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WO2024160390A1 - 5-méthoxy-n,n-diméthyltryptamine pour le traitement de la dépression post-partum - Google Patents

5-méthoxy-n,n-diméthyltryptamine pour le traitement de la dépression post-partum Download PDF

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Publication number
WO2024160390A1
WO2024160390A1 PCT/EP2023/076817 EP2023076817W WO2024160390A1 WO 2024160390 A1 WO2024160390 A1 WO 2024160390A1 EP 2023076817 W EP2023076817 W EP 2023076817W WO 2024160390 A1 WO2024160390 A1 WO 2024160390A1
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Prior art keywords
dmt
meo
pharmaceutically acceptable
acceptable salt
score
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Inventor
Theis Terwey
Conor Burke
Naoise GAFFNEY
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GH Research Ireland Ltd
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GH Research Ireland Ltd
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Priority claimed from PCT/EP2023/057883 external-priority patent/WO2023186835A1/fr
Application filed by GH Research Ireland Ltd filed Critical GH Research Ireland Ltd
Priority to KR1020257028944A priority Critical patent/KR20250135903A/ko
Priority to AU2023426967A priority patent/AU2023426967A1/en
Priority to CN202380095315.6A priority patent/CN120813348A/zh
Priority to EP23782215.0A priority patent/EP4658265A1/fr
Priority to IL322429A priority patent/IL322429A/en
Publication of WO2024160390A1 publication Critical patent/WO2024160390A1/fr
Priority to MX2025008755A priority patent/MX2025008755A/es
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention is directed to improved methods for the treatment of postpartum depression (PPD) comprising administering to a patient in need thereof a therapeutically effective amount of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or of a pharmaceutically acceptable salt thereof.
  • PPD postpartum depression
  • the invention also allows for treating PPD in a breastfeeding mother without substantial interruption of breastfeeding.
  • PPD leads to a wide range of negative consequences for the affected mother, her infant(s) and her family. For example, women with PPD may develop thoughts of self-harm or harming their child and they are at increased risk of suicide. PPD may further lead to disruptions in the interactions between mother and child, exemplified by higher rates of disengaged behaviour and lower rates of visual and vocal communication between mother and child. Evidence also suggests an association between PPD and child development, as illustrated by the fact that children of patients suffering from PPD have a greater risk of impaired cognitive development.
  • breastfeeding PPD patients may be confronted with a situation where a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy.
  • SSRIs selective serotonin reuptake inhibitors
  • brexanolone More recently in the U.S., brexanolone (Zulresso) received FDA approval - thus making it the first pharmacological therapy indicated specifically for PPD. Brexanolone is a positive allosteric modulator of GABAa receptors which is administered via a 60-hour infusion. The efficacy of brexanolone was displayed in two phase 3 trials - one of which showed significantly reduced Hamilton Rating Scale for Depression (HAM-D) scores 30 days after initiation of the infusion and one of which failed to show efficacy beyond 7 days. However, brexanolone requires a hospital admission for the 60-hour infusion, and significant side effects occur.
  • HAM-D Hamilton Rating Scale for Depression
  • Hallucinogens including psychedelics are chemical compounds, some naturally occurring, some synthetic, which are defined by their ability to induce in humans after consumption sensory distortions, such as changes in auditory and visual perception, as well as distortions of mood and cognition.
  • the term hallucinogen encompasses a rather broad group of psychoactive molecules with different modes of action. Some mental disorders have been suggested as in principle being amenable for treatment with psychoactive molecules, like psychedelics.
  • 5-methoxy-N,N-dimethyltrypta- mine 5-MeO-DMT.
  • TRD treatment resistant depression
  • an aim of the invention is in particular the provision of therapies which are more effective (i.e., a) larger percentage of patients experiencing a clinical response, b) a larger average clinical response, c) an earlier onset of the clinical response, and/or d) a more durable clinical response) than previously described therapies.
  • a still further aim of the current invention is to identify specific disease aspects and specific subgroups of disease aspects which benefit from such improved psychoactive therapies.
