: 2235-2231). Since the 5-MeO-DMT metabolic pathway involving N-oxidation plays only a minor role and results in a low proportion of non-apparently toxic metabolites that are rapidly excreted, the inventors determined that N-oxidation of 5-MeO-DMT does not involve metabolites that require restrictions on breastfeeding.

[0376] Based on the above, the inventors determined that breastfeeding can be resumed shortly after treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0377] Therefore, if the patient is a breastfeeding mother, she is advised to discontinue breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Specifically, she is advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0378] Preferably, breastfeeding must be interrupted for only 6 hours, more preferably, for only 3 hours, and most preferably, for only 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0379] This brief interruption and the possibility of resuming breastfeeding soon after treatment contribute to the success of treatment, particularly in terms of maternal function and the health and development of the infant.

[0380] Mode of administration

[0381] Therapeutically effective amounts of 5-MeO-DMT are administered intravenously, intramuscularly, or subcutaneously. Administration via these routes can ensure rapid onset of action. The most preferred route of administration is via the intravenous route, i.e., administration by intravenous injection.

[0382] 5-MeO-DMT can be used in the form of a pharmaceutically acceptable salt, preferably a hydrobromide salt, or in the form of a formulation for administration via injection, and examples of excipients and vehicles for such formulations are known in the art.

[0383] Dosage regimen

[0384] The present invention also provides dosage ranges, specific dosages and dosing regimens (administration regimens) and appropriate administration routes.

[0385] The present invention is based in part on the inventors' conclusion that peak psychedelic experiences occur during the acute phase following administration of 5-MeO-DMT, which drives the therapeutic benefit of 5-MeO-DMT in patients suffering from PPD, particularly one or more aspects defined above, either causally or at least as a surrogate behavioral marker for a potential unknown therapeutic mechanism.

[0386] Therefore, achieving peak experience more quickly in a greater proportion of patients and with better reproducibility in individual patients will result in a better therapeutic profile than previously tested psychedelics, dosing regimens, and routes of administration.

[0387] Furthermore, the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e., the absence of waning or loss of psychedelic effects upon re-administration) as a basis for enabling a dosing regimen of frequent re-administration (such as more than once daily or once daily) designed to increase the incidence of peak experiences, thereby increasing therapeutic benefit. Such repeated administrations over a short period of time also allow for intra-individual dose optimization, which reduces the risk of overdose, which may otherwise result in physical side effects such as serotonin syndrome, negative psychotic reactions (such as flashbacks of the experience at a later time point), induction of mania or hypomania, or less meaningful psychedelic experiences with little or no memory of the altered state (so-called "whiteouts"). Furthermore, starting with a low dose allows the patient to become familiar with the general psychedelic experience and allows for preparation for the more intense symptoms that occur at higher doses, which will have a positive impact on the experience at the higher doses. Furthermore, the prospect of being able to begin treatment at a low dose will increase patient acceptance of the treatment approach and improve overall compliance rates at the patient population level.

[0388] Frequent re-administration of serotonergic psychedelics to increase the frequency and modulate the repeatability of peak experiences and to enhance therapeutic efficacy, reduce side effects, and improve compliance rates may not be possible with other psychedelics due to the late onset and prolonged duration of psychedelic effects and the rapid development of tolerance (i.e., diminished or absent psychedelic effects following re-administration) that may persist for several days.

[0389] Patients diagnosed with postpartum depression as defined herein (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) are treated by administering 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy, i.e., the patient does not receive any treatment for PPD or symptoms associated with PPD.

[0390] In preferred amounts, the dosage range of 5-MeO-DMT administered to a patient diagnosed with postpartum depression as defined herein (including treatment-resistant forms of the disorder and including the disorder associated with suicidal ideation) is about 1 mg to about 10 mg, or any range therein, and is administered in the form of an administration formulation based on a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt, the weight of which can be calculated based on the specified weight of the 5-MeO-DMT free base assuming the use of equimolar amounts. Useful specific amounts of 5-MeO-DMT are, for example, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, and about 10 mg. Please note that in this specification, when a range is listed (such as "about 1 mg to about 10 mg"), the inventors consider all discrete values ​​within the range, some of which are explicitly mentioned, but not all of them - this is only for the purpose of brevity.

[0391] In a preferred embodiment, the improved method of treating a patient diagnosed with postpartum depression as defined herein (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) using a therapeutically effective amount of 5-MeO-DMT comprises the onset of a clinical response no later than about 2 hours after administration of the 5-MeO-DMT.

[0392] In preferred embodiments, improved methods of treating patients diagnosed with postpartum depression as defined herein, including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation, using a therapeutically effective amount of 5-MeO-DMT include a sustained clinical response, including a clinical response that occurs no later than about 2 hours after administration of 5-MeO-DMT, until at least about 6 days after the last administration of 5-MeO-DMT, preferably until at least about 14 days after the last administration of 5-MeO-DMT, and more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0393] In preferred embodiments, improved methods of treating patients diagnosed with postpartum depression as defined herein (including treatment-resistant forms of the disorder, and including the disorder associated with suicidal ideation) with a therapeutically effective amount of 5-MeO-DMT comprise administering more than a single dose of 5-MeO-DMT.

[0394] In a preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0395] In an even more preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 24 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0396] In a most preferred embodiment, the more than single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, the interval between each administration within each treatment block is about 1 to 4 hours, preferably 1 to 2 hours, and the interval between the end of one treatment block and the beginning of the next treatment block is no less than about 6 days.

[0397] In embodiments, the dosage of 5-MeO-DMT administered to an individual patient in each administration and each treatment block is constant for that individual patient and is selected from about 1 mg to about 10 mg.

[0398] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and then increased with each subsequent administration within each treatment block until reaching 10 mg, or all administrations within that treatment block have been administered, whichever is earlier.

[0399] In an even more preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient is selected from about 1 mg to about 2 mg at the first administration within each treatment block and is then increased with each subsequent administration within each treatment block until the earlier of: reaching 10 mg, or all administrations within that treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects.

[0400] For embodiments in which the dose of a subsequent administration is increased, the dose of the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dose of the previous administration. For example, if the first administration dose is 1 mg and the dose increase is 3 mg, the second administration dose is 4 mg unless one of the aforementioned stopping criteria has been met. Preferably, the third administration dose is 7 mg.

[0401] In a preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1 mg to about 3 mg at the first administration, and then increased to a dose selected from about 4 mg to about 6 mg at the second administration, and to a dose selected from about 7 mg to about 9 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician determines that further increases in the dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0402] In another preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 0.5 mg to about 1.5 mg at the first administration, and then increased to a dose selected from about 1.5 mg to about 2.5 mg at the second administration, and to a dose selected from about 2.5 mg to about 3.5 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0403] In a further preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in a first treatment block is selected from about 1 mg to about 2 mg, and then increased with each subsequent administration within the first treatment block until the earlier of: reaching 10 mg, or all administrations within the treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician determines that further increases in the dose are inappropriate based on observed side effects, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 8 mg, because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks is 8 mg.

[0404] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 1 mg to about 2 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration in the first treatment block will be increased to a dose selected from about 7 mg to about 9 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 2 mg, about 5 mg, and about 8 mg.

[0405] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient at the first administration in the first treatment block is selected from about 0.5 mg to about 1.5 mg, and then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further increases in dose are inappropriate based on observed side effects, the second administration in the first treatment block will be increased to a dose selected from about 1.5 mg to about 2.5 mg, and the third administration in the first treatment block will be increased to a dose selected from about 2.5 mg to about 3.5 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. Useful specific amounts for the first, second, and third administrations in the first treatment block are, for example, about 1 mg, about 2 mg, and about 3 mg.

