5-MEO-DMT 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 breast-feeding mothers without the need for almost complete interruption of breast-feeding. BACKGROUND

[0002] More than 50% of women can experience a transient low mood or crying after childbirth. However, a subset of women can develop PPD, which is a debilitating mood disorder that occurs during pregnancy or within 4 weeks after childbirth.

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

[0004] Studies have shown that PPD has a range of negative effects on the affected mother, her infant and her family. For example, women with PPD can develop thoughts of self-harm or harming the child, and their risk of suicide is increased. PPD can further lead to disruptions in the interaction between mother and child, exemplified by a higher incidence of disengaged behaviour and a lower incidence of visual and vocal communication. Evidence also suggests a link between PPD and child development, as exemplified by the fact that children of patients who suffer from PPD are at greater risk of impaired cognitive development.

[0005] More than 20% of women diagnosed with PPD remain depressed after a 12-month follow-up, and 13% of women still suffer from PPD 2 years after diagnosis. Furthermore, there is evidence that 40% of women relapse, and untreated cases of PPD can lead to recurring episodes of depression.

[0006] It is therefore clear that the burden of PPD is heavy from a number of perspectives, and that successful detection and treatment of PPD is of paramount importance.

[0007] Despite this clear need, treatment options are rather limited. In general, known treatments for depression have limited success rates, particularly for patients suffering from symptoms of mild or greater. In the case of PPD, a complicating factor is that patients often breast-feed. For many drugs, it is recommended that breast-feeding women stop breast-feeding during and for a period of time after drug administration, as the drug can be excreted with the milk, putting the breast-feeding infant at risk.

[0008] Furthermore, studies have shown that breast-feeding mothers can be reluctant to start drug treatment for a range of reasons.

[0009] Thus, PPD patients who are breastfeeding can be faced with the situation of having to decide whether to stop breastfeeding or to stop / abandon treatment.

[0010] Currently, PPD is treated mainly by psychotherapy or medication. The National Institute for Health and Care Excellence (NICE) guidelines recommend that a higher threshold for medication intervention should be discussed with the patient before starting treatment. Such treatments can 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) was approved by the FDA, thus becoming the first pharmacological treatment specifically for PPD. Brexanolone is a positive allosteric modulator of the GABAa receptor, administered by 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 Rating Scale for Depression (HAM-D) scores 30 days after starting the infusion, while the other did not show efficacy after 7 days. However, brexanolone requires hospitalization for a 60-hour infusion and produces severe side effects.

[0012] Another noteworthy fact is that patients must stop breastfeeding during the brexanolone infusion, and some insurance companies require patients planning to undergo treatment to comply with this criterion after the drug was approved.

[0013] Against this background, there is a need for improved treatment of PPD, in particular, not only effective in treating depression and producing a rapid clinical response, but also avoiding interference with the patient’s daily activities, in particular, care for the baby. The treatment should improve maternal functioning. Furthermore, there is a need for a PPD treatment that does not require almost complete discontinuation of breastfeeding.

[0014] Although there is currently great interest in using psychedelic substances for the treatment of mental disorders, they have not yet been used for the treatment of PPD. This is due to the general lack of relevant clinical data, which does not allow conclusions about the clinical utility of psychedelics in PPD, and due to the particular concern that the administration of psychedelics can not be suitable for breastfeeding mothers.

[0015] Psychedelics (including entheogens) are chemical compounds, some of which are naturally occurring and some of which are synthetic, which are defined as being able to cause distortions of sensory perception, such as visual and auditory alterations, as well as alterations of mood and cognition, after being ingested by a person. The term psychedelics covers a rather broad group of psychoactive molecules with different modes of action. Some mental disorders are in principle considered suitable for treatment with psychoactive substances, such as entheogens.

[0016] However, none of the psychedelic drugs has been approved by any regulatory agency. In fact, the clinical experience with such molecules remains quite limited.

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

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

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

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

[0021] It is another object of the present application to provide a treatment for lactating mothers diagnosed with PPD or other psychiatric disorders that enables them to continue breastfeeding without a severe interruption of treatment. SUMMARY

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

[0023] The present application also allows treating PPD in breastfeeding mothers without the need for almost complete interruption of breastfeeding.

[0024] In another aspect, the present application relates to treating a breast-feeding mother diagnosed with a psychiatric disorder.

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

[0026] DEFINITIONS

[0027] As used in the context of the present application, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT, unless otherwise specified. It is contemplated that pharmaceutically acceptable salts of 5-MeO-DMT can also be used. Such salts are in particular acid addition salts, wherein the acid can 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. It can be assumed that equimolar amounts are used, the appropriate weight of the salt to be administered being calculated from the weight of the free base.

[0028] As used in the context of the present application, a "patient" to be treated is a female diagnosed with postpartum depression (PPD) according to established medical criteria. The diagnosis will be made by a physician or psychologist. It is not sufficient that the human subject considers herself to be afflicted with the disorder.

[0029] The patient can be afflicted with a treatment-resistant disease. As used herein, "treatment-resistant" means that the patient has not been sufficiently improved after at least two full courses of treatment. The patient has in particular not been sufficiently improved after at least two full courses of treatment, wherein at least one of the two courses is a drug therapy; for example, the patient has not been sufficiently improved after at least two full courses of drug treatment.

[0030] As used in the context of the present application, "suicidal ideation" means thinking about, considering, or planning suicide. A physician or psychologist will diagnose whether a patient is suffering from suicidal ideation using established protocols and methods for diagnosing suicidality. In general, it is not sufficient that the patient considers herself to be afflicted with suicidal ideation. In some cases, a patient experiencing suicidal ideation will be at risk of imminent suicide, or be considered to have "suicidal intent".

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

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

[0033] "clinical response" includes, but is not limited to, improvement on rating scales 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 Postnatal Depression Scale (EPDS). Further relevant scales for assessing clinical outcome include the Clinician Administered Dissociative States Scale (CADSS), the Brief Psychiatric Rating Scale (BPRS), and the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0034] The Barkin Index of Mother's Functioning (BIMF) can be used to assess maternal functioning.

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

[0036] When assessing clinical response at early time points after administration of a drug (e.g., 2 hours) based on endpoints developed for longer recall periods (e.g., MADRS typically 7 days), reasonable modifications can be made to such endpoints (e.g., changing the recall period for MADRS to 2 hours, and carryover of sleep items recorded at baseline prior to administration of the drug).

[0037] The considerations outlined apply to early time points, as in one aspect the state of the patient prior to treatment should have as little influence as possible on any scores recorded after treatment for assessing clinical response, while in another aspect the sleep items cannot be assessed 2 hours after administration of the drug.

[0038] At later time points, e.g., at day 1 or later, all items of the relevant scales for assessing clinical response can typically be assessed using the appropriate recall period (if necessary) such that no carryover of any pre-treatment scores is necessary. For example, if the BIMF is assessed at day 7, a recall period of seven days will be used (rather than the standard recall period of 2 weeks).

[0039] As used in the context of the present application, the term "administration" (or "application") shall mean the introduction of an amount, which can be a predetermined amount, of an active compound or pharmaceutical ingredient into the body of a patient 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 application, 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 "dosing regimen" (or "dosing schedule") shall mean the defined sequence of one or more single administrations.

[0041] Postpartum depression

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

[0043] The patient to be treated according to the present application is preferably a female diagnosed with PPD and >4 weeks postpartum. Furthermore, the patient's postpartum time is preferably <9 months.

[0044] The depressive aspect of PPD can be assessed by HAM-D or MADRS score. 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., & Åsberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p. 382). It was designed as an adjunct to the Hamilton Depression Rating Scale (HAM-D) and is more sensitive to changes brought about by antidepressants and other forms of treatment. The higher the MADRS score, the more severe the depression. The items considered are apparent sadness; reported sadness; inner tension; reduced sleep; diminished appetite; difficulty in concentrating; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item is scored from 0 to 6. The total score ranges from 0 to 60.

[0046] The patient can have moderate or severe PPD, indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Rating Scale for Depression (HAM-D) score of 16 or higher. Further, the patient can have severe PPD, indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Rating Scale for Depression (HAM-D) score of 27 or higher. The patient can be diagnosed with a treatment-resistant form of PPD.

[0047] The patient treated according to the present application can have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher, or a 17-item Hamilton Rating Scale for Depression (HAM-D) score of 16 or higher.

[0048] Further, the patient treated according to the present application can have a MADRS score of 28 or higher, or a HAM-D score of 22 or higher.

[0049] Further, the patient treated according to the present application can 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 also believe that PPD impairs maternal functioning. In particular, the first year after childbirth is a critical window for both the mother and the child. In most cases, the mother is the primary caregiver and is therefore responsible for most of the work associated with infant care tasks.

[0051] Maternal functioning includes aspects of maternal ability related to infant interaction as well as maternal self-care.

[0052] Maternal functioning, including the emotional aspects of the mother, is also important for the development of the child. In fact, the quality of mother-child interaction in the first year after birth impacts the development of the infant. High levels of maternal functioning can be associated with positive infant development outcomes. Likewise, impaired functioning during the postpartum period can hinder optimal development of the infant.

[0053] The Barkin Index of Maternal Functioning (BIMF) was designed to measure functioning in the first year after childbirth. The BIMF is a 20-item self-report measure of functioning. Each item is scored from 0 to 6, making the maximum total score 120. The higher the score, the better the assessment of maternal functioning.

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

[0055] A BIMF score of 95 or below is considered herein to represent a mild impairment of maternal functioning, a score of 80 or below is considered herein to represent an impairment of maternal functioning, and a score of 65 or below is considered herein to represent a severe impairment of maternal functioning. The present invention can in particular improve maternal functioning in patients with a score of 80 or below before treatment and in patients with a score of 65 or below before treatment.

[0056] Active agent

[0057] The above discussion shows that PPD is characterized by several aspects that by themselves contribute to a significant disease burden and that require appropriate treatment. Thus, not only is there a need for treatment, in particular by pharmaceutical intervention, to improve the overall disease score, but there is also a need to improve specific aspects of the disease.

[0058] The inventors believe that a carefully selected psychedelic agent can lead to a treatment that improves important aspects of PPD and can lead to an overall improvement of the disease and maternal functioning.

[0059] The inventors further consider that a carefully selected psychedelic agent can allow to continue breastfeeding without almost complete interruption when treating a lactating mother suffering from PPD.

[0060] One group of psychedelic agents comprises compounds that bind to serotonin (5-HT) receptors, also known as 5-hydroxytryptamine receptors (7 families are described, 5-HT1 to 5-HT7, with several subtypes). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT). These serotonin-based agents are often referred to as “hallucinogens”, which emphasizes their primary ability to induce a qualitative change in the state 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 marginal.

[0061] From a chemical point of view, serotonin hallucinogens are either phenylalkylamines or indoleamines, which are in turn divided into two subsets, the ergolines and the tryptamines, the latter being derived from tryptamine.

[0062] The various serotonin hallucinogens have different binding affinities and activation potencies for the various serotonin receptors, in particular 5-HT1A, 5-HT2A, and 5-HT2C, and their activity can also be modulated by interactions with other targets, such as monoamine transporters and trace amine-related receptors.

[0063] Recent published studies using serotonergic psychedelics (such as LSD, psilocybin, and DMT (using ayahuasca, a DMT-containing brew)) in certain psychiatric disorders suggest that these compounds can offer an alternative approach to the treatment of certain psychiatric disorders currently available. However, there are reports that these compounds can induce mania in patients suffering from depressive symptoms and this can hinder their clinical use.

[0064] For example, Lake et al. (Lake, C. R., Stirba, A. L., Kinneman, R. E. Jr, Carlson, B., Holloway, H. C., 1981. Mania associated with LSD ingestion. American Journal of Psychiatry. 138(11): 1508-9) reported the case of a patient who developed a manic episode after taking LSD or LSD analogues. The patient developed acute LSD intoxication symptoms, which were mitigated, but a typical psychotic manic episode developed after about 3 weeks. Hendin and Penn (Hendin, H. M., Penn, A. D., 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, A. G., Valerio, M. P. and Jose M Smith, J. M., 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 drinking ayahuasca (a DMT-containing beverage).

[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 to reduce the risk of inducing mania or hypomania, the compound to be administered must be properly selected and preferably administered according to a specific dosing regimen.

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

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

[0069] The inhibition constants (K i values) of psilocin (the dephosphorylated form of psilocin that is formed after ingestion of psilocin), DMT and 5-MeO-DMT at 5-HT1A receptors located in the hippocampus of post-mortem human brain were 48, 38 and 1.80 nM, respectively, as further detailed in the Example section below. Thus, 5-MeO-DMT exhibits a high affinity for 5-HT1A receptors, while psilocin and DMT exhibit a moderate affinity. The inhibition constants (K i values) of psilocin, DMT and 5-MeO-DMT at 5-HT2A receptors located in the frontal cortex of post-mortem human brain were 37, 117 and 122 nM, respectively. Thus, psilocin exhibits a moderate / strong affinity for 5-HT2A receptors, while DMT and 5-MeO-DMT exhibit a relatively weaker affinity.

[0070] In comparison to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits an enhanced affinity for 5-HT1A receptors, in which case 5-MeO-DMT acts as a potent agonist. In comparison to 5-MeO-DMT, the contribution of 5-HT2A binding increases in the case of norbaeocystin and DMT, wherein 5-MeO-DMT exhibits the greatest differential affinity for 5-HT1A versus 5-HT2A of the three compounds. Thus, 5-HT1A binding plays a much greater role in the overall effect of 5-MeO-DMT in comparison to 5-HT2A binding than for the other two compounds.

[0071] 5-HT1A agonists are reported to reduce impulsivity and aggression, whereas 5-HT2A agonists cause a short-term increase in these same qualities. Furthermore, the dopamine system is implicated in causing mania, and increases in dopamine drive are associated with mania. In comparison to 5-MeO-DMT, LSD, baecocystin, and DMT exhibit increased affinity for multiple dopamine receptors.

[0072] In comparison to other psychedelic drugs, such as LSD, baecocystin, or DMT, it can be preferable to administer 5-MeO-DMT to a patient using a dosing regimen as described herein without a significant risk of inducing mania or hypomania in a patient suffering from a psychiatric or neurological disorder, including disorders characterized by depressive onset, such as major depressive disorder (MDD), postpartum depression (PPD), persistent depressive disorder, seasonal affective disorder, and bipolar disorder (BD), such as bipolar I disorder and bipolar II disorder; psychotic disorders, such as schizophrenia; or personality disorders, such as schizotypal personality disorder. A patient suffering from such a psychiatric or neurological disorder and treated according to the present application does not experience treatment-induced mania or hypomania.

[0073] It is also noteworthy that reports of treatment-induced mania or hypomania associated with the use of psychoactive substances appear to be associated with the use of large amounts of the respective compound (e.g., DMT / ayahuasca, baecocystin, LSD).

[0074] The inventors’ 5-MeO-DMT sequential up-titration method significantly reduces the risk of overdosing and the likelihood of accompanying adverse events.

[0075] Furthermore, 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 hypomania.

[0076] 5-MeO-DMT can induce peak experiences (i.e., experiences characterized by a shift in emotional perspective, described as a "loss of self," typically culminating 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 several hours with, for example, 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 were used to estimate nonspecific binding and to determine K i is 2.3 nM.

[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 implicated in, among other things, central processes such as learning and memory, sleep regulation and circadian rhythms, and nociception.

[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 regions of the brain. Disruption of this coordination leads to disease states, in particular disease states involving sleep disturbances. In patients suffering from sleep disturbances, resting state functional connectivity analysis reveals that functional connectivity between the suprachiasmatic nucleus and regions within the default mode network is altered.

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

[0083] The inventors believe that the binding of 5-MeO-DMT to 5-HT7 receptors, as a mediator of the pharmacological action of 5-MeO-DMT, involves a functional connectivity “resetting” of the network and a neuroplasticity effect, which contributes to the beneficial effect of 5-MeO-DMT in the treatment of patients suffering from sleep disturbances.

[0084] The inventors further believe that the binding of 5-MeO-DMT to 5-HT7 receptors and 5-HT1A receptors, as two mediators of the action of 5-MeO-DMT, involves a functional connectivity “resetting” of the network and a neuroplasticity effect, which allows a beneficial effect to be achieved in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thoughts or social / emotional withdrawal. This is supported by the clinical results shown in the studies cited herein.

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

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

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

[0088] The pharmacokinetic profile of inhaled 5-MeO-DMT showed that plasma concentrations dropped very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; 2 hours later, concentrations were 1% or less of Cmax; 3 hours later, 5-MeO-DMT was no longer detected in plasma. This applied to the entire dose range tested (6 mg, 12 mg, 18 mg). No accumulation was observed after repeated administration in the time range of 1 to 4 hours. The up-titration as disclosed herein does not lead to accumulation and thus to higher plasma concentrations, e.g. 10 minutes, 2 hours or 3 hours after administration.

[0089] The inventors have further determined that 5-MeO-DMT has a number of characteristics that make it an attractive PPD treatment method. In contrast to SSRIs, 5-MeO-DMT is a fast-acting agent (in the 5-MeO-DMT-TRD trial, 5 out of 8 TRD patients reached remission within 2 hours of dosing, 8 patients reached remission on day 1, and 7 patients maintained remission on day 7). Treatment of PPD patients with 5-MeO-DMT not only allows for a rapid improvement of depressive symptoms, but also a rapid improvement of maternal functioning. Furthermore, 5-MeO-DMT is administered during a single day of treatment, optionally without frequent repeat dosing, thus differing from SSRIs (which require a long-term daily dosing regimen with lower compliance) and brexanolone (which requires long-term infusion and hospitalization).

[0090] The present application thus also addresses the issue of compliance and patient convenience.

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

[0092] According to the present application, also isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof can be used. When reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the use of an isotopic variant 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 a form having a deuterium content higher than the deuterium content expected according to the natural abundance of this isotope.

[0095] A 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- deuterium-2-(5-methoxy-lH-indol-3-yl)-N,N-dimethylethanamine, 1,1-dideuterium-2-(5- methoxy-lH-indol-3-yl)-N,N-dimethylethanamine, 1,1,2,2-tetradeuterium-2-(5-methoxy- lH-indol-3-yl)-N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteromethoxy)- 1H-indol-3-yl]ethanamine.

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

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

[0099] According to the present application, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms with non-deuterated 5-MeO-DMT, mixtures of pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixtures of such salts, and mixtures of deuterated 5-MeO-DMT and salts of non-deuterated 5-MeO-DMT can also be used.

[0100] Furthermore, according to the present application, 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 application, prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs can also be used. Such prodrugs of 5-MeO-DMT can be converted metabolically into 5-MeO-DMT. Thus, when reference is made to the use of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, a 5-MeO-DMT prodrug or a salt thereof can be used instead.

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

[0103] Examples of suitable organic moieties are -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 , wherein each of R 1 , R 2 , R 3 and R 4 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] Preferred examples of organic moieties are -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , wherein R 1 , R 3 and R 4 are as defined above.

[0105] The prodrugs, in particular the prodrugs of the above structures, can also be used in the form of pharmaceutically acceptable salts.

[0106] A specific example of a prodrug is 5-MeO-DMT carboxyisopropylvalinate, preferably in the form of a salt, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylate) and 5-MeO-DMT methylpivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

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

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

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

[0110] Therapeutic aspects

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

[0112] To further support the clinical application of 5-MeO-DMT in patients suffering from PPD, the inventors evaluated clinical data associated with the use of 5-MeO-DMT in patients treated for mental illness and noted particular improvements in disease aspects that are also commonly observed in PPD patients. The inventors specifically noted improvements in various symptoms and combinations of symptoms that 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 Example section below). While 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 the design of a PPD treatment method.

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

[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). While the focus of the trial was to demonstrate treatment efficacy by an increase in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noted that several sub-core items were particularly relevant to PPD patients and associated with maternal functioning.

