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

Abstract

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

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 - 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 causes 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 cause 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 between mother and child. Evidence also suggests a link between PPD and child development, as exemplified by the fact that children of patients suffering 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 remain affected by 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, exposing the breast-feeding infant to 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 US, 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 adhere to 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 infant. 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 been used so far for the treatment of PPD. This is due to the general lack of relevant clinical data that would 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 invention 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) the clinical response occurs earlier, and / or d) the clinical response is more durable).

[0019] It is a further object of the present invention 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 invention 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 invention 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 invention 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 invention to improve maternal functioning in patients suffering from PPD. It is also an object of the present invention to improve maternal functioning in lactating mothers diagnosed with a psychiatric disorder.

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

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

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

[0024] Definitions

[0025] As used in the context of the present application, the term "5-MeO-DMT" refers to the free base 5-MeO-DMT, unless otherwise stated. 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.

[0026] 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.

[0027] 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. In particular, the patient has 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.

[0028] 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 has 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 with suicidal ideation will be at risk of imminent suicide, or be considered to have "suicidal intent".

[0029] As used in the context of the present application, unless otherwise stated, the terms "treating" and "treatment" shall include the management and care of a patient for purposes of combating a disease, condition, or disorder, and include the administration of compounds and methods according to the present application to alleviate signs and / or symptoms of the disease, or to eliminate the disease, condition, or disorder.

[0030] As used in the context of the present application, unless otherwise stated, the term "therapeutically effective amount" shall mean 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.

[0031] “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 to assess 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).

[0032] The Barkin Index of Mother’s Functioning (BIMF) can be used to assess mother’s functioning.

[0033] Individual items of the indicated scales, as well as subcombinations of individual items, can be used to assess specific disease aspects.

[0034] When assessing clinical response at early time points after administration of the drug (e.g., 2 hours), a reasonable modification of endpoints developed for longer recall periods (e.g., MADRS typically 7 days) can be made (e.g., changing the MADRS recall period to 2 hours and carryover the sleep item recorded at baseline prior to administration of the drug).

[0035] The outlined considerations 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 score recorded after treatment for assessing clinical response, while in another aspect the sleep item cannot be assessed 2 hours after administration of the drug.

[0036] 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 score 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).

[0037] As used in the context of the present invention, 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 by any route. Preferably, the active compound is administered by inhalation, nasally, by buccal administration or sublingual administration.

[0038] As used in the context of the present invention, 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, unless otherwise specified. The term "dosing regimen" (or "dosing schedule") shall mean the defined sequence of one or more single administrations.

[0039] As used herein, "aerosol" means a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and microscopic suspended solid and / or liquid particles. The term "degradation product" refers to a compound resulting from a chemical modification of 5-MeO-DMT due to a chemical reaction occurring during aerosol formation. Such reactions include, but are not limited to, oxidation. When describing the percentage of "degradation products" in the context of the present invention, this refers to the amount of 5-MeO-DMT degradation products present in a sample divided by the amount of 5-MeO-DMT plus the amount of 5-MeO-DMT degradation products present in the sample, multiplied by 100%, i.e., (sum of the amounts of all 5-MeO-DMT degradation products present in the sample) / ((amount of 5-MeO-DMT present in the sample) + (sum of the amounts of all 5-MeO-DMT degradation products present in the sample)) x 100%. As used herein, the term "impurity" refers to an unwanted compound contaminating a sample of 5-MeO-DMT (or a pharmaceutically acceptable salt thereof). Impurities can be contained in the starting materials before aerosol formation, or can be degradation products.

[0040] The term "purity" refers to 100% minus the percentage of all 5-MeO-DMT degradation products and all other impurities present, i.e., 100% - (sum of the amounts of all 5-MeO-DMT degradation products present + sum of the amounts of all other impurities present) / (amount of 5-MeO-DMT present + sum of the amounts of all 5-MeO-DMT degradation products present + sum of the amounts of all other impurities present) x 100%.

[0041] The term "mass median aerodynamic diameter" (MMAD) is the diameter below which 50% of the particles present in an aerosol are larger and 50% are smaller. The term "aerosol particle mass density" refers to the mass of aerosol particles per unit volume of aerosol. The term "aerosol particle formation rate" refers to the mass of 5-MeO-DMT aerosolized per unit of aerosolization time.

[0042] Postpartum depression

[0043] 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.

[0044] The patient treated according to the present application is preferably a woman diagnosed with PPD and >4 weeks postpartum. Further, the patient is preferably <9 months postpartum.

[0045] The depressive aspect of PPD can be assessed by HAM-D or MADRS score. Also the Edinburgh Postnatal Depression Scale (EPDS) can be used.

[0046] 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 a supplementary scale 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; poor concentration; passivity; 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.

[0047] The patient can suffer from moderate or severe PPD, which is expressed as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 16 or higher. It is further considered that the patient can suffer from severe PPD, which is expressed as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or higher, or a Hamilton Depression Rating Scale (HAM-D) score of 27 or higher. The patient can be diagnosed with a treatment-resistant form of PPD.

[0048] 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 Depression Rating Scale (HAM-D) score of 16 or higher.

[0049] Furthermore, 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.

[0050] Furthermore, 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.

[0051] In addition to the above, the inventors 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.

[0052] Maternal functioning includes aspects of maternal capability related to infant interaction as well as maternal self-care.

[0053] Maternal functioning, including the emotional aspects of maternal functioning, is also important for child development. In fact, the quality of mother-child interaction in the first year after birth impacts infant development. High levels of maternal functioning can be associated with positive infant development outcomes. Likewise, impaired functioning in the postpartum period can hinder optimal development of the infant.

[0054] 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.

[0055] The BIMF identifies the following key areas of functioning for the mother during the postpartum period: self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation.

[0056] A BIMF score of 95 or below is considered herein to represent mild impairment of maternal functioning, a score of 80 or below is considered herein to represent impairment of maternal functioning, and a score of 65 or below is considered herein to represent severe impairment of maternal functioning. The present application can in particular improve maternal functioning in patients with a score of 80 or below prior to treatment and in patients with a score of 65 or below prior to treatment.

[0057] Active agent

[0058] The above discussion shows that PPD is characterized by several aspects that in themselves contribute to a significant disease burden and that require appropriate treatment. Thus, not only is treatment, in particular by pharmaceutical intervention, required to improve the overall disease score, but also to improve specific aspects of the disease.

[0059] 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.

[0060] The inventors further consider that, when treating a lactating mother suffering from PPD, a carefully selected psychedelic might allow to continue breastfeeding without almost complete interruption.

[0061] One group of psychedelics 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 serotonergic agents are often referred to as “hallucinogens”, which emphasizes their main ability to induce qualitative changes 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.

[0062] From a chemical point of view, serotonergic hallucinogens are either phenylalkylamines or indoleamines, which are subdivided into two subsets, namely ergolines and tryptamines, the latter being derived from tryptamine.

[0063] Various serotonergic hallucinogens have different binding affinities and activation potencies for 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.

[0064] Recently published studies using serotonergic hallucinogens, such as LSD, psilocybin and DMT (using ayahuasca, a shamanic brew containing DMT), in certain psychiatric disorders suggest that these compounds can offer an alternative to the currently available treatments for certain psychiatric disorders. However, it has been reported that these compounds can induce mania in patients suffering from depressive symptoms, and this can hamper their clinical use.

[0065] 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 a case of a patient who developed a manic episode after taking LSD or LSD analogues. The patient developed acute LSD intoxication symptoms that resolved, but developed a typical psychotic manic episode about 3 weeks later. 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 case of 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 case of a man with bipolar disorder who switched to mania after drinking ayahuasca, a beverage containing DMT.

[0066] 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.

[0067] 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 administered must be properly selected and preferably administered according to a specific dosing regimen.

[0068] 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.

[0069] 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.

[0070] 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 high affinity for 5-HT1A receptors, while psilocin and DMT exhibit 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 moderate / strong affinity for 5-HT2A receptors, while DMT and 5-MeO-DMT exhibit relatively weaker affinity.

[0071] With respect to the other psychoactive compounds mentioned previously, 5-MeO-DMT exhibits enhanced affinity for 5-HT1A receptors, in which case 5-MeO-DMT acts as a potent agonist. With respect to 5-MeO-DMT, the contribution of 5-HT2A binding increases in the case of psilocin and DMT, with 5-MeO-DMT exhibiting the greatest differential affinity for 5-HT1A versus 5-HT2A among the three compounds. Thus, 5-HT1A binding plays a much greater role in the overall effect of 5-MeO-DMT than 5-HT2A binding, compared to the other two compounds.

[0072] 5-HT1A agonists are reported to decrease impulsivity and aggression, while 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. LSD, psilocybin, and DMT show increased affinity for multiple dopamine receptors relative to 5-MeO-DMT.

[0073] It can be preferred 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, as compared to other psychedelic drugs, such as LSD, psilocybin, or DMT. 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.

[0074] 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 compounds (e.g., DMT / ayahuasca, psilocybin, LSD).

[0075] The inventors’ 5-MeO-DMT sequential up-titration approach significantly reduces the risk of overdosing and the likelihood of adverse events accompanying it.

[0076] Further, antidepressants are reported to induce isolated hypomanic episodes in patients suffering from treatment-resistant depression (TRD) (Bader, Cynthia D., and David L. Dunner. "Antidepressant-induced hypomania in treatment-resistant depression." Journal of Psychiatric Practice 13.4 (2007): 233-237). However, a recently completed clinical trial of 5-MeO-DMT in patients with TRD showed no evidence of inducing hypomania.

[0077] 5-MeO-DMT can induce a peak experience (i.e. an experience characterized by a shift in emotional perspective, described as “ego-dissolution”, often culminating in an overwhelming sense of “oneness with the universe”) more rapidly than other psychedelics, and has a shorter duration of acute psychedelic effects (5 to 30 minutes after inhalation, compared to hours for oral psilocin and oral LSD, for example). These properties of 5-MeO-DMT are associated with an improved therapeutic profile, which can be explained by specific changes in resting state network (RSN) activity under 5-MeO-DMT treatment.

[0078] Furthermore, 5-MeO-DMT is a 5-HT7receptor agonist, with high affinity for said receptor. The inventors estimated the Ki using recombinant human 5-HT7receptors, [H]LSD as radioligand and serotonin to estimate non-specific binding, and determined a Ki of 2.3 nM. 3 H]LSD and serotonin to estimate non-specific binding, and determined a Ki of 2.3 nM.

[0079] Thus, in addition to the 5-HT1Aand 5-HT2Areceptors discussed above, 5-MeO-DMT also interacts with the 5-HT7receptor. 5-MeO-DMT acts as an agonist of this receptor, and exhibits a high (nanomolar) binding affinity.

[0080] The 5-HT7receptor plays a role in neurogenesis, synaptogenesis and dendritic spine formation. It is among others associated with central processes such as learning and memory, sleep regulation and circadian rhythm, and nociception.

[0081] The 5-HT7receptor is particularly expressed in the spinal cord, the raphe nuclei, the thalamus, the hypothalamus (including the suprachiasmatic nucleus), the hippocampus, the prefrontal cortex, the striatal complex, the amygdala, and the Purkinje neurons of the cerebellum.

[0082] The suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms across various regions of the brain. Disruption of this coordination will lead to disease states, in particular disease states involving sleep disturbances. In patients suffering from sleep disturbances, resting state functional connectivity analysis revealed altered functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.

[0083] The expression of the 5-HT7receptor in the suprachiasmatic nucleus corresponds to the role of said receptor in the regulation of the sleep / wake cycle. The inventors believe that this allows the treatment of patients suffering from sleep disturbances by 5-MeO-DMT acting on the receptor.

[0084] The inventors believe that the binding of 5-MeO-DMT to the 5-HT7receptor, as a mediator of the pharmacological action of 5-MeO-DMT, involves a functional connectivity “reset” of the network and a neuroplasticity effect, contributing to the beneficial effects of 5-MeO-DMT in patients suffering from sleep disorders.

[0085] The inventors further believe that the binding of 5-MeO-DMT to the 5-HT7receptor and to the 5-HT1Areceptor, as two mediators of the action of 5-MeO-DMT, involves a functional connectivity “reset” of the network and a neuroplasticity effect, allowing beneficial effects to be achieved in patients suffering from other symptoms or pathologies, such as cognitive dysfunction, anxiety, psychomotor slowness, negative thoughts or social / emotional withdrawal. This is supported by the clinical results shown in the studies cited herein.

[0086] Another characteristic of 5-MeO-DMT is its short half-life.

[0087] 5-MeO-DMT is inactivated mainly through a monoamine oxidase A-mediated deamination pathway and is O-demethylated by the cytochrome P450 2D6 (CYP2D6) enzyme.

[0088] The inventors have studied the pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during administration and immediately after administration.

[0089] Analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that the plasma concentration decreases very rapidly. 10 minutes after administration, the concentration drops to 10% or less of Cmax; 2 hours later, the concentration is 1% or less of Cmax; 3 hours later, 5-MeO-DMT is no longer detected in the plasma. This applies 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, for example 10 minutes, 2 hours or 3 hours after administration.

[0090] 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 after dosing, 8 patients reached remission on day 1, and 7 patients maintained remission on day 7). Treating PPD patients with 5-MeO-DMT not only rapidly improves depressive symptoms, but also rapidly improves maternal functioning. Furthermore, 5-MeO-DMT is administered during a single day of treatment, optionally without frequent repeat dosing, thus distinguishing it from SSRIs (which require long-term daily dosing regimens with lower compliance) and brexanolone (which requires long-term infusion and hospitalization).

[0091] The present application therefore also solves the problem of compliance and patient convenience.

[0092] 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.

[0093] 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.

[0094] These variants are in particular deuterated forms of 5-MeO-DMT and pharmaceutically acceptable salts of such forms.

[0095] A deuterated form of 5-MeO-DMT is a form having a deuterium content higher than that expected according to the natural abundance of this isotope.

[0096] A deuterated form of 5-MeO-DMT is a specific form in which deuterium is introduced at one or more defined hydrogen positions.

[0097] 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)- lH-indol-3-yl]ethanamine.

[0098] Further examples include forms of 5-MeO-DMT in which one or more of the hydrogen positions of the N-bound methyl group have been replaced by deuterium. 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.

[0099] Methods of preparation of these compounds are known in the art.

[0100] According to the present application, mixtures of deuterated forms of 5-MeO-DMT, mixtures of one or more deuterated forms and 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.