[0406] It will be appreciated that pharmaceutically acceptable salts of 5-MeO-DMT may also be used in all of the above dosing regimens and that the appropriate weight of the salt to be administered may be calculated based on the specified weight of the free base, assuming equimolar amounts are used.

[0407] According to the present invention, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0408] Patients can be identified as having a "peak psychedelic experience" by achieving at least 60% of the maximum possible score on each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item Revised Mystical Experience Questionnaire (MEQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).

[0409] Whether a patient has a “peak psychedelic experience” can also be determined by achieving at least 60% of the maximum possible score on the Oceanic Nothingness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018;8:974).

[0410] According to the present invention, whether a patient has a "peak psychedelic experience" is preferably identified by achieving a total score of at least 75 points in the Peak Experience Scale (PES), which is also called the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient's responses from 0 to 100 to the following three questions: 1. How intense was the experience; 2. How much loss of control was there; 3. How significant (i.e., profound and important) was the experience?

[0411] Other aspects of the invention

[0412] 1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient suffering from postpartum depression (PPD), wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

[0413] 2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 1, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher.

[0414] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 2, wherein the patient has a MADRS score of 28 or higher or a HAM-D score of 22 or higher.

[0415] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 2, wherein the patient has a MADRS score of 35 or higher or a HAM-D score of 27 or higher.

[0416] 5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 4, wherein the patient is diagnosed with a treatment-resistant form of postpartum depression.

[0417] 6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 5, wherein the patient also suffers from suicidal ideation.

[0418] 7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 6, wherein the patient also suffers from mildly impaired, impaired maternal function.

[0419] 8. 5-MeO-DMT or a pharmaceutically 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.

[0420] 9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 8, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

[0421] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 9, wherein a dose of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0422] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 9, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0423] 12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 9, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0424] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 10, wherein the 5-MeO-DMT or a salt thereof is administered at a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a higher dose than the previous administration unless the patient experiences a peak psychedelic experience.

[0425] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 10 or 13, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for the first administration, then increased to a dose of about 4 mg to about 6 mg for the second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for the third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

[0426] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 14, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0427] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 10 or 13, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for the first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for the second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for the third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

[0428] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 16, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0429] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 13 to 17, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.

[0430] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 9 to 18, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the Ocean-like Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

[0431] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 19, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

[0432] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 20, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

[0433] 22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 21, wherein the clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the clinical response is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

[0434] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 22, wherein the clinical response occurs on the first day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, such as about 24 hours, and the clinical response is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

[0435] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 23, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0436] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 24, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0437] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 25, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0438] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 27, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the clinical response is assessed as an improvement of at least 50% in MADRS or HAM-D score compared to the corresponding score before treatment.

[0439] 28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 27, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the clinical response is assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

[0440] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 24, wherein relief of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the relief of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0441] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 29, wherein relief of depressive symptoms occurs on the 1st day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, such as about 24 hours, and the relief of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0442] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 30, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0443] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 31, wherein there is a clinical response at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

[0444] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 32, wherein the patient is in remission of depressive symptoms on the 7th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0445] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 33, wherein the clinical response, assessed as an improvement of at least 50% in MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0446] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 34, wherein there is a clinical response at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

[0447] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 35, wherein the patient is in remission of depressive symptoms on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0448] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 36, wherein the clinical response, assessed as an improvement of at least 50% in MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0449] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 37, wherein there is a clinical response on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

[0450] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 38, wherein the patient is in remission of depressive symptoms on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms being assessed as an M[ADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0451] 40. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0452] 41. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0453] 42. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0454] 43. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0455] 44. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0456] 45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 44, wherein said treatment improves maternal function.

[0457] 46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspect 45, wherein the improvement relates to one or more, in particular two or more, functional areas selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

[0458] 47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 45 or 46, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

[0459] Example

[0460] The following examples are set forth to aid in the understanding of the present invention and are not intended to, and should not be construed to, limit the invention described in the claims that follow in any manner.

[0461] Example 1-5 - MeO-DMT Aerosol Generation and Administration

[0462] Step 1: Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask so that a 200 μl solution volume contains the target dose of 5-MeO-DMT free base to be administered to the volunteer or patient via inhalation. A typical target dose is 1 mg to 25 mg 5-MeO-DMT. For example, for a target dose of 18 mg 5-MeO-DMT, dissolve 90 mg of 5-MeO-DMT in 100% ethanol in a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

[0463] Step 2: 200 μl of the solution was transferred into a dosing capsule (Storz & Bickel, Germany) containing a drip pad and then the lid of the dosing capsule was closed.

[0464] Step 3: The dosing capsules filled with the 5-MeO-DMT ethanol solution were transferred to the filling chamber of the first Volcano Medic vaporizer, which was preheated and set to 55°C. The gas flow of the vaporizer was then turned on for 60 seconds at a preset rate of approximately 12 l / min. The heated air would flow through the dosing capsules, allowing the ethanol to evaporate, while the target dose of 5-MeO-DMT remained in the capsules as a thin layer covering the stainless steel mesh. The accurate preparation of the dosing capsules was confirmed by demonstrating that the final weight gain of the capsules was approximately equal to the target dose of 5-MeO-DMT compared to the empty capsule weight.

[0465] Step 4: The prepared dosing capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second VolcanoMedic vaporizer, which has been preheated, set to 210°C, and the airflow is turned on for at least 5 minutes, then turned off immediately before transfer. A valved inhalation balloon (Storz & Bickel, Germany) is mounted on the socket of the filling chamber, the filling chamber is tightly closed, and the airflow is immediately turned on at a preset flow rate of approximately 121 / min for 15 seconds and then turned off. This will allow the entire dose of 5-MeO-DMT to be aerosolized and distributed in the approximately 3 liters of air in the inhalation balloon. Accurate aerosolization of 5-MeO-DMT can be confirmed by demonstrating that the capsule weight has returned to approximately its initial weight.

[0466] Step 5: The balloon is then disconnected from the filling chamber, which automatically closes the valve. After the mouthpiece is connected to the balloon, the aerosol is ready to be immediately administered to the volunteer or patient.

[0467] Step 6: To prepare for administration, ask the patient to first take 1-2 deep breaths, exhale completely, and end the process with a deep exhalation. Then, hold the mouthpiece firmly against the lips, inhale the entire volume of the balloon in one breath, hold the breath for 10 (± 2.5) seconds, and then exhale normally. After completing the inhalation procedure, instruct the patient to lie down.

[0468] Further details regarding administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020 / 169850A1, the contents of which are incorporated herein by reference.

[0469] Example 2 - Preparation of High Purity 5-MeO-DMT

[0470] 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 volumes) at 35 to 40 ° C and then cooled to room temperature within 30 minutes. After stirring at room temperature for 50 minutes, no crystallization was observed, so the batch temperature was reduced to 7 to 12 ° C within 30 minutes. Crystallization occurred after stirring at 7 to 12 ° C for 10 minutes. It was then stirred at 7 to 12 ° C for 1 hour, and the batch was subsequently filtered. After washing with MTBE (1 mL, 0.5 volumes) at 7 to 12 ° C, the batch was dried under vacuum for 3.5 hours to obtain 1.02 g of light orange solid (50% recovery). As described in WO 2020 / 169850 A1, the purity of the separated solid was analyzed by HPLC. The purity is 99.74% area.

[0471] The analytical results further indicated that the level of individual impurities was less than 0.10% area. Solvent analysis of the sample indicated MTBE level was 17 ppm.