[0116] Several patients in the cohort recruited exhibited significant improvements in one or more of these sub-score items, a result that confirmed the inventors’ finding that 5-MeO-DMT is a compound that is suitable for treating PPD patients and improving maternal functioning in these patients.

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

[0118] According to the treatment of the present application, the aspect of the disease is reduced or eliminated (or improved or eliminated).

[0119] If the aspect is assessed according to the MADRS scale, there is an improvement (reduction) of at least one point or the patient is in complete remission (elimination) after the treatment, i.e. the respective aspect scores 0.

[0120] If the aspect is assessed according to the BPRS scale, there is an improvement (reduction) of at least one point or the patient is in complete remission (elimination) after the treatment, i.e. the respective aspect scores 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 application, a reduction in the CGI-S score means a reduction in the CGI-S 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 assume that the improvement observed in certain MADRS items will translate into an improvement in the aspect of maternal functioning.

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

[0124] The MADRS item "Inner tension" represents feelings of undefined discomfort, irritability, inner turmoil, increased mental tension as panic, fear or distress. It is assessed according to intensity, frequency, duration and degree of assurance required.

[0125] If the patient is calm and only has short inner tension, a score of 0 is given. If there is occasional irritability and undefined discomfort, a score of 2 is given. If there is persistent inner tension that the patient cannot control or intermittent panic, a score of 4 is given. If there is constant fear or distress and overwhelming panic, a score of 6 is given.

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

[0127] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the areas of mother-child interaction and / or maternal mental health of the BIMF functional domains.

[0128] In the trial described above involving TRD patients, in the study group receiving the individualized dosing regimen, the total score of the MADRS item “Inner tension” was 26 for all 8 patients at baseline. After 2 hours, the score was reduced to 11, which corresponds to an improvement of 15 points or 58%. On day 1 after treatment, the score was reduced to 6, which corresponds to an improvement of 20 points or 77%. On day 7 after treatment, the score was reduced to 12, which corresponds to an improvement of 14 points or 54%.

[0129] In the 12 mg group, the total score of the MADRS item “Inner tension” was 13 for all 4 patients at baseline. After 2 hours, the score was reduced to 2, which corresponds to an improvement of 11 points or 85%. On day 1 after treatment, the score was reduced to 3, which corresponds to an improvement of 10 points or 77%. On day 7 after treatment, the score was reduced to 5, which corresponds to an improvement of 8 points or 62%.

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

[0131] The improvement in inner tension is reflected at least in an improvement in the score of the MADRS item inner tension 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 later; on day 7; on day 14; and / or on day 28.

[0132] The improvement in inner tension, reflected in a reduction in the Clinical Global Impression - Severity of Illness (CGI-S) score, occurs not 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 the Clinical Global Impression - Severity of Illness (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] The improvement in inner tension, reflected at least in a score of “much improved” in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not 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 in a decrease in the CGI-S score or at least in a score of "much improved" in the CGI-I score or the PGI-I score) preferably lasts 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 have also concluded that the reduction or elimination of inner tension achieved by treating PPD patients not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, 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 at day 1, e.g. about 24 hours after, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0137] Since inner tension also affects other aspects of PPD, the inventors have concluded that the observed improvement in the "inner tension" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0138] The MADRS item "lassitude" indicates a slow pace in starting or initiating and performing daily activities.

[0139] A score of 0 means that there is hardly any difficulty at the start and no feeling of slowness. If the patient encounters difficulties in starting an activity, a score of 2 is given. A score of 4 means that it is difficult to start simple daily activities that require effort to complete. If the patient is completely lazy and cannot do anything without help, a score of 6 is given.

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

[0141] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the areas of baby care, self-care, mental health, management, and / or regulation of the BIMF functional domains.

[0142] In the study group receiving the individualized dosing regimen, the total score of the MADRS item “lassitude” for all 8 patients was 27 at baseline. After 2 hours, the score was reduced to 10, which corresponds to an improvement of 17 points or 63%. On day 1 after treatment, the score was reduced to 5, which corresponds to an improvement of 22 points or 81%. On day 7 after treatment, the score was reduced 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 “lassitude” for all 4 patients was 16 at baseline. After 2 hours, the score was reduced to 10, which corresponds to an improvement of 6 points or 38%. On day 1 after treatment, the score was reduced to 0, which corresponds to an improvement of 16 points or 100%. On day 7 after treatment, the score was reduced to 3, which corresponds to an improvement of 13 points or 81%.

[0144] The inventors conclude that 5-MeO-DMT can be used for the treatment of PPD patients to achieve a reduction or elimination of lassitude.

[0145] The improvement of lassitude is reflected at least in an improvement of the score of the MADRS item lassitude not later than about 2 hours; on day 1, e.g. about 24 hours after; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0146] The improvement of lassitude (reflected in a decrease of the Clinical Global Impression - Severity (CGI-S) score) occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0147] Additionally or alternatively, the decrease of the 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] The improvement of lassitude (reflected in a decrease of the Clinical Global Impression - Severity (CGI-S) score) occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

[0150] The inventors have also concluded that the reduction or elimination of apathy achieved by treating PPD patients not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, 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 at day 1, e.g. about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28. Since apathy also affects other aspects of PPD, the inventors have concluded that the observed improvement in the “apathy” item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0151] The MADRS item “sensation of being diminished” represents the subjective experience of a reduced interest in the surroundings or activities that normally bring pleasure. The ability to respond to the environment or people with appropriate emotions is reduced.

[0152] A score of 0 indicates normal interest in the surroundings and other people, and a score of 2 indicates a reduced ability to enjoy daily interests. If interest in the surroundings is lost and emotions towards friends and acquaintances are lost, a score of 4 is given. A score of 6 reflects emotional numbing, inability to feel anger, sadness or pleasure, and experiences of complete or even painful loss of emotions towards close friends and family.

[0153] The inventors have established that an increase in the score of the MADRS item “sensation of being diminished” has a negative impact on two aspects of maternal functioning, i.e. maternal ability to interact with the baby and maternal self-care. An increase in the score of the MADRS item “sensation of being diminished” impairs mother-child interaction and mental health.

[0154] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the BIMF functional domains of mother-child interaction and / or mental health.

[0155] In the study group receiving the individualized dosing regimen, the total score of the MADRS item “sensation of being diminished” was 36 for all 8 patients at baseline. After 2 hours, the score was reduced to 12, which corresponds to an improvement of 24 points or 67%. At day 1 after treatment, the score was reduced to 2, which corresponds to an improvement of 34 points or 94%. At day 7 after treatment, the score was reduced to 6, which corresponds to an improvement of 30 points or 83%.

[0156] In the 12 mg group, the total score of the MADRS item “sensation of being diminished” was 16 for all 4 patients at baseline. After 2 hours, the score was reduced to 9, which corresponds to an improvement of 7 points or 44%. At day 1 after treatment, the score was reduced to 1, which corresponds to an improvement of 15 points or 94%. At day 7 after treatment, the score was reduced to 1, which corresponds to an improvement of 15 points or 94%.

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

[0158] The improvement in anhedonia is reflected at least in an improvement in the score of the MADRS item anhedonia 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 later; on day 7; on day 14; and / or on day 28.

[0159] The improvement in anhedonia, reflected in a decrease in the Clinical Global Impression - Severity (CGI-S) score, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0160] Additionally or alternatively, the decrease in the 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] The improvement in anhedonia, reflected at least in a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0162] The improvement in anhedonia, reflected in a decrease in the CGI-S score or at least in a score of "much improved" in the CGI-I score or the PGI-I score, preferably lasts 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 conclude that the reduction or elimination of anhedonia by treating PPD patients not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, 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 on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.13Since the loss of sensation also affects other aspects of PPD, the inventors conclude that the observed improvement in the "loss of sensation" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0164] The MADRS item "difficulty in concentrating" represents the difficulty in gathering one's thoughts, resulting in an inability to concentrate.

[0165] If the patient has no difficulty concentrating, the score is 0. If it is occasionally difficult to gather one’s thoughts, the score is 2. If it is difficult to concentrate and maintain thoughts are difficult, resulting in reduced reading or conversation ability, the score is 4. If the patient cannot read or converse easily, the score is 6.

[0166] The inventors have determined that an increase in the MADRS item “difficulty concentrating” score has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the baby and maternal self-care). An increase in the MADRS item “difficulty concentrating” score impairs baby care and management.

[0167] Conversely, an improvement on this MADRS item leads to an improvement in maternal functioning, in particular in the BIMF functional domains baby care and / or management.

[0168] In the study group receiving the individualized dosing regimen, the total score on the MADRS item “difficulty concentrating” for all 8 patients was 30 at baseline. After 2 hours, the score was reduced to 11, which corresponds to an improvement of 19 points or 63%. On day 1 after treatment, the score was reduced to 1, which corresponds to an improvement of 29 points or 97%. On day 7 after treatment, the score was reduced to 9, which corresponds to an improvement of 21 points or 70%.

[0169] In the 12 mg group, the total score on the MADRS item “difficulty concentrating” for all 4 patients was 16 at baseline. After 2 hours, the score was reduced to 7, which corresponds to an improvement of 9 points or 56%. On day 1 after treatment, the score was reduced to 2, which corresponds to an improvement of 14 points or 88%. On day 7 after treatment, the score was reduced 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 achieve a reduction or elimination of difficulty concentrating.

[0171] The improvement in difficulty concentrating is reflected at least in an improvement in the MADRS item difficulty concentrating score 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 later; on day 7; on day 14; and / or on day 28.

[0172] The improvement in difficulty concentrating, reflected in a reduction in the Clinical Global Impression - Severity (CGI-S) score, 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 at day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0174] The improvement in difficulty concentrating, reflected as a reduction in CGI-S score or at least reflected as a score of "much improved" in CGI-I score or 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 as a reduction in CGI-S score or at least reflected as a score of "much improved" in CGI-I score or PGI-I score, preferably lasts 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 the alleviation or elimination of the difficulty concentrating by treating the PPD patient not only leads to a reduction in the MADRS total score, but also to an improvement in the mother functioning, reflected as 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 at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0177] Since the difficulty concentrating also affects other aspects of the PPD, the inventors concluded that the observed improvement in the "difficulty concentrating" item of the MADRS will also contribute to the overall improvement in the mother functioning.

[0178] The MADRS item "Pessimistic thoughts" represents thoughts of guilt, inferiority, self-reproach, sinfulness, remorse and annihilation.

[0179] A score of 0 is given if there are no pessimistic thoughts. A score of 2 is given if there are fluctuating thoughts of failure, self-reproach or self-depreciation. The score implies persistent self-accusation, or explicit but still reasonable thoughts of guilt or sinfulness, and increasing pessimism about the future by the patient. A score of 6 is given if there are delusions of annihilation, remorse or irrevocable sinfulness, and absurd and unshakable self-accusation.

[0180] The inventors have determined that an increase in the MADRS item “Pessimistic thoughts” has a negative impact on both aspects of maternal functioning (maternal ability related to interaction with the baby and maternal self-care). An increase in the MADRS item “Pessimistic thoughts” impairs mental health, social support and management.

[0181] In contrast, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the area of mental health, social support and / or management of the BIMF functional domains.

[0182] In the study arm receiving the individualized dosing regimen, the total score of the MADRS item “Pessimistic thoughts” was 28 for all 8 patients at baseline. After 2 hours, the score was reduced to 7, which corresponds to an improvement of 21 points or 75%. On day 1 after treatment, the score was reduced to 4, which corresponds to an improvement of 24 points or 86%. On day 7 after treatment, the score was reduced to 3, which corresponds to an improvement of 25 points or 89%.

[0183] In the 12 mg arm, the total score of the MADRS item “Pessimistic thoughts” was 16 for all 4 patients at baseline. After 2 hours, the score was reduced to 8, which corresponds to an improvement of 8 points or 50%. On day 1 after treatment, the score was reduced to 7, which corresponds to an improvement of 9 points or 56%. On day 7 after treatment, the score was reduced to 8, which corresponds to an improvement of 8 points or 50%.

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

[0185] The improvement in pessimistic thoughts is reflected at least in an improvement in the score of the MADRS item Pessimistic thoughts 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 later; on day 7; on day 14; and / or on day 28.

[0186] The improvement in pessimistic thoughts (reflected in a reduction in the Clinical Global Impression - Severity (CGI-S) score) occurs 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 the 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, reflected as a decrease in CGI-S score or at least reflected as a score of "much improved" in CGI-I score or 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] Improvement in pessimistic thoughts, reflected as a decrease in CGI-S score or at least reflected as a score of "much improved" in CGI-I score or 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.

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

[0191] Since pessimistic thoughts also affect other aspects of PPD, the inventors have concluded that the observed improvement in the "pessimistic thoughts" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0192] The MADRS item "reduced sleep" represents the experience of a reduction in the duration or depth of sleep compared to the normal pattern when the subject is healthy by herself / himself.

[0193] A score of 0 is given when the subject's sleep is normal. A score of 2 reflects slight difficulties in falling asleep, or a slight reduction, shallower or interrupted sleep. A score of 4 means a reduction or interruption of sleep of at least two hours. A score of 6 means a sleep time of less than two hours or three hours.

[0194] The inventors have determined that an increase in the score of the MADRS item "reduced sleep" has a negative impact on two aspects of maternal functioning, i.e. maternal ability to interact with the baby and maternal self-care. An increase in the score of the MADRS item "reduced sleep" impairs self-care, mental health and management.

[0195] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the areas of self-care, mental health and / or management of the BIMF functioning domain.

[0196] In the study arm receiving the individualized dosing regimen, the total score of MADRS item "reduced sleep" was 25 for all 8 patients at baseline. On day 1 after treatment, which is the earliest time point to assess the impact of the treatment on sleep, the score was reduced to 12, which corresponds to an improvement of 13 points or 52%. On day 7 after treatment, the score was reduced to 9, which corresponds to an improvement of 16 points or 64%.

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

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

[0200] The improvement in reduced sleep, reflected as a decrease in the Clinical Global Impression - Severity (CGI-S) score, occurs not later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0201] The improvement in reduced sleep, reflected at least by a score of "much improved" in the Clinical Global Impression - Improvement (CGI-I) score or the Patient Global Impression - Improvement (PGI-I) score, preferably occurs not later than about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0202] The improvement in reduced sleep, reflected as 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 lasts at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0203] The inventors have also concluded that alleviating or eliminating sleep reduction in PPD patients not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, 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 also be observed at day 1, e.g. about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0204] As sleep reduction also affects other aspects of PPD, the inventors have concluded that the observed improvement in the MADRS item “sleep reduction” will also contribute to the overall improvement in maternal functioning.

[0205] Another aspect of PPD that can be treated by administration of 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to a PPD patient to alleviate or eliminate suicidal ideation in said patient.

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

[0207] “Suicidal thoughts” represents a feeling that life is not worth living, a wish for natural death, having thoughts of suicide, and / or making preparations for suicide. Suicidal attempts per se should not influence the assessment of this MADRS item.

[0208] A score of 0 means that the patient enjoys life. If the PPD patient is tired of life, and / or has only fleeting thoughts of suicide, a score of 2 is given. A score of 4 means that the patient feels better dead, that thoughts of suicide are common and suicide is seen as a possible solution, but the patient has no specific plans or intentions. If the patient has a clear suicide plan and / or is actively preparing, a score of 6 is given.

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

[0210] The inventors have established that an increase in the score of the MADRS item “suicidal thoughts” has a negative impact on two aspects of maternal functioning, i.e. maternal ability to interact with the baby and maternal self-care. An increase in the score of the MADRS item “suicidal thoughts” impairs self-care, mental health and management.

[0211] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the BIMF functional domains of self-care, mental health and / or management.

[0212] In the study group receiving the individualized dosing regimen, the total score of the MADRS item “suicidal thoughts” was 11 for all 8 patients at baseline. After 2 hours, the score was reduced to 3, which corresponds to an improvement of 8 points or 73%. On day 1 after treatment, the score was reduced to 1, which corresponds to an improvement of 10 points or 91%. On day 7 after treatment, the score was reduced to 3, which corresponds to an improvement of 8 points or 73%.

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

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

[0215] Thus, according to the present application, the treatment of PPD patients suffering from suicidal ideation can reduce or eliminate suicidal ideation.

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

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

[0218] The improvement of suicidal ideation, reflected in a decrease of the Clinical Global Impression - Severity (CGI-S) score, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0219] Alternatively, the decrease of the 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 by a score of at least "much improved" in 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] Improvement in suicidal ideation (assessed 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 lasts 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 alleviating or eliminating suicidal thoughts by treating PPD patients not only leads to a decrease in the MADRS total score, but also to an improvement in maternal functioning, which is reflected by 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 at day 1, e.g. about 24 hours after, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0223] Since suicidal thoughts also affect other aspects of PPD, the inventors concluded that the observed improvement 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 deficit in expressing emotions during the interview. Possible scores are:

[0225] 1 - No emotional withdrawal.

[0226] 2 - Very mild. Lack of emotional involvement manifested by occasional unresponsive comments, occasional appearing absent-minded or stiff smile, but most of the time spontaneously interacting with the interviewer.

[0227] 3 - Mild. Lack of emotional involvement manifested by obvious unresponsive comments, appearing absent-minded or lack of enthusiasm, but responding when the interviewer approaches.

[0228] 4 - Moderate. There is no emotional contact during most of the interview as the subject does not respond in detail, does not make eye contact, seems not to care whether the interviewer is listening, or can be immersed in psychotic material.

[0229] 5 - Moderately severe. Same as 4, but no emotional communication was shown during most of the interview.

[0230] 6 - Severe. Active avoidance of emotional involvement. Frequently unresponsive or with yes / no answers (not solely due to persecutory delusions). Or minimal emotional response.

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

[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 the 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 group receiving the individualized dosing regimen, the total score for the BPRS item "Emotional Withdrawal" was 13 at baseline. After 3 hours, the score had dropped to 8, corresponding to an improvement of 5 points, or 38%. On the first day after treatment, the score had dropped to 8, corresponding to an improvement of 5 points, or 38%. On the seventh day after treatment, the score had dropped to 8, corresponding to an improvement of 5 points, or 38%.

[0235] In the 12 mg group, the total score for the BPRS item "Affective Withdrawal" was 13 at baseline. After 3 hours, the score had dropped to 11, corresponding to a 2-point or 15% improvement. On the first day after treatment, the score had dropped to 8, corresponding to a 5-point or 38% improvement. On the seventh day after treatment, the score had dropped to 6, corresponding to a 7-point or 54% improvement.

[0236] The inventors concluded 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 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.

[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 at day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0240] The improvement in affective flattening, reflected at least in a score of "much improved" in 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 flattening, reflected as a reduction in the CGI-S score or at least in a score of "much improved" in the CGI-I score or the PGI-I score, preferably lasts 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 the alleviation or elimination of affective flattening by treating PPD patients not only leads to a reduction in the BPRS total score, but also to an improvement in maternal functioning, 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 at day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28.

[0243] Since affective flattening also affects other aspects of PPD, the inventors concluded that the observed improvement in the "affective flattening" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0244] The BPRS item "affective blunting" relates to a restricted range of emotional expression in the face, voice, and gestures, and a marked indifference or flatness in affect even when discussing painful topics. Possible scores are:

[0245] 1 - No affective blunting.

[0246] 2 - Very mild. Affective range is slightly inhibited or reserved, but shows appropriate facial expression and tone of voice, within normal limits.

[0247] 3 - Mild. Affective range is generally diminished, inhibited, or reserved, with few spontaneous and appropriate affective responses. Voice tone is somewhat monotonous.

[0248] 4 - Moderate. Range of affect is markedly diminished, and the patient shows no affect, smile, or reaction to painful topics except in rare instances. Speech is monotone or spontaneous motor activity is markedly diminished. Presentation of affect or gestures usually results in affective flattening.

[0249] 5 - Moderately severe. Range of affect is very diminished, and the patient shows no affect, smile, or reaction to painful topics except for minimal, rare gestures, and facial expressions are not frequently changed. Speech is monotone most of the time.