  • Still further aims of the invention are to improve maternal functioning in patients suffering from PPD. Improvement of maternal functioning in a breastfeeding mother diagnosed with a mental disorder is also an aim of the invention.
  • the present invention relates to 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in treating postpartum depression (PPD).
  • the treatment not only improves depressive symptoms but also maternal functioning.
  • the invention also allows for treating PPD in a breastfeeding mother without substantial interruption of breastfeeding.
  • 5- MeO-DMT refers to the free base 5-MeO-DMT.
  • pharmaceutically acceptable salts of 5-MeO-DMT may also be used.
  • Such salts are in particular acid addition salts, wherein the acid may be selected from, for instance, acetic acid, benzoic acid, citric acid, fumaric acid, hydrobromic acid, hydrochloric acid, hydrofluoric acid, hydroiodic acid, oxalic acid, succinic acid and triflic acid.
  • a preferred example is the hydrobromide salt.
  • the appropriate weight amount of a salt to be administered can be calculated from the weight amount of the free base, assuming that equimolar amounts are used.
  • a "patient" to be treated is a woman who is diagnosed with postpartum depression (PPD) according to established medical standards. The diagnosis will be by a physician or a psychologist. It is not sufficient that the human subject herself considers that she is suffering from the disorder.
  • PPD postpartum depression
  • treatment resistance means that the patient had no adequate improvement after at least two adequate courses of therapy.
  • the patient in particular had no adequate improvement after at least two adequate courses of therapy, wherein at least one of the two courses was a pharmacotherapy; for instance, the patient had no adequate improvement after at least two adequate courses of pharmacotherapy.
  • suicidal ideation refers to thinking about, considering, or planning for suicide.
  • the presence of suicidal ideation in a patient will be diagnosed by a physician or a psychologist, using established protocols and methods for diagnosing suicidality. It is generally not sufficient that the patient himself considers that he is suffering from suicidal ideation. In some situations, a patient experiencing suicidal ideation will be at imminent risk of committing suicide, or will be considered to have 'intent to act.'
  • treating shall include the management and care of a patient for the purpose of combating a disease, condition, or disorder and includes the administration of compounds and methods according to the present invention to alleviate the signs and/or symptoms of the disease or eliminate the disease, condition, or disorder.
  • the term "therapeutically effective amount” shall mean the amount of active compound or pharmaceutical ingredient that elicits the biological or clinical response in a human that is being sought by a researcher, medical doctor or other clinician, which includes alleviation of the signs and/or symptoms of the disease, condition or disorder being treated.
  • CGI-S Clinical Global Impression - Severity scale
  • PKI-S Patient Global Impression - Severity scale
  • CGI-I Clinical Global Impression - Improvement scale
  • PPI-I Patient Global Impression - Improvement scale
  • EPDS Edinburgh Postnatal Depression Scale
  • CADSS Clinician Administered Dissociative States Scale
  • BPRS Brief Psychiatric Rating Scale
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • Maternal functioning may be assessed using the Barkin Index of Maternal Functioning (BIMF).
  • BIMF Barkin Index of Maternal Functioning
  • a rational modification of such endpoint e.g. changing the MADRS recall period to 2 hours and carrying forward the sleep item recorded at baseline before drug administration may be applied.
  • the term “administration” shall mean the introduction of an amount, which may be a predetermined amount, of active compound or pharmaceutical ingredient into a patient via any route.
  • the active compound is administered by inhalation, nasally, by buccal administration or by sublingual administration.
  • dose and “dosage” and “dosage amount” shall mean the amount of active compound or pharmaceutical ingredient which is administered to a patient in an individual administration.
  • dose regimen (or “dosing regimen”) shall mean a defined sequence of one or more individual administrations.
  • aerosol means a stable system consisting of a gaseous medium (a pharmaceutically acceptable gas, such as air) and miniscule suspended solid and/or liquid particles.
  • degradation product refers to a compound resulting from a chemical modification of 5-MeO-DMT as a result of a chemical reaction during aerosol formation. Such reaction includes, without limitation, oxidation.