[0101] 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.

[0102] 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.

[0103] Among suitable prodrugs, the hydrogen in position 1 of the indole moiety is replaced by an organic moiety which can be cleaved after administration.

[0104] 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 R 1 , R 2 , R 3 and R 4Each of is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.

[0105] A preferred example of an organic moiety is -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , where R 1 、R 3 and R 4 As defined above.

[0106] Prodrugs, especially those of the above structure, can also be used in the form of pharmaceutically acceptable salts.

[0107] Specific examples of prodrugs are 5-MeO-DMT carboxyisopropyl valine ester, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2-methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indole-1-carboxylic acid ditrifluoroacetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-methoxy-1H-indol-1-yl)methyl pivalate).

[0108] Methods for preparing prodrugs as discussed herein are known in the art.

[0109] According to the present invention, the T of the metabolite 5-MeO-DMT was measured in male Sprague-Dawley (SD) rats after oral administration of the prodrug at 10 mg / kg. max The value is preferably 1 hour or less, more preferably 0.7 hour or less, especially 0.5 hour or less.

[0110] Furthermore, according to the present invention, the amount of 5-MeO-DMT prodrugs and salts of 5-MeO-DMT prodrugs used is equimolar to the amount of the corresponding non-prodrug form.

[0111] Treatment

[0112] As described above, the present invention can treat patients suffering from PPD. Such treatment can not only reduce scores assessing depression severity, but also improve maternal functioning, as discussed in detail below.

[0113] 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 receiving treatment 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.

[0114] 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.

[0115] 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 invention are the group that received a single 12 mg dose, and the group that received an intra-day individualized dosing regimen (IDR) that allowed for multiple dose increases (6 mg, 12 mg, and 18 mg) within a day depending on the patient-reported intensity of the psychedelic experience.

[0116] 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 improvement in the overall MADRS score, the inventors focused on the items that make up the various rating scales and noted that several of the subscale items are particularly relevant to PPD patients and are associated with maternal functioning.

[0117] Several patients in the cohort recruited exhibited significant improvements in one or more of these subscale items, which 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.

[0118] The specific subscale items for each scale are explained 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.

[0119] Accordingly, the treatment according to the present invention reduces or eliminates (or improves or eliminates) certain aspects of the disease.

[0120] If the aspect is assessed according to the MADRS scale, there is at least an improvement (decrease) of one point or the patient is in complete remission (elimination) after the treatment, i.e. the respective aspect scores 0.

[0121] If the aspect is assessed according to the BPRS scale, there is at least an improvement (decrease) of one point or the patient is in complete remission (elimination) after the treatment, i.e. the respective aspect scores 1.

[0122] The clinical response can also be reflected by a decrease in the Clinical Global Impression - Severity (CGI-S) score. According to the present application, a decrease in the CGI-S score means that the CGI-S is decreased by at least one point. Preferably, the CGI-S is decreased by at least two points and / or to 0 points. Particularly preferably, the CGI-S is decreased by at least three points and / or to 0 points.

[0123] The inventors further assume that the improvement observed in certain MADRS items will translate into an improvement in the mother's functioning.

[0124] The particularly relevant MADRS items are discussed in more detail below.

[0125] The MADRS item "Inner tension" represents a feeling of undefined discomfort, restlessness, inner turmoil, increased mental tension as panic, fear or distress. It is assessed according to intensity, frequency, duration and degree of assurance required.

[0126] If the patient is calm and only has short inner tension, a score of 0 is given. If there is occasional restlessness 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.

[0127] The inventors have determined that an increase in the score of the MADRS item "Inner tension" has a negative impact on two aspects of the mother's functioning (mother's ability to interact with the baby and mother's 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 mother's mental health.

[0128] Conversely, an improvement in this MADRS item leads to an improvement in the mother's functioning, in particular in the areas of mother-child interaction and / or the mother's mental health of the BIMF functioning field.

[0129] In the above trial 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%.

[0130] 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%.

[0131] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of inner tension.

[0132] The improvement in inner tension is reflected at least in an improvement in the score of the MADRS item inner tension about 2 hours; on day 1, e.g. about 24 hours; on day 7; on day 14; and / or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0133] The improvement in inner tension (reflected in a reduction 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.

[0134] Additionally or alternatively, the reduction 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.

[0135] The improvement in inner tension (reflected 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.

[0136] The improvement in inner tension (reflected in a reduction 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 until at least 6 days; in particular until at least 14 days; more preferably until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0137] The inventors have also concluded that the reduction or elimination of inner tension achieved by treating PPD patients not only leads to a reduction 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.

[0138] 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.

[0139] The MADRS item “lassitude” indicates a slow pace in starting or initiating and performing daily activities.

[0140] 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.

[0141] The inventors have established that an increase in the score of the MADRS item “lassitude” 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 “lassitude” impairs baby care, self-care, mental health, management and regulation.

[0142] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the BIMF functional domains baby care, self-care, mental health, management and / or regulation.

[0143] In the study group receiving the individualized dosing regimen, the total score of the MADRS item “lassitude” was 27 for all 8 patients at baseline. After 2 hours, the score was reduced to 10, which corresponds to an improvement of 17 points or 63%. At day 1 after treatment, the score was reduced to 5, which corresponds to an improvement of 22 points or 81%. At day 7 after treatment, the score was reduced to 3, which corresponds to an improvement of 24 points or 89%.

[0144] In the 12 mg group, the total score of the MADRS item “lassitude” was 16 for all 4 patients at baseline. After 2 hours, the score was reduced to 10, which corresponds to an improvement of 6 points or 38%. At day 1 after treatment, the score was reduced to 0, which corresponds to an improvement of 16 points or 100%. At day 7 after treatment, the score was reduced to 3, which corresponds to an improvement of 13 points or 81%.

[0145] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of apathy.

[0146] The improvement in apathy is reflected at least in an improvement in the score of the item apathy of the MADRS 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.

[0147] The improvement in apathy, reflected in a decrease in the score 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.

[0148] Additionally or alternatively, the decrease in the score 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.

[0149] The improvement in apathy, reflected in a score of "much improved" in the Clinical Global Impression-Improvement (CGI-I) score or in 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.

[0150] The improvement in apathy, reflected in a decrease in the CGI-S score or at least in a score of "much improved" in the CGI-I score or in 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.

[0151] The inventors also conclude that the reduction or elimination of apathy achieved by treating PPD patients not only leads to a decrease in the total score of the MADRS, 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 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. Since apathy also affects other aspects of PPD, the inventors conclude that the observed improvement in the item "apathy" of the MADRS will also contribute to the overall improvement in maternal functioning.

[0152] The MADRS item “feelings of absence” 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.

[0153] 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 numbness, inability to feel anger, sadness or pleasure, and experiences of complete or even painful loss of emotions towards loved ones.

[0154] The inventors have established that an increase in the score of the MADRS item “feelings of absence” 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 score of the MADRS item “feelings of absence” impairs mother-infant interaction and mental health.

[0155] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the domains of mother-infant interaction and / or mental health of the BIMF functional domain.

[0156] In the study group receiving the individualized dosing regimen, the total score of the MADRS item “feelings of absence” 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%. On day 1 after treatment, the score was reduced to 2, which corresponds to an improvement of 34 points or 94%. On day 7 after treatment, the score was reduced to 6, which corresponds to an improvement of 30 points or 83%.

[0157] In the 12 mg group, the total score of the MADRS item “feelings of absence” 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%. On day 1 after treatment, the score was reduced to 1, which corresponds to an improvement of 15 points or 94%. On day 7 after treatment, the score was reduced to 1, which corresponds to an improvement of 15 points or 94%.

[0158] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of feelings of absence.

[0159] The improvement in feelings of absence is reflected at least in an improvement in the score of the MADRS item feelings of absence 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.

[0160] The improvement in feelings of absence, 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.

[0161] 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.

[0162] The improvement in anhedonia (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.

[0163] The improvement in anhedonia (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.

[0164] The inventors have also concluded that the reduction or elimination of anhedonia by treating PPD patients not only leads to a reduction 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 is achieved rapidly, i.e. within about 2 hours, and an increase in the BIMF score is also 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.13Since anhedonia also affects other aspects of PPD, the inventors have concluded that the observed improvement in the "feeling of loss" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0165] The MADRS item "difficulty in concentrating" represents the difficulty in gathering one's thoughts, resulting in an inability to concentrate.

[0166] A score of 0 is given if the patient has no difficulty in concentrating. A score of 2 is given if it is occasionally difficult to gather one's thoughts. A score of 4 is given if it is difficult to concentrate and maintain thoughts, resulting in a reduced ability to read or converse. A score of 6 is given if the patient is unable to read or converse easily.

[0167] The inventors have determined that an increase in the score of the MADRS item "difficulty in concentrating" has a negative impact on two aspects of maternal functioning (maternal ability to interact with the baby and maternal self-care). An increase in the score of the MADRS item "difficulty in concentrating" impairs baby care and management.

[0168] In contrast, the improvement on the MADRS item led to an improvement in the mother's functioning, in particular in the BIMF functional domain of baby care and / or management.

[0169] In the study arm receiving the individualized dosing regimen, the total score on the MADRS item "difficulty concentrating" was 30 for all 8 patients 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%.

[0170] In the 12 mg arm, the total score on the MADRS item "difficulty concentrating" was 16 for all 4 patients 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%.

[0171] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of difficulty concentrating.

[0172] The improvement in difficulty concentrating is reflected at least by an improvement in the score on the MADRS item difficulty concentrating at about 2 hours; at day 1, e.g. about 24 hours after; 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.

[0173] The improvement in difficulty concentrating, 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.

[0174] Additionally or alternatively, the decrease in the 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.

[0175] The improvement in difficulty concentrating, 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 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0176] The improvement in difficulty concentrating, reflected in a decrease in CGI-S score or at least in 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.

[0177] The inventors have also concluded that alleviating or eliminating the difficulty concentrating by treating the PPD patient 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 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.

[0178] Since the difficulty concentrating also affects other aspects of PPD, the inventors have concluded that the observed improvement in the "difficulty concentrating" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0179] The MADRS item "Pessimistic thoughts" represents thoughts of guilt, inferiority, self-reproach, sinfulness, remorse and annihilation.

[0180] 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-deprecation. 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.

[0181] The inventors have established that an increase in the score of the MADRS item "Pessimistic 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 "Pessimistic thoughts" impairs mental health, social support and management.

[0182] Conversely, an improvement in this MADRS item leads to an improvement in maternal functioning, in particular in the areas of mental health, social support and / or management of the BIMF functioning domains.

[0183] 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%.

[0184] 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%.

[0185] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of pessimistic thoughts.

[0186] 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.

[0187] The improvement in pessimistic thoughts, 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.

[0188] 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.

[0189] The improvement in pessimistic thoughts, 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.

[0190] The improvement in pessimistic thoughts, 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.

[0191] The inventors also concluded that alleviating or eliminating pessimistic thoughts by treating PPD patients not only leads to a reduction 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.

[0192] As pessimistic thoughts also affect other aspects of PPD, the inventors concluded that the observed improvement in the “pessimistic thoughts” item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0193] 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 themselves.

[0194] A score of 0 reflects normal sleep when the subject is healthy by themselves. A score of 2 reflects that there is slight difficulty falling asleep, or that the sleep time is slightly reduced, lighter or interrupted. A score of 4 means that the sleep time is reduced or interrupted for at least two hours. A score of 6 means that the sleep time is less than two hours or three hours.

[0195] 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, namely the mother’s ability to interact with the baby and to self-care. An increase in the score of the MADRS item “reduced sleep” impairs self-care, mental health and management.

[0196] 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.

[0197] In the study arm receiving the individualized dosing regimen, the total score of the MADRS item “reduced sleep” was 25 for all 8 patients at baseline. At day 1 after treatment, 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%. At day 7 after treatment, the score was reduced to 9, which corresponds to an improvement of 16 points or 64%.

[0198] In the 12 mg arm, the total score of the MADRS item “reduced sleep” was 12 for all 4 patients at baseline. At day 1 after treatment, the score was reduced to 10, which corresponds to an improvement of 2 points or 17%. At day 7 after treatment, the score was reduced to 6, which corresponds to an improvement of 6 points or 50%.

[0199] The inventors concluded that 5-MeO-DMT can be used to treat PPD patients to achieve an alleviation or elimination of reduced sleep.

[0200] The reduction or elimination of sleep reduction is reflected at least in an improvement in the score of the MADRS item sleep reduction at day 1, e.g. about 24 hours after; 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.

[0201] The improvement in sleep reduction, 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.

[0202] The improvement in sleep reduction, 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 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0203] The improvement in sleep reduction, reflected as 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.

[0204] The inventors also concluded that the reduction or elimination of sleep reduction 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 24 hours, and an increase in the BIMF score will also be observed at day 1, e.g. about 24 hours after; 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.

[0205] Since sleep reduction also affects other aspects of PPD, the inventors concluded that the observed improvement in the "sleep reduction" item of the MADRS will also contribute to the overall improvement in maternal functioning.

[0206] Another aspect of PPD that can be treated by the administration of 5-MeO-DMT is suicidal ideation. 5-MeO-DMT can be administered to a PPD patient to reduce or eliminate suicidal ideation in said patient.

[0207] In the above-mentioned clinical study involving the administration of 5-MeO-DMT, the MADRS item "suicidal thoughts" was assessed, among others.

[0208] “Suicidal thoughts” represent a feeling that life is not worth living, a wish for natural death, having suicidal thoughts, and / or preparing for suicide. Suicidal attempts per se should not influence the assessment of this MADRS item.

[0209] A score of 0 means that the patient enjoys life. A score of 2 means that the PPD patient is tired of life and / or has only brief suicidal thoughts. A score of 4 means that the patient feels better dead, that suicidal thoughts are common and suicide is seen as a possible solution, but the patient has no specific plans or intentions. A score of 6 means that the patient has a clear suicide plan and / or is actively preparing.

[0210] This MADRS scale item is particularly relevant to suicidal ideation.

[0211] The inventors have determined that an increase in the score of the MADRS item “suicidal thoughts” has a negative impact on two aspects of maternal functioning, namely the mother’s ability to interact with the baby and the mother’s self-care. An increase in the score of the MADRS item “suicidal thoughts” impairs self-care, mental health and management.

[0212] 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.