[0472] Example 3-5-Preparation of MeO-DMT Hydrobromide

[0473] 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0474] 5-MeO-DMT free base was combined with isopropyl acetate (10 vol) and the resulting 5-MeO-DMT solution was heated to 50° C. HBr (1 M in ethanol, 1 eq) was charged in a single aliquot. The mixture was maintained at this temperature and equilibrated for 3 hours.

[0475] After 1 hour, a suspension was formed. The suspension was finally cooled to room temperature and equilibrated for 18 hours. The solid was isolated by filtration and dried in vacuo at 40°C for 18 hours.

[0476] An off-white crystalline material was obtained.

[0477] The salt has a melting point of 174°C and is characterized in that it has an X-ray diffraction pattern comprising peaks at 14.5°2·±0.2°2·; 16.7°2·±0.2°2·; 17.0°2·±0.2°2·; 20.6°2·±0.2°2·; 20.7°2·±0.2°2·; 21.4°2·±0.2°2·; 24.2°2·±0.2°2·; 24.8°2·±0.2°2·; 25.3°2·±0.2°2·; 27.4°2·±0.2°2·; which is measured using Cu K· radiation.

[0478] Example 4 - Determination of Inhibition Constants of Central 5-HT1A and 5-HT2A Receptors in Postmortem Human Brain Membranes Preparations

[0479] In the present study, the affinity of three psychedelic test compounds (psilocybin dephosphate, 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.

[0480] Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors died suddenly, had no history of coma, psychiatric or neurological disease, were under 65 years old, and had a postmortem interval of less than or equal to 72 hours.

[0481] Binding to 5-HT1A receptors in postmortem human hippocampus

[0482] The hippocampus was homogenized in ice-cold 0.25M sucrose (1:30 weight / volume) using an electric Teflon pestle (grinding 12 times at 120rpm). Myelin and cell debris were removed by centrifugation at 1,000g for 10 minutes. The supernatant was stored on ice, and the pellet was homogenized again in 0.25M sucrose (1:15 weight / volume) and centrifuged at 750g for 10 minutes. The supernatants were combined and diluted with ice-cold membrane preparation buffer (1:100 weight / volume), using a tightly fitting glass / Teflon homogenizer (12 times, 800rpm), and centrifuged at 20,500g for 10 minutes. The pellet was resuspended in ice-cold membrane preparation buffer and incubated at 37°C for 10 minutes, then centrifuged at 20,500g for 10 minutes. The pellet was resuspended and centrifuged for the last time to wash the tissue (20,500xg, 10 minutes). The resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equal to 3.125 mg tissue wet weight / ml. All centrifugations were performed at 4°C. The membrane preparation buffer consisted of 50 mM Tris-HCl, pH 7.7, 4 mM CaCl 2 The assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCl 2, 0.1% ascorbic acid and 10 μM Pargyline.

[0483] For saturation binding assays, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue / tube) were incubated with 50 μl of 0.075-9.6 nM [ 3 H] 8-OH-DPAT and 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY 100635 (non-specific binding) were incubated for 30 minutes at 25° C. Wash buffer consisted of 50 mM Tris, pH 7.7.

[0484] In the displacement assay, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue / tube) were mixed with 50 μl of 0.6 nM [ 3 H] 8-OH-DPAT and 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 ten concentrations between 1 and 10000 nM were incubated at 25°C for 30 min.

[0485] Membrane-bound radioactivity was recovered by vacuum filtration through Skatron 11731 filters presoaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. The filters were quickly washed with ice-cold wash buffer (wash settings 0,9,9) and radioactivity was determined by liquid scintillation counting (1 ml Packard MV Gold scintillation counter).

[0486] Nonlinear regression was used to calculate the compound concentration required to inhibit specific binding by 50% (IC 50 ) and the Hill slope. K was calculated using a single-site binding model that allowed for ligand depletion. i .

[0487] Binding to 5-HT2A receptors in postmortem human frontal cortex

[0488] The frontal cortex was homogenized in ice-cold 0.25M sucrose (1:30 weight / volume) using an electric Teflon pestle (12 times at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 minutes. The supernatant was stored on ice, and the pellet was re-homogenized in 0.25M sucrose (1:15 weight / volume) and centrifuged at 750 g for 10 minutes. The supernatants were combined and diluted with ice-cold 50 mM Tris-HCl assay buffer, pH 7.4 (1:100 weight / volume), homogenized using a tightly fitting glass / Teflon homogenizer (12 times, 800 rpm), and centrifuged at 20,500 g for 10 minutes. The pellet was further centrifuged twice to wash the tissue (20,500 x g, 10 minutes). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, with a tissue concentration equal to 10 mg tissue wet weight / ml. All centrifugations were performed at 4°C.

[0489] For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg tissue wet weight / tube) were mixed with 50 μl of 0.00625-0.8 nM [ 3 H]MDL-100,907 and 50 μl of assay buffer or 50 μl of 10 μM ketanserin (non-specific binding) were incubated for 60 minutes at 25° C. Assay and wash buffers consisted of 50 mM Tris-HCl buffer pH 7.4.

[0490] In the displacement assay, frontal cortex membranes (400 μl; equivalent to 4 mg wet weight tissue / tube) were incubated 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 (nonspecific binding) or 50 μl of one of ten concentrations of test compound between 1 and 10000 nM for 60 min at 25°C.

[0491] Membrane-bound radioactivity was recovered and determined as described above. Data analysis was also performed as described above.

[0492] result

[0493] Confirmed 3 The dissociation constant (K) of 8-OH-DPAT for 5-HT1A receptors in the hippocampal membrane of postmortem human brain tissue from three donors d The obtained dissociation constant (K d values) were 0.51, 0.28 and 0.52 nM, respectively.

[0494] Average inhibition constants (K) of dephosphorylated psilocybin, DMT, and 5-MeO-DMTi The Hill slopes of all compounds were close to unity, indicating a single-site binding model.

[0495] Confirmed 3 Dissociation constant (K) of MDL-100,907 for 5-HT2A receptors in the frontal cortex membranes of postmortem human brain tissue from three donors d The obtained dissociation constant (K d values) were 0.11, 0.08 and 0.08 nM respectively.

[0496] Average inhibition constants (K) of dephosphorylated psilocybin, DMT, and 5-MeO-DMT i The Hill slopes for all compounds were close to unity, indicating a single-site binding model.

[0497] The selectivity ratios of dephosphorylated psilocybin, DMT, and 5-MeO-DMT for 5-HT2A receptors over 5-HT1A receptors are 0.78, 3.1, and 68, respectively.

[0498] Example 5 - Clinical Trial in Patients Suffering from TRD

[0499] A Phase 1 / 2 clinical trial of 5-MeO-DMT administered via inhalation as described herein has been completed in patients with treatment-resistant major depressive disorder (TRD). This trial is designed in two parts. Part A is an open-label, single-arm, single-dose Phase 1 trial with two dose levels (12 mg (n=4) and 18 mg (n=4)). Part B is an open-label, single-arm Phase 2 trial with an individualized dosing regimen and a step-wise increase in the 5-MeO-DMT dose within the patient. Patients (n=8) receive at least one and up to three doses of 5-MeO-DMT (6 mg, 12 mg, and 18 mg) per day, with higher doses only being administered when the previously administered dose does not achieve a peak experience. The primary endpoint of Part A is to evaluate the safety and tolerability of a single dose of 5-MeO-DMT in TRD patients. The primary endpoint of Part B is to evaluate the effect on depression severity, as assessed by the proportion of patients who are relieved on the seventh day after administration, with relief defined as a total MADRS score of less than or equal to 10.

[0500] In Part A, 3 of 4 patients in both groups (12 mg and 18 mg) experienced at least one ADR, all of which were mild and resolved spontaneously. No SAEs were reported.