  • a percentage of a “degradation product” refers to the quantity of 5-MeO-DMT degradation products present in a sample divided by the quantity of 5-MeO-DMT plus 5-MeO-DMT degradation products present in the sample multiplied by 100%, i.e., (Sum of quantities of all 5-MeO-DMT degradation products present in the sample) I ((Quantity of 5-MeO-DMT present in the sample) + (Sum of quantities of all 5-MeO-DMT degradation products present in the sample)) x 100%.
  • impurity refers to unwanted compounds contaminating a sample of 5- MeO-DMT (or of a pharmaceutically acceptable salt thereof). Impurities may be contained in the starting material before aerosol formation or may be degradation products.
  • purity refers to 100% minus the percent of all 5-MeO-DMT degradation products and all other impurities present, i.e., 100% - (Sum of quantities of all 5-MeO-DMT degradation products present + Sum of quantities of all other impurities present) I (Quantity of 5-MeO-DMT present + Sum of quantities of all 5-MeO-DMT degradation products present + Sum of quantities of all other impurities present) x 100%.
  • MMAD mass median aerodynamic diameter
  • Aerosol particle mass density refers to the mass of aerosol particles per unit volume of aerosol.
  • Aerosol particle formation rate refers to the aerosolized mass of 5-MeO-DMT per unit of aerosolization time.
  • Postpartum depression is a complex mix of physical, emotional, and behavioral changes that happen in some women after giving birth. PPD is also known as major depressive disorder with peripartum onset. According to DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition) criteria, PPD is diagnosed when major depressive disorder (MDD) symptoms begin during pregnancy or within four weeks of delivery. A patient treated according to the present invention is preferably a woman diagnosed with PPD and > 4 weeks postpartum. Further, the patient will preferably be ⁇ 9 months postpartum.
  • PPD PPD Depressive aspects of PPD may be assessed by the HAM-D or the MADRS score.
  • the Edinburgh Postnatal Depression Scale (EPDS) can also be used.
  • the Montgomery-Asberg Depression Rating Scale is a ten-item diagnostic questionnaire used to measure the severity of depressive episodes in patients with mood disorders (Montgomery, S. A., & Asberg, M. (1979). A new depression scale designed to be sensitive to change. The British Journal of Psychiatry 134, p.382). It was designed as an adjunct to the Hamilton Rating Scale for Depression (HAM-D), which would be more sensitive to the changes brought on by antidepressants and other forms of treatment. Higher MADRS score indicates more severe depression.
  • the items considered are apparent sadness; reported sadness; inner tension; reduced sleep; reduced appetite; concentration difficulties; lassitude; inability to feel; pessimistic thoughts; and suicidal thoughts, and each item yields a score of 0 to 6.
  • the overall score ranges from 0 to 60.
  • a patient may suffer from moderate or severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or by a Hamilton Depression Rating Scale (HAM-D) score of 16 or more. It is further considered that the patient may suffer from severe PPD as indicated by a Montgomery-Asberg Depression Rating Scale (MADRS) score of 35 or more or by a Hamilton Depression Rating Scale (HAM- D) score of 27 or more.
  • the patient may be diagnosed with a treatment-resistant form of PPD.
  • a patient treated according to the invention may have a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or more.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • HAM-D 17-item Hamilton Depression Rating Scale
  • a patient treated according to the invention may have a MADRS score of 28 or more or a HAM-D score of 22 or more.
  • a patient treated according to the invention may have a MADRS score of 35 or more or a HAM-D score of 25 or more.
  • PPD PPD compromises maternal functioning.
  • the first year after childbirth marks a critical window for both mother and child.
  • mothers are the primary caregivers and are, therefore, responsible for the majority of the work related to infant care tasks.
  • Maternal functioning includes aspects of maternal competence relating to interactions with the infant(s) as well as maternal self-care.
  • Maternal functioning including the emotional aspect of mothering, is also important for the child’s development.
  • the quality of mother-child interaction in the year after birth affects infant development.
  • High levels of maternal functioning are likely to correlate with positive infant development outcomes.
  • impaired functioning in the postpartum period might impede optimal infant development.
  • the Barkin Index of Maternal Functioning was designed to measure functioning in the year after childbirth.