[0213] 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 decreased to 3, which corresponds to an improvement of 8 points or 73%. On the first day after treatment, the score decreased to 1, which corresponds to an improvement of 10 points or 91%. On the seventh day after treatment, the score decreased to 3, which corresponds to an improvement of 8 points or 73%.

[0214] 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 decreased to 3, which corresponds to an improvement of 5 points or 63%. On the first day after treatment, the score decreased to 5, which corresponds to an improvement of 3 points or 38%. On the seventh day after treatment, the score decreased to 7, which corresponds to an improvement of 1 point or 13%.

[0215] Thus, the score of the scale item “suicidal thoughts”, which is particularly relevant to suicidal ideation, improved significantly, at least in the individualized dosing regimen patients. The inventors conclude that 5-MeO-DMT can be used to treat suicidal ideation in PPD patients.

[0216] Thus, according to the present application, the treatment of PPD patients suffering from suicidal ideation can reduce or eliminate suicidal ideation.

[0217] The reduction or elimination of suicidal ideation is reflected at least by an improvement in the score of the MADRS item Suicidal Thoughts 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 later; at day 7; at day 14; and / or at day 28.

[0218] If the patient suffers from suicidal ideation, the improvement in suicidal ideation is reflected by a decrease in the Clinical Global Impression-Severity (CGI-S) score 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 later; at day 7; at day 14; and / or at day 28.

[0219] The improvement in suicidal ideation, 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.

[0220] Alternatively, the decrease in the 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.

[0221] The improvement in suicidal ideation, assessed at least as a score of "much improved" in the Clinical Global Impression-Improvement (CGI-I) score or in 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.

[0222] The improvement in suicidal ideation, assessed as a decrease in the CGI-S score or at least as a score of "much improved" in the CGI-I score or in 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.

[0223] The inventors also concluded that the reduction or elimination of suicidal thoughts by treating PPD patients not only leads to a decrease in the MADRS total score, but also to an improvement in the maternal functioning, 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 later; 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.

[0224] Since suicidal ideation also affects other aspects of PPD, the inventors concluded that the observed improvement in the MADRS item “suicidal ideation” would also contribute to the overall improvement in maternal functioning.

[0225] The BPRS item “emotional withdrawal” is related to the patient’s deficit in the ability to express emotions during the interview. Possible scores are:

[0226] 1 - No emotional withdrawal.

[0227] 2 - Very mild. Lack of emotional involvement manifested by occasional failure to respond, occasional appearing absent-minded, or smiling unnaturally, but most of the time spontaneously conversing with the interviewer.

[0228] 3 - Mild. Lack of emotional involvement manifested by obvious failure to respond, appearing absent-minded or lacking enthusiasm, but responding when the interviewer approaches.

[0229] 4 - Moderate. Emotional communication is not often seen in the interview because the interviewee does not respond in detail, does not make eye contact, does not seem to care if the interviewer is listening, or can be preoccupied with psychotic material.

[0230] 5 - Moderate-severe. Same as “4” but no emotional communication is shown during most of the interview.

[0231] 6 - Severe. Active avoidance of emotional involvement. Often no response or yes / no answers (not only due to persecutory delusions). Minimal emotional response only.

[0232] 7 - Extreme. Always avoids emotional involvement. No response or yes / no answers (not only due to persecutory delusions). Can leave or not respond at all during the interview.

[0233] The inventors have determined that an increase in the score of the BPRS item “emotional withdrawal” has a negative impact on two aspects of maternal functioning (maternal ability related to infant interaction and maternal self-care). An increase in the score of the BPRS item “emotional withdrawal” impairs mental health, mother-child interaction, and social support.

[0234] Conversely, an improvement in this BPRS item leads to an improvement in maternal functioning, particularly in the BIMF functional domains of mental health, mother-child interaction, and / or social support.

[0235] In the study group receiving the individualized dosing regimen, the total score of the BPRS item “emotional withdrawal” was 13 at baseline. After 3 hours, the score decreased to 8, which corresponds to an improvement of 5 points or 38%. On the first day after treatment, the score decreased to 8, which corresponds to an improvement of 5 points or 38%. On the seventh day after treatment, the score decreased to 8, which corresponds to an improvement of 5 points or 38%.

[0236] In the 12 mg group, the total score for the BPRS item "emotional withdrawal" was 13 at baseline. After 3 hours, the score was reduced to 11, which corresponds to an improvement of 2 points or 15%. On day 1 after treatment, the score was reduced to 8, which corresponds to an improvement of 5 points or 38%. On day 7 after treatment, the score was reduced to 6, which corresponds to an improvement of 7 points or 54%.

[0237] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of emotional withdrawal.

[0238] The reduction or elimination of emotional withdrawal is reflected at least by an improvement in the score for the BPRS item emotional 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 later; on day 7; on day 14; and / or on day 28.

[0239] The improvement in emotional withdrawal, reflected as 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.

[0240] 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.

[0241] The improvement in emotional withdrawal, 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 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0242] The improvement in emotional withdrawal, 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 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.

[0243] The inventors also concluded that reducing or eliminating emotional withdrawal by treating PPD patients not only results in a decrease in the BPRS total score, but also results in an improvement in maternal function, which is reflected in an increase in the BIMF score. This improvement is achieved rapidly, i.e., within about 2 hours, and an increase in the BIMF score is also observed on the 1st day, e.g., about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on the 7th day; on the 14th day; and / or on the 28th day.

[0244] Because emotional withdrawal also affects other aspects of PPD, the inventors concluded that the observed improvements in the "emotional withdrawal" item of the BPRS would also contribute to overall improvements in maternal functioning.

[0245] The BPRS item "Blunting of Emotion" involves a restricted range of facial, vocal, and gestural emotional expressions, as well as a marked apathy or flatness even when discussing painful topics. Possible scores are:

[0246] 1 - No emotional blunting.

[0247] 2 - Very Mild. Emotional range is slightly muffled or reserved, but facial expressions and voice intonation are appropriate and within normal range.

[0248] 3 - Mild. Overall, emotional range is reduced, muted, or reserved, without many spontaneous and appropriate emotional responses. The tone is somewhat monotonous.

[0249] 4 - Moderate. Emotional range is markedly reduced, and except in rare cases, the patient does not show emotion, smile, or respond to distressing topics. Speech may be monotonous or spontaneous movements may be markedly reduced. Displays of emotion or gestures are usually followed by a return to apathy.

[0250] 5 - Moderate to severe. The emotional range is very limited. The patient does not show emotion, smile, or respond to painful topics. Facial expressions do not change often, except for minimal, infrequent gestures. The voice is monotonous much of the time.

[0251] 6 - Severe. Emotional range or expression is very limited. Speech and gestures are mechanical most of the time. Facial expression remains unchanged. Voice tone is monotonous most of the time.

[0252] 7 - Extreme. There is little emotional range or expression, and movements are rigid. Speech is monotonous at all times.

[0253] 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 both infant interaction and maternal self-care). An increase in the score of the BPRS item “blunted affect” impairs mental health and mother-child interaction.

[0254] In contrast, an improvement in this BPRS item leads to an improvement in maternal functioning, in particular in the area of mental health and / or mother-child interaction of the BIMF functional domain.

[0255] 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 day 1 after treatment, the score decreased to 8, which corresponds to an improvement of 7 points or 47%. On day 7 after treatment, the score decreased to 8, which corresponds to an improvement of 7 points or 47%.

[0256] 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 day 1 after treatment, the score decreased to 6, which corresponds to an improvement of 5 points or 45%. On day 7 after treatment, the score decreased to 5, which corresponds to an improvement of 6 points or 55%.

[0257] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of blunted affect.

[0258] The reduction or elimination of blunted affect is reflected at least in an improvement in the score of the BPRS item blunted affect 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.

[0259] The improvement in blunted affect, reflected in 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.

[0260] 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.

[0261] The improvement in blunted affect, reflected 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.

[0262] The improvement in blunted affect (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 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.

[0263] The inventors also concluded that the alleviation or elimination of blunted affect by treating the PPD patient 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 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.

[0264] 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 maternal functioning.

[0265] The BPRS item "guilt feelings" is related to excessive concern or remorse about past behavior. Possible scores are:

[0266] 1 - No guilt feelings.

[0267] 2 - Very mild. Worried about disappointing someone or about something failing, but not absentminded. Can easily shift thoughts to other things.

[0268] 3 - Mild. Worried about disappointing someone or about something failing with a little absentmindedness. Tendency to express guilt to others.

[0269] 4 - Moderate. Excessive preoccupation with guilt, doing something wrong, hurting someone because of doing or not doing something, but can easily shift attention to other things.

[0270] 5 - Moderate-severe. Preoccupied with guilt, disappointing someone or something failing, can shift attention to other things, but with great effort. Not delusional.

[0271] 6 - Severe. Delusional guilt or irrational self-accusation that is very out of keeping with the environment. There is moderate absentmindedness.

[0272] 7 - Extreme. Delusional guilt or irrational self-accusation that is extremely out of keeping with the environment. The subject is very preoccupied with guilt and can reveal it to others or act on delusions.

[0273] The inventors have determined that an increase in the score of the BPRS item “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 “Guilt” impairs self-care, mother-infant interaction, mental health, and management.

[0274] Conversely, an improvement in this BPRS item leads to an improvement in maternal functioning, in particular in the BIMF functional domains of self-care, mother-infant interaction, mental health, and / or management.

[0275] In the study arm receiving the individualized dosing regimen, the total score of the BPRS item “Guilt” was 34 for all 8 patients at baseline. After 3 hours, the score was reduced to 14, which corresponds to an improvement of 20 points or 59%. On day 1 after treatment, the score was reduced to 11, which corresponds to an improvement of 23 points or 68%. On day 7 after treatment, the score was reduced to 10, which corresponds to an improvement of 24 points or 71%.

[0276] In the 12 mg arm, the total score of the BPRS item “Guilt” was 18 for all 4 patients at baseline. After 3 hours, the score was reduced to 9, which corresponds to an improvement of 9 points or 50%. On day 1 after treatment, the score was reduced to 5, which corresponds to an improvement of 13 points or 72%. On day 7 after treatment, the score was reduced to 5, which corresponds to an improvement of 13 points or 72%.

[0277] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of guilt.

[0278] The reduction or elimination of guilt is reflected at least in 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.

[0279] The improvement in guilt, reflected as 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.

[0280] 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.

[0281] Improvement in guilt (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.

[0282] Improvement in guilt (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.

[0283] The inventors also concluded that alleviating or eliminating guilt by treating PPD patients not only leads to a decrease in the BPRS total score, but also to an improvement in maternal 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 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.

[0284] Since guilt also affects other aspects of PPD, the inventors concluded that the observed improvement in the "guilt" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0285] The BPRS item "anxiety" is related to reported worry, tension, fear, panic, or apprehension. Possible scores are:

[0286] 1 - No anxiety.

[0287] 2 - Very mild. Some discomfort reported due to worry or infrequent worry that occurs more often than in most normal individuals.

[0288] 3 - Mild. Worried frequently, but able to shift attention easily to other things.

[0289] 4 - Moderate. Most of the time in a worried state and unable to shift attention easily to other things, but functioning is not impaired; or anxiety occurs occasionally with autonomic symptoms, but functioning is not impaired.

[0290] 5 - Moderate-severe. Anxiety occurs frequently (but not daily) with autonomic symptoms, or some areas of functioning are disturbed by anxiety or worry.

[0291] 6 - Severe. Anxiety every day with autonomic symptoms but not all day, or many areas of functioning are disturbed by anxiety or constant worry.

[0292] 7 - Extreme. Anxiety all day with autonomic symptoms, or most areas of functioning are disturbed by anxiety or constant worry.

[0293] 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.

[0294] Conversely, an improvement on this BPRS item leads to an improvement in maternal functioning, in particular in the BIMF functional domains of mental health, social support, and / or management.

[0295] In the study group receiving the individualized dosing regimen, the total score of the BPRS item “anxiety” for all 8 patients was 37 at baseline. After 3 hours, the score decreased to 19, which corresponds to an improvement of 18 points or 49%. On day 1 after treatment, the score decreased to 16, which corresponds to an improvement of 21 points or 57%. On day 7 after treatment, the score decreased to 17, which corresponds to an improvement of 20 points or 54%.

[0296] In the 12 mg group, the total score of the BPRS item “anxiety” for all 4 patients was 25 at baseline. After 3 hours, the score decreased to 11, which corresponds to an improvement of 14 points or 56%. On day 1 after treatment, the score decreased to 6, which corresponds to an improvement of 19 points or 76%. On day 7 after treatment, the score decreased to 6, which corresponds to an improvement of 19 points or 76%.

[0297] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of anxiety.

[0298] The reduction or elimination of anxiety is reflected at least in 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, for example about 24 hours later; on day 7; on day 14; and / or on day 28.

[0299] The improvement in anxiety, reflected as 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.

[0300] 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.

[0301] The improvement in anxiety, reflected as a reduction in CGI-S score or at least 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.

[0302] The improvement in anxiety, reflected as a reduction in CGI-S score or at least 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.

[0303] The inventors also concluded that the reduction or elimination of anxiety by treating PPD patients not only leads to a reduction in the BPRS total score, but also to an improvement in maternal 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 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.

[0304] Since anxiety also affects other aspects of PPD, the inventors concluded that the observed improvement in the "anxiety" item of the BPRS will also contribute to the overall improvement in maternal functioning.

[0305] The BPRS item "tension" is related to observable physical and motor manifestations of tension, "anxiety", and agitation. Possible scores are

[0306] 1 - No tension.

[0307] 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.

[0308] 3 - Mild. Same as "2" but signs of tension more frequent or more dramatic.

[0309] 4 - Moderate. Many and frequent motor signs of tension, sometimes with one or more signs occurring simultaneously, e.g. twisting hands while tapping foot. Sometimes signs of tension are not present.

[0310] 5 - Moderate. Many and frequent motor tension signs, often accompanied by one or more signs simultaneously. There are still very few cases where there are no signs of tension.

[0311] 6 - Severe. Same as “5”, but the signs of tension are persistent.

[0312] 7 - Extreme. Persistent multiple motor manifestations of tension, such as persistent pacing and hand twisting.

[0313] 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, maternal ability to interact with the infant and maternal self-care. An increase in the score of the BPRS item “tension” impairs mother-infant interaction and mental health.

[0314] Conversely, an improvement in this BPRS item leads to an improvement in maternal functioning, in particular in the BIMF functional domains of mother-infant interaction and / or mental health.