[0501] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission on day 7 after dosing, and another patient (25%) in the 18 mg group had MADRS clinical response on day 7 after dosing. The mean MADRS change from baseline on day 7 was -21.0 (-65%) in the 12 mg group and -12.8 (-41%) in the 18 mg group.

[0502] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0503] At day 7, seven of eight patients (87.5%) achieved MADRS remission, achieving the primary endpoint (p<0.0001).The mean MADRS change from baseline at day 7 was 24.4 (76%).

[0504] No clinically significant changes were observed in any safety laboratory analyses, vital signs, psychiatric safety assessments, or measures of cognitive function in Part A or Part B.

[0505] The results are summarized in the table below.

[0506]

[0507]

[0508] Table 2-A Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing regimen (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment 2 hours (MADRS) or 3 hours (BPRS) after administration of the last dose.

[0509] Scale items Scale Baseline IDR Day 1 Improvement on Day 1 Percent Improvement Reduced sleep MADRS 25 12 13 52.00％ Difficulty concentrating MADRS 30 1 29 96.67％ Laziness MADRS 27 5 22 81.48％ Loss of sensation MADRS 36 2 34 94.44％ Inner tension MADRS 26 6 20 76.92％ Pessimistic thoughts MADRS 28 4 24 8571％ Suicidal thoughts MADRS 11 1 10 90.91％ Guilt BPRS 34 11 23 67.65％ nervous BPRS 16 11 5 31.25％ anxiety BPRS 37 16 21 56.76％ Emotional withdrawal BPRS 13 8 5 38.46％ Emotional blunting BPRS 15 8 7 46.67％

[0510] Table 2-B Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment on Day 1.

[0511]

[0512]

[0513] Table 2-C. Scores recorded for relevant MADRS and BPRS items for patients assigned to intra-day individualized dosing (IDR). Item scores represent the sum of individual patient scores for all patients in the IDR group (n=8). Assessment on Day 7.

[0514]

[0515] Table 3-A Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment 2 hours (MADRS) or 3 hours (BPRS) after dose administration.

[0516]

[0517]

[0518] Table 3-B Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 1.

[0519]

[0520] Table 3-C. Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessment on Day 7.

[0521] Example 6-5-Pharmacokinetic Evaluation of MeO-DMT and Toxoplasmamine

[0522] To study the pharmacokinetic properties of 5-MeO-DMT, three groups of 8 subjects were divided. Subjects were administered a single dose of 6 mg, 12 mg, or 18 mg 5-MeO-DMT via inhalation. Blood samples were obtained at 1, 2, 4, 7, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, and 4 hours after administration, respectively.

[0523] 5-MeO-DMT concentrations were determined using LC-MS / MS. PK parameters were generated by algebraic analysis of concentration versus time plots for each individual. Analysis was performed using Phoenix WinNonlin 6.3 software.

[0524] The median Cmax values ​​obtained for the three groups were 11.85 ng / ml (6 mg group), 22.90 ng / ml (12 mg group), and 38.45 ng / ml (18 mg group), respectively.

[0525] Table 4 below shows the median percentage of plasma concentration relative to Cmax determined at the indicated time points.

[0526]

[0527] Pharmacokinetic measurements were also performed for a dosing regimen that relied on up-titration, and substantially similar results were obtained.

[0528] The blood concentration of the 5-MeO-DMT metabolite bufotoxin was also determined. Only in a few samples were the concentrations above the lower limit of quantification (LLOQ) (25 pg / ml). From 15 minutes onwards, the bufotoxin concentrations were always below the LLOQ.

[0529] Essentially similar observations were made when subjects who received an up-titration regimen were included.

[0530] Example 7-5-Toxicology Testing of MeO-DMT

[0531] 5-MeO-DMT did not induce mutations in four histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101). These conditions included treatment at concentrations up to 5000 μg / plate (the maximum concentration recommended according to current regulatory guidelines) in the absence and presence of a rat liver metabolic activation system (S-9).

[0532] Example 8-5-Binding of MeO-DMT to human plasma proteins

[0533] In vitro binding of 5-MeO-DMT to plasma proteins was determined using high throughput dialysis. Equilibrium times and nonspecific binding were determined using human plasma at a nominal 5-MeO-DMT concentration of 1 μM. After evaluation of the equilibrium data, plasma protein binding was studied at nominal concentrations of 0.1, 1, and 10 μM using a 4 hour dialysis time. The concentration of 5-MeO-DMT in samples from the plasma and buffer compartments was determined by LC-MS / MS. The protein binding results are shown below:

[0534] Table 5 Percentage of 5-MeO-DMT free fraction in human plasma

[0535] 5-MeO-DMT(μM) people 0.1 78.7 1 77.3 10 87.0

[0536] Example 9-5-Human Metabolism of MeO-DMT

[0537] Nominal concentrations of 1 μM and 10 μM of 5-MeO-DMT were incubated with human hepatocytes (1×10 6 cells / mL) suspended in Leibovitz L-15 medium.

[0538] A 20 mM 5-MeO-DMT standard stock solution was prepared in ethanol and further diluted to a concentration of 2 mM with Leibovitz L-15 medium. For incubation with cryopreserved hepatocytes, the 2 mM stock solution was diluted to a concentration of 20 μM or 2 μM with Leibovitz L-15 medium. Aliquots (250 μL) of the 20 μM and 2 μM test substance preparations were appropriately added to each hepatocyte incubation sample (250 μL) so that the final test substance concentration in the incubation solution was 10 μM or 1 μM, respectively, and the incubation solution contained less than 1% (volume / volume) of solvent.

[0539] Incubations were performed in a shaking water bath at approximately 37°C (total incubation volume was 0.5 mL). For 1 μM, incubations were terminated after 0, 5, 10, 20, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile (0.5 mL). For 10 μM, incubations were terminated after 0, 10, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile containing an internal standard (1 μg / mL dephosphopsilocybin-d10).

[0540] The samples were vortexed and centrifuged at approximately 13,000 rpm for 10 minutes at room temperature. After centrifugation, the protein-free supernatant was removed for analysis.

[0541] Blank control incubations were performed using Leibovitz L-15 medium instead of the test substance. For the cell-free control samples, Leibovitz L-15 medium was used instead of the hepatocytes. Aliquots of the blank control samples were taken at 120 minutes, while for the 1 μM incubations, cell-free control samples were taken at 0, 30 and 120 minutes, and for the 10 μM incubations, cell-free control samples were taken at 0 and 120 minutes.

[0542] All 1 μM incubations were performed in duplicate, while all 10 μM incubations were performed in single runs. All samples were stored at -80°C (nominal) prior to analysis.

[0543] Developed suitable chromatographic conditions to retain the parent compound and give suitable chromatographic response. 0, 30 and 120 minutes of incubation samples produced after 10 μM 5-MeO-DMT incubation were analyzed using reversed phase LC-MS analysis to generate high energy and low energy mass spectra (MSE). Before sample analysis, 100 μL aliquots of each sample were evaporated to near dryness at room temperature under a stable nitrogen stream, and then redissolved in 50 μL mobile phase A (0.1% formic acid in water). Each sample (0, 30 and 120 minutes, 10 μM) was analyzed using accurate mass LC-MS to determine the relative level of the parent compound at each time point, and to determine the profile of the metabolites formed. Appropriate blank samples and control samples were also analyzed. 10 μM incubation samples at 10 minutes and 60 minutes were not analyzed and stored at -80°C (nominal).

[0544] The presence of metabolites in the data was queried using screening software (UNIFI version 1.9.4) and user-defined search parameters by comparing retention times to test substance reference standards and based on the accurate masses of potential metabolites. To confirm suspected metabolites, the measured accurate mass of peaks detected in samples for structural elucidation had to be within 5 ppm of the theoretical mass to confirm the molecular formula.