  • the BIMF is a 20-item self-report measure of functioning. Each item is assigned a score between 0 and 6 so that the maximum total score is 120. The higher the score, the better maternal functioning is rated.
  • the BIMF identifies the key functional domains of a mother during the postnatal period as: self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.
  • a Bl MF score of 95 or below is considered herein as representing slightly compromised maternal functioning
  • score of 80 or below is considered herein as representing compromised maternal functioning
  • a score of 65 or below is considered herein as representing severely compromised maternal functioning.
  • the invention in particular allows improving maternal functioning in patients having a score of 80 or below before treatment and in patients having a score of even 65 or below.
  • the Active Agent is the Active Agent
  • the inventors further considered that a carefully chosen hallucinogen may allow continuing breastfeeding without substantial interruption in case of treatment of a breastfeeding mother suffering from PPD.
  • One group of hallucinogens entails compounds which bind to the 5-hydroxytryptamine (5-HT) receptors, which are also referred to as serotonin receptors (described are 7 families 5-HT1 to 5-HT7 with several subtypes). Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT).
  • 5-HT 5-hydroxytryptamine
  • serotonin receptors 7 families 5-HT1 to 5-HT7 with several subtypes. Examples are lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT).
  • serotonergic agents are often referred to as "psychedelics", which emphasizes their predominant ability to induce qualitatively altered states of consciousness such as euphoria, trance, transcendence of time and space, spiritual experiences, dissolution of self-boundaries, or even near-death experiences, while other effects such as sedation, narcosis, or excessive stimulation are only minimal.
  • serotonergic psychedelics are either phenylalkylamines or indoleamines, with the indoleamine class being divided into two subsets, ergolines and tryptamines, the latter being derived from tryptamine.
  • the various serotonergic psychedelics have different binding affinity and activation potency for various serotonin receptors, particularly 5-HT1A, 5-HT2A, and 5-HT2C, and their activity may also be modulated by interaction with other targets such as monoamine transporters and trace amine-associated receptors.
  • 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) report about a patient who suffered a manic attack after ingesting LSD or an LSD analogue. The patient experienced acute symptoms of LSD intoxication, which resolved but were followed in about 3 weeks by a typical manic episode of psychotic magnitude. Hendin and Penn (Hendin, H.M., Penn, A. D., 2021.
  • the compound administered in order to avoid the induction of mania or hypomania or at least reduce the risk of induction of mania or hypomania, the compound administered must be appropriately chosen and preferably is administered in a particular dosing regimen.
  • 5-methoxy-N,N-dimethyltryptamine 5-MeO-DMT
  • 5-MeO-DMT 5-methoxy-N,N-dimethyltryptamine
  • 5-MeO-DMT is a potent, fast-acting, naturally occurring serotonin (5-HT) agonist, acting at both the 5-HT 1 A and the 5-HT2A receptor, with higher affinity for the 5-HT 1 A receptor subtype compared to other classical psychedelics.
  • Inhibition constants Kj values as further detailed on the example section below for psilocin (the dephosphorylated from of psilocybin which is formed after uptake of psilocybin), DMT and 5-MeO-DMT are 48, 38 and 1.80 nM, respectively, at 5-HT1 A receptors located in the hippocampus of post-mortem human brain.
  • 5-MeO-DMT exhibits high affinity and psilocin and DMT exhibit moderate affinity for 5-HT1A receptors.
  • Inhibition constants (Kj values) for psilocin, DMT and 5-MeO-DMT are 37, 117 and 122 nM, respectively, at 5-HT2A receptors located in the frontal cortex of post-mortem human brain. Therefore, psilocin exhibits moderate/strong affinity and DMT and 5-MeO-DMT exhibit comparatively weak affinity for 5-HT2A receptors.
  • 5-MeO-DMT displays an enhanced affinity for the 5-HT1 A receptor, where it acts as a potent agonist.