[0250] 6 - Severe. Range or expression of affect is very minimal. Speech and gestures are mechanical most of the time. Facial expressions are unchanged. Speech is monotone most of the time.

[0251] 7 - Extreme severity. There is almost no range or expression of affect, and motor activity is rigid. Speech is monotone all of the time.

[0252] The inventors have determined that an increase in the score of the BPRS item “blunted affect” 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 BPRS item “blunted affect” impairs mental health and mother-infant interaction.

[0253] Conversely, an improvement in this BPRS item leads to an improvement in maternal functioning, in particular in the area of mental health and / or mother-infant interaction of the BIMF functioning domain.

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

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

[0257] The reduction or elimination of blunted affect is reflected at least by an improvement in the score of the item blunted affect of the BPRS 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 later; on day 7; on day 14; and / or on day 28.

[0258] The improvement in blunted affect, reflected as a decrease in the score of the Clinical Global Impression - Severity of Illness (CGI-S), 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 decrease in the score of the Clinical Global Impression - Severity of Illness (CGI-S) occurs on day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0260] The improvement in blunted affect, reflected at least by a score of "much improved" in the score of the Clinical Global Impression - Improvement (CGI-I) or the Patient Global Impression - Improvement (PGI-I), 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 blunted affect, reflected as a decrease in the score of the CGI-S or at least by a score of "much improved" in the score of the CGI-I or the PGI-I, preferably lasts at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; in particular at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; more preferably at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0262] The inventors also concluded that the reduction or elimination of blunted affect by treating PPD patients not only leads to a decrease in the total score of the BPRS, but also to an improvement in the maternal functioning, reflected as an increase in the score of the BIMF. This improvement will be achieved quickly, i.e. within about 2 hours, and an increase in the score of the BIMF will also be observed on day 1, e.g. about 24 hours later; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0263] Since blunted affect also affects other aspects of PPD, the inventors concluded that the observed improvement in the "blunted affect" item of the BPRS will also contribute to the overall improvement in the maternal functioning.

[0264] The BPRS item "guilt feelings" is related to excessive concern or remorse about past behavior. Possible scores are:

[0265] 1 - no guilt feelings.

[0266] 2 - Very mild. Worried about disappointing someone or worried about something failing, but not absentminded. Can easily shift focus to other things.

[0267] 3 - Mild. Worried about disappointing someone or worried about something failing with a little absentmindedness. Tends to express guilt to others.

[0268] 4 - Moderate. Overly immersed in guilt, doing something wrong, hurting someone else because of doing something or not doing something, but can easily shift focus to other things.

[0269] 5 - Moderate-severe. Immersed in guilt, disappointing someone or something failing, can shift focus to other things but with great effort. Not delusional.

[0270] 6 - Severe. Delusional guilt or irrational self-accusation that is very out of proportion to the circumstances. There is moderate absentmindedness.

[0271] 7 - Extreme. Delusional guilt or irrational self-accusation that is extremely out of proportion to the circumstances. The subject is very immersed in guilt and can reveal it to others or act on delusions.

[0272] The inventors have determined that an increase in the score of the BPRS item “Feelings of Guilt” has a negative impact on two aspects of maternal functioning (maternal ability related to mother-infant interaction and maternal self-care). An increase in the score of the BPRS item “Feelings of Guilt” impairs self-care, mother-infant interaction, mental health, and management.

[0273] Conversely, an improvement in this BPRS item leads to an improvement in maternal functioning, in particular in the areas of self-care, mother-infant interaction, mental health, and / or management of the BIMF functional domains.

[0274] In the study group receiving the individualized dosing regimen, the total score of the BPRS item “Feelings of Guilt” for all 8 patients was 34 at baseline. After 3 hours, the score decreased to 14, which corresponds to an improvement of 20 points or 59%. On day 1 after treatment, the score decreased to 11, which corresponds to an improvement of 23 points or 68%. On day 7 after treatment, the score decreased 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 “Feelings of Guilt” for all 4 patients was 18 at baseline. After 3 hours, the score decreased to 9, which corresponds to an improvement of 9 points or 50%. On day 1 after treatment, the score decreased to 5, which corresponds to an improvement of 13 points or 72%. On day 7 after treatment, the score decreased 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.

[0277] The reduction or elimination of guilt is reflected at least by an improvement in the score of the BPRS item Guilt 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 later; on day 7; on day 14; and / or on day 28.

[0278] The improvement in guilt (reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score) 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 decrease in the 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] The improvement in guilt (reflected at least by a score of "much improved" in 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 (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 lasts 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 conclude that the reduction or elimination of guilt by treating PPD patients not only leads to a decrease in the BPRS total score, but also to an improvement in maternal functioning, which is reflected by 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 day 1, e.g. about 24 hours later; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

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

[0284] The BPRS item "anxiety" is related to reports of worry, tension, fear, panic, or apprehension. Possible scores are:

[0285] 1 - No anxiety.

[0286] 2 - Very mild. Some discomfort reported due to worry more often than most normal people or worry occasionally.

[0287] 3 - Mild. Worried often, but easily able to turn attention to other things.

[0288] 4 - Moderate. Worried most of the time, unable to turn attention easily to other things, but no impairment of functioning, occasional anxiety with autonomic symptoms, but no impairment of functioning.

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

[0290] 6 - Severe. Daily anxiety with autonomic symptoms but not constant throughout the day, or many areas of functioning disturbed by anxiety or constant worry.

[0291] 7 - Extreme. Anxiety with autonomic symptoms constant throughout the day, or most areas of functioning disturbed by anxiety or constant worry.

[0292] The inventors have determined that an increase in the score of the BPRS item "anxiety" has a negative impact on two aspects of maternal functioning (maternal ability related to interaction with the baby and maternal self-care). An increase in the score of the BPRS item "anxiety" impairs mental health, social support, and management.

[0293] Conversely, an improvement in this BPRS item leads to an improvement in maternal functioning, in particular in the BIMF functional areas of mental health, social support, and / or management.

[0294] In the study group receiving an individualized dosing regimen, the total score of the BPRS item "anxiety" for all 8 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 for the BPRS "Anxiety" item was 25 at baseline for all four patients. After 3 hours, the score had dropped to 11, corresponding to an improvement of 14 points, or 56%. On the first day after treatment, the score had dropped to 6, corresponding to an improvement of 19 points, or 76%. On the seventh day after treatment, the score had dropped to 6, corresponding to an improvement of 19 points, or 76%.

[0296] The inventors concluded that 5-MeO-DMT can 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; on day 1, such as about 24 hours; on day 7; on day 14; and / or on 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, eg, about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0300] Improvement in anxiety (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.

[0301] The improvement in anxiety (as reflected by a decrease in the CGI-S score or at least a score of "much improved" on 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; and more preferably, until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0302] The inventors have also concluded that reducing or eliminating anxiety in PPD patients through treatment results in not only a decrease in the BPRS total score, but also an improvement in maternal functioning, 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 at day 1, e.g. about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28 after the last administration.

[0303] As anxiety also affects other aspects of PPD, the inventors have concluded that the observed improvement in the “anxiety” item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0304] The BPRS item “tension” relates to observable physical and motor manifestations of tension, “anxiety” and agitation. Possible scores are

[0305] 1 - No tension.

[0306] 2 - Very mild. More irritable than most people but within normal range. Some brief signs of tension, e.g. picking at nails, tapping foot, scratching scalp or tapping fingers.

[0307] 3 - Mild. Same as “2” but signs of tension more frequent or more pronounced.

[0308] 4 - Moderate. Many and frequent motor signs of tension, sometimes one or more signs occurring simultaneously, e.g. twisting hands while tapping foot. Sometimes no signs of tension present.

[0309] 5 - Moderate-severe. Many and frequent motor signs of tension, often one or more signs occurring simultaneously. Still, there are rare instances where no signs of tension are present.

[0310] 6 - Severe. Same as “5” but signs of tension are constant.

[0311] 7 - Extreme. Multiple motor signs of tension are constantly present, e.g. constant pacing and twisting hands.

[0312] The inventors have determined that an increase in the score of the BPRS item “tension” has a negative impact on two aspects of maternal functioning, i.e. maternal ability to interact with the baby and maternal self-care. An increase in the score of the BPRS item “tension” will impair mother-child interaction and mental health.

[0313] Conversely, an improvement in this BPRS item will result in an improvement in maternal functioning, in particular in the BIMF functional domains of mother-child interaction and / or mental health.

[0314] In the study arm receiving the individualized dosing regimen, the total score of the BPRS item “anxiety” for all 8 patients was 16 at baseline. After 3 hours, the score was reduced to 11, which corresponds to an improvement of 5 points or 31%. On day 1 after treatment, the score was reduced to 11, which corresponds to an improvement of 5 points or 31%. On day 7 after treatment, the score was reduced to 10, which corresponds to an improvement of 6 points or 38%.

[0315] In the 12 mg arm, the total score of the BPRS item “anxiety” for all 4 patients was 14 at baseline. After 3 hours, the score was reduced to 9, which corresponds to an improvement of 5 points or 36%. On day 1 after treatment, the score was reduced to 6, which corresponds to an improvement of 8 points or 57%. On day 7 after treatment, the score was reduced to 6, which corresponds to an improvement of 8 points or 57%.

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

[0317] The reduction or elimination of anxiety is reflected at least by an improvement in the score of the BPRS item anxiety 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 later; on day 7; on day 14; and / or on day 28.

[0318] The improvement in anxiety (reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score) occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0319] Additionally or alternatively, the decrease in the 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] The improvement in anxiety (reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score) occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0321] 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 lasts 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 distress in PPD patients by treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof not only leads to a reduction in the BPRS total score, but also to an improvement in maternal functioning, 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 at day 1, e.g. about 24 hours after, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0323] As distress also affects other aspects of PPD, the inventors concluded that the observed improvement in the "distress" 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 lead to an overall improvement. Preferably, the treatment will lead to remission.

[0325] Remission of depressive symptoms can be reflected in a MADRS score of equal to or less than 10, and occurring not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g. about 24 hours after, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0326] Alternatively or in addition, remission of depressive symptoms can be reflected in a HAM-D score of equal to or less than 7, and occurring not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 1, e.g. about 24 hours after, day 7, day 14, and / or day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0327] From the above it follows that treatment of PPD patients with 5-MeO-DMT or a pharmaceutically acceptable salt thereof not only leads to a reduction in the MADRS score, in particular including the sub-scores detailed above, but also to an improvement in the domains of the BIMF scale. As discussed in the Example section below, the clinical data confirm the reduction in the MADRS score as well as the improvement in maternal functioning.

[0328] Improvement in maternal functioning includes an improvement in the self-care functioning domain. For example, an improvement in the MADRS items listlessness and / or reduced sleep will lead to an increase in the BIMF scale score reflecting self-care. The improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0329] Improvement in maternal functioning includes improvement in the area of infant care. For example, improvement in MADRS items lethargy and / or difficulty concentrating leads to an increase in the BIMF scale score reflecting infant care. Improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 15%, more preferably at least 25%.

[0330] Improvement in maternal functioning includes improvement in the area of mother-child interaction. For example, improvement in MADRS items feeling of absence and inner tension leads to an increase in the BIMF scale score reflecting mother-child interaction. Improvement in the cumulative score of the BIMF scale items reflecting mother-child interaction is preferably at least 5%, more preferably at least 15%.

[0331] Improvement in maternal functioning includes improvement in the area of mental health. For example, improvement in MADRS items lethargy, pessimistic thoughts, feeling of absence, inner tension and / or reduced sleep leads to an increase in the BIMF scale score reflecting mental health. Improvement in the cumulative score of the BIMF scale items reflecting mental health is preferably at least 25%, more preferably at least 35%.

[0332] Improvement in maternal functioning includes improvement in the area of social support. For example, improvement in MADRS items pessimistic thoughts leads to an increase in the BIMF scale score reflecting social support. Improvement in the cumulative score of the BIMF scale items reflecting social support is preferably at least 10%, more preferably at least 20%.

[0333] Improvement in maternal functioning includes improvement in the area of management. For example, improvement in MADRS items lethargy, pessimistic thoughts and / or difficulty concentrating leads to an increase in the BIMF scale score reflecting management. Improvement in the cumulative score of the BIMF scale items reflecting management is preferably at least 20%, more preferably at least 30%.

[0334] Improvement in maternal functioning includes improvement in the area of regulation. For example, improvement in MADRS items lethargy leads to an increase in the BIMF scale score reflecting regulation. Improvement in 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, of the functional areas selected from self-care, infant care, mother-child interaction, mental health of the mother, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

[0336] Improvement in the total BIMF score of 10% or more, preferably 20% more.

[0337] Breastfeeding

[0338] The term breastfeeding as used herein is the process of feeding a child with human breast milk. Breastfeeding includes feeding the child directly from the breast as well as expressing the breast milk and then feeding the child from a bottle.

[0339] As mentioned above, for many drugs, breastfeeding patients can face the situation that they have to decide whether to stop breastfeeding or to stop / abandon the treatment.

[0340] If the decision is made to stop breastfeeding in order to receive the treatment, this decision will have a negative impact on the mother’s functioning, in particular on the functional domains of mother-child interaction and mental health.

[0341] The present invention also addresses the need to treat a psychiatric or neurological disorder in a breastfeeding mother without almost completely interrupting breastfeeding.

[0342] According to the present invention, breastfeeding can be resumed shortly after the treatment.

[0343] The inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT in order to determine from which time point after administration of 5-MeO-DMT or a pharmaceutically acceptable salt breastfeeding can be performed without exposing the breastfeeding infant to any associated risks.

[0344] Furthermore, breast milk was obtained from a breastfeeding patient suffering from PPD who received treatment with 5-MeO-DMT. As described in more detail in the examples section, the breastfeeding patient suffering from PPD received a dose of 6 mg 5-MeO-DMT, followed 1 hour later by a dose of 12 mg 5-MeO-DMT.

[0345] At several time points after the last administration of 5-MeO-DMT, breast milk samples as well as serum and urine samples were analyzed for the presence of 5-MeO-DMT, bufotenine (the main metabolite of 5-MeO-DMT) and 5-MIAA (the final metabolite of 5-MeO-DMT).

[0346] With regard to the administered compound 5-MeO-DMT, absorption and distribution are rapid per se, e.g. when administered by inhalation or injection, the maximum concentration and pharmacological effect can be observed during and immediately after administration.

[0347] The plasma protein binding is low (13-23%).

[0348] The pharmacokinetic profile of inhaled 5-MeO-DMT showed that plasma concentrations dropped very rapidly. Ten minutes after administration, concentrations dropped to 10% or less of Cmax; 2 hours later, concentrations were 1% or less of Cmax; and 3 hours later, 5-MeO-DMT was no longer detected in 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 lead to accumulation and thus to higher plasma concentrations of 5-MeO-DMT, e.g. 10 minutes, 2 hours or 3 hours after administration.

[0349] The rapid drop in plasma concentrations resulted in a short time period during which 5-MeO-DMT was able to enter breast milk. Therefore, 5-MeO-DMT will only be found in breast milk for a short period of time.

[0350] The patient data obtained confirmed that the concentration of 5-MeO-DMT in breast milk dropped rapidly (see Example 12). No 5-MeO-DMT was detected at the measurement after 24 hours.

[0351] When determining the possible effects of maternal drug administration on breastfed infants, the standard practice is to calculate the relative infant dose (RID) (Bennett, P. N. and L. J. Notarianni. "Risk from drugs in breastmilk: an analysis by relative dose." Br J Clin Pharmacol 42.5 (1996): P673-4). The RID is the dose to which an infant is exposed by ingesting breast milk (in pg / kg / day), divided by the dose received by the mother (in pg / kg / day).

[0352] From the estimated values for breast milk daily intake and feeding frequency, and the measured breast milk concentrations, the exposure of the infant can be determined.

[0353] For example, published estimates of breast milk intake per day in relation to infant weight are 150 ml / kg / day. To simulate exposure, a 5 kg infant is assumed to be fed three times in 24 hours with 250 ml of breast milk each time. For the first feeding, a 5-MeO-DMT concentration of 2167.0 pg / ml (value measured at 1 hour) is assumed, for the second feeding a concentration of 560.6 pg / ml (value measured at 2.5 hours), and for the third feeding a concentration of 42.1 pg / ml (value measured at 8.5 hours). On this basis, the total exposure of the infant (daily infant dose, DID) is 692425 pg 5-MeO-DMT / day (0.000692425 mg / day), which corresponds to 0.000138485 mg / kg / day.

[0354] For maternal 5-MeO-DMT exposure, the total dose is 18 mg (6 mg for the first dose and 12 mg for the second dose according to the up-titration regimen applied).

[0355] Since the actual dose delivered to the patient can be lower than the labeled dose, the RID is also calculated assuming that the actual amount delivered is only 50% of the labeled dose, to avoid any potential underestimation of the infant exposure.

[0356] Assuming a maternal standard weight of 60 kg, the RID can be calculated to be 0.092% (based on a maternal exposure of 9 mg) to 0.046% (based on a maternal exposure of 18 mg).

[0357] The accepted threshold for a “low risk” RID is 10%. It is clear from the calculated values that the 5-MeO-DMT RID is significantly below this threshold.

[0358] Furthermore, it is worth noting that the range of 0.046% to 0.092% is a conservative estimate. Assuming that the concentration of 5-MeO-DMT remains constant until the next feeding (although the actual concentration will decrease rapidly), and ignoring the fact that there can be more than three feedings per day, i.e. smaller volumes per feeding, the concentration of 5-MeO-DMT to which the infant is exposed decreases gradually over time.

[0359] Furthermore, it is assumed that no breast milk is expressed and discarded when estimating.

[0360] Therefore, the actual RID will be lower than the estimated value.

[0361] To identify possible metabolites of 5-MeO-DMT that can occur in the human body to assess the potential relevance of such metabolites. In an in vitro metabolic identification study in human hepatocytes, 5-MeO-DMT free base was incubated at 10 μΜ for up to 120 minutes. The compounds identified and their relative ratios are shown in Table 1 below:

[0362] Table 1

[0363]

[0364] It is noteworthy that subsequent assays failed to detect the presence of 5-methoxytryptophol on multiple occasions, but repeatedly indicated the presence of 5-MIAA as the main metabolite. 5-Methoxytryptophol does not play any significant role in vivo.

[0365] The metabolites listed in the table above are formed by three different pathways.

[0366] The two most important metabolites, 5-methoxyindoleacetic acid and 5-methoxyindol-3-ethanol, are formed by oxidative deamination. This involves the enzymatic removal of the N-methyl group and oxidation so that an aldehyde is formed:

[0367]

[0368] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0369] No secondary amines, primary amines, and aldehydes were identified, which indicates that they are not present at significant concentrations at any time.

[0370] The aldehyde intermediate metabolite undergoes 2 independent biotransformations in human hepatocytes. The aldehyde intermediate metabolite is either oxidized to 5-methoxyindoleacetic acid (5-MIAA) or reduced to 5-methoxyindol-3-ethanol.

[0371]

[0372] Both 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 Biochemistry of the Pineal in Melatonin and the Mammalian Pineal Gland. Arendt J (ed.) Chapman & Hall, 1995; Chapter 3 Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium in Melatonin in the Promotion of Health. Watson RR (ed.) CRC Press 2012).

[0373] Since the main pathway of 5-MeO-DMT metabolism rapidly produces a metabolite that is also part of an endogenous metabolic pathway, the inventors determined that the oxidative deamination of 5-MeO-DMT does not involve a metabolite that would require restrictions on breast-feeding.

[0374] In addition, as described in detail in the Examples section, incubation of 5-methoxytryptophol with human hepatocytes showed a high metabolic turnover rate, with the compound being completely eliminated within 24 h. At a test concentration of 1 μΜ, the in vitro intrinsic clearance of 5-methoxytryptophol was 16.2 μl / min / million cells (half-life of 142 min).