[0545] Table 1 above summarizes the results obtained.

[0546] Example 10- Metabolic stability of 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptol in a human hepatocyte co-culture model

[0547] In the Hμrel co-culture assay with human hepatocytes (Hμrel HumanPool TM The metabolic stability of 5-MIAA and 5-methoxytryptol was studied in a primary liver co-culture model (from Visikol Inc.).

[0548] Incubations were performed using 1 and 10 μM initial concentrations and samples were taken at 0, 1, 2, 4, 8, 24, 48 and 72 hours (h) time points. The samples were analyzed using UPLC / QE-orbitrap-MS.

[0549] The table below shows the remaining LC / MS peak area of ​​the test compounds detected using the Hμrel co-incubation assay after each incubation time point relative to the corresponding 0 min incubation sample. The results of the control diazepam assay (disappearance half-life) indicated that the enzyme activity was within normal levels.

[0550] Table 6 - Relative LC / MS peak areas of 5-MIAA after 0-72h incubation. Initial substrate concentrations were 1 and 10 μM (n=2 at 1 μM, n=1 at 10 μM).

[0551]

[0552] Table 7 - Relative LC / MS peak areas of 5-methoxytryptol after 0-72 h incubation. Initial substrate concentrations were 1 and 10 μM (n=2 at 1 μM, n=1 at 10 μM).

[0553]

[0554] A low metabolic turnover of 5-MIAA was observed, with a residual abundance of 75-82% after 72 h in the presence of hepatocytes, whereas no disappearance was observed in stromal cell controls.

[0555] For 5-methoxytryptol, a high metabolic turnover was observed, with complete disappearance within 24 h in the presence of hepatocytes but not in stromal cell controls.

[0556] Using human hepatocytes and a 1 μM test concentration, the in vitro intrinsic clearance of 5-MIAA was 0.15 μl / min / million cells (half-life 15400 min), while the corresponding value for 5-methoxytryptol was 16.2 μl / min / million cells (half-life 142 min).

[0557] The predicted hepatic extractability of 5-MIAA is 2% and that of 5-methoxytryptol is 67%.

[0558] Example 11-5- Plasma Binding of MIAA

[0559] Binding to human plasma proteins was determined. Unbound scores (fu) from triplicate experiments are reported as well as the mean unbound score, standard deviation and mean % recovery (Table 8).

[0560]

[0561] Example 12 - Clinical Trial of Administering 5-MeO-DMT to Patients with Postpartum Depression via Inhalation

[0562] This single-arm, open-label clinical trial will involve 15 adult female patients clinically diagnosed with postpartum depression (PPD).

[0563] Patients received a single-day individualized 5-MeO-DMT dosing regimen via vaporized inhalation.

[0564] More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.

[0565] 1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

[0566] 2. The second dose (12 mg) will be administered only in the following cases:

[0567] a. Peak experience (total score ≥ 75) not achieved after 6 mg dose, and

[0568] b. According to the researchers, the 6 mg dose was safe and well tolerated.

[0569] c. Any psychoactive effects (PsE) from the previous dose have resolved, and

[0570] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0571] 3. Similarly, the third dose (18 mg) will only be administered if:

[0572] a. Peak experience not achieved after 12 mg dose (total score ≥ 75), and

[0573] b. According to the researchers, the 12 mg dose was safe and well tolerated, and

[0574] c. Any PsE from the previous dose has resolved, and

[0575] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0576] Patients will be assessed for peak psychedelic experience (based on a patient-rated visual analog scale, or PE scale), sedation, and other endpoints after dosing. Follow-up visits are planned on days 1 and 7 after dosing.

[0577] All patients considered for participation in a clinical trial must meet the following criteria:

[0578] 1. Be female and be between 18 and 45 years old (inclusive) at the time of screening.

[0579] 2. Body mass index (BMI) at screening is between 18.5 and 35 kg / m 2 is within the range of (including the end value).

[0580] 3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or registered psychologist:

[0581] a. A diagnosis of major depressive disorder without psychotic features confirmed by the Mini-International Neuropsychiatric Interview (MINI), with perinatal onset no earlier than pregnancy and no later than the first 4 weeks postpartum.

[0582] b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at screening and on Day 0 before dosing.

[0583] 6. Patients must stop breastfeeding at the time of screening; or if they are still breastfeeding or actively breastfeeding at the time of screening, they must agree to temporarily stop breastfeeding from before receiving the study drug on Day 0 to 24 hours after the last dose, and express and discard all breast milk within these 24 hours as needed, but they need to express / discard breast milk 2.5 hours after the last dose and 24 hours after the last dose before they can resume breastfeeding.

[0584] 4. Must agree to complete abstinence (completely avoid heterosexual intercourse) or use highly effective (failure rate <1%), medically approved contraceptive methods 30 days before administration and 90 days after 5-MeO-DMT administration. Patients must have negative pregnancy test results at screening and the day before the test (Day 1).

[0585] 5. Willing to postpone the start of other antidepressant or antianxiety medications until after the end of the trial on Day 7, and agree to keep any psychological therapy unchanged during the trial.

[0586] Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

[0587] 1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder, manic or hypomanic episodes, psychotic disorders, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient unsuitable for the trial.

[0588] 2. 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).

[0589] 3. The patient is at significant risk of suicide based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as judged by the trial psychiatrist or registered psychologist.

[0590] 4. Taking antidepressants within 14 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

[0591] 5. Any other drug with monoamine oxidase inhibitor (MAOI) activity has been taken within 14 days or 5 half-lives (whichever is longer) before administration.

[0592] 6. Previous serious adverse reactions to hallucinogenic or psychedelic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) based on the investigator's judgment.

[0593] 7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

[0594] 8. Any current or past clinically significant illness that, in the investigator's judgment, makes the patient unsuitable for participation in the trial (e.g., severe infection, lung disease, uncontrolled hypertension, new-onset gestational hypertension disorder during pregnancy or postpartum (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia), uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness).

[0595] 9. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

[0596] 10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

[0597] 11. Patient has a positive pregnancy test at Screening or the day before testing (Day -1), is pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT administration.

[0598] 12. The patient has a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0599] The primary objective of the trial was to determine the onset and 7-day durability of the antidepressant effect of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult female patients with PPD.

[0600] Secondary objectives were to determine the antidepressant effects, anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE) of a single-day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult women with PPD; and effects on cognitive outcomes.

[0601] The exploratory objective was to determine the amounts of 5-MeO-DMT and metabolites, bufotoxin, and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine (metabolite identification screening may be performed as needed) following single-day administration of a single individualized IDR (6 mg, 12 mg, and 18 mg 5-Meo-DMT) to adult female PPD patients as measured by LC / MS / MS.

[0602] The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

[0603] Secondary endpoints included evaluation of the antidepressant effect of 5-MeO-DMT by:

[0604] The antidepressant effects of 5-MeO-DMT were evaluated by:

[0605] o Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

[0606] ο Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

[0607] o Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0608] o Change from baseline in Clinical Global Impression-Severity (CGI-S) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0609] Effects on maternal behavior, as assessed by change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores;

[0610] Exposure to 5-MeO-DMT and bufotoxin in breast milk obtained on the day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, on the evening of Day 0, and on Days 1 and 7;

[0611] 5-MeO-DMT and bufotoxin exposure in blood obtained one day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, and on Days 1 and 7;

[0612] To evaluate the safety and tolerability of 5-MeO-DMT by:

[0613] ο Reporting of treatment-emergent adverse events (TEAEs);

[0614] ο Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, peak flow spirometry;

[0615] o Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA / S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

[0616] o Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0617] o Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0618] ο Change from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0619] ο Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0620] Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

[0621] ο PsE assessment using the Peak Experience (PE) scale to assess the achievement of PE (PE scale total score ≥ 75);

[0622] ο Challenging Experience Questionnaire (CEQ);

[0623] οMystical Experience Questionnaire (MEQ-30);

[0624] PsE duration was defined as the time from study drug administration to when PsE had resolved (investigator-rated and patient-rated), which was completed within 30 to 60 minutes after each dose.