  • 5-HT2A binding there is an increased contribution of 5-HT2A binding, relative to 5-MeO-DMT, with the latter displaying the largest differential affinity for 5- HT1A over 5-HT2A of the three compounds. Therefore, 5-HT1A binding plays a much bigger role in the overall effect of 5-MeO-DMT relative to 5-HT2A binding compared to the other two compounds.
  • 5-HT1A agonism reduces impulsivity and aggression
  • 5-HT2A agonism can result in short-term increases in these same traits.
  • the dopamine system has been implicated in contributing to mania, with increased dopamine drive being linked to mania. LSD, psilocybin and DMT all display increased affinity for a variety of dopamine receptors relative to 5-MeO-DMT
  • 5-MeO-DMT can be administered to patients, preferably using dosing schemes as described herein, without a significant risk of inducing mania or hypomania in a patient suffering from a mental or nervous system disorder, including a disorder characterized by depressive episodes, for example, 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; a Psychotic Disorder, such as Schizophrenia; or a personality disorder, such as Schizotypal Personality Disorder.
  • MDD Major Depressive Disorder
  • PPD Postpartum Depression
  • BD Persistent Depressive Disorder
  • BD Seasonal Affective Disorder and Bipolar Disorder
  • BD Bipolar I Disorder and Bipolar II Disorder
  • a Psychotic Disorder such as Schizophrenia
  • a personality disorder such as Schizotypal Personality Disorder.
  • the patient suffering from such a mental or nervous system disorder, treated according to the invention does not
  • the inventors’ approach of sequential up-titration of 5-MeO-DMT significantly reduces the risk of excessive dose administration with its potential for attendant adverse events.
  • 5-MeO-DMT can induce peak experiences, i.e., experiences characterized by an emotional perspective shift, which is described as "loss of ego” which often culminates in an overwhelming sense of "oneness with the universe", more rapidly than other psychedelics and has a short duration of acute psychedelic effects (5 to 30 minutes after inhalation compared with several hours for e.g. oral psilocybin and oral LSD).
  • These characteristics of 5-MeO-DMT are associated with an improved therapeutic profile which can be explained by specific alterations of Resting State Network (RSN) activity under 5-MeO-DMT treatment.
  • RSN Resting State Network
  • 5-MeO-DMT is a 5-HT7 receptor agonist showing high affinity towards the receptor.
  • the inventors determined, using recombinant human 5-HT7 receptor, [ 3 H]LSD as a radio ligand and serotonin to estimate non-specific binding, a Kj of 2.3 nM.
  • 5-MeO-DMT also interacts with the 5-HT7 receptor.
  • 5-MeO-DMT act as an agonist on this receptor and shows a high (nanomolar) binding affinity.
  • the 5-HT7 receptor has a role in neurogenesis, synaptogenesis and dendritic spine formation. It is, among other things, associated with central processes such as learning and memory, with sleep regulation and circadian rhythm and with nociception.
  • the 5-HT7 receptor is in particular expressed in the spinal cord, raphe nuclei, thalamus, hypothalamus including the suprachiasmatic nucleus, hippocampus, prefrontal cortex, striatal complex, amygdala and in the Purkinje neurons of the cerebellum.
  • the suprachiasmatic nucleus is the central pacemaker of the circadian timing system. It coordinates circadian rhythms in various brain regions. Disruption of this coordination will result in disease states, in particular disease states involving sleep disturbance. In patients suffering from sleep disturbance resting state functional connectivity analysis reveals alterations in functional connectivity between the suprachiasmatic nucleus and regions within the default mode network.
  • the expression of the 5-HT7 receptor in the suprachiasmatic nucleus corresponds to the function of the receptor in regulation of sleep/wake cycles.
  • the inventors consider that this allows treatment of patients suffering from sleep disturbance by 5-MeO-DMT which acts on the receptor.
  • the inventors consider that binding of 5-MeO-DMT to the 5-HT7 receptor as one mediator of the pharmacological effects of 5-MeO-DMT, which involve functional connectivity "resets" of networks and neuroplasticity effects, contributes to the beneficial effects of 5- MeO-DMT in the treatment of patients suffering from sleep disturbance.