[0375] Therefore, the plasma concentration of 5-methoxytryptophol, if formed, would rapidly decrease and reach endogenous levels.

[0376] 5-MIAA has been identified as the main human metabolite.

[0377] Incubation of 5-MIAA with human hepatocytes indicated a low metabolic turnover rate, with the concentration of 5-MIAA remaining at 75-82% after 72 h. 5-MIAA is considered to be the final metabolite of 5-MeO-DMT.

[0378] 5-MIAA showed a relatively low plasma binding rate of about 50% (mean unbound fraction (Fu); see Examples section). After renal clearance, 5-MIAA remains in the circulation.

[0379] If endogenous formation of 5-MIAA is disregarded and if it is assumed that after a single administration of a single dose of 5-MeO-DMT the compound is immediately converted into 5-MIAA, then according to the standard glomerular filtration rate (90-120 ml / min) it is concluded that 5-MIAA will be cleared from the circulation and excreted via the urine within about 1-2 hours.

[0380] For example, the 5-MIAA urine concentration measured after 2.5 hours at 12 980 501 pg / ml (about 12.98 mg / l) indicates that most of the formed 5-MIAA is rapidly excreted.

[0381] Therefore, the plasma concentration of 5-MIAA will rapidly decrease.

[0382] In order to more accurately estimate the development of the plasma concentration of 5-MIAA, a number of factors must be taken into account, including the size of the patient and the increase in blood volume during pregnancy. It is understood that there are individual differences in the glomerular filtration rate and the rate of metabolism of 5-MeO-DMT.

[0383] Furthermore, although the formation of 5-MIAA is rapid, the pharmacokinetic data of healthy volunteers as well as PPD patients indicate that there can still be a small amount of 5-MeO-DMT (corresponding to less than 10% of Cmax) after about 1 hour. Therefore, after administration of 5-MeO-DMT, 5-MIAA is actually formed for a period of time.

[0384] Furthermore, in the case of administration of more than one dose of 5-MeO-DMT, if the administration interval is at least about 1 hour, no accumulation of 5-MeO-DMT will occur, since at 2.5 hours there is still a measurable amount of 5-MIAA in the serum, which will accumulate to some extent if the subject is dosed at 1 hour intervals.

[0385] 5-MIAA is a weak acid, which will exist in ionized form in the plasma, thereby reducing the likelihood of the compound entering the breast milk.

[0386] Nevertheless, it can be assumed that during the limited period of time in which the plasma concentration of 5-MIAA is relatively high, a certain amount of 5-MIAA will enter the breast milk.

[0387] For further information on the concentration-time profile, see the measured concentrations of 5-MIAA in breast milk described in Example 12. With these data, the exposure of the infant to 5-MIAA can be calculated.

[0388] For the first feeding of 250 ml, the 5-MIAA concentration was assumed to be 13945.2 pg / ml (value measured at 1 hour), the second feeding concentration was 13240.9 pg / ml (value measured at 2.5 hours), and the third feeding concentration was 359.4 pg / ml (value measured at 8.5 hours). On this basis, the total exposure (DID) of the infant was 0.00688638 mg 5-MIAA / day, which corresponds to 0.00137728 mg / kg / day.

[0389] It is worth noting that the concentration of 5-MIAA in breast milk at 24 hours is nearly 400 times lower than at one hour, so the relevant exposure will no longer exist after 1 day.

[0390] The amount of maternal exposure to 5-MIAA can be estimated based on the amount of 5-MeO-DMT administered and the proportion of 5-MeO-DMT that is converted to 5-MIAA.

[0391] In the above metabolism experiment, the mixture contained approximately 60% 5-MIAA after 2 hours. Due to incomplete metabolism, the actual proportion of 5-MeO-DMT converted to 5-MIAA will be higher. It can be assumed that more than 60% to nearly 100% of 5-MeO-DMT will be converted to the final metabolite 5-MIAA, which is subsequently excreted out of the body.

[0392] Taking into account the molecular weights (218.29 g / mol for 5-MeO-DMT and 205.21 g / mol for 5-MIAA), a total dose of 18 mg 5-MeO-DMT would result in 10.15 mg 5-MIAA (60% conversion) to 16.92 mg 5-MIAA (100% conversion). As mentioned above, assuming that only 9 mg of 5-MeO-DMT is delivered, then 5.08 mg 5-MIAA (60% conversion) to 8.46 mg 5-MIAA (100% conversion) is formed.

[0393] Therefore, the maternal exposure will be between 0.085 mg / kg / day and 00.282 mg / kg / day. This results in an estimated value for RID between 0.49% and 1.62%.

[0394] As mentioned, the acceptable threshold for a “low risk” RID is 10%, and it is clear from the calculated values, which represent conservative estimates, that the 5-MIAA RID is well below this threshold.

[0395] Furthermore, given that the daily RID value for 5-MIAA does not reach the threshold and that the compound is an endogenous metabolite of certain naturally occurring tryptophan derivatives such as serotonin, it is considered to be of low risk.

[0396] Finally, the levels of bufotenine, the main metabolite of 5-MeO-DMT, were assessed in urine, serum and breast milk as described in Example 12. It is noteworthy that bufotenine was not detected in serum and breast milk at any time point and only in urine at the 2.5 hour time point (32.3 pg / ml). This data further demonstrates that bufotenine does not increase the risk of 5-MeO-DMT.

[0397] The above calculations are based on an up-titration regimen involving 5-MeO-DMT doses of 6 mg and 12 mg. The resulting conclusions are equally applicable to single doses of up to 12 mg, which would result in lower exposure to 5-MeO-DMT and its metabolites.

[0398] Assuming a linear relationship between dose increase and breast milk concentration (and thus infant exposure), it is concluded that for breast-feeding mothers treated with higher doses of 5-MeO-DMT (e.g. 18 mg or 25 mg, either as a single dose or as the final dose in an up-titration regimen), the RID of 5-MeO-DMT and 5-MIAA will remain significantly below 10%.

[0399] This remains true even when taking into account the depot effect of 5-MIAA in breast milk.

[0400] Based on the observed linear pharmacokinetic characteristics of 5-MeO-DMT, linear extrapolation is reasonable.

[0401] Finally, when considering the risk to the infant, it is important to consider the single day administration, as this does not require consideration of the cumulative exposure of the infant over a longer period of time, which is required for chronic treatment regimens.

[0402] Another identified metabolite, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The formed metabolite is then glucuronidated under the catalysis of UGT:

[0403]

[0404] As part of the pharmacokinetic study, it was determined that bufotenine is almost not detectable in human serum. In any case, bufotenine was not detected 15 minutes after administration of 5-MeO-DMT. A small amount was detected in urine at 2.5 hours (Example 12).

[0405] Bufotenine glucuronide does not bind to the receptor and does not exert any effect. Moreover, the concentration of bufotenine glucuronide is so low that it is not detectable in the hepatocyte assay. Bufotenine glucuronide is further converted to 5-hydroxyindoleacetic acid:

[0406]

[0407] 5-hydroxyindoleacetic acid is an endogenous substance, for example, it is present in the metabolism of melatonin and serotonin (cf. above).

[0408] Since the O-demethylation pathway of 5-MeO-DMT plays only a minor role and leads to the main metabolite bufotenine, which is rapidly cleared from the plasma and further metabolized to compounds that are only present in very low concentrations and finally to metabolites that are also part of the endogenous metabolic pathway, the inventors determined that O-demethylation of 5-MeO-DMT does not involve metabolites that would require restrictions on breastfeeding.

[0409] The third metabolic pathway involves N-oxidation:

[0410]

[0411] In computer simulations of the formed metabolites, 5-MeO-DMT-N-oxide was considered to be non-genotoxic, which is in line with the negative in vitro genotoxicity assessment of the parent molecule. The compound is soluble in water and excreted rapidly as confirmed by observations on rats (Sitaram, B.R., Lockett, L., Blackman, G. L., McLeod, W. R., 1987. Urinary excretion of 5-methoxy-N,N-dimethyltryptamine, N,N-dimethyltryptamine and their N-oxides in the rat. Biochemical Pharmacology 36: 2235-2231). Since the metabolic pathway of 5-MeO-DMT involving N-oxidation plays only a minor role and leads to a low proportion of metabolites that are not significantly toxic, which are rapidly excreted, the inventors determined that N-oxidation of 5-MeO-DMT does not involve metabolites that would require restrictions on breastfeeding.

[0412] 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.

[0413] For breastfed patients, only temporary cessation of breastfeeding is safe. During the actual treatment, i.e. the administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and during the subsequent psychedelic experience, breastfeeding is usually not possible. However, once the immediate effects of the administration have subsided, breastfeeding can be safely resumed for breastfed patients.

[0414] Early resumption of breastfeeding has significant advantages for breastfeeding patients, their mental health, and the mental health of their infants.

[0415] It can be recommended that a mother receiving treatment temporarily ceases breastfeeding, e.g. for a certain period of time or until a certain event has occurred.

[0416] Cessation of breastfeeding means that the infant is no longer fed directly through the breast and no longer fed through expressed breast milk when breastfeeding is not recommended. However, previously prepared breast milk can be fed with a bottle. Decisive is the point in time when the breast milk is expressed (not when the child is fed).

[0417] After the specified period of time or event, breastfeeding can be resumed immediately.

[0418] For example, it is recommended that a mother temporarily ceases breastfeeding only during the actual treatment, e.g. until the discharge readiness clinical assessment (CADR) shows that the discharge readiness has been achieved.

[0419] The discharge readiness clinical assessment (CADR) is performed to determine that the patient is ready to go home without clinical obstacles.

[0420] According to the CADR, the following is confirmed to determine the discharge readiness requirements: any adverse events have been resolved or are not an obstacle to discharge; the patient is fully awake; the patient has no hallucinations or perceptual distortions; the patient is alert (immediate response to a person’s name spoken in a normal tone; (modified observer’s alertness / sedation assessment score of 5); there are no clinically significant changes in vital signs compared to baseline; and the treating physician considers the patient to be ready for discharge.

[0421] The CADR can be administered about 1 hour after the last dose. Alternatively, a licensed professional can perform the discharge readiness assessment on their own based on relevant factors such as patient vital signs and / or alertness / sedation.

[0422] It is recommended that the patient does not resume breastfeeding after discharge and within 6 hours after the last dose (whichever is later); preferably after discharge or within 3 hours after the last dose (whichever is later); more preferably after discharge or within 2 hours after the last dose (whichever is later); in particular after discharge or within 1 hour after the last dose (whichever is later).

[0423] It is also possible to wait longer before resuming breastfeeding, for example until the concentration of 5-MeO-DMT and / or its metabolites in the breast milk sample has fallen below a certain threshold.

[0424] For example, breastfeeding can be temporarily stopped until the concentration of 5-MeO-DMT in the breast milk sample has fallen below 2000 pg / ml, 500 pg / ml or 75 pg / ml, and / or the concentration of 5-MIAA in the breast milk has fallen below 14000 pg / ml, 2000 pg / ml or 75 pg / ml.

[0425] Alternatively, breast milk can be pumped and discarded until the concentration of 5-MeO-DMT and / or 5-MIAA has fallen below a specified level.

[0426] Furthermore, based on clinical experience, breastfeeding can be temporarily stopped for a certain period of time when the concentration of 5-MeO-DMT and / or its metabolites in the breast milk reaches a certain level. In one example, the patient is advised to stop breastfeeding until 48 hours after the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof has been received. The patient is preferably advised to stop breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, more preferably to stop breastfeeding until 12 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof. Still more preferably, breastfeeding has to be interrupted for only 6 hours, even more preferably for only 3 hours, in particular for only 2 hours, and most preferably for only 1 hour after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0427] This short interruption and the possibility to resume breastfeeding shortly after treatment contribute to the success of the treatment and in particular to the mother's functioning as well as the health and development of the baby.

[0428] In order to avoid any associated risks to the non-weaned child, it is desirable to reduce the concentration of 5-MeO-DMT and / or 5-MIAA in the breast milk as much as possible. As long as any expressed breast milk is discarded when the concentration of 5-MeO-DMT and / or 5-MIAA in the breast milk exceeds a predetermined threshold, or breastfeeding is resumed only when the concentration of 5-MeO-DMT and / or the concentration of 5-MIAA in the breast milk is below the predetermined threshold, any associated risks to the non-weaned child can be avoided. In a preferred embodiment, the threshold for 5-MeO-DMT in the breast milk should be as low as possible. In another preferred embodiment, the threshold for 5-MIAA in the breast milk should be as low as possible. In the most preferred embodiment, the thresholds for 5-MeO-DMT and 5-MIAA in the breast milk should be as low as possible.

[0429] The following provides different preferred thresholds for 5-MeO-DMT and / or 5-MIAA in expressed breast milk:

[0430]

[0431] Delivered infant dose (DID) of 5-MeO-DMT and / or 5-MIAA

[0432] The delivered infant dose (DID) of 5-MeO-DMT and / or 5-MIAA should be kept as low as possible. In a preferred embodiment, the DID of 5-MeO-DMT is kept as low as possible. In another preferred embodiment, the DID of 5-MIAA is kept as low as possible. In the most preferred embodiment, the DID of 5-MeO-DMT and 5-MIAA is kept as low as possible.

[0433] The relevant DID of 5-MeO-DMT and / or 5-MIAA according to the present invention is as follows:

[0434]

[0435] To achieve the above mentioned DID, adjustments to breast feeding are required. Such adjustments are selected from the group consisting of choosing an appropriate time point to resume breast feeding, performing an appropriate number of feedings within the first 24 hours after resuming breast feeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

[0436] Relative infant dose (RID) of 5-MeO-DMT and / or 5-MIAA

[0437] The relative infant dose (RID) of 5-MeO-DMT and / or 5-MIAA should be as low as possible. In a preferred embodiment, the RID of 5-MeO-DMT is kept as low as possible. In another preferred embodiment, the RID of 5-MIAA is kept as low as possible. In the most preferred embodiment, the RID of 5-MeO-DMT and 5-MIAA is kept as low as possible.

[0438] The relevant RID of 5-MeO-DMT and / or 5-MIAA according to the present invention is as follows:

[0439]

[0440] To achieve the above mentioned RID, adjustments to breast feeding are required. Such adjustments are selected from the group consisting of choosing an appropriate time point to resume breast feeding, performing an appropriate number of feedings within the first 24 hours after resuming breast feeding, expressing and discarding breast milk for an appropriate period of time, or a combination of these measures.

[0441] Combination of delivered infant dose (DID) and relative infant dose (RID) of 5-MeO-DMT and / or 5-MIAA

[0442] The DID and RID of 5-MeO-DMT and / or 5-MIAA are described as important aspects of the present invention. While each individual aspect is equally important, in preferred embodiments of the present invention, both the DID of 5-MeO-DMT and / or 5-MIAA and the RID of 5-MeO-DMT and / or 5-MIAA are considered in combination. The present invention provides combinable relevant DID and relevant RID.

[0443] In one embodiment, the DID of 5-MeO-DMT and the RID of 5-MeO-DMT are combined. In preferred embodiments, the DID and RID of 5-MeO-DMT are kept as low as possible. The present invention provides combinable relevant DID and relevant RID.

[0444] In another embodiment, the DID of 5-MIAA and the RID of 5-MIAA are combined. In preferred embodiments, the DID and RID of 5-MIAA are kept as low as possible. The present invention provides combinable relevant DID and relevant RID.

[0445] In another embodiment, the DID of 5-MeO-DMT and the RID of 5-MIAA are combined. In preferred embodiments, the DID of 5-MeO-DMT and the RID of 5-MIAA are kept as low as possible. The present invention provides combinable relevant DID and relevant RID.

[0446] In another embodiment, the RID of 5-MeO-DMT and the DID of 5-MIAA are combined. In preferred embodiments, the RID of 5-MeO-DMT and the DID of 5-MIAA are kept as low as possible. The present invention provides combinable relevant DID and relevant RID.

[0447] In a more preferred embodiment, the DID of 5-MeO-DMT and 5-MIAA and the RID of 5-MeO-DMT and 5-MIAA are combined. In preferred embodiments, the DID of 5-MeO-DMT and 5-MIAA and the RID of 5-MeO-DMT and 5-MIAA are kept as low as possible. The present invention provides combinable relevant DID and relevant RID.

[0448] Mode of administration

[0449] The therapeutically effective amount of 5-MeO-DMT is administered by intravenous administration, intramuscular administration or subcutaneous administration. Administration via these routes ensures rapid onset of action. The most preferred route of administration is via the intravenous route, i.e. administration by intravenous injection.

[0450] 5-MeO-DMT can be used in the form of a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation for administration via injection, examples of excipients and vehicles for such formulations are known in the art.

[0451] Dosing regimen

[0452] The present application also provides dosage ranges, specific dosages, and dosing regimens (administration regimens) and appropriate routes of administration.

[0453] The present application is based in part on the inventors' conclusion that a peak psychedelic experience occurs during the acute phase following administration of 5-MeO-DMT, which drives the therapeutic benefit of 5-MeO-DMT in patients suffering from PPD, in particular one or more aspects as defined above, either causally or at least as a surrogate behavioral marker for the underlying, unknown therapeutic mechanism.

[0454] Thus, achieving the peak experience more rapidly in a greater proportion of patients and with better reproducibility in individual patients compared to previously tested psychedelic agents, dosing regimens and routes of administration will lead to a better therapeutic profile.

[0455] Furthermore, the present application also relies on the short duration of action of 5-MeO-DMT and the absence of associated tolerance (i.e. the absence of a reduction or disappearance of the psychedelic effect upon re-administration) as a basis for implementing a dosing regimen of frequent re-administration (such as more than once per day or once per day) designed to increase the incidence of peak experiences and thus the therapeutic benefit. Such repeated administration in a short time also allows for intra-individual dose optimization, which reduces the risk of overdosing, which can otherwise lead to somatic side effects such as serotonin syndrome, negative mental reactions such as experiencing flashbacks at later time points, induce mania or hypomania, or lead to altered state of consciousness with little or no memory of the meaning of the psychedelic experience (so-called "whiteout"). Furthermore, starting from low doses allows the patient to familiarize themselves with the general psychedelic experience and to prepare for the more intense symptoms that occur at higher doses, which will have a positive impact on the experience at higher doses. Moreover, the prospect of being able to start treatment at low doses will increase patient acceptance of the treatment method and increase overall adherence at the patient population level.

[0456] Frequent re-administration of serotonin psychedelics to increase the frequency of peak experiences and modulate the reproducibility of peak experiences, and to increase the therapeutic effect, reduce side effects, increase adherence, which can not be achieved with other psychedelics, as the psychedelic effect takes longer to take effect and lasts longer, and tolerance develops rapidly (i.e. the psychedelic effect is reduced or disappears upon re-administration), which can last for several days.

[0457] Treatment of a patient diagnosed with postpartum depression, including treatment-resistant forms of this disorder and including this disorder associated with suicidal ideation, as defined herein, by administration of 5-MeO-DMT. In preferred embodiments, 5-MeO-DMT is administered as a monotherapy, i.e., the patient does not receive any treatment for PPD or symptoms associated with PPD.

[0458] In preferred amounts, the dose of 5-MeO-DMT administered to a patient diagnosed with postpartum depression, including treatment-resistant forms of this disorder and including this disorder associated with suicidal ideation, as defined herein, ranges from 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 5-MeO-DMT free base assuming 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 when a range is listed in this specification, such as “about 1 mg to about 10 mg”, the inventors contemplate all discrete values within that range, some of which are explicitly mentioned, but not all - this is merely for purposes of brevity.

[0459] In preferred embodiments, the improved method of treating a patient diagnosed with postpartum depression, including treatment-resistant forms of this disorder and including this disorder associated with suicidal ideation, as defined herein, using a therapeutically effective amount of 5-MeO-DMT includes the presence of a clinical response no later than about 2 hours after administration of 5-MeO-DMT.