[0315] In the study group receiving individualized dosing regimens, the total score of the BPRS item “tension” for all 8 patients was 16 at baseline. After 3 hours, the score decreased to 11, which corresponds to an improvement of 5 points or 31%. On day 1 after treatment, the score decreased to 11, which corresponds to an improvement of 5 points or 31%. On day 7 after treatment, the score decreased to 10, which corresponds to an improvement of 6 points or 38%.

[0316] In the 12 mg group, the total score of the BPRS item “tension” for all 4 patients was 14 at baseline. After 3 hours, the score decreased to 9, which corresponds to an improvement of 5 points or 36%. On day 1 after treatment, the score decreased to 6, which corresponds to an improvement of 8 points or 57%. On day 7 after treatment, the score decreased to 6, which corresponds to an improvement of 8 points or 57%.

[0317] The inventors conclude that 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of tension.

[0318] The reduction or elimination of tension is reflected at least by an improvement in the score of the BPRS item tension about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; on day 1, for example about 24 hours later; on day 7; on day 14; and / or on day 28.

[0319] The improvement in tension, reflected as 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.

[0320] Additionally or alternatively, the reduction in the 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.

[0321] The improvement in tension, reflected as a reduction in the CGI-S score or at least reflected as a score of "much improved" in the CGI-I score or the 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.

[0322] The improvement in tension, reflected as a reduction in the CGI-S score or at least reflected as a score of "much improved" in the CGI-I score or the 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.

[0323] The inventors also concluded that the alleviation or elimination of tension by treating the PPD patient not only leads to a reduction in the BPRS total score, but also to an improvement in the maternal 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 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.

[0324] Since tension also affects other aspects of PPD, the inventors concluded that the observed improvement in the "tension" item of the BPRS will also contribute to the overall improvement in the maternal functioning.

[0325] The improvement in one or more aspects of PPD will also lead to an overall improvement. Preferably, the treatment will lead to remission.

[0326] The remission of depressive symptoms can be reflected as a MADRS score equal to or less than 10, and occurs 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 the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof; at day 7; at day 14; and / or at day 28.

[0327] Alternatively or additionally, remission of depressive symptoms can be reflected in a HAM-D score of equal to or less than 7 and occurring no later than about 2 hours after the last administration of 5-MeO-DMT, or a pharmaceutically acceptable salt thereof; occurring at day 1, e.g., about 24 hours later; day 7; day 14; and / or day 28.

[0328] As can be seen from the above, treatment of PPD patients with 5-MeO-DMT, or a pharmaceutically acceptable salt thereof, not only results in a decrease in MADRS score, particularly including the subscores detailed above, but also improves domains of the BIMF scale. As discussed in the Example section below, clinical data confirm the decrease in MADRS score as well as the improvement in maternal functioning.

[0329] Improvement in maternal functioning includes improvement in the self-care functioning domain. For example, improvement in the MADRS items lethargy and / or reduced sleep results in an increase in the BIMF scale score reflecting self-care. Improvement in the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10%, more preferably at least 20%.

[0330] Improvement in maternal functioning includes improvement in the infant care functioning domain. For example, improvement in the MADRS items lethargy and / or difficulty concentrating results in 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%.

[0331] Improvement in maternal functioning includes improvement in the mother-child interaction functioning domain. For example, improvement in the MADRS items anhedonia and inner tension results in 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%.

[0332] Improvement in maternal functioning includes improvement in the psychological well-being functioning domain. For example, improvement in the MADRS items lethargy, pessimistic thoughts, anhedonia, inner tension, and / or reduced sleep results in an increase in the BIMF scale score reflecting psychological well-being. Improvement in the cumulative score of the BIMF scale items reflecting psychological well-being is preferably at least 25%, more preferably at least 35%.

[0333] Improvement in maternal functioning includes improvement in the social support functioning domain. For example, improvement in the MADRS item pessimistic thoughts results in 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%.

[0334] Improvement in maternal functioning includes improvement in the domain 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%.

[0335] Improvement in maternal functioning includes improvement in the domain of regulation. For example, improvement in MADRS item 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%.

[0336] Improvement in maternal functioning relates to one or more, in particular two or more, of the functional domains selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

[0337] The BIMF total score is improved by 10% or more, preferably by 20% more.

[0338] Breastfeeding

[0339] The term breastfeeding as used herein is the process of feeding a child with human breast milk. Breastfeeding includes feeding the breast milk directly from the breast, as well as first expressing the breast milk and then feeding it to the child in a bottle.

[0340] As mentioned above, for many drugs, a breastfeeding patient can be faced with the situation that a decision has to be made whether to stop breastfeeding or to stop / abandon the treatment.

[0341] If the decision is made to stop breastfeeding in order to receive the treatment, this decision will have a negative impact on maternal functioning, in particular on the functional domains of mother-child interaction and mental health.

[0342] The present invention also addresses the need to treat a psychiatric or neurological disorder in a breastfeeding mother without almost completely interrupting breastfeeding.

[0343] According to the present invention, breastfeeding can be resumed shortly after the treatment.

[0344] The inventors investigated the pharmacokinetic properties and metabolism of 5-MeO-DMT 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.

[0345] Furthermore, breast milk was obtained from a breastfed patient who underwent PPD treatment with 5-MeO-DMT. As described in more detail in the examples section, the breastfed 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.

[0346] 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).

[0347] With regard to the administered compound 5-MeO-DMT, rapid absorption and distribution is observed, e.g. upon administration by inhalation, with maximum concentrations and pharmacological effects observed during and immediately after administration.

[0348] The plasma protein binding is low (13-23%).

[0349] The analysis of the pharmacokinetic properties of 5-MeO-DMT after inhalation shows that the plasma concentrations decrease very rapidly. 10 minutes after administration, the concentrations are at 10% or below of Cmax; 2 hours later, the concentrations are at 1% or below of Cmax; 3 hours later, 5-MeO-DMT is no longer detected in plasma. This applies to the complete 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 of 5-MeO-DMT, e.g. 10 minutes, 2 hours or 3 hours after administration.

[0350] The rapid decrease of plasma concentrations leads to a short time period during which 5-MeO-DMT is able to enter breast milk. Therefore, 5-MeO-DMT will only be found in breast milk for a short time period.

[0351] The obtained patient data confirm that the concentration of 5-MeO-DMT in breast milk decreases rapidly (see Example 12). No 5-MeO-DMT was detected at the measurement after 24 hours.

[0352] In determining the potential impact 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). RID is the dose to which an infant is exposed through ingestion of breast milk (in pg / kg / day), divided by the dose received by the mother (in pg / kg / day).

[0353] From the estimated values of daily breast milk intake and feeding frequency, and the measured breast milk concentrations, the exposure of the infant can be determined.

[0354] For example, published estimates of daily breast milk intake in relation to infant weight are 150 ml / kg / day. To simulate the exposure, assume an infant of 5 kg is fed three times in 24 hours with 250 ml of breast milk each time. For the first feeding, assume a 5-MeO-DMT concentration of 2167.0 pg / ml (value measured at 1 hour), 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.

[0355] With respect to 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 regime applied).

[0356] Since the actual dose delivered to the patient can be lower than the labelled dose, the RID is also calculated assuming that the actual delivered amount is only 50% of the labelled dose, to avoid any potential underestimation of the exposure of the infant.

[0357] Assuming a maternal standard weight of 60 kg, this results in a RID of 0.092% (based on a maternal exposure of 9 mg) to 0.046% (based on a maternal exposure of 18 mg).

[0358] The accepted threshold for a "low risk" RID is 10%. From the calculated values it is clear that the 5-MeO-DMT RID is well below this threshold.

[0359] In addition, 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 will gradually decrease over time.

[0360] In addition, it was assumed that no breast milk was expressed and discarded in the estimation.

[0361] Therefore, the actual RID will be lower than the estimated value.

[0362] Metabolites of 5-MeO-DMT that can occur in humans were identified in order 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:

[0363] Table 1

[0364]

[0365] It is worth noting 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.

[0366] The metabolites listed in the table above are formed by three different pathways.

[0367] 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:

[0368]

[0369] The reaction shown is catalyzed by monoamine oxidase A (MAO-A).

[0370] No secondary amines, primary amines and aldehydes were identified, which indicates that they are not present in significant concentrations at any time.

[0371] 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.

[0372]

[0373] Both resulting metabolites are endogenous substances and are formed in the human body, for example, during the synthesis and metabolism of melatonin and serotonin (see, for example, Chapter 3 Biochemistry of the Pineal. in Melatonin and the Mammalian Pineal Gland.

[0374] Arendt J (ed.) Chapman & Hall, 1995; Chapter 3. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium in Slominski R and Slominski AT. Melatonin in the Promotion of Health. Watson RR (ed.) CRC Press 2012.

[0375] Because the major pathway of 5-MeO-DMT metabolism rapidly produces metabolites that are also part of the endogenous metabolic pathway, the inventors determined that the oxidative deamination of 5-MeO-DMT does not involve metabolites that would require restrictions on breastfeeding.

[0376] Furthermore, as described in detail in the Examples section, incubation of 5-methoxytryptol with human hepatocytes showed a high metabolic turnover rate, with the compound completely eliminated within 24 h. At a test concentration of 1 μM, the in vitro intrinsic clearance of 5-methoxytryptol was 16.2 μl / min / million cells (with a half-life of 142 min).

[0377] Therefore, the plasma concentration of 5-methoxytryptol, even if formed, will decline rapidly and reach endogenous levels.

[0378] 5-MIAA has been identified as the major human metabolite.

[0379] Incubation of 5-MIAA with human hepatocytes showed a low metabolic turnover rate, with the remaining 5-MIAA concentration being 75-82% after 72 h. 5-MIAA is considered the final metabolite of 5-MeO-DMT.

[0380] 5-MIAA shows a relatively low plasma binding of approximately 50% (mean unbound fraction (Fu); see Examples section). After renal clearance, 5-MIAA remains in the circulation.

[0381] If endogenous formation of 5-MIAA is disregarded and if it is assumed that a single dose of 5-MeO-DMT is immediately converted to 5-MIAA, then based on the standard glomerular filtration rate (90-120 ml / min), 5-MIAA is cleared from the circulation and excreted in the urine within approximately 1-2 hours.

[0382] For example, the urine concentration of 5-MIAA measured after 2.5 hours at 12 980 501 pg / ml (approximately 12.98 mg / l) shows that most of the 5-MIAA formed is rapidly excreted.

[0383] As a result, the plasma concentration of 5-MIAA will decrease rapidly.

[0384] To more accurately estimate the development of 5-MIAA plasma concentrations, several factors must be considered, including the patient's size and the increase in blood volume during pregnancy. It should be understood that there are individual differences in glomerular filtration rate and the metabolic rate of 5-MeO-DMT.

[0385] Furthermore, although 5-MIAA is rapidly formed, pharmacokinetic data from healthy volunteers and patients with PPD suggest that small amounts of 5-MeO-DMT (corresponding to less than 10% of Cmax) may still be present after approximately 1 hour. Therefore, 5-MIAA formation actually occurs over a period of time after administration of 5-MeO-DMT.

[0386] Furthermore, in cases where more than one dose of 5-MeO-DMT is administered, accumulation of 5-MeO-DMT does not occur if the administrations are separated by at least about 1 hour, because measurable amounts of 5-MIAA are still present in the serum at 2.5 hours, whereas some accumulation of this metabolite occurs if subjects are dosed 1 hour apart.

[0387] 5-MIAA is a weak acid that will be present in plasma in an ionized form, thereby reducing the possibility of the compound entering breast milk.

[0388] Nevertheless, it can be assumed that a certain amount of 5-MIAA enters breast milk during limited periods of relatively high plasma 5-MIAA concentrations.

[0389] For additional information on the concentration-time profile, see the measured concentrations of 5-MIAA in breast milk described in Example 12. Using these data, the infant's exposure to 5-MIAA can be calculated.

[0390] 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.

[0391] 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.

[0392] 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.

[0393] 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.

[0394] 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.

[0395] 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%.

[0396] 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.

[0397] 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.

[0398] 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.

[0399] 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.

[0400] 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%.

[0401] This remains true even when taking into account the depot effect of 5-MIAA in breast milk.

[0402] Based on the observed linear pharmacokinetic characteristics of 5-MeO-DMT, linear extrapolation is reasonable.

[0403] 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 when considering chronic treatment regimens.

[0404] Another identified metabolite, bufotenine, is the result of O-demethylation catalyzed by CYP2D6. The formed metabolite is then glucuronidated under the catalysis of UGT:

[0405]

[0406] 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).

[0407] Bufotenine glucuronide does not bind to the receptor and does not exert any effect. Furthermore, 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:

[0408]

[0409] 5-hydroxyindoleacetic acid is an endogenous substance, for example, it is present in the metabolism of melatonin and serotonin (cf. above).

[0410] 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.

[0411] The third metabolic pathway involves N-oxidation:

[0412]

[0413] 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.

[0414] 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.

[0415] 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.

[0416] Early resumption of breastfeeding has significant advantages for breastfeeding patients, their mental health, and the mental health of their infants.

[0417] 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.

[0418] 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).

[0419] Breastfeeding can be resumed immediately after the specified period of time or event.

[0420] 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 discharge readiness has been achieved.

[0421] The discharge readiness clinical assessment (CADR) is performed to determine that the patient is ready to go home without clinical obstacles.

[0422] According to the CADR, discharge readiness is confirmed by the following: 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.

[0423] The CADR can be administered about 1 hour after the last dose. Alternatively, a licensed professional can perform a discharge readiness assessment on their own based on relevant factors such as patient vital signs and / or alertness / sedation.

[0424] It is recommended that the patient does not resume breastfeeding after discharge and within 6 hours (whichever is later) after the last dose; preferably after discharge or within 3 hours (whichever is later) after the last dose; more preferably after discharge or within 2 hours (whichever is later) after the last dose; in particular after discharge or within 1 hour (whichever is later) after the last dose.

[0425] 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.

[0426] 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.

[0427] 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.

[0428] 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.

[0429] 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.

[0430] 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.

[0431] The following provides different preferred thresholds for 5-MeO-DMT and / or 5-MIAA in expressed breast milk:

[0432]

[0433] Delivered infant dose (DID) of 5-MeO-DMT and / or 5-MIAA

[0434] 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.

[0435] The relevant DID of 5-MeO-DMT and / or 5-MIAA according to the present invention is as follows:

[0436]

[0437] 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.