  • the inventors further consider that binding of 5-MeO-DMT to the 5-HT7 receptor as well as to the 5-HT1A receptor as two mediators of effects exerted by 5-MeO-DMT, which include functional connectivity "resets" of networks and neuroplasticity effects, allows achieving beneficial effects also in patients suffering from other symptoms or conditions, such as cognitive dysfunction, anxiety, psychomotor retardation, negative thinking or so- cial/emotional withdrawal. This is supported by the clinical results demonstrated in studies referred to herein.
  • 5-MeO-DMT is mainly inactivated through a deamination pathway mediated by monoamine oxidase A, and it is O-demethylated by cytochrome P4502D6 (CYP2D6) enzyme.
  • the inventors investigated pharmacokinetic properties of 5-MeO-DMT and observed rapid absorption and distribution of inhaled 5-MeO-DMT, with maximum concentrations and pharmacological effects observed during and immediately after dosing.
  • 5-MeO-DMT offers various characteristics that renders it an attractive treatment for PPD.
  • it is a rapid-acting agent (in a 5-MeO-DMT-TRD trial, 5/8 patients with TRD achieved a remission within 2h after dosing, and 8/8 patients achieved a remission on day 1 , with 7/8 patients maintaining their remission at Day 7).
  • 5-MeO-DMT to treat PPD patients, not only can a rapid improvement of depressive symptoms be achieved, but also a rapid improvement of maternal functioning.
  • 5-MeO-DMT is administered during a single-day treatment session, with optional infrequent redosing, thus differentiating it from SSRIs, which require a chronic daily dosing regimen associated with low compliance, and from brexanolone, requiring protracted infusions and hospital admission.
  • the present invention thus also addresses compliance and patient convenience. Furthermore, the inventors determined that a treatment of PPD with 5-MeO-DMT or a pharmaceutically acceptable salt thereof allows continuing breastfeeding with only a short interruption for the treatment.
  • isotopic variants of 5-MeO-DMT and pharmaceutically acceptable salts thereof can also be used.
  • isotopic variants are also contemplated.
  • Deuterated forms of 5-MeO-DMT are forms having a higher deuterium content than expected based on the natural abundance of this isotope.
  • Deuterated forms of 5-MeO-DMT are in particular forms wherein deuterium has been introduced at one or more defined hydrogen positions.
  • Examples of deuterated forms of 5-MeO-DMT include, without limitation, 1-deuterio-2- (5-methoxy-1 H-indol-3-yl)-N,N-dimethylethanamine, 1 ,1-dideuterio-2-(5-methoxy-1 H-in- dol-3-yl)-N,N-dimethylethanamine, 1 ,1 ,2,2-tetradeuterio-2-(5-methoxy-1H-indol-3-yl)- N,N-dimethylethanamine, and N,N-dimethyl-2-[5-(trideuteriomethoxy)-1 H-indol-3-yl]eth- anamine.
  • mixtures of deuterated forms of 5-MeO-DMT mixtures of one or more deuterated form with non-deuterated 5-MeO-DMT, pharmaceutically acceptable salts of deuterated forms of 5-MeO-DMT, mixture of such salts as well as mixtures of salts of deuterated and non-deuterated 5-MeO-DMT can also be used.
  • deuterated 5-MeO-DMT and salts of deuterated 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-deuterated forms.
  • prodrugs of 5-MeO-DMT and pharmaceutically acceptable salts of such prodrugs can also be used.
  • Such prodrugs of 5-MeO-DMT can be metabol- ically converted to 5-MeO-DMT.
  • this can be replaced by a 5-MeO- DMT prodrug or a salt thereof.
  • the hydrogen in position 1 of the indole moiety is substituted by an organic moiety which can be split off after administration.
  • Suitable organic moieties are -C(O)OR 1 , -C(O)R 2 , -CH(R 3 )OR 4 , - C(O)OCH(R 3 )OC(O)R 4 , -C(O)OCH(R 3 )OC(O)OR 4 , -CH(R 3 )C(O)R 4 , -CH(R 3 )OC(O)R 4 , - CH(R 3 )OC(O)OR 4 , wherein each of R 1 , R 2 , R 3 , and R 4 is independently hydrogen, alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, and heteroaryl is independently substituted or unsubstituted.