[0460] In preferred embodiments, the improved method of treating a patient diagnosed with postpartum depression, including treatment-resistant forms of this disorder and including this disorder associated with suicidal ideation, as defined herein, using a therapeutically effective amount of 5-MeO-DMT includes a sustained clinical response, including a clinical response present 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, more preferably until at least about 28 days after the last administration of 5-MeO-DMT.

[0461] In preferred embodiments, the improved method of treating a patient diagnosed with postpartum depression, including treatment-resistant forms of this disorder and including this disorder associated with suicidal ideation, as defined herein, using a therapeutically effective amount of 5-MeO-DMT includes administration of more than a single dose of 5-MeO-DMT.

[0462] In preferred embodiments, the plurality of doses 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 start of the next treatment block is no less than about 6 days.

[0463] In even more preferred embodiments, the plurality of doses 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 start of the next treatment block is no less than about 6 days.

[0464] In most preferred embodiments, the plurality of doses 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 start of the next treatment block is no less than about 6 days.

[0465] In embodiments, the dose 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.

[0466] In preferred embodiments, the dose of 5-MeO-DMT administered to an individual patient at the first administration within each treatment block is selected from about 1 mg to about 2 mg, then increases with each subsequent administration within each treatment block until either 10 mg is reached, or all of the administrations within the treatment block have been administered.

[0467] In even more preferred embodiments, the dose of 5-MeO-DMT administered to an individual patient at the first administration within each treatment block is selected from about 1 mg to about 2 mg, then increases with each subsequent administration within each treatment block until either 10 mg is reached, or all of the administrations within the treatment block have been administered, or the patient experiences a peak psychedelic experience, or the attending physician decides that further dose increases are not advisable based on observed side effects.

[0468] For embodiments in which the dose is increased for subsequent administrations, the dose for the next administration is determined by adding about 0.25 mg to about 3 mg, preferably about 0.5 mg to about 3 mg, to the dose of the previous administration. For example, if the dose for the first administration is 1 mg and the dose is increased by 3 mg, the dose for the second administration is 4 mg, unless one of the previously mentioned stopping criteria has been reached. Preferably, the dose for the third administration is 7 mg.

[0469] 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, 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 decides that the dose should not be increased further 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.

[0470] 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, 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 the dose should not be increased further 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.

[0471] In another preferred embodiment, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 1.5 mg to about 2.5 mg at the first administration, then increased to a dose selected from about 3.5 mg to about 4.5 mg at the second administration, and to a dose selected from about 5.5 mg to about 6.5 mg at the third administration, unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that the dose should not be increased further based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 2 mg, about 4 mg, and about 6 mg.

[0472] In a further preferred embodiment, the dose of 5-MeO-DMT administered to the individual patient in each treatment block is selected from about 2.5 mg to about 3.5 mg at the first administration, then increased to a dose selected from about 4.5 mg to about 5.5 mg at the second administration unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further dose increase is not advisable based on observed side effects, and increased to a dose selected from about 6.5 mg to about 7.5 mg at the third administration. Useful specific amounts for the first, second and third administrations are for example about 3 mg, about 5 mg and about 7 mg.

[0473] In a further preferred embodiment, the dose of 5-MeO-DMT administered to the individual patient in each treatment block is selected from about 2 mg to about 3 mg at the first administration, then increased to a dose selected from about 4.5 mg to about 5.5 mg at the second administration unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further dose increase is not advisable based on observed side effects, and increased to a dose selected from about 7 mg to about 8 mg at the third administration. Useful specific amounts for the first, second and third administrations are for example about 2.5 mg, about 5 mg and about 7.5 mg.

[0474] In a further preferred embodiment, the dose of 5-MeO-DMT administered to the individual patient at the first administration of the first treatment block is selected from about 1 mg to about 2 mg, then increased with each subsequent administration within this first treatment block until the earlier of: 10 mg is reached, or all administrations within this treatment block have been administered, or the patient has experienced a peak psychedelic experience, or the attending physician decides that further dose increase is not advisable 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 these subsequent treatment blocks. For example, if the highest dose in the first treatment block was 8 mg because the patient experienced a peak psychedelic experience at this dose, then the dose for all subsequent treatment blocks and administrations within these subsequent treatment blocks is 8 mg.

[0475] In particularly preferred embodiments, the dose of 5-MeO-DMT administered to an individual patient at the first administration of the first treatment block is selected from about 1 mg to about 2 mg, then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further dose increases are not advisable based on observed side effects, the second administration of the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration of the first treatment block will be increased to a dose selected from about 7 mg to about 9 mg, with the highest dose in the first treatment block to 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.

[0476] In particularly preferred embodiments, the dose of 5-MeO-DMT administered to an individual patient at the first administration of the first treatment block is selected from about 0.5 mg to about 1.5 mg, then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further dose increases are not advisable based on observed side effects, the second administration of 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 of the first treatment block will be increased to a dose selected from about 2.5 mg to about 3.5 mg, with the highest dose in the first treatment block to 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.

[0477] In particularly preferred embodiments, the dose of 5-MeO-DMT administered to an individual patient at the first administration of the first treatment block is selected from about 1 mg to about 3 mg, then unless the patient has experienced a peak psychedelic experience within the treatment block or the attending physician decides that further dose increases are not advisable based on observed side effects, the second administration of the first treatment block will be increased to a dose selected from about 3 mg to about 5 mg, and the third administration of the first treatment block will be increased to a dose selected from about 5 mg to about 7 mg, with the highest dose in the first treatment block to 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 4 mg, and about 6 mg.

[0478] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to the individual patient at the first administration of the first treatment block is selected from about 2 mg to about 4 mg, then unless the patient has experienced a peak psychedelic experience within said treatment block or the attending physician decides that further dose increase is not advisable due to observed side effects, the second administration of the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration of the first treatment block will be increased to a dose selected from about 6 mg to about 8 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within these subsequent treatment blocks. Useful specific amounts for the first, second and third administration in the first treatment block are for example about 3 mg, about 5 mg and about 7 mg.

[0479] In a particularly preferred embodiment, the dose of 5-MeO-DMT administered to the individual patient at the first administration of the first treatment block is selected from about 1.5 mg to about 3.5 mg, then unless the patient has experienced a peak psychedelic experience within said treatment block or the attending physician decides that further dose increase is not advisable due to observed side effects, the second administration of the first treatment block will be increased to a dose selected from about 4 mg to about 6 mg, and the third administration of the first treatment block will be increased to a dose selected from about 6.5 mg to about 8.5 mg, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within these subsequent treatment blocks. Useful specific amounts for the first, second and third administration in the first treatment block are for example about 2.5 mg, about 5 mg and about 7.5 mg.

[0480] It is understood that pharmaceutically acceptable salts of 5-MeO-DMT can also be used in all of the above dosing regimens, and that the appropriate weight of the salt to be administered can be calculated from the prescribed weight of the free base, assuming the use of equimolar amounts.

[0481] According to the present application, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0482] A patient can be identified to have experienced a “peak psychedelic experience” if he or she achieves at least 60% of the highest possible score in each of the four subscales of the 30-item revised Mystical Experience Questionnaire (MEQ-30) (mystical, positive mood, transcendence of time and space, and unspeakability) (as described in Barrett FS, J Psychopharmacol. 2015; 29(11): 1182-90).

[0483] Whether the patient has a "peak psychedelic experience" can also be determined by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire (as described in Roseman L et al., Front Pharmacol. 2018; 8:974).

[0484] According to the present application, whether the patient has a "peak psychedelic experience" is preferably identified by achieving at least 75 points in the Peak Experience Scale (PES) total score, also known as the Peak Psychedelic Experience Questionnaire (PPEQ), which calculates the average score of the patient's answers from 0 to 100 points to the following three questions: 1. How intense was the experience? 2. How much loss of control? 3. How significant was the experience (i.e., profound and important)?

[0485] Further aspects of the present application

[0486] 1. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient suffering from postpartum depression (PPD), wherein the 5-MeO-DMT is administered via an intravenous, intramuscular or subcutaneous route.

[0487] 2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 1, wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or more.

[0488] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 2, wherein the patient has a MADRS score of 28 or more or a HAM-D score of 22 or more.

[0489] 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 more or a HAM-D score of 27 or more.

[0490] 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.

[0491] 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.

[0492] 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 functioning.

[0493] 8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 7, wherein the patient has a Barkin Index of Mother Function (BIMF) score of 95 or lower, such as 80 or lower, in particular 65 or lower.

[0494] 9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 8, wherein the 5-MeO-DMT or salt thereof is administered in a dose or dose regimen that causes the patient to experience a peak psychedelic experience.

[0495] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 9, wherein a dose of about 1 mg to about 10 mg 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0496] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to 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 the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0497] 12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to 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 the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0498] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered at a first dose at a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein the dose used at each subsequent administration is higher than the previous administration unless the patient experiences a peak psychedelic experience.

[0499] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 10 or 13, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg at a first administration, then increased to a dose of about 4 mg to about 6 mg at a second administration unless the patient has already experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg at a third administration unless the patient has already experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0500] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 14, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 5 mg, and the third dose of 5-MeO-DMT is about 8 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0501] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to 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 at a first time, then increased to a dose of about 1.5 mg to about 2.5 mg at a second time unless the patient has already experienced a peak mystical experience, then increased to a dose of about 2.5 mg to about 3.5 mg at a third time unless the patient has already experienced a peak mystical experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0502] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 16, wherein the first dose of 5-MeO-DMT is about 1 mg, the second dose of 5-MeO-DMT is about 2 mg, and the third dose of 5-MeO-DMT is about 3 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0503] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 13 to 17, wherein the interval between two administrations is no less than 1 hour and no more than 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.

[0504] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 9 to 18, wherein the occurrence of a peak mystical experience is identified by achieving at least 60% of the highest possible score in each of the four subscales of the 30-item revised Mystical Experience Questionnaire (MEQ30) (Mystical, Positive Emotions, Transcendence of Time and Space, and Ineffability), or by achieving at least 60% of the highest 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.

[0505] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 19, wherein the occurrence of a peak mystical experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

[0506] 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.

[0507] 22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 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, the clinical response reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score.

[0508] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 22, wherein a clinical response occurs on day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score.

[0509] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 23, wherein a clinical response persists for at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score.

[0510] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 24, wherein a clinical response persists for at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score.

[0511] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 25, wherein a clinical response persists for at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score.

[0512] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to 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, the clinical response assessed as an improvement in MADRS or HAM-D score of at least 50% compared to the respective score prior to treatment.

[0513] 28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 27, 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, the clinical response being assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0514] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 24, wherein remission of depressive symptoms occurs no later than about 2 hours 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 of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0515] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 29, wherein remission of depressive symptoms occurs on day 1, e.g. about 24 hours, 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 of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0516] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 30, wherein the clinical response lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0517] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 31, wherein there is a clinical response on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0518] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 32, wherein the patient is in remission of depressive symptoms on day 7 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 of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0519] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 33, wherein the clinical response is sustained until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0520] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to 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 at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0521] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 35, wherein the patient is in remission of depressive symptoms at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms being assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7.

[0522] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 36, wherein the clinical response is sustained until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0523] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 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, the clinical response being assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0524] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 38, wherein the patient is in remission of depressive symptoms at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms being assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7.

[0525] 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.

[0526] 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.

[0527] 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.

[0528] 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.

[0529] 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.

[0530] 45. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to aspects 1 to 44, wherein the treatment improves maternal functioning.

[0531] 46. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to aspect 45, wherein the improvement relates to one or more, in particular two or more functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-infant interaction, maternal mental health, social support, management and regulation.

[0532] 47. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to aspects 45 or 46, wherein the BIMF score is improved by 10% or more, preferably 20% or more. SUMMARY

[0533] 1. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in the treatment of a patient suffering from postpartum depression (PPD), wherein the 5-MeO-DMT is administered via an intravenous, intramuscular or subcutaneous route.

[0534] 2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 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.

[0535] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 2, wherein the patient has a MADRS score of 28 or higher or a HAM-D score of 22 or higher.

[0536] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 2, wherein the patient has a MADRS score of 35 or higher or a HAM-D score of 27 or higher.

[0537] 5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 4, wherein the patient is diagnosed with a treatment-resistant form of postpartum depression.

[0538] 6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 5, wherein the patient also suffers from suicidal ideation.

[0539] 7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 6, wherein the patient also suffers from mildly impaired, impaired or severely impaired maternal functioning.

[0540] 8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 7, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 95 or lower, such as 80 or lower, in particular 65 or lower.

[0541] 9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 8, wherein the 5-MeO-DMT or salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

[0542] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 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 the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0543] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 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 the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0544] 12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 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 the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0545] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered at a first dose at a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein, unless the patient experiences a peak psychedelic experience, the dose used for each subsequent administration is higher than the previous administration.

[0546] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 10 or 13, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg at a first administration, then increased to a dose of about 4 mg to about 6 mg at a second administration unless the patient has already experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg at a third administration unless the patient has already experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0547] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 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.

[0548] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 1 to 10 or 13, wherein the first administration of the 5-MeO-DMT is at a dose of about 0.5 mg to about 1.5 mg, then unless the patient has already experienced a peak psychedelic experience, the second administration is increased to a dose of about 1.5 mg to about 2.5 mg, then unless the patient has already experienced a peak psychedelic experience, the third administration is increased to a dose of about 2.5 mg to about 3.5 mg, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0549] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 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.

[0550] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 13 to 17, wherein the interval between two administrations is no less than 1 hour and no more than 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.

[0551] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 9 to 18, wherein the occurrence of a peak psychedelic experience is identified by achieving at least 60% of the highest possible score in each of the four subscales of the 30-item revised Mystical Experience Questionnaire (MEQ30) (Mystical, Positive Emotions, Transcendence of Time and Space, and Noetic), or by achieving at least 60% of the highest 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.

[0552] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 19, wherein the occurrence of a peak psychedelic experience is identified by achieving a peak experience scale (PES) total score of at least 75.

[0553] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 1 to 20, wherein the 5-MeO-DMT or pharmaceutically acceptable salt thereof is administered via intravenous injection.

[0554] 22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 21, wherein the clinical response, reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0555] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 22, wherein the clinical response, reflected as a decrease 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.

[0556] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 23, wherein the clinical response, reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score, lasts at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 24, wherein the clinical response, reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score, lasts at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0558] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 25, wherein the clinical response, reflected as a decrease in Clinical Global Impression - Severity (CGI-S) score, lasts at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0559] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 27, wherein the clinical response, assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0560] 28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 27, wherein the clinical response, assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0561] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 24, wherein remission of depressive symptoms occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms assessed as a MADRS score of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0562] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 29, wherein remission of depressive symptoms occurs on day 1, e.g., about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms assessed as a MADRS score of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0563] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 30, wherein the clinical response lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0564] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 31, wherein there is a clinical response on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0565] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 32, wherein the patient is in remission of depressive symptoms on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the remission of depressive symptoms assessed as a MADRS score of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0566] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 33, wherein the clinical response lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0567] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 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, said clinical response being assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0568] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 35, wherein the patient is in remission of depressive symptoms at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said remission of depressive symptoms being assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7.

[0569] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 36, wherein the clinical response lasts until at least day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said clinical response being assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0570] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 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, said clinical response being assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0571] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 38, wherein the patient is in remission of depressive symptoms at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, said remission of depressive symptoms being assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7.

[0572] 40. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of items 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.

[0573] 41. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of items 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.

[0574] 42. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt thereof, for use according to any one of items 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.

[0575] 43. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt thereof, for use according to any one of items 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.

[0576] 44. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt thereof, for use according to any one of items 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.

[0577] 45. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to items 1 to 44, wherein the treatment improves maternal functioning.

[0578] 46. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to item 45, wherein the improvement relates to one or more, in particular two or more functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-infant interaction, maternal mental health, social support, management and regulation.

[0579] 47. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to item 45 or 46, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

[0580] Other specific items

[0581] 1. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), or a pharmaceutically acceptable salt thereof, for use in the treatment of a patient suffering from postpartum depression (PPD), wherein the patient suffers from moderate or severe depression and impaired or severely impaired maternal functioning, wherein the 5-MeO-DTP, or a pharmaceutically acceptable salt thereof, is administered via an intravenous, intramuscular or subcutaneous route.

[0582] 2. 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, for use according to item 1, wherein the patient suffers from severe depression and impaired or severely impaired maternal functioning.

[0583] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 1, wherein the patient suffers from severe depression and suffers from severely impaired maternal functioning.

[0584] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 2, wherein the patient has a MADRS score of 20 or higher.

[0585] 5. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 2, wherein the patient has a MADRS score of 35 or higher.

[0586] 6. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 1, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 80 or lower, in particular 65 or lower.

[0587] 7. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 1, wherein the impaired or severely impaired maternal functioning affects the functional domains of mother-child interaction and / or management.

[0588] 8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 1, wherein the score according to the Barkin Index of Maternal Functioning (BIMF) assigned to the functional domains of mother-child interaction and / or management does not exceed 60% of the maximum score of the functional domain.

[0589] 9. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 8, wherein the patient is in remission of depressive symptoms at day 7.

[0590] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 9, wherein the patient is in remission of depressive symptoms at day 28.

[0591] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 10, wherein maternal functioning is improved at day 7 compared to the functioning before treatment.

[0592] 12. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 11, wherein maternal functioning is improved at day 28 compared to the functioning before treatment.

[0593] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 12, wherein the BIMF score is improved by at least 10%, preferably at least 20% at day 7.

[0594] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 13, wherein the BIMF score is improved by at least 10 points, preferably by at least 20 points, in particular by at least 30 points at day 7.

[0595] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 14, wherein the treatment results in an improvement of the score according to the Barkin Index of Maternal Function (BIMF) assigned to the functional domains of the mother-child interaction and / or management to more than 60% of the maximum possible score, preferably to more than 80% of the maximum possible score in the respective functional domain at day 7.

[0596] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 15, wherein the BIMF score is improved by at least 10%, preferably by at least 20% at day 28.

[0597] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 16, wherein the BIMF score is improved by at least 10 points, preferably by at least 20 points, in particular by at least 30 points at day 28.

[0598] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 17, wherein the treatment results in an improvement of the score according to the Barkin Index of Maternal Function (BIMF) assigned to the functional domains of the mother-child interaction and / or management to more than 60% of the maximum possible score, preferably to more than 80% of the maximum possible score at day 28.

[0599] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 18, wherein the 5-MeO-DMT or salt thereof is administered in a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

[0600] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 19, wherein a dose of about 1 mg to about 10 mg 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0601] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 20, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0602] 22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 20, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0603] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 20, wherein a dose of about 2 mg; or about 4 mg; or about 6 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0604] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 20, wherein the 5-MeO-DMT or salt thereof is administered at a first dose at a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein the dose used at each subsequent administration is higher than the previous administration unless the patient experiences a peak psychedelic experience.

[0605] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 20 or 24, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg at a first administration, then increased to a dose of about 4 mg to about 6 mg at a second administration unless the patient has already experienced a peak psychedelic experience, then increased to a dose of about 7 mg to about 9 mg at a third administration unless the patient has already experienced a peak psychedelic experience, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0606] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 25, 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.

[0607] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 20 or 24, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, which is 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, and which is 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.

[0608] 28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in item 27, 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.

[0609] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 20 or 24, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 3 mg for a first administration, which is then increased to a dose of about 4 mg to about 5 mg for a second administration unless the patient has experienced a peak psychedelic experience, and which is then increased to a dose of about 6 mg to about 7.5 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.

[0610] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in claim 29, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 4 mg, and the third dose of 5-MeO-DMT is about 6 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

[0611] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 24 to 30, 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 1 to 2 hours.

[0612] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 19, wherein a dose of about 1 mg to about 5 mg 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0613] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 32, wherein a dose of about 1 mg or about 5 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0614] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 32, wherein the 5-MeO-DMT or salt thereof is administered at a first dose at a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein the dose used at each subsequent administration is higher than the previous administration unless the patient experiences a peak psychedelic experience.