[0438] Relative infant dose (RID) of 5-MeO-DMT and / or 5-MIAA

[0439] 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.

[0440] The relevant RID of 5-MeO-DMT and / or 5-MIAA according to the present invention is as follows:

[0441]

[0442] 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.

[0443] Combination of delivered infant dose (DID) and relative infant dose (RID) of 5-MeO-DMT and / or 5-MIAA

[0444] 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.

[0445] 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.

[0446] 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.

[0447] 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.

[0448] 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.

[0449] 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.

[0450] Mode of administration

[0451] The therapeutically effective amount of 5-MeO-DMT is administered by inhalation, by nasal administration, by buccal administration, or by sublingual administration. Administration via these routes can ensure rapid onset of action. The most preferred route of administration is by inhalation. Preferably, the therapeutically effective amount of 5-MeO-DMT is inhaled in a single breath.

[0452] For nasal administration, 5-MeO-DMT can be used as the pure substance or in the form of a nasal administration formulation, examples of which are known in the art. For nasal administration, 5-MeO-DMT can be used as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation of a pharmaceutically acceptable salt, preferably the hydrobromide salt. Examples of suitable devices are known in the art.

[0453] Buccal administration or sublingual administration can also rely on a pharmaceutically acceptable salt of 5-MeO-DMT, preferably the hydrobromide salt, as such or in the form of a formulation, such as tablets, films, sprays, creams, as is well known in the art.

[0454] Administration is in particular by inhalation of an aerosol. Such an aerosol comprises (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, in particular about 2 mg / l to about 9 mg / l. The pharmaceutically acceptable gas is preferably air.

[0455] The aerosol particles preferably contain less than 1 wt.% of impurities, in particular less than 0.5 wt.% of impurities. Furthermore, they preferably contain less than 0.5 wt.% of 5-MeO-DMT degradation products, in particular less than 0.2 wt.% of 5-MeO-DMT degradation products, said degradation products being due to chemical modifications of 5-MeO-DMT resulting from chemical reactions during aerosol formation.

[0456] In a further preferred aspect, the aerosol consists essentially of (a) air; (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0457] The aerosol particles preferably contain 5-MeO-DMT in free base form.

[0458] The aerosol preferably features a mass median aerodynamic diameter of less than 3 pm and more than 0.1 pm, in particular a mass median aerodynamic diameter of less than 2 pm and more than 0.1 pm.

[0459] The aerosol can be formed by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof disposed on a solid support to thermal energy, and b) passing air through the thin layer of 5-MeO-DMT to produce aerosol particles. The thin layer can have a thickness of less than about 10 μιη, in particular less than about 7.5 μιη. The thin layer can have a thickness in the range of about 0.1 μιη to about 10 μιη, in particular in the range of about 0.3 μιη to about 7.5 μιη.

[0460] The thin layer of 5-MeO-DMT disposed on a solid support can be exposed to thermal energy via air passing through the thin layer. Alternatively, the thin layer of 5-MeO-DMT disposed on a solid support can be exposed to thermal energy via the solid support.

[0461] The air passing through the thin layer can have a temperature in the range of about 180 °C to about 260 °C. The air passing through the thin layer can in particular have a temperature of about 210 °C, and pass through the thin layer at a rate of about 12 1 / min for about 15 seconds.

[0462] The aerosol particles can be contained in a volume equal to or less than about 3 liters, in particular in a volume of about 1 to about 3 liters, such as about 2 to about 3 liters. Delivery to a patient is preferably via a single inhalation.

[0463] 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical setting. 5-MeO-DMT and pharmaceutically acceptable salts thereof are provided in the form of aerosols. These aerosols have a suitable aerosol particle mass density such that a therapeutically effective dose of the aerosol can be administered to a patient via a single inhalation.

[0464] Aerosols useful in the present application can be formed using thermal energy. When thermal energy is used to form an aerosol of a compound, it is difficult to predict which conditions are suitable for safe, efficient, and predictable aerosolization, particularly where the aerosol is to be used to deliver the compound systemically to a patient via the lungs. Relevant variables in this context include a) the dose of the compound, b) the morphological state of the compound (e.g., crystalline form or thin layer form) that can be used for aerosolization, c) the amount of thermal energy to which the compound is exposed (defined by temperature and duration of exposure), and d) the volume of air introduced to form the aerosol (defined by flow rate and duration of air flow).

[0465] The compositions and methods described herein are for the safe, efficient, and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient by inhalation. By "safe" it is meant that the aerosol particles should contain only a very small amount of impurities and 5-MeO-DMT degradation products, by "efficient" it is meant that the dose is aerosolized to a specified degree, preferably almost completely aerosolized or completely aerosolized, i.e. the aerosol has the desired physical properties so that 5-MeO-DMT or a pharmaceutically acceptable salt thereof is delivered systemically via the lungs primarily via absorption in the alveoli, and the patient can inhale the aerosol in a single inhalation, i.e. within one deep breath, and by "predictable" it is meant that the amount of degradation products, the degree of aerosolization, and the physical properties of the aerosol vary little or not at all.

[0466] A suitable aerosol can be achieved by a) providing a therapeutically effective amount of 5-MeO-DMT in the form of a thin layer on a solid support, b) exposing the 5-MeO-DMT thin layer to elevated controlled temperature for a short time, and c) providing a controlled amount of air so that an aerosol is formed.

[0467] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can comprise an aerosol, wherein the aerosol is formed by a) exposing a 5-MeO-DMT thin layer configured on a solid support to thermal energy, and b) passing air through the 5-MeO-DMT thin layer; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% by weight of impurities and less than 0.5% of 5-MeO-DMT degradation products, 3) it can be delivered to a patient via a single inhalation.

[0468] By defining the following a) the dose of 5-MeO-DMT contained in the 5-MeO-DMT thin layer, b) the thickness of the 5-MeO-DMT thin layer, c) the thermal energy to which the 5-MeO-DMT thin layer is exposed (defined by temperature and duration of exposure), and d) the total amount of air passed through the 5-MeO-DMT thin layer (defined by air flow rate and duration of air flow), an aerosol can be generated that is characterized by a mass median aerodynamic diameter of less than 3 microns, less than 1% by weight of impurities, and less than 0.5% by weight of 5-MeO-DMT drug degradation products, and the aerosol volume can be delivered to a patient via a single inhalation.

[0469] Preferably, the 5-MeO-DMT thin layer is exposed to thermal energy via air passing through the thin layer, in which case the air is heated. The heated air passing through the thin layer can have a temperature in the range of about 180 °C to about 260 °C. The air passing through the thin layer can in particular have a temperature of about 210 °C.

[0470] Alternatively, the 5-MeO-DMT thin layer is exposed to thermal energy via a solid support, in which case the air passing through the thin layer is not heated, but the solid support is heated. The heated solid support can have a temperature in the range of about 180 °C to about 420 °C.

[0471] Preferably, the 5-MeO-DMT used to form the thin layer on the solid support is of high purity, at least 99%, preferably at least 99.5%.

[0472] Preferably, the dose of 5-MeO-DMT contained in the 5-MeO-DMT thin layer disposed on the solid support is about 1 mg to about 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg. Specific amounts that are useful are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. Preferred specific amounts are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0473] The solid support on which the 5-MeO-DMT or pharmaceutically acceptable salt thereof is provided can have a variety of shapes. Examples of such shapes include, but are not limited to, cylinders less than 1.0 mm in diameter, boxes less than 1.0 mm in thickness, and virtually any shape that is full of small holes (e.g., less than 1.0 mm in size). Preferably, the solid support provides a large surface area to volume ratio (e.g., greater than 100 / m) and a large surface area to mass ratio (e.g., greater than 1 cm 2 / gram).

[0474] A solid support of one shape can also be transformed into another shape with different properties. For example, a flat sheet of 0.25 mm thickness has a surface area to volume ratio of about 8,000 / m. Rolling the sheet into a hollow cylinder of 1 cm diameter results in a support that retains the high surface area to mass ratio of the original sheet, but has a lower surface area to volume ratio (about 400 / m).

[0475] A variety of different materials are used to construct the solid support. Categories of such materials include, but are not limited to, metals, inorganic materials, carbonaceous materials, and polymers. Examples of categories of materials are: aluminum, silver, gold, stainless steel, copper, and tungsten; silica, glass, silicon, and alumina; graphite, porous carbon, carbon yarn, and carbon felt; polytetrafluoroethylene, and polyethylene glycol. Combinations of materials and coated variants of materials can also be used.

[0476] When aluminum is used as the solid support, aluminum foil is a suitable material. Examples of silica, alumina, and silicon-based materials include amorphous silica S-5631 (Sigma, St. Louis, Mo.), BCR171 (an alumina with a defined surface area greater than 2 m 2 / g) and silicon wafers used in the semiconductor industry. Carbon wools and carbon felts are available from American Kynol, Inc., New York, N.Y.

[0477] Preferably, the thin layer of 5-MeO-DMT disposed on the solid support has a thickness of less than about 10 μm, particularly less than about 7.5 μm. The thin layer can have a thickness in the range of about 0.1 μm to about 10 μm, particularly 0.3 μm to 7.5 μm.

[0478] Preferably, the total amount of air passing through the thin layer of 5-MeO-DMT is defined as a flow rate of about 6 liters / minute to about 40 liters / minute, preferably about 8 liters / minute to about 16 liters / minute, and the duration of the air flow is selected so that the total volume of the aerosol does not exceed about 3 liters, preferably about 1 liter to 3 liters, such as 2 liters to 3 liters. For example, at an air flow rate of about 6 liters / minute, the air flow duration should be less than about 30 seconds. One useful particular air flow rate and duration is about 12 liters / minute and about 15 seconds, resulting in an aerosol volume of about 3 liters. Another useful particular air flow rate and duration is 10 liters / minute and about 15 seconds, resulting in an aerosol volume of about 2.5 liters. Another useful particular air flow rate and duration is 8 liters / minute and about 15 seconds, resulting in an aerosol volume of about 2 liters. Another useful particular air flow rate and duration is 10 liters / minute and about 12 seconds, resulting in an aerosol volume of about 2 liters.

[0479] The aerosol forms at a rate greater than 0.1 mg / second.

[0480] The aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, such as about 0.5 mg / l to about 12.5 mg / l, preferably about 1.3 mg / l to about 10 mg / l, particularly about 2 mg / l to about 9 mg / l.

[0481] The 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 microns and greater than 0.1 microns, preferably less than 2.5 microns and greater than 0.1 microns, most preferably less than 2 microns and greater than 0.1 microns. The 5-MeO-DMT aerosol particles are characterized by less than 1 wt% impurities, preferably less than 0.5 wt% impurities.

[0482] 5-MeO-DMT aerosol particles are characterized by less than 0.5 wt% 5-MeO-DMT degradation products, preferably less than 0.2 wt% 5-MeO-DMT degradation products.

[0483] A composition for delivering a therapeutically effective amount of 5-MeO-DMT can comprise an aerosol, wherein the aerosol is formed by a) exposing a 12 mg dose of 5-MeO-DMT configured as a thin layer of less than 5 microns in thickness on a solid support to a temperature of 210 °C for 15 seconds via passing heated air through the thin layer; wherein the aerosol has one or more of the following characteristics: 1) it contains aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, 2) it contains aerosol particles characterized by less than 1% impurities and less than 0.5 wt% 5-MeO-DMT degradation products, 3) it can be delivered to a patient via a single inhalation.

[0484] A person skilled in the art, who is aware of the aerosol properties and aerosolization conditions defined in the present invention, can determine a suitable vaporization device or system, which leads to the desired aerosol properties. Examples of such suitable vaporization devices or systems include, for example, the Volcano Medic vaporization system with associated dosing capsules (Storz & Bickel, Germany; disclosed, for example, in EP 0 933 093 B1 and EP 1 884 254 B1 and registered Community Design 003387299-0001) and the Staccato device (Alexza Pharmaceuticals, Mountain View, USA; disclosed, for example, in US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2). The generated aerosol can be collected in a balloon and inhaled by the patient from the balloon.

[0485] Dosing regimen

[0486] The present invention also provides dosage ranges, specific dosages, and dosing regimens (administration regimens).

[0487] The present invention is based in part on the inventors’ conclusion that a peak psychedelic experience occurs during the acute phase after administration of 5-MeO-DMT, which drives the therapeutic benefit of 5-MeO-DMT for patients suffering from PPD, in particular one or more aspects defined above, either causally or at least as a surrogate behavioral marker for the underlying, unknown therapeutic mechanism.

[0488] Thus, achieving peak experience more rapidly in a greater proportion of patients and with better reproducibility in individual patients compared to previously tested psychedelic agents and dosing regimens will result in a better therapeutic profile.

[0489] 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 could 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 “blanching”). 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 appear 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 improve the patient’s acceptance of the therapeutic approach and improve overall adherence at the patient population level.

[0490] Frequent re-administration of the serotonin psychedelic to increase the frequency of peak experiences and modulate the reproducibility of peak experiences, and to improve the therapeutic effect, reduce side effects, improve adherence, which can not be achieved with other psychedelic agents, as the psychedelic effect takes longer to take effect and lasts longer, and rapid tolerance develops (i.e. a reduction or disappearance of the psychedelic effect upon re-administration), which can last for several days.

[0491] Treatment of a patient diagnosed with postpartum depression as defined herein (including treatment-resistant forms of this disorder, and including this disorder associated with suicidal ideation) by administration of 5-MeO-DMT. In a preferred embodiment, 5-MeO-DMT is administered as a monotherapy, i.e. the patient does not receive any treatment for PPD or symptoms associated with PPD.

[0492] 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, is in the range of about 1 mg to about 25 mg, or any amount within range thereof, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg, and most preferably about 4 mg to about 12 mg. Particular amounts useful are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg. The patient can also receive treatment with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt. Note that in this specification, when a range is listed (such as “about 1 mg to about 25 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.

[0493] 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 comprises the occurrence of a clinical response no later than about 2 hours after administration of 5-MeO-DMT.

[0494] 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 comprises a sustained clinical response, including a clinical response occurring 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.

[0495] 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 comprises the administration of more than a single dose of 5-MeO-DMT.

[0496] In preferred embodiments, the more than a single dose of 5-MeO-DMT is administered to the patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, the interval between each administration within each treatment block is no less than about 1 hour and no more than about 24 hours, and the interval between the end of one treatment block and the start of the next treatment block is no less than about 6 days.

[0497] 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.

[0498] 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.