[0625] Currently, one patient diagnosed with postpartum depression by a psychiatrist has been recruited to participate in the clinical trial. The diagnosis of major depressive disorder without psychotic features was confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2) with perinatal onset no earlier than during pregnancy and no later than the first 4 weeks postpartum. The patient was diagnosed with postpartum depression after the birth of her third child. The patient completed all scheduled clinic days. The inhalation procedure was adequately performed by the patient and well tolerated, with no adverse events related to the inhalation.

[0626] result

[0627] Apart from a transient, clinically insignificant increase in heart rate and blood pressure shortly after 5-MeO-DMT administration, no other noteworthy changes in vital parameters occurred. ECG (3 hours after administration) and safety laboratory analysis (7 days), CADSS (3 hours, 1 day, and 7 days) were unremarkable. The few adverse events reported (left abdominal cramping pain and headache, both on day 0) were mild, transient, and resolved spontaneously by the end of the study.

[0628] Regarding the intensity of the psychedelic experience, the PES score achieved upon exposure to the nominal dose of 6 mg was recorded to be 17.3. This score indicates that a subsequent higher dose of 12 mg is required as per the design of the individualized dosing regimen. The PES score achieved at this dose was 85.7 and ≥75, indicating that this patient experienced a peak psychedelic experience and completed the IDR.

[0629] Importantly, patients reported significant improvements in their depressive symptoms, as assessed by MADRS at the earliest assessment time point (2 hours) after drug administration, and the effect was maintained over time (Table 9). Patients also met the criteria for MADRS response (at least 50% improvement relative to baseline) and MADRS remission (MADRS total score equal to or less than 10).

[0630] Table 9-MADRS / BPRS scoring table

[0631]

[0632] Significant improvements were noted in particular for several MADRS items. The individual items are summarized in Table 9. Patients had baseline scores for several items that reflected the absence of symptoms (decreased appetite, difficulty concentrating, suicidal thoughts), while scores for items that reflected severe symptoms (e.g., decreased sleep, inner tension) improved significantly.

[0633] Likewise, several BPRS items improved, including somatic problems, anxiety, emotional withdrawal, guilt, and tension.

[0634] Additionally, as summarized in Table 10, improvements in maternal function were demonstrated by the improvement in BIMF scores recorded on Day 7, with the total score increasing from 92 to 105, an improvement of 14% (total score can be 120).

[0635] Several domains of maternal functioning as defined by Barkin et al were also assessed. Table 11 summarizes the improvements in each domain of functioning in more detail.

[0636] Here, significant improvements in self-care, mental health and management were achieved, with % improvements ranging from 18% (management) to (44%) % (self-care). These improvements reinforced the relationship between improvements in depression items, as assessed by MADRS and improvements in maternal functioning.

[0637] It is noteworthy that the patient's scores were relatively high before treatment. In some functional areas, the scores were at or near the maximum (see Table 11), making the scope for improvement through treatment limited.

[0638] Table 10-BIMF score table

[0639]

[0640]

[0641] Table 11-BIMF functional area scoring table

[0642]

[0643] Summary and Conclusion

[0644] A. An individualized dosing regimen of 6 mg 5-MeO-DMT followed by 12 mg 5-MeO-DMT via inhalation was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

[0645] B. Rapid clinical response within 2 hours after 5-MeO-DMT administration. This rapid onset of action is not common and has not been seen in traditional antidepressant classes, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), etc., which usually take 4 to 6 weeks to show effects.

[0646] C. According to the IDR, the patient experienced clinical remission within 2 hours of 5-MeO-DMT administration. This is superior to any approved treatment for postpartum depression as well as all previously tested psychedelics.

[0647] D. Although 5-MeO-DMT was only administered once and is no longer effectively present in the body within this time frame (see pharmacokinetic data in Example 6 above), a significant clinical response persisted over the 7-day follow-up period. This observation supports the superior clinical profile of 5-MeO-DMT and allows for convenient dosing intervals.

[0648] E. In addition to the antidepressant effects, endpoints assessing other symptoms (such as somatic problems, emotional withdrawal, anxiety, guilt, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

[0649] F. In addition to the antidepressant effects, endpoints assessing maternal functioning such as self-care, psychological well-being, and management assessed using the BIMF were also positively affected, supporting the idea that 5-MeO-DMT has additional benefits beyond improving core depressive symptoms in patients with PPD.

[0650] The salient aspects demonstrate that, when used in accordance with the present invention, 5-MeO-DMT has significantly improved efficacy compared to approved pharmacotherapy for postpartum depression and all previously tested psychedelics.

[0651] Combined with the short duration of the acute psychedelic effect and the favorable safety profile, these data suggest that the present invention solves the technical problem of providing improved psychoactive therapies for patients with postpartum depression.

[0652] Example 13 - Clinical Trial of Administering 5-MeO-DMT to Postpartum Depression Patients Via Intravenous Injection - Prophetic Example

[0653] This clinical trial will involve adult female patients clinically diagnosed with postpartum depression (PPD).

[0654] Patients receive a single daily individualized 5-MeO-DMT dosing regimen by intravenous injection. 5-MeO-DMT will be provided in the form of its hydrobromide salt and an intravenous injection formulation. It should be understood that the doses of 5-MeO-DMT mentioned below are related to the weight of the free base, while the doses of 5-MeO-DMT hydrobromide salt can be calculated assuming the use of equimolar amounts.

[0655] More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 2 mg, 5 mg, and 8 mg.

[0656] 1. All patients will receive an initial dose of 2 mg 5-MeO-DMT.

[0657] 2. The second dose (5 mg) will be administered only in the following cases:

[0658] a. Peak experience not achieved after 2 mg dose (total score ≥ 75), and

[0659] b. According to the researchers, the 2 mg dose was safe and well tolerated,

[0660] c. Any psychoactive effects (PsE) from the previous dose have resolved, and

[0661] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0662] 3. Similarly, the third dose (8 mg) will only be administered if:

[0663] a. Peak experience not achieved after 5 mg dose (total score ≥ 75), and

[0664] b. According to the researchers, the 5 mg dose was safe and well tolerated,

[0665] c. Any PsE from the previous dose has resolved, and

[0666] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0667] Patients will be assessed for peak psychedelic experience (based on a patient-rated visual analog scale, or PE scale), sedation, and other endpoints after dosing. Follow-up visits are planned on days 1 and 7 after dosing.

[0668] All patients considered for participation in a clinical trial must meet the following criteria:

[0669] 1. Be female and be between 18 and 45 years old (inclusive) at the time of screening.

[0670] 2. Body mass index (BMI) at screening is between 18.5 and 35 kg / m 2 is within the range of (including the end value).

[0671] 3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or registered psychologist:

[0672] a. A diagnosis of major depressive disorder without psychotic features confirmed by the Mini-International Neuropsychiatric Interview (MINI), with perinatal onset no earlier than pregnancy and no later than the first 4 weeks postpartum.

[0673] b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at screening and on Day 0 before dosing.

[0674] 6. Patients must stop breastfeeding at the time of screening; or if they are still breastfeeding or actively breastfeeding at the time of screening, they must agree to temporarily stop breastfeeding from before receiving the study drug on Day 0 to 24 hours after the last dose, and express and discard all breast milk within these 24 hours as needed, but they need to express / discard breast milk 2.5 hours after the last dose and 24 hours after the last dose before they can resume breastfeeding.