[0615] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 34, wherein the interval between two administrations is no less than 1 hour and no more than 24 hours, such as about 1 to 4 hours, preferably 1 to 2 hours.

[0616] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 19 to 35, wherein the occurrence of a peak psychedelic experience is identified by achieving at least 60% of the maximum possible score in each of the four subscales of the 30-item revised Mystical Experience Questionnaire (MEQ30) (Mystical, Positive Emotions, Transcendence of Time and Space, and Ineffability), or by achieving at least 60% of the maximum possible score on the Oceanic Boundlessness (OBN) dimension of the Altered States of Consciousness (ASC) Questionnaire, or by achieving a Peak Experience Scale (PES) total score of at least 75.

[0617] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 36, wherein the occurrence of a peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

[0618] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 37, wherein the 5-MeO-DMT or pharmaceutically acceptable salt thereof is administered via intravenous injection.

[0619] EMBODIMENTS

[0620] The following examples are set forth to assist in understanding the application and should not be construed as specifically limiting the application described in the claims.

[0621] Example 1 - 5-MeO-DMT aerosol generation and administration

[0622] Step 1 : Prepare a stock solution of 5-MeO-DMT free base in 100% ethanol in a volumetric flask such that 200 μΐ of solution volume contains the target dose of 5-MeO-DMT free base to be administered to a volunteer or patient via inhalation. A typical target dose is 1 mg to 25 mg of 5-MeO-DMT. For example, for a target dose of 18 mg of 5-MeO-DMT, 90 mg of 5-MeO-DMT is dissolved in 100% ethanol for a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

[0623] Step 2: Transfer 200 μΐ of solution into a dosing capsule (Storz & Bickel, Germany) containing a water dropper pad, then cap the dosing capsule.

[0624] Step 3: Transfer the dosing capsule containing the 5-MeO-DMT ethanol solution into the fill chamber of a first Volcano Medic vaporizer, which has been preheated with a temperature setting of 55°C. Then, turn on the air flow of the vaporizer at a pre-set rate of about 12 1 / min for 60 seconds. The heated air will flow through the dosing capsule, allowing the ethanol to evaporate, while the target dose of 5-MeO-DMT remains in the capsule as a thin layer covering the stainless steel wire mesh. The accurate preparation of the dosing capsule can be confirmed by demonstrating that the final weight of the capsule has increased by approximately the target dose of 5-MeO-DMT compared to the weight of an empty capsule.

[0625] Step 4: Remove the prepared dosing capsule from the fill chamber. Then transfer it into the fill chamber of a second Volcano Medic vaporizer, which has been preheated with a temperature setting of 210°C, and turn on the air flow for at least 5 minutes, then turn it off immediately before transfer. Install a valved inhalation balloon (Storz & Bickel, Germany) into the socket of the fill chamber, close the fill chamber tightly, then immediately turn on the air flow at a pre-set rate of about 12 1 / min for 15 seconds, then turn it off. This will allow the full dose of 5-MeO-DMT to be aerosolized and distributed in approximately 3 liters of air in the inhalation balloon. The accurate aerosolization of 5-MeO-DMT can be confirmed by demonstrating that the weight of the capsule has returned to approximately its initial weight.

[0626] Step 5: The balloon is then disconnected from the fill chamber, which automatically closes the valve. Once the mouthpiece is attached to the balloon, the aerosol is ready to be administered immediately to the volunteer or patient.

[0627] Step 6: To prepare for administration, the patient is asked to take 1-2 deep breaths, exhale completely, and end the process with a deep breath. Then, the mouthpiece is firmly pressed against the lips, the full volume of the balloon is inhaled in one breath, breath is held for 10 (± 2.5) seconds, and then exhaled normally. After the inhalation procedure is complete, the patient is instructed to lie down.

[0628] Further details regarding the administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020 / 169850 Al, the contents of which are incorporated herein by reference.

[0629] Example 2 - Preparation of high purity 5-MeO-DMT

[0630] The 5-MeO-DMT (2.0 g) was dissolved in MTBE (4 mL, 2.0 volumes) at 35 to 40 °C, then cooled to room temperature over 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 over 30 minutes. Crystallization occurred after stirring at 7 to 12 °C for 10 minutes. The batch was then stirred at 7 to 12 °C for 1 hour, followed by filtration of the batch. 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 give 1.02 g of a light orange solid (50% recovery). The purity of the isolated solid was analyzed by HPLC as described in WO 2020 / 169850 Al. The purity was 99.74% area.

[0631] The analytical results further indicated that the level of individual impurities was below 0.10% area. Solvent analysis of the sample indicated a level of 17 ppm of MTBE.

[0632] Example 3 - Preparation of 5-MeO-DMT hydrobromide

[0633] 5-MeO-DMT HBr was prepared on a 100 mg scale.

[0634] The 5-MeO-DMT free base was combined with isopropyl acetate (10 volumes), and the resulting 5-MeO-DMT solution was heated to 50 °C. HBr (1 M in ethanol, 1 equivalent) was charged in one single aliquot. The mixture was kept at this temperature and equilibrated for 3 hours.

[0635] 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 under vacuum at 40 °C for 18 hours.

[0636] A grey-white crystalline material was obtained.

[0637] The salt has a melting point of 174 °C and is characterized by an X-ray diffraction pattern comprising peaks at 14.5 °2Q ± 0.2 °2Q; 16.7 °2Q ± 0.2 °2Q; 17.0 °2Q ± 0.2 °2Q; 20.6 °2Q ± 0.2 °2Q; 20.7 °2Q ± 0.2 °2Q; 21.4 °2Q ± 0.2 °2Q; 24.2 °2Q ± 0.2 °2Q; 24.8 °2Q ± 0.2 °2Q; 25.3 °2Q ± 0.2 °2Q; 27.4 °2Q ± 0.2 °2Q; measured using Cu Ka radiation.

[0638] Example 4 - Determination of inhibition constants for central 5-HT1A and 5-HT2A receptors in post-mortem human brain membrane preparations

[0639] In this study, the affinity of three psychedelic test compounds (norbaeocystin, DMT and 5-MeO-DMT) for 5-HT1A and 5-HT2A receptors in post-mortem human brain tissue (hippocampus and frontal cortex, respectively) was determined using radioligand binding techniques.

[0640] Human brain samples were obtained from the Edinburgh Sudden Death Brain Bank. All donors were sudden deaths, with no history of coma, psychiatric or neurological illness, were less than 65 years of age and had a post-mortem interval of less than or equal to 72 hours.

[0641] Binding to 5-HT1A receptors in post-mortem human hippocampus

[0642] Use electric Teflon pestle (grinding 12 times at 120 rpm) to homogenize hippocampus in ice-cold 0.25 M sucrose (1:30 weight / volume). Remove myelin and cell debris by centrifugation at 1,000 g for 10 minutes. The supernatant is stored on ice, and the precipitation is homogenized again in 0.25 M sucrose (1:15 weight / volume), and centrifuged at 750 g for 10 minutes. The supernatant is merged, and diluted with ice-cold membrane preparation buffer (1:100 weight / volume), using a tightly fitting glass / Teflon homogenizer (12 times, 800 rpm), and centrifuged at 20,500 g for 10 minutes. The precipitation is resuspended in ice-cold membrane preparation buffer, and incubated at 37 ° C for 10 minutes, then centrifuged at 20,500 g for 10 minutes. The precipitation is resuspended and centrifuged for the last time to wash the tissue (20,500 x g, 10 minutes). The resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equal to 3.125 mg of 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 CaCl2, and 0.1% ascorbic acid. The assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCl2, 0.1% ascorbic acid, and 10 μM pargyline.

[0643] For saturation binding assays, hippocampal membranes (400 μl; equivalent to 1.25 mg wet weight tissue / tube) were mixed with 50 μl of 0.075-9.6 nM [ 3 H]8-0H-DPAT and 50 μl of assay buffer (total binding) or 50 μl of 1 μM WAY100635 (nonspecific binding) were incubated for 30 minutes at 25°C. Wash buffer consisted of 50 mM Tris, pH 7.7.

[0644] 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 (nonspecific 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 minutes.

[0645] Membrane-bound radioactivity was recovered by vacuum filtration using Skatron cell harvesters with Skatron 11731 filters pre-soaked in 0.5% polyethylenimine (PEI). 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).

[0646] Non-linear regression was used to calculate the concentration of compound required to inhibit 50% of specific binding (IC 50 ) and Hill slope. The K i was calculated using a one-site binding model allowing for ligand depletion.

[0647] Binding to 5-HT2A receptors in post-mortem human frontal cortex

[0648] Frontal cortex was homogenized in ice-cold 0.25 M sucrose (1 :30 weight / volume) using a motorized Teflon pestle (12 strokes at 120 rpm). Myelin and cellular debris were removed by centrifugation at 1,000 g for 10 min. The supernatant was stored on ice and the pellet was re-homogenized in 0.25 M sucrose (1 :15 weight / volume) and centrifuged at 750 g for 10 min. 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 tight-fitting glass / Teflon homogenizer (12 strokes at 800 rpm) and centrifuged at 20,500 g for 10 min. The pellet was further centrifuged twice to wash the tissue (20,500 x g, 10 min). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, at a tissue concentration equal to 10 mg tissue wet weight / ml. All centrifugations were performed at 4°C.

[0649] For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg tissue wet weight / tube) were incubated with 50 μl 0.00625 - 0.8 nM [ 3 ] MDL-100,907 and 50 μl assay buffer or 50 μl 10 μM ketanserin (non-specific binding) for 60 min at 25°C. The assay and wash buffers consisted of 50 mM Tris-HCl buffer, pH 7.4.

[0650] In displacement assays, frontal cortex membranes (400 μl; equivalent to 4 mg wet weight of 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 (non-specific binding) or 50 μl of one of ten concentrations between 1 and 10,000 nM of test compound for 60 min at 25°C.

[0651] Membrane-bound radioactivity was recovered and determined as described above. Data analysis was also performed as described above.

[0652] Results

[0653] The dissociation constants (K 3 values) of [3H]8-OH-DPAT for 5-HT1A receptors in hippocampal membranes from post-mortem human brain tissue from each of the three donors were determined. d The dissociation constants (K d values) obtained were 0.51, 0.28 and 0.52 nM, respectively.

[0654] The mean inhibition constants (K i values) of desphospho-hHallucinum, DMT and 5-MeO-DMT were 48, 38 and 1.80 nM, respectively (mean n = 3). The Hill slopes of all compounds were close to unity, indicating a one-site binding model.

[0655] The dissociation constants (K 3 values) of [3H]MDL-100,907 for 5-HT2A receptors in frontal cortex membranes from post-mortem human brain tissue from each of the three donors were determined. d The dissociation constants (K d values) obtained were 0.11, 0.08 and 0.08 nM, respectively.

[0656] The mean inhibition constants (K i values) of desphospho-hHallucinum, DMT and 5-MeO-DMT were 37, 117 and 122 nM, respectively (mean n = 3). The Hill slopes of all compounds were close to unity, indicating a one-site binding model.

[0657] The selectivity ratios of desphospho-hHallucinum, DMT and 5-MeO-DMT for 5-HT2A receptors over 5-HT1A receptors were 0.78, 3.1 and 68, respectively.

[0658] Example 5 - Clinical trial in patients suffering from TRD

[0659] A phase 1 / 2 clinical trial of 5-MeO-DMT via inhalation administration as described herein has been completed in treatment-resistant major depressive disorder (TRD) patients. The trial was designed in two parts. Part A was 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 was an open-label, single-arm phase 2 trial with an individualized dosing regimen and stepwise escalation of 5-MeO-DMT dose within patients. Patients (n=8) received at least one and up to three doses of 5-MeO-DMT (6 mg, 12 mg, and 18 mg) per day, with higher doses administered only if the previously administered dose did not achieve a peak experience. The primary endpoint for Part A was to assess the safety and tolerability of a single dose of 5-MeO-DMT in TRD patients. The primary endpoint for Part B was to assess the effect on depression severity as assessed by the proportion of patients in remission at day 7 post-dose, defined as a MADRS total score of less than or equal to 10.

[0660] 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.

[0661] Two of four patients (50%) in the 12 mg group and one of four patients (25%) in the 18 mg group had MADRS remission at day 7 post-dose, and another patient (25%) in the 18 mg group had a MADRS clinical response at day 7 post-dose. The mean change in MADRS from baseline at day 7 was -21.0 (-65%) for the 12 mg group and -12.8 (-41%) for the 18 mg group.

[0662] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0663] At day 7, seven of eight patients (87.5%) achieved MADRS remission, achieving the primary endpoint (p<0.0001). The mean change in MADRS from baseline at day 7 was 24.4 (76%).

[0664] 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.

[0665] Results are summarized in the table below.

[0666]

[0667] Table 2-A. Scores recorded for the relevant MADRS and BPRS items for patients assigned to the intra-day individual dosing regimen (IDR). Item scores represent the sum of the individual patient scores for all patients (n=8) in the IDR group. Assessments 2 hours (MADRS) or 3 hours (BPRS) after administration of the last dose.

[0668]

[0669] Table 2-B. Scores recorded for the relevant MADRS and BPRS items for patients assigned to the intra-day individual dosing regimen (IDR). Item scores represent the sum of the individual patient scores for all patients (n=8) in the IDR group. Assessments on Day 1.

[0670]

[0671] Table 2-C. Scores recorded for the relevant MADRS and BPRS items for patients assigned to the intra-day individual dosing regimen (IDR). Item scores represent the sum of the individual patient scores for all patients (n=8) in the IDR group. Assessments on Day 7.

[0672]

[0673] Table 3-A. Scores recorded for the relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of the individual patient scores for all patients (n=4) in the 12 mg group. Assessments 2 hours (MADRS) or 3 hours (BPRS) after administration of the dose.

[0674]

[0675] Table 3-B. Scores recorded for the relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of the individual patient scores for all patients (n=4) in the 12 mg group. Assessments on Day 1.

[0676]

[0677] Table 3-C. Scores recorded for the relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of the individual patient scores for all patients (n=4) in the 12 mg group. Assessments on Day 7.

[0678] Example 6 - Pharmacokinetic assessment of 5-MeO-DMT and Bufotenine

[0679] To investigate the pharmacokinetic properties of 5-MeO-DMT, three groups of 8 subjects each were formed. 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; 4 hours after administration.

[0680] 5-MeO-DMT concentrations were determined using LC-MS / MS. PK parameters were generated by algebraic analysis of the concentration versus time profiles for each individual. Analysis was performed using the software Phoenix WinNonlin 6.3.

[0681] 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.

[0682] Table 4 below shows the median percentage of plasma concentrations relative to Cmax determined at the indicated time points.

[0683]

[0684] Pharmacokinetic measurements were also performed for the dosing regimen dependent up-titration. Substantially similar results were obtained.

[0685] Blood concentrations of the 5-MeO-DMT metabolite bufotenine were also determined. Concentrations were above the lower limit of quantification (LLOQ) (25 pg / ml) in only a few samples. From 15 minutes onwards, bufotenine concentrations were consistently below the LLOQ.

[0686] Substantially similar observations were also made when including subjects who received the up-titration regimen.

[0687] Example 7 - Toxicology testing of 5-MeO-DMT

[0688] 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). Treatments were performed in the absence and presence of rat liver metabolic activation system (S-9) at concentrations up to 5000 pg / plate (maximum concentration recommended according to current regulatory guidelines).

[0689] Example 8 - Binding of 5-MeO-DMT to human plasma proteins

[0690] In vitro binding of 5-MeO-DMT to plasma proteins was determined using high flux dialysis. Equilibration time and non-specific binding were determined using human plasma at a nominal 5-MeO-DMT concentration of 1 μΜ. After evaluation of the equilibration data, plasma protein binding was investigated at nominal concentrations of 0.1, 1, and 10 μΜ using a 4 hour dialysis time. Concentrations of 5-MeO-DMT in samples from the plasma and buffer compartments were determined by LC-MS / MS. Protein binding results are shown below:

[0691] Table 5 Percentage of free fraction of 5-MeO-DMT in human plasma

[0692]

[0693] Example 9 - Human metabolism of 5-MeO-DMT

[0694] 5-MeO-DMT at nominal concentrations of 1 μΜ and 10 μΜ was incubated with human hepatocytes (1 X 106cells / mL) suspended in Leibovitz L-15 medium.

[0695] A 20 mM stock solution of 5-MeO-DMT was prepared in ethanol and further diluted with Leibovitz L-15 medium to a concentration of 2 mM. For incubation with cryopreserved hepatocytes, the 2 mM stock solution was diluted with Leibovitz L-15 medium to a concentration of 20 μΜ or 2 μΜ. Aliquots (250 μί) of the 20 μΜ and 2 μΜ test substance preparations were added to each hepatocyte incubation sample (250 μί) as appropriate, such that the final test substance concentration in the incubation fluid was 10 μΜ or 1 μΜ, respectively, and the incubation fluid contained less than 1% (v / v) solvent.

[0696] Incubations were performed in a shaking water bath at approximately 37 °C (total incubation volume was 0.5 mL). For 1 μΜ, incubations were terminated by the addition of ice-cold acetonitrile (0.5 mL) after 0, 5, 10, 20, 30, 60, and 120 minutes. For 10 μΜ, incubations were terminated by the addition of ice-cold acetonitrile containing an internal standard (1 μg / mL baeocin-dio) after 0, 10, 30, 60, and 120 minutes.

[0697] Samples were vortex mixed and centrifuged at approximately 13,000 rpm for 10 minutes at room temperature. After centrifugation, the protein-free supernatant was removed for analysis.

[0698] Blank control incubations were performed using Leibovitz L-15 medium instead of test substance. For cell-free control samples, Leibovitz L-15 medium was used instead of hepatocytes. Aliquots of blank control samples were taken at 120 minutes, while for 1 mM incubations, cell-free control samples were taken at 0, 30 and 120 minutes, and for 10 mM incubations, cell-free control samples were taken at 0 and 120 minutes.

[0699] All 1 mM incubations were performed in duplicate, while all 10 mM incubations were performed in single. All samples were stored at -80 °C (nominal) prior to analysis.

[0700] Suitable chromatographic conditions were developed to retain the parent compound and give a suitable chromatographic response. Analysis by reverse phase LC-MS was used to analyse the 0, 30 and 120 minute incubation samples produced following 10 mM 5-MeO-DMT incubation to generate high and low energy mass spectra (MSE). Prior to sample analysis, 100 pL aliquots of each sample were evaporated to near dryness at room temperature under a steady stream of nitrogen gas and then reconstituted in 50 pL of mobile phase A (0.1% formic acid in water). Each sample (0, 30 and 120 minutes, 10 mM) was analysed using accurate mass LC-MS to determine the relative level of parent compound at each time point and to determine the profile of metabolites formed. Appropriate blank and control samples were also analysed. The 10 minute and 60 minute 10 mM incubation samples were not analysed and were stored at -80 °C (nominal).

[0701] Metabolites were queried for their presence in the data using screening software (UNIFI version 1.9.4) and user defined search parameters by comparing retention time to test substance reference standards and based on the accurate mass of potential metabolites. To confirm suspected metabolites, the measured accurate mass of the peak detected in the sample used for structure resolution must be within 5 ppm of the theoretical mass to confirm the molecular formula.

[0702] The results obtained are summarised in Table 1 above.

[0703] Example 10 - Metabolic stability of 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol in a human hepatocyte co-culture model

[0704] The metabolic stability of 5-MIAA and 5-methoxytryptophol was investigated in a Hμrel co-culture assay with human hepatocytes (Hμrel HumanPool TM , a primary hepatocyte co-culture model from Visikol Inc.).

[0705] Incubations were performed using initial concentrations of 1 and 10 μΜ, and samples were taken at 0, 1, 2, 4, 8, 24, 48 and 72 hours (h) time points. Samples were analyzed using UPLC / QE-orbitrap-MS.