[0499] 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 25 mg, preferably about 2 mg to about 20 mg, more preferably about 4 mg to about 20 mg, and most preferably about 4 mg to about 12 mg. Particular amounts that are useful are, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, and about 20 mg.

[0500] 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 2 mg to about 8 mg, and then increases with each subsequent administration within each treatment block until either 20 mg is reached, or all of the administrations within the treatment block have been administered.

[0501] 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 2 mg to about 8 mg, and then increases with each subsequent administration within each treatment block until either 20 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.

[0502] For embodiments in which the dose is increased for subsequent administrations, the dose for the next administration is determined by adding about 2 mg to about 10 mg, preferably about 4 mg to about 8 mg, most preferably about 6 mg to the dose of the previous administration. For example, if the dose for the first administration is 6 mg and the dose is increased by 6 mg, then the dose for the second administration is 12 mg, unless one of the aforementioned stopping criteria has been reached. Preferably, the dose for the third administration is 18 mg.

[0503] In preferred embodiments, the dose of 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg at the first administration, then increased to a dose selected from about 8 mg to about 14 mg at the second administration, and to a dose selected from about 14 mg to about 20 mg at the third administration, unless the patient has experienced a peak psychedelic experience within that treatment block or the attending physician decides that further dose increases are not advisable based on observed side effects. Useful specific amounts for the first, second, and third administrations are, for example, about 6 mg, about 12 mg, and about 18 mg.

[0504] In further 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 2 mg to about 8 mg, then increased with each subsequent administration within that first treatment block until the earlier of 20 mg is reached, or all administrations within that 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, wherein the highest dose in the first treatment block will be used as the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dose in the first treatment block is 18 mg because the patient experienced a peak psychedelic experience at that dose, then the dose for all subsequent treatment blocks and administrations within those subsequent treatment blocks is 18 mg.

[0505] In the most 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 8 mg, then unless the patient has experienced a peak psychedelic experience within that 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 8 mg to about 14 mg, and the third administration of the first treatment block will be increased to a dose selected from about 14 mg to about 20 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 6 mg, about 12 mg and about 18 mg.

[0506] It is understood that pharmaceutically acceptable salts of 5-MeO-DMT can also be used for all of the above dosing regimens and that, given the use of equimolar amounts, the appropriate weight of the salt to be administered can be calculated from the prescribed weight of the free base.

[0507] According to the present application, 5-MeO-DMT is preferably not administered together with a MAO inhibitor.

[0508] Whether a patient has experienced a “peak psychedelic experience” can be identified by reaching at least 60% of the highest possible score in each of the four subscales of the revised Mystical Experience Questionnaire (MEQ-30) of 30 items (mystical, positive emotions, transcendence of time and space, and unspeakability) (as described in Barrett FS, J Psychopharmacol. 2015; 29(11): 1182-90).

[0509] Whether a patient has experienced a “peak psychedelic experience” can also be determined by reaching at least 60% of the highest possible score in 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).

[0510] According to the present application, whether a patient has experienced a “peak psychedelic experience” is preferably identified by reaching 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)?

[0511] Further aspects of the present application

[0512] 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).

[0513] 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 higher or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or higher.

[0514] 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 higher or a HAM-D score of 22 or higher.

[0515] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 2, wherein the patient has a MADRS score of 35 or higher or a HAM-D score of 27 or higher.

[0516] 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.

[0517] 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.

[0518] 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 or severely impaired maternal functioning.

[0519] 8. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 7, wherein the patient has a Barkin Index of Maternal Functioning (BIMF) score of 95 or lower, such as 80 or lower, in particular 65 or lower.

[0520] 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 dosage regimen that causes the patient to experience a peak psychedelic experience.

[0521] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 9, wherein a dose of about 4 mg to about 20 mg 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0522] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 9, wherein a dose of about 6 mg; or about 12 mg; or about 18 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0523] 12. 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.

[0524] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 12, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 8 mg at a first administration, then increased to a dose of about 8 mg to about 14 mg at a second administration unless the patient has already experienced a peak psychedelic experience, then increased to a dose of about 14 mg to about 20 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.

[0525] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 13, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0526] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 12 to 14, wherein the interval between two administrations is no less than 1 hour and no more than 24 hours, such as about 1 to 4 hours, preferably about 1 to 2 hours.

[0527] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 9 to 15, 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 Ineffability), or by achieving at least 60% of the highest 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.

[0528] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 16, wherein the occurrence of a peak psychedelic experience is identified by achieving a peak experience scale (PES) total score of at least 75.

[0529] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 17, wherein the 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered via inhalation, or by nasal, buccal or sublingual administration.

[0530] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 18, wherein 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, such as to about 12.5 mg / l.

[0531] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 19, wherein the aerosol is generated by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof configured on a solid support to thermal energy, and b) passing air through the thin layer to produce aerosol particles.

[0532] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 18 to 20, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled by a single breath.

[0533] 22. 5-MeO-DMT for use according to aspects 18 to 21, wherein the 5-MeO-DMT is used in the form of the free base.

[0534] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 22, wherein a 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.

[0535] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 23, wherein the clinical response occurs at day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, reflected as a decrease in Clinical Global Impression-Severity (CGI-S) score.

[0536] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 24, wherein the clinical response persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, reflected as a decrease in Clinical Global Impression-Severity (CGI-S) score.

[0537] 26. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 25, wherein the clinical response persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, reflected as a decrease in Clinical Global Impression-Severity (CGI-S) score.

[0538] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 26, wherein the clinical response persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, reflected as a decrease in Clinical Global Impression-Severity (CGI-S) score.

[0539] 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, assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0540] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 28, 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, assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0541] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 29, wherein the 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, assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7.

[0542] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 30, wherein remission of depressive symptoms occurs at day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as a MADRS score of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0543] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 31, wherein the clinical response lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0544] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 32, wherein there is a clinical response at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0545] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 33, wherein the patient is in remission of depressive symptoms at day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as a MADRS score of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0546] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 34, wherein the clinical response lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0547] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspects 1 to 35, wherein there is a clinical response at day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0548] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any of aspects 1 to 36, 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, assessed as a MADRS score of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0549] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any of aspects 1 to 37, wherein the clinical response persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0550] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any of aspects 1 to 38, wherein there is a clinical response at day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score before treatment.

[0551] 40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any of aspects 1 to 39, 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, assessed as a MADRS score of equal to or less than 10 or a HAM-D score of equal to or less than 7.

[0552] 41. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any of aspects 1 to 40, 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.

[0553] 42. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any of aspects 1 to 40, 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.

[0554] 43. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any of aspects 1 to 40, 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.

[0555] 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 40, wherein the patient is a breastfeeding mother who has been advised to stop breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0556] 45. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of aspects 1 to 40, wherein the patient is a breastfeeding mother who has been advised to stop breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0557] 46. ​​5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in aspects 1 to 45, wherein the treatment improves maternal function.

[0558] 47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 46, wherein the improvement relates to one or more, in particular two or more, areas of functioning selected from self-care, infant care, mother-child interaction, maternal mental health, social support, management and regulation according to the Barkin Index of Maternal Functioning (BIMF).

[0559] 48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to aspect 46 or 47, wherein the BIMF score is improved by 10% or more, preferably by 20% or more. Summary of the Invention

[0560] 1. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating patients suffering from postpartum depression (PPD).

[0561] 2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in 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.

[0562] 3. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in item 2, wherein the patient has a MADRS score of 28 or higher or a HAM-D score of 22 or higher.

[0563] 4. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in item 2, wherein the patient has a MADRS score of 35 or higher or a HAM-D score of 27 or higher.

[0564] 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.

[0565] 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.

[0566] 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.

[0567] 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.

[0568] 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 in a dose or dosage regimen that causes the patient to experience a peak psychedelic experience.

[0569] 10. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 9, wherein a dose of about 4 mg to about 20 mg 5-MeO-DMT is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0570] 11. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 9, wherein a dose of about 6 mg; or about 12 mg; or about 18 mg is administered, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0571] 12. 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 in 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.

[0572] 13. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 12, wherein the first administration of the 5-MeO-DMT is at a dose of about 2 mg to about 8 mg, then unless the patient has already experienced a peak psychedelic experience, the second administration is increased to a dose of about 8 mg to about 14 mg, then unless the patient has already experienced a peak psychedelic experience, the third administration is increased to a dose of about 14 mg to about 20 mg, or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0573] 14. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 13, wherein the first dose of 5-MeO-DMT is about 6 mg, the second dose of 5-MeO-DMT is about 12 mg, and the third dose of 5-MeO-DMT is about 18 mg; or wherein an equimolar amount of the pharmaceutically acceptable salt is administered in place of 5-MeO-DMT.

[0574] 15. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 12 to 14, 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.

[0575] 16. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 9 to 15, 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 Noetic), 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.

[0576] 17. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 16, wherein the occurrence of a peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

[0577] 18. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 17, wherein the 5-MeO-DMT or pharmaceutically acceptable salt thereof is administered via inhalation, or is administered by nasal, buccal, or sublingual administration.

[0578] 19. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 18, wherein 5-MeO-DMT or a pharmaceutically acceptable salt thereof is administered in the form of an aerosol comprising (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof, wherein the aerosol has an aerosol particle mass density of about 0.5 mg / l to about 18 mg / l, such as to about 12.5 mg / l.

[0579] 20. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 19, wherein the aerosol is generated by a) exposing a thin layer of 5-MeO-DMT or a pharmaceutically acceptable salt thereof configured on a solid support to thermal energy, and b) passing air through the thin layer to produce aerosol particles.

[0580] 21. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 18 to 20, wherein the dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to be administered to the patient is inhaled in a single breath.

[0581] 22. 5-MeO-DMT for use according to items 18 to 21, wherein the 5-MeO-DMT is used in the form of the free base.

[0582] 23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 22, wherein a 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.

[0583] 24. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 23, wherein a 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.

[0584] 25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 24, wherein a 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.

[0585] 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 reduction in Clinical Global Impression- Severity (CGI-S) score, lasts until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0586] 27. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 26, wherein the clinical response, reflected as a reduction in Clinical Global Impression- Severity (CGI-S) score, lasts until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0587] 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 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.

[0588] 29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 28, 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.

[0589] 30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 29, wherein remission of depressive symptoms, assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7, occurs no later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0590] 31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 30, wherein remission of depressive symptoms, assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7, occurs on day 1, e.g. about 24 hours, after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0591] 32. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 31, wherein the clinical response, assessed as at least 50% improvement in MADRS or HAM-D score compared to the respective score before treatment, lasts until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0592] 33. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 32, wherein a clinical response is present 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, as assessed by an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

[0593] 34. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 33, wherein the patient is in remission of depressive symptoms 7 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0594] 35. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 34, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0595] 36. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 35, wherein there is a clinical response on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, the clinical response being assessed as an improvement of at least 75% in the MADRS or HAM-D score compared to the corresponding score before treatment.

[0596] 37. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 36, wherein the patient is in remission of depressive symptoms on the 14th day after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, and the remission of depressive symptoms is assessed as a MADRS score equal to or less than 10 or a HAM-D score equal to or less than 7.

[0597] 38. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as described in items 1 to 37, wherein the clinical response, assessed as an improvement of at least 50% in the MADRS or HAM-D score compared to the corresponding score before treatment, persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.

[0598] 39. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 38, 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 assessed as at least 75% improvement in MADRS or HAM-D score compared to the respective score prior to treatment.

[0599] 40. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 39, 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 assessed as MADRS score equal to or less than 10 or HAM-D score equal to or less than 7.

[0600] 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 40, 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.

[0601] 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 40, 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.

[0602] 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 40, 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.

[0603] 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 40, 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.

[0604] 45. 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use according to any one of items 1 to 40, 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.

[0605] 46. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to items 1 to 45, wherein the treatment improves maternal functioning.

[0606] 47. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 46, 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 psychological well-being, social support, management and regulation.

[0607] 48. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to item 46 or 47, wherein the BIMF score is improved by 10% or more, preferably 20% or more.

[0608] Examples

[0609] The following examples are set forth to assist in understanding the application and are not intended, and should not be interpreted, to present any definition in terms of the application scope. Numeric ranges recited within the specification are inclusive of the numbers defining the

[0610] Example 1 - 5-MeO-DMT aerosol generation and administration

[0611] 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, with a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.

[0612] Step 2: Transfer 200 μΐ of solution into a dosing capsule (Storz & Bickel, Germany) containing a water dropper pad, then cap the dosing capsule.

[0613] Step 3: The dosing capsule containing the 5-MeO-DMT ethanol solution is transferred to the filling chamber of the first Volcano Medic vaporizer, which has been preheated with a temperature setting of 55 °C. Then, the air flow of the vaporizer is turned on for a preset 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 is 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 the empty capsule.

[0614] Step 4: The prepared dosing capsule is removed from the filling chamber. It is then transferred to the filling chamber of the second Volcano Medic vaporizer, which has been preheated with a temperature setting of 210 °C, and the air flow is turned on for at least 5 minutes and then turned off immediately before the transfer. A valve-equipped inhalation balloon (Storz & Bickel, Germany) is mounted on the socket of the filling chamber, the filling chamber is tightly closed, and then the air flow is turned on immediately at a preset rate of about 12 1 / min for 15 seconds and then turned 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 is confirmed by demonstrating that the weight of the capsule has returned to approximately its initial weight.

[0615] Step 5: The balloon is then disconnected from the filling chamber, which automatically closes the valve. After connecting a mouthpiece to the balloon, the aerosol is ready to be administered immediately to the volunteer or patient.

[0616] Step 6: To prepare for administration, the patient is asked to perform 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 inhalation balloon is inhaled in one breath, breath is held for 10 (± 2.5) seconds, and then exhaled normally. After completing the inhalation procedure, the patient is instructed to lie down.

[0617] Further details on the administration of 5-MeO-DMT by inhalation are disclosed in Example 1 of WO 2020 / 169850 A1, the content of which is incorporated herein by reference.

[0618] Example 2 - Preparation of high purity 5-MeO-DMT

[0619] Dissolve 5-MeO-DMT (2.0 g) in MTBE (4 mL, 2.0 volumes) at 35 to 40 °C, then cool 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 isolated solid was analyzed for purity by HPLC as described in WO 2020 / 169850 Al. The purity was 99.74% area.

[0620] 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.

[0621] Example 3 - Preparation of 5-MeO-DMT hydrobromide

[0622] Prepare 5-MeO-DMT HBr on a 100 mg scale.