[0675] 4. Must agree to complete abstinence (completely avoid heterosexual intercourse) or use highly effective (failure rate <1%), medically approved contraceptive methods 30 days before administration and 90 days after 5-MeO-DMT administration. Patients must have negative pregnancy test results at screening and the day before the test (Day 1).

[0676] 5. Willing to postpone the start of other antidepressant or antianxiety medications until after the end of the trial on Day 7, and agree to keep any psychological therapy unchanged during the trial.

[0677] Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

[0678] 1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder, manic or hypomanic episodes, psychotic disorders, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient unsuitable for the trial.

[0679] 2. 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).

[0680] 3. The patient is at significant risk of suicide based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as judged by the trial psychiatrist or registered psychologist.

[0681] 4. Taking antidepressants within 14 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

[0682] 5. Any other drug with monoamine oxidase inhibitor (MAOI) activity has been taken within 14 days or 5 half-lives (whichever is longer) before administration.

[0683] 6. Previous serious adverse reactions to hallucinogenic or psychedelic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) based on the investigator's judgment.

[0684] 7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

[0685] 8. Any current or past clinically significant illness that, in the investigator's judgment, makes the patient unsuitable for participation in the trial (e.g., severe infection, lung disease, uncontrolled hypertension, new-onset gestational hypertension disorder during pregnancy or postpartum (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia), uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness).

[0686] 9. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

[0687] 10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

[0688] 11. Patient has a positive pregnancy test at Screening or the day before testing (Day -1), is pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT administration.

[0689] 12. The patient has a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0690] The primary objectives of the trial were to determine the onset and 7-day durability of the antidepressant effect of a single-day individualized dosing regimen (2 mg, 5 mg, and 8 mg 5-MeO-DMT) in adult female patients with PPD.

[0691] Secondary objectives were to determine the antidepressant effects, anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE) of a single-day individualized dosing regimen (2 mg, 5 mg, and 8 mg 5-MeO-DMT) in adult women with PPD; and effects on cognitive outcomes.

[0692] The exploratory objective was to determine the amounts of 5-MeO-DMT and metabolites, bufotoxin, and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine (metabolite identification screening could be performed as needed) following single-day administration of a single individualized IDR (2 mg, 5 mg, and 8 mg 5-MeO-DMT) to adult female PPD patients as measured by LC / MS / MS.

[0693] The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

[0694] Secondary endpoints included evaluation of the antidepressant effects of 5-MeO-DMT by:

[0695] The antidepressant effects of 5-MeO-DMT were evaluated by:

[0696] o Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

[0697] ο Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

[0698] o Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0699] o Change from baseline in Clinical Global Impression-Severity (CGI-S) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0700] Effects on maternal behavior, as assessed by change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores;

[0701] Exposure to 5-MeO-DMT and bufotoxin in breast milk obtained on the day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, on the evening of Day 0, and on Days 1 and 7;

[0702] 5-MeO-DMT and bufotoxin exposure in blood obtained one day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, and on Days 1 and 7;

[0703] To evaluate the safety and tolerability of 5-MeO-DMT by:

[0704] ο Reporting of treatment-emergent adverse events (TEAEs);

[0705] ο Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, peak flow spirometry;

[0706] o Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA / S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

[0707] o Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0708] o Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0709] ο Change from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0710] ο Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0711] Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

[0712] ο PsE assessment using the Peak Experience (PE) scale to assess the achievement of PE (PE scale total score ≥ 75);

[0713] ο Challenging Experience Questionnaire (CEQ);

[0714] οMystical Experience Questionnaire (MEQ-30);

[0715] Duration of PsE was defined as the time from the time of study drug administration to the time when PsE had resolved (investigator-rated and patient-rated), which was completed within 30 to 60 minutes after each dose;

[0716] Example 14 - Clinical Trial of Administering 5-MeO-DMT to Postpartum Depression Patients Via Intravenous Injection - Prophetic Example

[0717] This clinical trial will involve adult female patients clinically diagnosed with postpartum depression (PPD).

[0718] Patients receive a single daily individualized 5-MeO-DMT dosing regimen by intravenous injection. 5-MeO-DMT will be provided in the form of its hydrobromide salt and an intravenous injection formulation. It should be understood that the doses of 5-MeO-DMT mentioned below are related to the weight of the free base, while the doses of 5-MeO-DMT hydrobromide salt can be calculated assuming the use of equimolar amounts.

[0719] More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 1 mg, 2 mg, and 3 mg.

[0720] 1. All patients will receive an initial dose of 1 mg 5-MeO-DMT.

[0721] 2. The second dose (2 mg) will be administered only in the following cases:

[0722] a. Peak experience not achieved after 1 mg dose (total score ≥ 75), and

[0723] b. According to the researchers, the 1 mg dose was safe and well tolerated,

[0724] c. Any psychoactive effects (PsE) from the previous dose have resolved, and

[0725] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0726] 3. Similarly, the third dose (3 mg) will only be administered if:

[0727] a. Peak experience not achieved after 2 mg dose (total score ≥ 75), and

[0728] b. According to the researchers, the 2 mg dose was safe and well tolerated,

[0729] c. Any PsE from the previous dose has resolved, and

[0730] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges, or if outside the normal range, were of no clinical significance according to the investigator.

[0731] Patients will be assessed for peak psychedelic experience (based on a patient-rated visual analog scale, or PE scale), sedation, and other endpoints after dosing. Follow-up visits are planned on days 1 and 7 after dosing.

[0732] All patients considered for participation in a clinical trial must meet the following criteria:

[0733] 1. Be female and be between 18 and 45 years old (inclusive) at the time of screening.

[0734] 2. Body mass index (BMI) at screening is between 18.5 and 35 kg / m 2 is within the range of (including the end value).

[0735] 3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or registered psychologist:

[0736] a. A diagnosis of major depressive disorder without psychotic features confirmed by the Mini-International Neuropsychiatric Interview (MINI), with perinatal onset no earlier than pregnancy and no later than the first 4 weeks postpartum.

[0737] b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at screening and on Day 0 before dosing.

[0738] 6. Patients must stop breastfeeding at the time of screening; or if they are still breastfeeding or actively breastfeeding at the time of screening, they must agree to temporarily stop breastfeeding from before receiving the study drug on Day 0 to 24 hours after the last dose, and express and discard all breast milk within these 24 hours as needed, but they need to express / discard breast milk 2.5 hours after the last dose and 24 hours after the last dose before they can resume breastfeeding.

[0739] 4. Must agree to complete abstinence (completely avoid heterosexual intercourse) or use highly effective (failure rate <1%), medically approved contraceptive methods 30 days before administration and 90 days after 5-MeO-DMT administration. Patients must have negative pregnancy test results at screening and the day before the test (Day 1).

[0740] 5. Willing to postpone the start of other antidepressant or antianxiety medications until after the end of the trial on Day 7, and agree to keep any psychological therapy unchanged during the trial.

[0741] Potential patients who meet any of the following key exclusion criteria will be excluded from this trial:

[0742] 1. Based on medical history, psychiatric assessment and MINI evaluation, currently or previously diagnosed with bipolar disorder, manic or hypomanic episodes, psychotic disorders, major depressive disorder (MDD) or other mood disorders with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual disability, or any other psychiatric comorbidity that, in the investigator's judgment, makes the patient unsuitable for the trial.

[0743] 2. 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).

[0744] 3. The patient is at significant risk of suicide based on medical history, psychiatric evaluation, and assessment of suicidal ideation and behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), as judged by the trial psychiatrist or registered psychologist.