[0706] The following table shows the remaining LC / MS peak area of the test compounds relative to the corresponding 0 min incubation sample detected using the Hμrel co-culture assay after each incubation time point. The results of the assay control diazepam (disappearance half-life) indicate that the enzyme activity is within normal levels.

[0707] Table 6 - Relative LC / MS peak area of 5-MIAA after 0 - 72 h incubation. Initial substrate concentrations were 1 and 10 μΜ (n = 2 at 1 μΜ, n = 1 at 10 μΜ).

[0708]

[0709] Table 7 - Relative LC / MS peak area of 5-methoxytryptophol after 0 - 72 h incubation. Initial substrate concentrations were 1 and 10 μΜ (n = 2 at 1 μΜ, n = 1 at 10 μΜ).

[0710]

[0711] A low metabolic turnover rate was observed for 5-MIAA, with a remaining abundance of 75 - 82% after 72 h in the presence of hepatocytes, while no disappearance was observed in the stromal cell control.

[0712] For 5-methoxytryptophol, a high metabolic turnover rate was observed, with complete disappearance within 24 h in the presence of hepatocytes, while no disappearance in the stromal cell control.

[0713] Using human hepatocytes and a test concentration of 1 μΜ, the in vitro intrinsic clearance of 5-MIAA was 0.15 μl / min / million cells (half-life 15 400 min), while the corresponding value for 5-methoxytryptophol was 16.2 μl / min / million cells (half-life 142 min).

[0714] The predicted hepatic extraction ratio for 5-MIAA was 2%, and for 5-methoxytryptophol 67%.

[0715] Example 11 - Plasma binding of 5-MIAA

[0716] Binding to human plasma proteins was determined. The unbound score (fu) of triplicate experiments is reported, as well as the average unbound score, standard deviation and average recovery % (Table 8).

[0717]

[0718] Example 12 - Clinical trial of 5-MeO-DMT administration via inhalation to patients with postpartum depression

[0719] This single-arm, open-label clinical trial will involve 15 adult female patients who are clinically diagnosed with postpartum depression (PPD).

[0720] Patients will receive a single day individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0721] More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.

[0722] 1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

[0723] 2. The second dose (12 mg) will only be administered if:

[0724] a. the peak experience was not achieved after the 6 mg dose (total score > 75), and

[0725] b. the 6 mg dose was safe and well tolerated according to the investigator,

[0726] c. any psychoactive effects (PsE) from the previous dose have resolved, and

[0727] d. pre-dose vital signs and forced expiratory volume in one second (FEVi) are within normal limits or, if outside of normal limits, are not clinically significant according to the investigator.

[0728] 3. Similarly, the third dose (18 mg) will only be administered if:

[0729] a. the peak experience was not achieved after the 12 mg dose (total score > 75), and

[0730] b. the 12 mg dose was safe and well tolerated according to the investigator, and

[0731] c. any PsE from the previous dose have resolved, and

[0732] d. pre-dose vital signs and FEVi are within normal limits or, if outside of normal limits, are not clinically significant according to the investigator.

[0733] Patients will be assessed for peak psychedelic experience (based on patient ratings on a visual analog scale, the PE scale), sedation, and other endpoints after dosing. Follow-up visits are planned on Day 1 and Day 7 after dosing.

[0734] All patients considered for participation in the clinical trial must meet the following criteria:

[0735] 1. Be female and between the ages of 18 and 45 years, inclusive, at the time of screening.

[0736] 2. Have a body mass index (BMI) at the time of screening in the range of 18.5 to 35 kg / m 2 , inclusive.

[0737] 3. Meet the trial criteria for PPD assessed by a trial psychiatrist or licensed psychologist:

[0738] a. Be diagnosed with major depressive disorder without psychotic features by the Mini-International Neuropsychiatric Interview (MINI) and have a peripartum onset of no earlier than the pregnancy and no later than the first 4 weeks postpartum.

[0739] b. Have a Montgomery-Asberg Depression Rating Scale (MADRS) total score of 28 or greater at the time of screening and prior to dosing on Day 0.

[0740] 6. Must be weaned from breastfeeding at the time of screening; or if still breastfeeding or actively engaged in breastfeeding at the time of screening, must agree to temporarily stop breastfeeding from the time of receiving the study drug on Day 0 until 24 hours after the last dose and to express and discard all breast milk as needed during these 24 hours, but then be allowed to resume breastfeeding after 2.5 hours after the last dose and 24 hours after the last dose.

[0741] 4. Must agree to abstain completely (avoid heterosexual intercourse completely) or use a highly effective (failure rate <1%) medically accepted method of contraception from 30 days prior to dosing and for 90 days after the 5-MeO-DMT dosing. Patients must have a negative pregnancy test result at the time of screening and the day before testing (Day -1).

[0742] 5. Be willing to defer the initiation of other antidepressant or anxiolytic medications until after the end of the 7-day trial and agree to keep any psychotherapy unchanged during the trial.

[0743] Potential patients who meet any of the following key exclusion criteria will be excluded from the trial:

[0744] 1. Currently or previously diagnosed with bipolar disorder, mania or hypomanic episode, psychotic disorder, major depressive disorder (MDD) or other mood disorder with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual impairment, or any other psychiatric comorbidity that, in the investigator’s judgment, renders the patient unsuitable for participation in the trial, according to history, psychiatric evaluation, and MINI assessment.

[0745] 2. Has 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).

[0746] 3. Significant risk of suicide, according to history, psychiatric evaluation, and evaluation of suicidal ideation and suicidal behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), in the judgment of the trial psychiatrist or registered psychologist.

[0747] 4. Took an antidepressant medication within 14 days or 5 half-lives, whichever is longer, prior to dosing (exception: within the past 5 weeks in the case of fluoxetine).

[0748] 5. Took any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives, whichever is longer, prior to dosing.

[0749] 6. Previously had a serious adverse reaction to a psychedelic or entheogenic drug (e.g., psilocybin, Psilocybe cubensis mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline), according to the investigator’s judgment.

[0750] 7. Known hypersensitivity or hypersensitivity to 5-MeO-DMT or any other contraindication.

[0751] 8. Has any current or past clinically significant illness that, in the investigator’s judgment, renders the patient unsuitable for participation in the trial (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of hypertensive disorders of pregnancy (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia) during pregnancy or postpartum, uncontrolled diabetes, severe cardiovascular disease, severe liver or kidney dysfunction, severe brain disorder (including epilepsy, stroke, dementia, degenerative neurological disease, meningitis, encephalitis, and head injury with loss of consciousness).

[0752] 9. Takes any medication or other substance that, in the investigator’s judgment, renders the patient unsuitable for participation in the trial.

[0753] 10. Has clinically significant abnormalities by investigator judgment in physical examination, vital signs, ECG, or clinical laboratory parameters that render the patient unsuitable for participation in the trial.

[0754] 11. Patient has a positive pregnancy test at screening or on the day prior to 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.

[0755] 12. Patient has a DSM-5 substance or alcohol use disorder within 6 months prior to screening.

[0756] The primary objective of the trial is to determine the onset of antidepressant effect and 7-day persistence of a single day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult female PPD patients.

[0757] The secondary objectives are to determine the antidepressant effect, anxiolytic effect, effect on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE), effect on cognitive outcomes of a single day individualized dosing regimen (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult female PPD patients.

[0758] The exploratory objective is to determine the amount of 5-MeO-DMT and metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine following a single day administration of a single day individualized IDR (6 mg, 12 mg, and 18 mg 5-Meo-DMT) in adult female PPD patients (metabolite identification screening can be performed as needed), measured by LC / MS / MS.

[0759] The primary endpoint of the study is to assess the antidepressant effect of 5-MeO-DMT by the change from baseline in MADRS assessed on Day 7.

[0760] The secondary endpoints include assessing the antidepressant effect of 5-MeO-DMT by:

[0761] • Assessing the antidepressant effect of 5-MeO-DMT by:

[0762] o Proportion of patients in remission (MADRS < 10) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0763] o Change from baseline in MADRS assessed at 2 hours post-final study drug administration on Day 0 and Day 1;

[0764] o Proportion of responders (MADRS total score reduction > 50% from baseline) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0765] o Change from baseline in Clinical Global Impression-Severity (CGI-S) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0766] • Impact on maternal behavior as assessed by change from baseline to Day 7 in Barkin Mothering Function Index (BIMF) total and subscale scores;

[0767] • Exposure of 5-MeO-DMT and Bufotenine in breast milk obtained at 1 hour post-final study drug administration on the day before testing (Day -1), at discharge, at night on Day 0, and at Day 1 and Day 7;

[0768] • Exposure of 5-MeO-DMT and Bufotenine in blood obtained at 1 hour post-final study drug administration on the day before testing (Day -1), at discharge, and at Day 1 and Day 7;

[0769] • Safety and tolerability of 5-MeO-DMT assessed by:

[0770] o Reporting of treatment-emergent adverse events (TEAEs);

[0771] o Clinically significant changes from baseline in ECG, vital signs, safety laboratory assessments, peak flow respiratory assessments;

[0772] o Sedation assessments (modified Observer’s Assessment of Alertness / Sedation scale [MOAA / S]) after each dosing (when PsE resolution and 60 minutes after each study drug administration) and as part of the discharge evaluation on Day 0;

[0773] o Change from baseline in Clinical Assessment of Disorganized States Scale (CADSS) assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0774] o Change from baseline in Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0775] o Change from baseline in C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0776] o Change from baseline in YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0777] • Patient experienced PsE reported 30 to 60 minutes after each dose, at which time the PsE had resolved:

[0778] o PsE assessment of achievement of PE using the Peak Experience (PE) scale (PE scale total score > 75);

[0779] o Challenge Experience Questionnaire (CEQ);

[0780] o Mystery Experience Questionnaire (MEQ-30);

[0781] • PsE duration defined as the time from study drug dosing to the time at which the PsE had resolved (investigator rating and patient rating), completed 30 to 60 minutes after each dose.

[0782] First Patient

[0783] Currently, one patient diagnosed with postpartum depression by a psychiatrist has been enrolled 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) and the peripartum onset was no earlier than the 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 visit days. The inhalation procedure was performed adequately by the patient and was well tolerated with no adverse events related to inhalation.

[0784] Results - First Patient

[0785] There were no other notable changes in vital parameters except for a temporary, clinically irrelevant increase in heart rate and blood pressure shortly after administration of 5-MeO-DMT. There were no abnormalities in the assessment of ECG (3 hours post administration) and safety laboratory analysis (7 days), CADSS (3 hours, 1 day, and 7 days). The few adverse events reported (left abdominal cramping pain and headache, both occurring on Day 0) were mild in symptom, short in duration, and resolved spontaneously at the end of the study.

[0786] Regarding the intensity of the psychedelic experience, the PES score achieved upon exposure to the 6 mg nominal dose was recorded as 17.3. This score indicated that a subsequent higher dose of 12 mg needed to be administered according to the design of the individualized dosing regimen. This dose achieved a PES score of 85.7 and > 75, indicating that the patient had a peak psychedelic experience and completed the IDR.

[0787] Importantly, the patient reported significant improvement in her depressive symptoms, as assessed by MADRS at the earliest assessment time point after drug administration (2 hours), and the effect was maintained over time (Table 9). The patient also met criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score equal to or less than 10).

[0788] Table 9 - MADRS / BPRS Score Table

[0789]

[0790] Particular attention is drawn to the significant improvement in several MADRS items. Individual items are summarized in Table 9. The patient's baseline scores on some items reflect the absence of symptoms (decreased appetite, difficulty concentrating, suicidal thoughts), while there is a significant improvement in the scores on items reflecting severe symptoms (e.g., decreased sleep, inner tension).

[0791] Similarly, several BPRS items also improved, including somatic concerns, anxiety, emotional withdrawal, guilt feelings, and tension.

[0792] In addition, as summarized in Table 10, the improvement in BIMF scores recorded on Day 7 demonstrates an improvement in maternal functioning, with a total score improving from 92 to 105, an improvement of 14% (total score can be up to 120).

[0793] Several functional domains of maternal functioning, as defined by Barkin et al., were also assessed. Table 11 provides more detail on the improvement in each functional domain.

[0794] Here, significant improvements were achieved in self-care, mental health, and management, ranging from 18% (management) to (44%) (self-care). These improvements reinforce the relationship between the improvements in depressive items, as assessed by MADRS and improvements in maternal functioning.

[0795] It is notable that the patient's scores were relatively high prior to treatment. In some functional domains, the scores were at or near the maximum (see Table 11), leaving limited room for improvement through therapy.

[0796] Table 10 - BIMF Score Table

[0797]

[0798] Table 11 - BIMF Functional Domain Score Table

[0799]

[0800] Summary and Conclusion

[0801] A. Individualized dosing regimen was adopted, i.e. 6 mg 5-MeO-DMT was administered first via inhalation, followed by 12 mg 5-MeO-DMT, which was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

[0802] B. Rapid onset of clinical response within 2 hours after 5-MeO-DMT administration. This rapid onset process is uncommon and has not been seen in the traditional antidepressant classes including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), etc., which typically require 4 to 6 weeks to show effects.

[0803] C. According to the IDR, patients experienced clinical remission within 2 hours after administration of 5-MeO-DMT. This is superior to any approved treatment for postpartum depression and all previously tested psychedelics.

[0804] D. Despite 5-MeO-DMT being given only once and not effectively present in the body within this time frame (see pharmacokinetic data in Example 6 above), a significant clinical response persisted for 7 days of follow-up. This observation supports the superior clinical profile of 5-MeO-DMT and allows for a convenient dosing interval.

[0805] E. In addition to the antidepressant effect, 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 diseases.

[0806] F. In addition to the antidepressant effect, endpoints assessing maternal functioning such as self-care, psychological well-being, and management assessed using the BIMF were also positively affected. This supports 5-MeO-DMT having additional benefits for patients suffering from PPD beyond improving core depressive symptoms.

[0807] Second patient

[0808] A second patient diagnosed with postpartum depression by a psychiatrist has been enrolled 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) and the peripartum onset was not earlier than the pregnancy and not later than the first 4 weeks postpartum. The patient completed all scheduled visit days (here day 5 instead of day 7). The inhalation procedure was fully performed by the patient and was well tolerated without inhalation-related adverse events.

[0809] Results - Second Patient

[0810] There were no other notable changes in vital signs parameters. ECG (3 hours post-administration) and safety laboratory analyses (3 hours and 7 days), assessment of CADSS (3 hours, 1 day and 7 days) were all unremarkable. The few adverse events reported (vomiting on Day 0, headache on Day 5) were mild in symptom, short in duration, and resolved spontaneously by the end of the study.

[0811] With respect to the intensity of the psychedelic experience, the PES score recorded at the time of exposure to the 6 mg nominal dose was 1. This score indicated that a subsequent higher dose of 12 mg was required to continue the administration of the personalized dosing regimen one hour after the first dose. This dose achieved a PES score of 94.7 and >75, indicating that the patient had a peak psychedelic experience and completed the IDR.

[0812] Importantly, the patient reported a significant improvement in his depressive symptoms, as assessed by the MADRS at the earliest assessment time point after drug administration (2 hours), and the effect was maintained over time (Table 12). The patient also met the criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score equal to or less than 10).

[0813] Table 12: MADRS / BPRS Score Table

[0814]

[0815] Significant improvements were noted in several MADRS items. Table 12 summarizes the items. While the patient’s baseline score for suicidal ideation reflected a lower severity relative to other symptoms, the scores for all other items reflecting severe symptoms were significantly improved.

[0816] Similarly, several BPRS items were also improved, including anxiety, emotional withdrawal, disorganized thinking, guilt feelings, and tension.

[0817] In addition, as summarized in Table 13, the improvement in BIMF score recorded on Day 7 demonstrated an improvement in maternal functioning, with the total score improving from 74 to 104, an improvement of (total score can be up to 120).

[0818] Several functional domains of maternal functioning, as defined by Barkin et al., were also assessed. Table 14 outlines the improvement in each functional domain in more detail.

[0819] Here, all domains improved significantly except for infant care (which was at maximum score at baseline), with percent improvement ranging from approximately 27% (social support) to 450% (adjustment). These improvements reinforced the relationship between improvements in the depression program, as assessed by MADRS and improvements in maternal functioning.

[0820] Table 13 - BIMF Score Table

[0821]

[0822] Table 14 - BIMF Functioning Domain Score Table

[0823]

[0824] Summary and Conclusion - Second Patient

[0825] A. The individualized dosing regimen, i.e., 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 a patient formally diagnosed with postpartum depression.

[0826] B. The clinical response emerged rapidly within 2 hours after 5-MeO-DMT administration. This rapid onset process is uncommon and has not been seen in the traditional antidepressant classes, including tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), etc., which typically require 4 to 6 weeks to show effects.

[0827] C. The patient achieved clinical remission within 2 hours after 5-MeO-DMT administration according to the IDR. This is superior to any approved treatment for postpartum depression and all previously tested psychedelics.

[0828] D. Despite the fact that 5-MeO-DMT was only given once and was no longer effectively present in the body within this time frame (see pharmacokinetic data in Example 7 above), the significant clinical response persisted over a 5-day follow-up period. This observation supports the superior clinical properties of 5-MeO-DMT and allows for a convenient dosing interval.

[0829] E. In addition to the antidepressant effects, endpoints assessing other symptoms such as emotional withdrawal, anxiety, guilt, conceptual disorganization, and tension were also positively affected, which supports the use of 5-MeO-DMT in patients with other psychiatric diseases.

[0830] F. In addition to the antidepressant effects, endpoints assessing maternal functioning such as self-care, mental health, mother-child interaction, social support, regulation and management assessed using the BIMF were also positively affected. This supports the additional benefits of 5-MeO-DMT for patients suffering from PPD beyond the improvement of core depressive symptoms.

[0831] Final Conclusion

[0832] The salient aspects indicate that 5-MeO-DMT has a significantly improved efficacy when used according to the present application compared to approved postpartum depression medication therapies and all previously tested psychedelic agents.

[0833] In combination with the short duration of acute psychedelic effects and the good safety profile, these data indicate that the present application solves the technical problem of providing an improved psychoactive therapy for patients suffering from postpartum depression.

[0834] Additional Results - Second Patient

[0835] The second patient was lactating and according to the clinical trial protocol, breast milk samples were collected before dosing and at multiple time points after administration of the last dose. Subsequently, these samples were analyzed by LC-MS / MS assay to detect 5-MeO-DMT, bufotenine (the main metabolite of 5-MeO-DMT) and 5-MIAA (the final metabolite of 5-MeO-DMT). Similar analysis was performed on patient serum and urine samples. The data are summarized in the following table.

[0836]

[0837] ND: Not determined.

[0838] BLQ: Below limit of quantification. The lower limit of quantification for 5-MeO-DMT and 5-MIAA in serum and breast milk was 25 pg / ml; the lower limit of quantification for 5-MeO-DMT in urine was 25 pg / ml and the lower limit of quantification for 5-MIAA in urine was 250 pg / ml.

[0839] The data show that 5-MeO-DMT was rapidly cleared from serum at the first measurement time point, 1 hour after the last dose, at which time a concentration of 132.9 pg / ml was detected, with concentrations at all subsequent time points being below the lower limit of quantification for the assay. In addition, endogenous levels of 5-MIAA were confirmed in serum prior to dosing, with the highest concentration detected at the first measurement time point (1 hour post-dose), and returning to baseline levels within 1 day. Urine assay data showed that the concentration of 5-MeO-DMT was approximately four times the concentration detected in serum at 1 hour (indicating substantial excretion at this time), with a rapid decline to undetectable levels after this time point; while the concentration of 5-MIAA peaked at 2.5 hours, at approximately 127 times the concentration detected in serum, and rapidly declined to endogenous levels within 7 days. Bufotenine was not detected in urine at any time point other than 2.5 hours post-dose. Taken together, these data confirm the rapid metabolism and clearance of 5-MeO-DMT in vivo.