[0623] Combine 5-MeO-DMT free base with isopropyl acetate (10 volumes) and heat the resulting 5-MeO-DMT solution to 50 °C. Charge HBr (1 M in ethanol, 1 equivalent) in one single aliquot. Keep the mixture at this temperature and equilibrate for 3 hours.

[0624] After 1 hour, a suspension is formed. Finally, cool the suspension to room temperature and equilibrate for 18 hours. Isolate the solid by filtration and dry at 40 °C under vacuum for 18 hours.

[0625] Obtain an off-white crystalline material.

[0626] 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.

[0627] Example 4 - Determination of inhibition constants for central 5-HTiA and 5-HT2A receptors in post-mortem human brain membrane preparations

[0628] In the present 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.

[0629] Human brain samples were obtained from the Edinburgh sudden death brain bank. All donors were sudden deaths, had no history of coma, psychiatric or neurological illness, were below 65 years of age and had a post-mortem interval of less than or equal to 72 hours.

[0630] Binding to 5-HT1A receptors in post-mortem human hippocampus

[0631] The hippocampus was homogenised in ice-cold 0.25 M sucrose (1 :30 weight / volume) using a motorised Teflon pestle (12 strokes at 120 rpm). Myelin and cellular debris were removed by centrifugation at 1,000 g for 10 minutes. The supernatant was stored on ice and the pellet re-homogenised in 0.25 M sucrose (1 :15 weight / volume) and centrifuged at 750 g for 10 minutes. The supernatants were combined and diluted with ice-cold membrane preparation buffer (1 :100 weight / volume), using a tight-fitting glass / Teflon homogeniser (12 strokes at 800 rpm) and centrifuged at 20,500 g for 10 minutes. The pellet was re-suspended in ice-cold membrane preparation buffer and incubated at 37 °C for 10 minutes, then centrifuged at 20,500 g for 10 minutes. The pellet was re-suspended and centrifuged a final time to wash the tissue (20,500 x g, 10 minutes). The resulting pellet was then re-suspended in ice-cold assay buffer, with a tissue concentration equivalent to 3.125 mg wet tissue weight / ml. All centrifugations were performed at 4 °C. The membrane preparation buffer consisted of 50 mM Tris-HCl, pH 7.7, 4 mM CaCI2and 0.1 % ascorbic acid. The assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCI2, 0.1 % ascorbic acid and 10 μΜ Pargyline.

[0632] For saturation binding analysis, hippocampal membranes (400 μΐ; equivalent to 1.25 mg wet weight tissue / tube) were incubated with 50 μΐ 0.075 - 9.6 nM [ 3 H]8-OH-DPAT and 50 μΐ assay buffer (total binding) or 50 μΐ of 1 μΜ WAY100635 (non-specific binding) for 30 minutes at 25 °C. The wash buffer consisted of 50 mM Tris, pH 7.7.

[0633] In displacement assays, hippocampal membranes (400 μΐ; equivalent to 1.25 mg wet weight tissue / tube) were incubated with 50 μΐ 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 min.

[0634] Membrane-bound radioactivity was recovered by vacuum filtration through Skatron 11731 filters pre-soaked in 0.5% polyethyleneimine (PEI) using a Skatron cell harvester. The filters were quickly washed with ice-cold wash buffer (wash settings 0,9,9) and radioactivity was determined by liquid scintillation counting (1 ml Packard MV Gold scintillation counter).

[0635] Nonlinear regression was used to calculate the compound concentration required to inhibit specific binding by 50% (IC 50 ) and the Hill slope. K was calculated using a single-site binding model that allowed for ligand depletion. i .

[0636] Binding to 5-HT2A receptors in postmortem human frontal cortex

[0637] The frontal cortex was homogenized in ice-cold 0.25 M sucrose (1:30 weight / volume) using an electric Teflon pestle (grinding 12 times at 120 rpm). Myelin and cell debris were removed by centrifugation at 1,000 g for 10 minutes. The supernatant was stored on ice, and the pellet was homogenized again in 0.25 M sucrose (1:15 weight / volume) and centrifuged at 750 g for 10 minutes. The supernatants were combined and diluted with ice-cold 50 mM Tris-HCl assay buffer, pH 7.4 (1:100 weight / volume), homogenized using a tightly fitting glass / Teflon homogenizer (12 times at 800 rpm), and centrifuged at 20,500 g for 10 minutes. The pellet was further centrifuged twice to wash the tissue (20,500 x g, 10 minutes). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCl assay buffer, pH 7.4, at a tissue concentration equal to 10 mg tissue wet weight / ml. All centrifugations were performed at 4°C.

[0638] For saturation binding assays, frontal cortex membranes (400 μl; equivalent to 4 mg tissue wet weight / tube) were mixed with 50 μl of 0.00625 - 0.8 nM [ 3H]MDL-100,907 and 50 μl assay buffer or 50 μl of 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.

[0639] In the displacement assay, 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 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 of test compound ranging between 1 and 10000 nM for 60 min at 25°C.

[0640] Membrane-bound radioactivity was recovered and determined as described above. Data analysis was also performed as described above.

[0641] Results

[0642] The dissociation constants (K 3 values) of [3H]8-OH-DPAT for 5-HT1A receptors in hippocampal membranes from the post-mortem human brain tissue of 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.

[0643] 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 the presence of a one-site binding model.

[0644] The dissociation constants (K 3 values) of [3H]MDL-100,907 for 5-HT2A receptors in frontal cortex membranes from the post-mortem human brain tissue of 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.

[0645] 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 the presence of a one-site binding model.

[0646] The selectivity ratios of depophospho-psilocin, DMT, and 5-MeO-DMT for 5-HT2A relative to 5-HT1A receptors were 0.78, 3.1, and 68, respectively.

[0647] Example 5 - Clinical trial in patients with TRD

[0648] A phase 1 / 2 clinical trial of 5-MeO-DMT via inhalation administration as described herein in the treatment of patients with treatment-resistant major depressive disorder (TRD) has been completed. 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 step-up of 5-MeO-DMT doses 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 patients with TRD. The primary endpoint for Part B was to assess the effect on the severity of depression as assessed by the proportion of patients in remission, defined as a MADRS total score of less than or equal to 10, at day 7 post-dose.

[0649] 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.

[0650] 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.

[0651] In Part B, 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.

[0652] 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%).

[0653] No clinically significant changes were observed in any of the safety laboratory analyses, vital signs, psychiatric safety assessments, or measures of cognitive function in Part A or Part B.

[0654] Results are summarized in the tables below.

[0655]

[0656] Table 2-A. Scores recorded for relevant MADRS and BPRS items for patients assigned to the within-day individualized dosing regimen (IDR). Item scores represent the sum of individual patient scores for all patients (n=8) in the IDR group. Assessments 2 hours (MADRS) or 3 hours (BPRS) after the last dose was administered.

[0657]

[0658] Table 2-B. Scores recorded for relevant MADRS and BPRS items for patients assigned to the within-day individualized dosing regimen (IDR). Item scores represent the sum of individual patient scores for all patients (n=8) in the IDR group. Assessments on Day 1.

[0659]

[0660] Table 2-C. Scores recorded for relevant MADRS and BPRS items for patients assigned to the within-day individualized dosing regimen (IDR). Item scores represent the sum of individual patient scores for all patients (n=8) in the IDR group. Assessments on Day 7.

[0661]

[0662] Table 3-A. Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessments 2 hours (MADRS) or 3 hours (BPRS) after the dose was administered.

[0663]

[0664] Table 3-B. Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients (n=4) in the 12 mg group. Assessments on Day 1.

[0665]

[0666] Table 3-C. Scores recorded for relevant MADRS and BPRS items for patients assigned to the 12 mg dosing regimen. Item scores represent the sum of individual patient scores for all patients in the 12 mg group (n=4). Assessments at day 7.

[0667] Example 6 - Pharmacokinetic evaluation of 5-MeO-DMT and Bufotenine

[0668] 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; 12 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, respectively.

[0669] 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.

[0670] 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.

[0671] The following table 4 shows the median percentage of plasma concentrations relative to Cmax determined at the indicated time points.

[0672]

[0673] Pharmacokinetic measurements were also performed for the dosing regimen dependent up-titration. Essentially similar results were obtained.

[0674] 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.

[0675] Essentially similar observations were also made when including subjects receiving the up-titration regimen.

[0676] Example 7 - Toxicology testing of 5-MeO-DMT

[0677] 5-MeO-DMT did not induce mutations in four histidine-requiring strains of Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and one tryptophan-requiring strain of Escherichia coli (WP2 uvrA pKM101). These conditions included treatment at concentrations up to 5000 μg / plate (the maximum concentration recommended according to current regulatory guidelines), in the absence and presence of rat liver metabolic activation system (S-9).

[0678] Example 8 - Binding of 5-MeO-DMT to human plasma proteins

[0679] In vitro binding of 5-MeO-DMT to plasma proteins was determined using high throughput 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:

[0680] Table 5 Percentage of 5-MeO-DMT free fraction in human plasma

[0681]

[0682] Example 9 - Human metabolism of 5-MeO-DMT

[0683] 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.

[0684] 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.

[0685] Incubations were performed in a shaking water bath at approximately 37°C (total incubation volume 0.5 mL). For 1 μM, incubations were terminated after 0, 5, 10, 20, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile (0.5 mL). For 10 μM, incubations were terminated after 0, 10, 30, 60, and 120 minutes by the addition of ice-cold acetonitrile containing an internal standard (1 μg / mL desphosphopsilin-d10).

[0686] The samples were vortexed and centrifuged at approximately 13,000 rpm for 10 minutes at room temperature. After centrifugation, the protein-free supernatant was removed for analysis.

[0687] Blank control incubations were performed using Leibovitz L-15 medium instead of the test substance. For cell-free control samples, Leibovitz L-15 medium was used instead of hepatocytes. Aliquots of the blank control sample were taken at 120 minutes, while for the 1 μM incubation, cell-free control samples were taken at 0, 30, and 120 minutes, and for the 10 μM incubation, cell-free control samples were taken at 0 and 120 minutes.

[0688] All 1 μM incubations were performed in duplicate, while all 10 μM incubations were performed in single incubation. All samples were stored at -80°C (nominal) until analysis.

[0689] Appropriate chromatographic conditions were developed to retain the parent compound and give an appropriate chromatographic response. Reverse-phase LC-MS analysis was used to analyze the 0, 30, and 120 minute incubation samples produced after incubation with 10 μM 5-MeO-DMT to generate high-energy and low-energy mass spectra (MSE). Prior to sample analysis, a 100 μL aliquot of each sample was evaporated to near dryness at room temperature under a steady stream of nitrogen and then reconstituted in 50 μL of mobile phase A (0.1% formic acid in water). Each sample (0, 30, and 120 minutes, 10 μM) was analyzed using accurate mass LC-MS to determine the relative levels of the parent compound at each time point and to determine the profile of the metabolites formed. Appropriate blank and control samples were also analyzed. The 10 μM incubation samples at 10 and 60 minutes were not analyzed and stored at -80°C (nominal).

[0690] The data were queried for the presence of metabolites by comparing retention times with test substance reference standards and based on the accurate masses of potential metabolites using screening software (UNIFI version 1.9.4) and user-defined search parameters. To confirm suspected metabolites, the measured accurate mass of the peak detected in the sample used for structural elucidation had to be within 5 ppm of the theoretical mass to confirm the molecular formula.

[0691] Table 1 above summarizes the results obtained.

[0692] Example 10 - Metabolic stability of 5-methoxyindole-3-acetic acid (5-MIAA) and 5-methoxytryptophol in a human hepatocyte co-culture model

[0693] 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 liver co-culture model from Visikol Inc.).

[0694] 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.

[0695] The following table shows the remaining LC / MS peak area of the test compounds relative to the respective 0 min incubation sample detected using the Hμrel co-culture assay after each incubation time point. The results (disappearance half-lives) of the assay control diazepam indicate that the enzyme activity is within normal levels.

[0696] 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).

[0697]

[0698] 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).

[0699]

[0700] 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.

[0701] For 5-methoxytryptophol, a high metabolic turnover rate was observed, with complete disappearance within 24 h in the presence of hepatocytes, while no disappearance was observed in the stromal cell control.

[0702] 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).

[0703] The predicted hepatic extraction ratio for 5-MIAA is 2% and for 5-methoxytryptophol is 67%.

[0704] Example 11 - Plasma binding of 5-MIAA

[0705] Binding to human plasma proteins was determined. The unbound fraction (fu) for triplicate experiments is reported, as well as the mean unbound fraction, standard deviation, and mean recovery % (Table 8).

[0706]

[0707] Example 12 - Clinical trial of 5-MeO-DMT administration to postpartum depression patients via inhalation

[0708] This single-arm, open-label clinical trial will involve 15 adult female patients who are clinically diagnosed with postpartum depression (PPD).

[0709] Patients will receive a single day individualized 5-MeO-DMT dosing regimen via vaporization followed by inhalation.

[0710] More specifically, patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.

[0711] 1. All patients will receive an initial dose of 6 mg 5-MeO-DMT.

[0712] 2. The second dose (12 mg) will only be administered if:

[0713] a. the peak experience was not achieved (total score > 75) after the 6 mg dose, and

[0714] b. the 6 mg dose was safe and well tolerated according to the investigator,

[0715] c. any psychoactive effects (PsE) from the previous dose have resolved, and

[0716] 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.

[0717] 3. Similarly, the third dose (18 mg) will only be administered if:

[0718] a. the peak experience was not achieved (total score > 75) after the 12 mg dose, and

[0719] b. the 12 mg dose was safe and well tolerated according to the investigator, and

[0720] c. Any PsE from a prior dose has resolved, and

[0721] 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.

[0722] Patients will receive assessments of 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.

[0723] All patients considered for participation in the clinical trial must meet the following criteria:

[0724] 1. Are female and between the ages of 18 and 45 years, inclusive, at the time of screening.

[0725] 2. Have a body mass index (BMI) at the time of screening that is in the range of 18.5 to 35 kg / m2, inclusive. 2

[0726] 3. Meet the trial criteria for PPD as assessed by a trial psychiatrist or licensed psychologist:

[0727] a. Are diagnosed with major depressive disorder without psychotic features by the Mini-International Neuropsychiatric Interview (MINI) and have a perinatal onset of no earlier than the pregnancy and no later than the first 4 weeks postpartum.