[0745] 4. Taking antidepressants within 14 days or 5 half-lives (whichever is longer) before administration (exception: in the case of fluoxetine, within the past 5 weeks).

[0746] 5. Any other drug with monoamine oxidase inhibitor (MAOI) activity has been taken within 14 days or 5 half-lives (whichever is longer) before administration.

[0747] 6. Previous serious adverse reactions to hallucinogenic or psychedelic drugs (e.g., psilocybin, Psilocybe spp. mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) based on the investigator's judgment.

[0748] 7. Known allergy or hypersensitivity to 5-MeO-DMT or any other contraindications.

[0749] 8. Any current or past clinically significant illness that, in the investigator's judgment, makes the patient unsuitable for participation in the trial (e.g., severe infection, lung disease, uncontrolled hypertension, new-onset gestational hypertension disorder during pregnancy or postpartum (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia), uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness).

[0750] 9. Taking any medication or other substance that, in the judgment of the researcher, makes the patient unsuitable for participating in the trial.

[0751] 10. Clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that render the patient unsuitable for the trial, based on the investigator's judgment.

[0752] 11. Patient has a positive pregnancy test at Screening or the day before testing (Day -1), is pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT administration.

[0753] 12. The patient has a DSM-5 drug or alcohol use disorder within 6 months prior to screening.

[0754] The primary objectives of the trial were to determine the onset and 7-day durability of the antidepressant effect of a single-day individualized dosing regimen (1 mg, 2 mg, and 3 mg 5-MeO-DMT) in adult female patients with PPD.

[0755] Secondary objectives were to determine the antidepressant effects, anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE) of a single-day individualized dosing regimen (1 mg, 2 mg, and 3 mg 5-MeO-DMT) in adult women with PPD; and effects on cognitive outcomes.

[0756] The exploratory objective was to determine the amounts of 5-MeO-DMT and metabolites, bufotoxin, and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine (metabolite identification screening could be performed as needed) following single-day administration of a single individualized IDR (1 mg, 2 mg, and 3 mg 5-MeO-DMT) to adult female PPD patients, as measured by LC / MS / MS.

[0757] The primary endpoint of this study was to evaluate the antidepressant effect of 5-MeO-DMT as assessed by the change from baseline in the MADRS at day 7.

[0758] Secondary endpoints included evaluation of the antidepressant effects of 5-MeO-DMT by:

[0759] The antidepressant effects of 5-MeO-DMT were evaluated by:

[0760] o Proportion of patients in remission (MADRS ≤ 10) 2 hours after the final dose of study drug on Day 0, Day 1, and Day 7;

[0761] ο Change from baseline in MADRS assessed 2 hours after the final study drug dose on Day 0 and on Day 1;

[0762] o Proportion of responders (reduction in MADRS total score ≥50% from baseline) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0763] o Change from baseline in Clinical Global Impression-Severity (CGI-S) 2 hours after the final study drug dose on Day 0, Day 1, and Day 7;

[0764] Effects on maternal behavior, as assessed by change from baseline to day 7 in the Barkin Index of Maternal Functioning (BIMF) total and subscale scores;

[0765] Exposure to 5-MeO-DMT and bufotoxin in breast milk obtained on the day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, on the evening of Day 0, and on Days 1 and 7;

[0766] 5-MeO-DMT and bufotoxin exposure in blood obtained one day before testing (Day 1), 1 hour after the last dose of study drug, at discharge, and on Days 1 and 7;

[0767] To evaluate the safety and tolerability of 5-MeO-DMT by:

[0768] ο Reporting of treatment-emergent adverse events (TEAEs);

[0769] ο Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, peak flow spirometry;

[0770] o Sedation assessment (Modified Observer Assessment of Alertness and Sedation [MOAA / S]) was performed after each dose (when PsE resolved and 60 minutes after each study drug dose) and as part of the discharge evaluation on Day 0;

[0771] o Change from baseline in the Clinically Administered Dissociative State Scale (CADSS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0772] o Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Days 0, 1, and 7;

[0773] ο Change from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0774] ο Change from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0775] Patient-experienced PsE was reported 30 to 60 minutes after each dose, at which time PsE had resolved:

[0776] ο PsE assessment using the Peak Experience (PE) scale to assess achievement of PE (PE scale total score ≥ 75):

[0777] ο Challenging Experience Questionnaire (CEQ);

[0778] οMystical Experience Questionnaire (MEQ-30);

[0779] PsE duration was defined as the time from study drug administration to when PsE had resolved (investigator-rated and patient-rated), which was completed within 30 to 60 minutes after each dose.

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating a patient suffering from postpartum depression (PPD), wherein the 5-MeO-DMT is administered via intravenous, intramuscular or subcutaneous routes.

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 1, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher.

3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 2, wherein the patient has a MADRS score of 28 or higher or a HAM-D score of 22 or higher.

4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 2, wherein the patient has a MADRS score of 35 or higher or a HAM-D score of 27 or higher.

5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 4, wherein the patient is diagnosed with a treatment-resistant form of postpartum depression.

6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 5, wherein the patient also suffers from suicidal ideation.

7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 6, wherein the patient also suffers from mildly impaired, impaired or severely impaired maternal function.

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 7, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 95 or less, such as 80 or less, in particular 65 or less.

9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 8, wherein the 5-MeO-DMT or a salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 9, wherein a dosage of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 9, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 9, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of said pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 10, wherein the 5-MeO-DMT or a salt thereof is administered in a first dose in a first administration; and the 5-MeO-DMT or a salt thereof is administered in zero to six subsequent administrations; wherein, Unless the patient is experiencing a peak psychedelic experience, each subsequent administration uses a higher dose than the previous one.

14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 10 or 13, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for a first administration, then increased to a dose of about 4 mg to about 6 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 14, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 10 or 13, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, then increased to a dose of about 1.5 mg to about 2.5 mg for a second administration unless the patient has experienced a peak psychedelic experience, then increased to a dose of about 2.5 mg to about 3.5 mg for a third administration unless the patient has experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of the 5-MeO-DMT.

17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 16, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 13 to 17, wherein the interval between two administrations is not less than 1 hour and not more than 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 9 to 18, wherein the occurrence of the peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales (mystical, positive emotions, transcendence of time and space, and ineffable) of the 30-item revised Mystical Experience Questionnaire (MEQ30), or by achieving at least 60% of the maximum possible score in the 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.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 19, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 20, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 21, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 22, wherein the clinical response occurs on the 1st day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, such as about 24 hours, and the clinical response is reflected in a decrease in the Clinical Global Impression-Severity (CGI-S) score.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 23, wherein the clinical response as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 24, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 25, wherein the clinical response, as reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 27, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 27, wherein a clinical response occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as assessed by an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 24, wherein relief of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 29, wherein relief of depressive symptoms occurs on the 1st day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, such as about 24 hours, and the relief of depressive symptoms is assessed as a MADRS score of 10 or less or a HAM-D score of 7 or less.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 30, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 31, wherein there is a clinical response at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as assessed by an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 32, wherein the patient is in remission of depressive symptoms as assessed by a MADRS score of 10 or less or a HAM-D score of 7 or less on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 33, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 34, wherein there is a clinical response at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as assessed by an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 35, wherein the patient is in remission of depressive symptoms on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms being assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 36, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 37, wherein there is a clinical response at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as assessed by an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 38, wherein the patient is in remission of depressive symptoms on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms being assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

40. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

41. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

42. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

43. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

44. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use as claimed in any one of claims 1 to 39, wherein the patient is a breastfeeding mother who is advised to stop breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

45. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 44, wherein said treatment improves maternal function.

46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 45, wherein the improvement relates to one or more, in particular two or more, areas of functioning selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 45 or 46, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

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