[0840] Maternal milk sample analysis indicated the absence of bufotenine, while the concentration of 5-MeO-DMT was 2167 pg / ml at 1 hour post-administration, rapidly declining to a level similar to the endogenous level in serum prior to dosing at 8.5 hours post-administration. A similar trend was observed for 5-MIAA.

[0841] Example 13 - Clinical trial of 5-MeO-DMT administration to patients with postpartum depression via intravenous injection - prophetic example

[0842] This clinical trial will involve adult female patients who are clinically diagnosed with postpartum depression (PPD).

[0843] Patients will receive a single day individualized 5-MeO-DMT dosing regimen via intravenous injection. 5-MeO-DMT will be provided in the form of its hydrobromide salt and intravenous injection formulation. It will be understood that the doses of 5-MeO-DMT mentioned below relate to the weight of the free base, while the doses of 5-MeO-DMT hydrobromide can be calculated assuming the use of equimolar amounts.

[0844] More specifically, patients will receive up to three doses of 5-MeO-DMT on day 0: 2 mg, 5 mg, and 8 mg.

[0845] 1. All patients will receive an initial dose of 2 mg 5-MeO-DMT.

[0846] 2. The second dose (5 mg) will only be administered if:

[0847] a. the peak experience was not achieved (total score > 75) after the 2 mg dose, and

[0848] b. According to the researchers, the 2 mg dose was safe and well tolerated,

[0849] c. Any psychoactive effects (PsE) from the previous dose have resolved, and

[0850] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges or, if outside the normal range, were not clinically significant according to the investigator.

[0851] 3. Similarly, the third dose (8 mg) will be administered only if:

[0852] a. Peak experience (total score ≥ 75) not achieved after 5 mg dose, and

[0853] b. According to the researchers, the 5 mg dose was safe and well tolerated,

[0854] c. Any PsE from the previous dose has resolved, and

[0855] d. Pre-dose vital signs and forced expiratory volume in one second (FEV1) were within normal ranges or, if outside the normal range, were not clinically significant according to the investigator.

[0856] 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.

[0857] All patients considered for participation in a clinical trial must meet the following criteria:

[0858] 1. Be female and be between 18 and 45 years old (inclusive) at the time of screening.

[0859] 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).

[0860] 3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or registered psychologist:

[0861] 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 four weeks postpartum.

[0862] b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at screening and on Day 0 before dosing.

[0863] 6. Must stop breastfeeding at screening; or if still breastfeeding or actively breastfeeding at screening, must agree to temporarily stop breastfeeding from the time of receiving the first dose of study drug until 24 hours after the last dose, and to express and discard all breast milk as needed during these 24 hours, but must express / discard breast milk at 2.5 hours after the last dose and 24 hours after the last dose before resuming breastfeeding.

[0864] 4. Must agree to abstain completely (avoid sexual intercourse with a male partner) or use a highly effective (failure rate <1%) medically accepted method of contraception for the entire 30 days prior to dosing and for 90 days after the 5-MeO-DMT dosing. The patient must have a negative pregnancy test result at screening and on the day prior to testing (Day -1).

[0865] 5. Willing to defer the initiation of other antidepressant or anxiolytic medications until after the end of the Day 7 trial, and agree to keep any psychotherapy unchanged during the trial.

[0866] Potential patients who meet any of the following key exclusion criteria will be excluded from the trial:

[0867] 1. Currently or previously diagnosed with bipolar disorder, manic or hypomanic episodes, psychotic disorder, major depressive disorder (MDD), or other mood disorder with psychotic features, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder, borderline personality disorder, schizophrenia, delusional disorder, paranoid personality disorder, schizoaffective disorder, clinically significant intellectual impairment, or any other psychiatric comorbidity that, in the judgment of the investigator, renders the patient unsuitable for participation in the trial, according to medical history, psychiatric evaluation, and MINI assessment.

[0868] 2. Has one or more first- or second-degree relatives who are currently or have been previously diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

[0869] 3. Significant risk of suicide according to medical history, psychiatric evaluation, and evaluation of suicidal ideation and suicidal behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS), in the judgment of the trial psychiatrist or registered psychologist.

[0870] 4. Took an antidepressant medication within 14 days or 5 half-lives, whichever is longer, prior to dosing (exception: within the past 5 weeks in the case of fluoxetine).

[0871] 5. Took any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives, whichever is longer, prior to dosing.

[0872] 6. Has had a serious adverse reaction to a psychedelic or hallucinogenic drug (e.g., psilocybin, Psilocybe cubensis mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) in the judgment of the investigator.

[0873] 7. Known hypersensitivity or hypersensitivity to 5-MeO-DMT or any other contraindication.

[0874] 8. Has any current or past clinically significant illness that, in the judgment of the investigator, would make the patient unsuitable for participation in the trial (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of a hypertensive disorder of pregnancy (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia) during pregnancy or postpartum, uncontrolled diabetes mellitus, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder including epilepsy, stroke, dementia, degenerative neurological disease, meningitis, encephalitis, and head injury with loss of consciousness).

[0875] 9. Is taking any medication or other substance that, in the judgment of the investigator, would make the patient unsuitable for participation in the trial.

[0876] 10. Has clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that, in the judgment of the investigator, would make the patient unsuitable for participation in the trial.

[0877] 11. The patient has a positive pregnancy test at screening or on 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.

[0878] 12. The patient has a DSM-5 substance or alcohol use disorder within 6 months prior to screening.

[0879] The primary objective of the trial is to determine the onset time and 7-day persistence of antidepressant effects of a single day individualized dosing regimen (2 mg, 5 mg, and 8 mg 5-MeO-DMT) in adult female PPD patients.

[0880] The secondary objectives are to determine the antidepressant effects, anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE), effects on cognitive outcomes of a single day individualized dosing regimen (2 mg, 5 mg, and 8 mg 5-MeO-DMT) in adult female PPD patients.

[0881] Exploratory objectives are to determine the amount of 5-MeO-DMT and metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood and urine following single day administration of single day individualized IDRs (2 mg, 5 mg and 8 mg 5-MeO-DMT) in adult female PPD patients (metabolite identification screening can be performed as needed) measured by LC / MS / MS.

[0882] The primary endpoint of this study is to assess the antidepressant effect of 5-MeO-DMT by change in MADRS from baseline assessed on day 7.

[0883] Secondary endpoints include assessing the antidepressant effect of 5-MeO-DMT by:

[0884] • Assessing the antidepressant effect of 5-MeO-DMT by:

[0885] o Proportion of patients in remission (MADRS < 10) at 2 hours post-final study drug administration on Day 0, Day 1 and Day 7;

[0886] o Change in MADRS from baseline assessed at 2 hours post-final study drug administration on Day 0 and Day 1;

[0887] o Proportion of responders (MADRS total score reduced by > 50% compared to baseline) at 2 hours post-final study drug administration on Day 0, Day 1 and Day 7;

[0888] o Change in Clinical Global Impression-Severity (CGI-S) from baseline at 2 hours post-final study drug administration on Day 0, Day 1 and Day 7;

[0889] • Effects on maternal behavior as assessed by changes in Barkin Mothering Function Index (BIMF) total and subscale scores from baseline to Day 7;

[0890] • Exposure of 5-MeO-DMT and bufotenine in breast milk obtained on the day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, on the night of Day 0, and on Day 1 and Day 7;

[0891] • Exposure of 5-MeO-DMT and bufotenine in blood obtained on the day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, and on Day 1 and Day 7;

[0892] • Assessing the safety and tolerability of 5-MeO-DMT by:

[0893] • Reporting of adverse events (TEAEs) that occur during treatment;

[0894] • ECGs, vital signs, safety laboratory assessments, peak flow breathing assessments for clinically significant changes from baseline;

[0895] • Sedation assessments (modified observer’s alertness and sedation scale [MOAA / S]) after each dosing (when PsE resolved and 60 minutes after each study drug administration) and as part of the discharge evaluation on Day 0;

[0896] • Changes from baseline in the Clinical Global Impression of dissociative states scale (CADSS) assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0897] • Changes from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0898] • Changes from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0899] • Changes from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0900] • Patient experienced PsE reported 30 to 60 minutes after each dosing, at which time the PsE had resolved:

[0901] • PsE assessment using the Peak Experience (PE) scale for achievement of PE (PE scale total score > 75);

[0902] • Challenge Experience Questionnaire (CEQ);

[0903] • Mystical Experience Questionnaire (MEQ-30);

[0904] • PsE duration defined as the time from study drug administration to the time the PsE had resolved (investigator rating and patient rating), completed 30 to 60 minutes after each dosing;

[0905] Example 14 - Clinical trial of 5-MeO-DMT administration to patients with postpartum depression via intravenous injection - prophetic example

[0906] This clinical trial will involve adult female patients who are clinically diagnosed with postpartum depression (PPD).

[0907] Patients will receive a single day individualized 5-MeO-DMT dosing regimen via intravenous injection. The 5-MeO-DMT will be provided in the form of its hydrobromide salt and intravenous injection formulation. It should be understood that the dosages of 5-MeO-DMT mentioned below relate to the weight of the free base, while dosages of 5-MeO-DMT hydrobromide can be calculated assuming the use of equimolar amounts.

[0908] More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 1 mg, 2 mg, and 3 mg.

[0909] 1. All patients will receive an initial dose of 1 mg 5-MeO-DMT.

[0910] 2. A second dose (2 mg) will only be administered if:

[0911] a. Peak experience was not achieved (total score > 75) after the 1 mg dose, and

[0912] b. The 1 mg dose was safe and well tolerated, according to the investigator,

[0913] c. Any psychoactive effects (PsE) of the previous dose have resolved, and

[0914] d. Pre-dose vital signs and forced expiratory volume in one second (FEVi) are within the normal range, or if outside the normal range, are not clinically significant, according to the investigator.

[0915] 3. Similarly, a third dose (3 mg) will only be administered if:

[0916] a. Peak experience was not achieved (total score > 75) after the 2 mg dose, and

[0917] b. The 2 mg dose was safe and well tolerated, according to the investigator,

[0918] c. Any PsE of the previous dose have resolved, and

[0919] d. Pre-dose vital signs and FEVi are within the normal range, or if outside the normal range, are not clinically significant, according to the investigator.

[0920] Patients will receive assessments of peak psychedelic experience (based on patient scores on a visual analog scale, the PE scale), sedation, and other endpoints post-dose. Follow-up visits are planned on Day 1 and Day 7 post-dose.

[0921] All patients considered for participation in the clinical trial must meet the following criteria:

[0922] 1. Female, and between 18 and 45 years of age, inclusive, at the time of screening.

[0923] 2. Body Mass Index (BMI) within the range of 18.5 to 35 kg / m2, inclusive, at the time of screening. 2

[0924] 3. Meet the trial criteria for PPD assessed by the trial psychiatrist or licensed psychologist:

[0925] a. Diagnosed with major depressive disorder without psychotic features by the Mini-International Neuropsychiatric Interview (MINI) and with a peripartum onset no earlier than the pregnancy and no later than the first 4 weeks postpartum.

[0926] b. Montgomery-Asberg Depression Rating Scale (MADRS) total score equal to or greater than 28 at the time of screening and at the pre-dose on Day 0.

[0927] 6. Must be willing to stop breastfeeding at the time of screening; or if still breastfeeding or actively engaged in breastfeeding at the time of screening, must agree to temporarily stop breastfeeding from the time of receiving the study drug on Day 0 until 24 hours after the last dose, and to express and discard all breast milk as needed during these 24 hours, but to resume breastfeeding after the 2.5-hour post-dose and 24-hour post-dose breast milk expressions / discardings.

[0928] 4. Must agree to be abstinent (completely avoid sexual intercourse with a male partner) or use a highly effective (failure rate <1%) medically accepted method of contraception for the entire 30 days prior to dosing and for 90 days after the 5-MeO-DMT dose. The patient must have a negative pregnancy test result at the time of screening and on the day prior to testing (Day -1).

[0929] 5. Willing to defer the initiation of other antidepressant or anxiolytic medications until after the end of the 7-day trial, and agree to keep any psychotherapy unchanged during the trial.

[0930] Potential patients who meet any of the following key exclusion criteria will be excluded from the trial:

[0931] 1. 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 impairment, or any other psychiatric comorbidity that, in the investigator’s judgment, renders the patient unsuitable for participation in the trial, according to the medical history, psychiatric evaluation, and MINI assessment. ​

[0932] 2. Has one or more first- or second-degree relatives who currently or previously have been diagnosed with bipolar disorder, psychotic disorder, or other mood disorder with psychotic features (including MDD).

[0933] 3. Has significant risk of suicide as judged by the trial psychiatrist or registered psychologist based on history, psychiatric evaluation, and assessment of suicidal ideation and suicidal behavior based on the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0934] 4. Has taken an antidepressant medication within 14 days or 5 half-lives, whichever is longer, prior to dosing (exception: within the past 5 weeks in the case of fluoxetine).

[0935] 5. Has taken any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives, whichever is longer, prior to dosing.

[0936] 6. Has had a history of severe adverse reactions to a psychedelic or entheogenic drug (e.g., psilocybin, Psilocybe cubensis mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline) according to the investigator’s judgment.

[0937] 7. Is known to be allergic or hypersensitive to 5-MeO-DMT or has any other contraindication.

[0938] 8. Has any current or past clinically significant illness that, in the investigator’s judgment, renders the patient unsuitable for participation in the trial (e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of a hypertensive disorder of pregnancy (e.g., gestational hypertension, preeclampsia-eclampsia, superimposed preeclampsia) during pregnancy or postpartum, uncontrolled diabetes mellitus, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including epilepsy, stroke, dementia, degenerative neurological disease, meningitis, encephalitis, and head injury with loss of consciousness).

[0939] 9. Is taking any medication or other substance that, in the investigator’s judgment, renders the patient unsuitable for participation in the trial.

[0940] 10. Has clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that, in the investigator’s judgment, render the patient unsuitable for participation in the trial.

[0941] 11. Is pregnant at the time of screening or on the day prior to testing (Day -1), has been pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT administration.

[0942] 12. Patient has a DSM-5 substance or alcohol use disorder within 6 months prior to screening.

[0943] The primary objective of the trial is to determine the onset of antidepressant effects and 7-day persistence of single-day individualized dosing regimen (1 mg, 2 mg, and 3 mg 5-MeO-DMT) in adult female PPD patients.

[0944] The secondary objectives are to determine the antidepressant effects, anxiolytic effects, effects on maternal behavior, safety and tolerability, intensity and duration of psychoactive effects (PsE) of single-day individualized dosing regimen (1 mg, 2 mg, and 3 mg 5-MeO-DMT) in adult female PPD patients; effects on cognitive outcomes.

[0945] The exploratory objective is to determine the amount of 5-MeO-DMT and metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA) in breast milk, blood, and urine (metabolite identification screening can be performed as needed) following single-day administration of single-day individualized IDR (1 mg, 2 mg, and 3 mg 5-MeO-DMT) in adult female PPD patients, measured by LC / MS / MS.

[0946] The primary endpoint of the study is to assess the antidepressant effects of 5-MeO-DMT by change from baseline in MADRS assessed on Day 7.

[0947] The secondary endpoints include assessing the antidepressant effects of 5-MeO-DMT by:

[0948] • Assessing the antidepressant effects of 5-MeO-DMT by:

[0949] o Proportion of patients in remission (MADRS < 10) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0950] o Change from baseline in MADRS assessed at 2 hours post-final study drug administration on Day 0 and Day 1;

[0951] o Proportion of responders (≥ 50% reduction in MADRS total score from baseline) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0952] o Change from baseline in Clinical Global Impression-Severity (CGI-S) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0953] • Effects on maternal behavior, as assessed by changes from baseline to Day 7 in Barkin Mothering Function Index (BIMF) total and subscale scores;

[0954] • Exposure of 5-MeO-DMT and Bufotenine in breast milk obtained on the day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, at night on Day 0, and at times on Day 1 and Day 7;

[0955] • Exposure of 5-MeO-DMT and Bufotenine in blood obtained on the day before testing (Day -1), 1 hour after the last dose of study drug, at discharge, and at times on Day 1 and Day 7;

[0956] • Safety and tolerability of 5-MeO-DMT was evaluated by:

[0957] o Reporting of treatment-emergent adverse events (TEAEs);

[0958] o Clinical significant changes from baseline in ECG, vital signs, safety laboratory assessments, peak flow respiratory assessments;

[0959] o Sedation assessments (modified observer’s alertness and sedation scale [MOAA / S]) after each dose (when PsE resolved and 60 minutes after each dose of study drug) and as part of the discharge evaluation on Day 0;

[0960] o Changes from baseline in the Clinical Global Impression of dissociative states scale (CADSS) assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0961] o Changes from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0962] o Changes from baseline in the C-SSRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0963] o Changes from baseline in the YMRS assessed as part of the discharge evaluation on Day 0, Day 1, and Day 7;

[0964] • Patient experienced PsE reported 30 to 60 minutes after each dose, at which time the PsE had resolved:

[0965] o PsE assessment using the Peak Experience (PE) scale to assess achievement of PE (PE scale total score > 75);

[0966] o Challenge Experience Questionnaire (CEQ);

[0967] o Mystical Experience Questionnaire (MEQ-30);

[0968] • PsE duration was defined as the time from study drug administration to the time PsE had resolved (investigator and patient scores), completed 30 to 60 minutes after each administration.

Claims

1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof is used to treat a patient suffering from postpartum depression (PPD), wherein the patient suffers from moderate or severe depression and suffers from impaired or severely impaired maternal function, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous, intramuscular or subcutaneous route.

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

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

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

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

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

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

8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the score assigned to the mother-child interaction and / or management functional domain according to the Barkin Index of Maternal Functioning (BIMF) does not exceed 60% of the maximum score of the functional domain.

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

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

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

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

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

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

15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 14, wherein the treatment results in an improvement in the score assigned to the functional domain of mother-child interaction and / or management according to the Barkin Index of Maternal Function (BIMF) to more than 60% of the maximum possible score of the corresponding functional domain on day 7, preferably more than 80% of the maximum possible score.

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

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

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

19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 18, wherein the 5-MeO-DMT or salt thereof is administered at a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 19, wherein a dose of about 1 mg to about 10 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 20, wherein a dose of about 2 mg; or about 5 mg; or about 8 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

22. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 20, wherein a dose of about 1 mg; or about 2 mg; or about 3 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 20, wherein a dose of about 2 mg; or about 4 mg; or about 6 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 20, wherein the 5-MeO-DMT or a salt thereof is administered as 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.

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 20 or 24, wherein the 5-MeO-DMT is administered at a dose of about 1 mg to about 3 mg for a first administration, which is 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, and which is 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.

26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 25, 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.

27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 20 or 24, wherein the 5-MeO-DMT is administered at a dose of about 0.5 mg to about 1.5 mg for a first administration, which is 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, and which is 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.

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 27, 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.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 20 or 24, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 3 mg for a first administration, which is then increased to a dose of about 4 mg to about 5 mg for a second administration unless the patient has experienced a peak psychedelic experience, and which is then increased to a dose of about 6 mg to about 7.5 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.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 29, wherein the first dose of 5-MeO-DMT is about 2 mg, the second dose of 5-MeO-DMT is about 4 mg, and the third dose of 5-MeO-DMT is about 6 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 24 to 30, 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 1 to 2 hours.

32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 19, wherein a dose of about 1 mg to about 5 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 32, wherein a dose of about 1 mg or about 5 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered instead of 5-MeO-DMT.

34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 32, wherein the 5-MeO-DMT or a salt thereof is administered as 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.

35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 34, 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 1 to 2 hours.

36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 19 to 35, wherein the occurrence of the peak psychedelic experience is identified 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 (MEQ30), or by achieving at least 60% of the maximum possible score on 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.

37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 36, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claims 1 to 37, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via intravenous injection.

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