[0728] 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.

[0729] 6. Must be not breastfeeding at the time of screening; or if still breastfeeding or actively engaged in breastfeeding at the time of screening, must agree to temporarily discontinue 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 those 24 hours, but then must resume breastfeeding after the 2.5-hour post-dose and 24-hour post-dose breast milk expressions / discardings.

[0730] 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 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 on the day prior to testing (Day -1).

[0731] ​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.

[0732] Potential patients who meet any of the following key exclusion criteria will be excluded from the trial:

[0733] 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 investigator’s judgment, renders the patient unsuitable for participation in the trial, according to medical history, psychiatric evaluation, and MINI assessment.

[0734] 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.

[0735] 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.

[0736] 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).

[0737] 5. Took any other medication with monoamine oxidase inhibitor (MAOI) activity within 14 days or 5 half-lives, whichever is longer, prior to dosing.

[0738] 6. Previously had a serious adverse reaction to a hallucinogenic or psychedelic medication (e.g., psilocybin, Psilocybe cubensis mushrooms, 5-MeO-DMT, DMT, ayahuasca, LSD, mescaline), according to the investigator’s judgment.

[0739] 7. Known hypersensitivity or hypersensitivity to 5-MeO-DMT or any other contraindication.

[0740] 8. Has, in the investigator’s judgment, any current or past clinically significant illness that would render the patient inappropriate 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 nervous system disease, meningitis, encephalitis, and head injury with loss of consciousness) during pregnancy or postpartum.

[0741] 9. Is, in the investigator’s judgment, taking any medication or other substance that would render the patient inappropriate for participation in the trial.

[0742] 10. Has, in the investigator’s judgment, clinically significant abnormalities in physical examination, vital signs, ECG, or clinical laboratory parameters that would render the patient inappropriate for participation in the trial.

[0743] 11. The 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.

[0744] 12. The patient has a DSM-5 substance or alcohol use disorder within 6 months prior to screening.

[0745] 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 patients with PPD.

[0746] 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 patients with PPD.

[0747] 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 a single day administration of a single day individualized IDR (6 mg, 12 mg, and 18 mg 5-MeO-DMT) in adult female patients with PPD (metabolite identification screening can be performed as needed) measured by LC / MS / MS.

[0748] The primary endpoint of the study is to assess the antidepressant effect of 5-MeO-DMT by the change in MADRS from baseline assessed on Day 7.

[0749] Secondary endpoints include evaluation of the antidepressant effect of 5-MeO-DMT by:

[0750] • Evaluation of the antidepressant effect of 5-MeO-DMT by:

[0751] o Proportion of patients in remission (MADRS <10) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0752] o Change from baseline in MADRS assessed at 2 hours post-final study drug administration on Day 0 and Day 1;

[0753] o Proportion of responders (MADRS total score reduction >50% compared to baseline) at 2 hours post-final study drug administration on Day 0, Day 1, and Day 7;

[0754] 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;

[0755] • Effect on maternal behavior as assessed by change from baseline to Day 7 in Barkin Mothering Function Index (BIMF) total and subscale scores;

[0756] • Exposure of 5-MeO-DMT and bufotenin in breast milk obtained at 1 hour post-final study drug administration on Day -1, at discharge, on Day 0 evening, and on Day 1 and Day 7;

[0757] • Exposure of 5-MeO-DMT and bufotenin in blood obtained at 1 hour post-final study drug administration on Day -1, at discharge, and on Day 1 and Day 7;

[0758] • Evaluation of the safety and tolerability of 5-MeO-DMT by:

[0759] o Reporting of treatment-emergent adverse events (TEAEs);

[0760] o Clinically significant changes from baseline in ECGs, vital signs, safety laboratory assessments, peak flow respiratory assessments;

[0761] o Sedation assessments (modified Observer’s Assessment of Alertness / Sedation scale [MOAA / S]) after each dose administration (when PsE resolved and 60 minutes after each study drug administration) and as part of the discharge evaluation on Day 0;

[0762] o Change from baseline in the Clinical Global Impression of Change (CGIC) assessed as part of the Day 0, Day 1, and Day 7 discharge evaluations;

[0763] o Change from baseline in the Brief Psychiatric Rating Scale (BPRS) assessed as part of the Day 0, Day 1, and Day 7 discharge evaluations;

[0764] o Change from baseline in the C-SSRS assessed as part of the Day 0, Day 1, and Day 7 discharge evaluations;

[0765] o Change from baseline in the YMRS assessed as part of the Day 0, Day 1, and Day 7 discharge evaluations;

[0766] • Patient experienced PsE reported 30 to 60 minutes after each dose, at which time the PsE had resolved:

[0767] o PsE assessment of achievement of peak experience (PE) using the PE scale (PE scale total score > 75);

[0768] o Challenge experience questionnaire (CEQ);

[0769] o Mystical experience questionnaire (MEQ-30);

[0770] • PsE duration defined as the time from study drug dosing to the time at which the PsE had resolved (investigator and patient scores), completed 30 to 60 minutes after each dose.

[0771] First Patient

[0772] Currently, one patient diagnosed with postpartum depression by a psychiatrist has been enrolled in the clinical trial. Confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2) to have a major depressive disorder without psychotic features and a peripartum onset of 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.

[0773] Results - First Patient

[0774] There were no other notable changes in vital signs 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 ECG (3 hours post-administration) and safety laboratory analyses (7 days), assessment of 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.

[0775] Regarding the intensity of the psychedelic experience, the PES score recorded at exposure to the 6 mg nominal dose was 17.3. This score indicated that a subsequent higher dose of 12 mg was needed to continue the personalized 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.

[0776] Importantly, the patient reported a major 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).

[0777] Table 9 - MADRS / BPRS Score Table

[0778]

[0779] Particular attention is drawn to the significant improvement in several MADRS items. The individual items are summarized in Table 9. The patient’s baseline scores for some items reflect the absence of symptoms (decreased appetite, difficulty concentrating, suicidal thoughts), while there was a significant improvement in the scores for items reflecting severe symptoms (e.g., decreased sleep, inner tension).

[0780] Likewise, several BPRS items also improved, including somatic concerns, anxiety, emotional withdrawal, guilt feelings, and tension.

[0781] In addition, as summarized in Table 10, the improvement in BIMF scores recorded on Day 7 demonstrated an improvement in maternal functioning, with the total score improving from 92 to 105, an improvement of 14% (the total score can reach 120).

[0782] 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.

[0783] Here, significant improvements in self-care, mental health and management were achieved, ranging from 18% (management) to (44%) (self-care). These improvements reinforced the relationship between improvements in the depression program, as assessed by the MADRS and improvements in maternal functioning.

[0784] It is noteworthy that the patients’ scores were already relatively high before treatment. In some functional domains, the scores were at or close to the maximum (see Table 11), leaving limited room for improvement through therapy.

[0785] Table 10 - BIMF score table

[0786]

[0787] Table 11 - BIMF functional domain score table

[0788]

[0789] Summary and conclusions

[0790] A. The individualized dosing regimen, i.e. administering 6 mg 5-MeO-DMT followed by 12 mg 5-MeO-DMT via inhalation, was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

[0791] 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 take 4 to 6 weeks to show effects.

[0792] C. According to the IDR, patients achieved clinical remission within 2 hours after 5-MeO-DMT administration. This is superior to any approved treatment for postpartum depression and all previously tested psychedelics.

[0793] D. Despite 5-MeO-DMT being given only once and not effectively present in the body anymore within this time frame (see pharmacokinetic data in Example 6 above), the significant clinical response persisted over a 7-day follow-up period. This observation supports the superior clinical profile of 5-MeO-DMT and allows for a convenient dosing interval.

[0794] E. In addition to the antidepressant effects, endpoints assessing other symptoms (such as somatic problems, emotional withdrawal, anxiety, guilt, and tension) were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

[0795] F. In addition to the antidepressant effects, endpoints assessing maternal functioning (such as self-care, psychological well-being, and management) assessed using the BIMF were also positively affected, supporting the idea that 5-MeO-DMT may have additional benefits beyond improving core depressive symptoms in patients with PPD.

[0796] The second patient

[0797] A second patient, diagnosed with postpartum depression by a psychiatrist, was 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), with perinatal onset no earlier than during pregnancy and no later than the first four weeks postpartum. The patient attended all scheduled clinic visits (here, day 5, not day 7). The inhalation procedure was adequately performed and well tolerated by the patient, with no adverse events related to the inhalation.

[0798] Results - Second patient

[0799] Aside from a transient, clinically unrelated increase in heart rate shortly after 5-MeO-DMT administration, no other significant changes in vital parameters occurred. ECG (3 hours after administration) and safety laboratory analyses (3 hours and 7 days) and CADSS (3 hours, 1 day, and 7 days) were unremarkable. The few adverse events reported (vomiting on day 0, headache on day 5) were mild, transient, and resolved spontaneously by the end of the study.

[0800] Regarding the intensity of the psychedelic experience, a PES score of 1 was recorded for exposure to the nominal 6 mg dose. This score indicates that a subsequent, higher dose of 12 mg was necessary one hour after the first dose, as per the personalized dosing regimen. The PES score achieved with this dose was 94.7 and ≥75, indicating that the patient experienced a peak psychedelic experience and completed the IDR.

[0801] Importantly, patients reported significant improvements in their depressive symptoms, as assessed by MADRS at the earliest assessment time point (2 hours) after drug administration, and the effects were maintained over time (Table 12). Patients also met the criteria for MADRS response (at least 50% improvement relative to baseline) and MADRS remission (MADRS total score equal to or less than 10).

[0802] Table 12: MADRS / BPRS scoring table

[0803]

[0804] Notable improvements were seen in several MADRS items. Table 12 summarizes the items. While the patient’s score for suicidal thoughts at baseline reflects its lower severity relative to other symptoms, scores for all other items reflecting severe symptoms were significantly improved.

[0805] Similarly, several BPRS items were also improved, including anxiety, emotional withdrawal, disorganized thinking, guilt feelings, and tension.

[0806] In addition, as summarized in Table 13, the increase in BIMF scores recorded on Day 7 demonstrated an improvement in maternal functioning, with the total score increasing from 74 to 104, a 40% increase (total score can reach 120).

[0807] 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.

[0808] Here, with the exception of infant care (which had reached the maximum score at baseline), all domains achieved significant improvements, with the percent improvement ranging from approximately 27% (social support) to 450% (adjustment). These improvements reinforce the relationship between the improvements in depressive items, as assessed by the MADRS and the improvement in maternal functioning.

[0809] Table 13 - BIMF Score Table

[0810]

[0811] Table 14 - BIMF Functional Domain Score Table

[0812]

[0813] Summary and Conclusions

[0814] A. The individualized dosing regimen, i.e., administering 6 mg 5-MeO-DMT followed by 12 mg 5-MeO-DMT via inhalation, was well tolerated and induced a surprising and highly significant clinical response in patients formally diagnosed with postpartum depression.

[0815] B. The clinical response emerged rapidly within 2 hours after 5-MeO-DMT administration. This rapid onset process is not common 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 take 4-6 weeks to show effects.

[0816] C. According to the IDR, the patient 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.

[0817] 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 for 5 days of follow-up. This observation supports the superior clinical profile of 5-MeO-DMT and allows for a convenient administration interval.

[0818] E. In addition to the antidepressant effect, endpoints assessing other symptoms such as emotional withdrawal, anxiety, guilt, conceptual disorganization, and tension were also positively affected, supporting the use of 5-MeO-DMT in patients with other psychiatric disorders.

[0819] F. In addition to the antidepressant effect, endpoints assessing maternal functioning such as self-care, psychological well-being, 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.

[0820] Final Conclusion

[0821] The outstanding aspects indicate that 5-MeO-DMT has a significantly improved therapeutic efficacy when used according to the present application compared to approved medications for postpartum depression and all previously tested psychedelics.

[0822] 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 with postpartum depression.

[0823] Additional results - second patient

[0824] The second patient was lactating and, in accordance with the clinical trial protocol, breast milk samples were collected pre-dose and at multiple time points post administration of the last dose. These samples were subsequently analyzed by LC-MS / MS assay to detect 5-MeO-DMT, bufotenine (the major 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 table below.

[0825]

[0826] ND: not determined.

[0827] BLQ: below limit of quantitation. The lower limit of quantitation for 5-MeO-DMT and 5-MIAA in serum and breast milk was 25 pg / ml; the lower limit of quantitation for 5-MeO-DMT in urine was 25 pg / ml and the lower limit of quantitation for 5-MIAA in urine was 250 pg / ml.

[0828] The data show that 5-MeO-DMT was rapidly cleared from serum at the first measured time point, 1 hour post last dose, at which time a concentration of 132.9 pg / ml was detected, followed by concentrations below the lower limit of quantitation for the assay at all subsequent time points. In addition, endogenous levels of 5-MIAA were confirmed in serum pre-dose, with the highest concentration detected at the first measured time point (1 hour post dose) and returning to baseline levels within 1 day. Urine assay data show 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), rapidly decreasing 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, rapidly decreasing to endogenous levels within 7 days. Bufotenine was not detected in urine at any time point except 2.5 hours post dose. Taken together, these data confirm the rapid metabolism and clearance of 5-MeO-DMT in vivo.

[0829] Breast milk sample analysis showed the absence of bufotenine, while the concentration of 5-MeO-DMT was 2167 pg / ml at 1 hour post administration, rapidly decreasing to a level similar to the endogenous level in serum pre-dose at 8.5 hours post administration. A similar trend was observed for 5-MIAA.

Claims

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

2. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the patient suffers from 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 4 mg to about 20 mg of 5-MeO-DMT is administered, or wherein an equimolar amount of said 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 19, wherein a dose of about 6 mg; or about 12 mg; or about 18 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 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.

23. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 1 to 22, wherein the 5-MeO-DMT is administered at a dose of about 2 mg to about 8 mg for a first administration, which is then increased to a dose of about 8 mg to about 14 mg for a second administration unless the patient has experienced a peak psychedelic experience, and which is then increased to a dose of about 14 mg to about 20 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.

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

25. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 22 to 24, 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.

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

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

28. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use according to claim 26, wherein the 5-MeO-DMT or a salt thereof is administered 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.

29. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 28, 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.

30. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claims 19 to 29, 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.

31. 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as claimed in claim 30, wherein the occurrence of the peak psychedelic experience is identified by achieving a Peak Experience Scale (PES) total score of at least 75.

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

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

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

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

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

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