  • organic moieties are -CH(R 3 )OC(O)R 4 and -C(O)OR 1 , wherein R 1 , R 3 , and R 4 are defined as above.
  • Prodrugs especially those of the above structure, can also be used on the form of pharmaceutically acceptable salts.
  • prodrugs are 5-MeO-DMT carboxy-isopropyl valinate, preferably in salt form, in particular as ditrifluoroacetate (1-(((S)-2-amino-3-methylbutanoyl)oxy)-2- methylpropyl 3-(2-(dimethylamino)ethyl)-5-methoxy-1 H-indole-1-carboxylate di-trifluoro- acetate) and 5-MeO-DMT methyl pivalate (3-(2-(dimethylamino)ethyl)-5-rnethoxy-1 H-in- dol-1-yl)methyl pivalate).
  • the T ma x value of the metabolite 5-MeO-DMT as measured in male Sprague-Dawley (SD) rats following oral dosing of the prodrug at 10 mg/kg is preferably 1 hour or less, more preferably 0.7 hours or less and in particular 0.5 hours or less.
  • prodrugs of 5-MeO-DMT and salts of prodrugs of 5- MeO-DMT are used in amounts that are equimolar to the amounts of the corresponding non-prodrug forms.
  • the present invention allows treating patients suffering from PPD.
  • the treatment does not only lead to reductions in scores assessing the severity of depression, but also improves maternal functioning as discussed in detail below.
  • the inventors assessed clinical data relating to the use of 5-MeO-DMT in patients treated because of mental disease and noted particular improvements in disease aspects typically also observed in patients with PPD.
  • the inventors in particular noted improvements in various symptoms and combinations of symptoms which the inventors determined to be also associated with maternal functioning.
  • the data stem from a recently completed clinical trial investigating the use of 5-MeO- DMT in the treatment of patients diagnosed with Treatment Resistant Depression (TRD; see also the examples section below). While the completed trial did not involve patients suffering from PPD, the inventors determined, as discussed in detail below, that certain clinical observations are made in the trial are relevant for devising a treatment for PPD.
  • TRD Treatment Resistant Depression
  • 5-MeO-DMT was administered via inhalation (as described in more detail in the example section below).
  • Patients were assigned to different groups.
  • the group who received a single, 12 mg dose and the group who underwent an intra-day individualized dosing regimen (I DR) that allowed for multiple, escalating doses (6 mg, 12 mg and 18 mg) within a single day, driven by the intensity of the patient-reported psychedelic experience are of interest.
  • the data gathered include the assessment of the treated patients against several scales including the Montgomery Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS). While the focus of the trial was on demonstrating treatment efficacy through improvements in overall MADRS score, the inventors focused on the items comprising the various rating scales and noticed that several of the subcore items are of particular relevance for PPD patients and are related to maternal functioning.
  • MADRS Montgomery Asberg Depression Rating Scale
  • BPRS Brief Psychiatric Rating Scale
  • a treatment according to the invention reduces or eliminates (or improves or eliminates) an aspect of the disease.
  • the aspect is assessed on the MADRS scale, there is an improvement by at least one point (reduction) or the patient is in complete remission after the treatment (elimination), i.e. , the respective aspect is scored 0.
  • the aspect is assessed on the BPRS scale, there is an improvement by at least one point (reduction) or the patient is in complete remission after the treatment (elimination), i.e., the respective aspect is scored 1.
  • a clinical response may also be reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score.
  • CGI-S Clinical Global Impression - Severity
  • a reduction in the CGI-S score means that the CGI-S is reduced by at least 1.
  • the CGI-S is reduced by at least 2 and/or to a score of 0. It is especially preferred if the CGI-S is reduced by at least 3 and/or to a score of 0.
  • the inventors further consider that improvements observed in certain MADRS items will translate into improvements in aspects of maternal functioning.
  • the MADRS item "inner tension” represents feelings of ill-defined discomfort, edginess, inner turmoil, mental tension mounting to either panic, dread or anguish. It is rated according to intensity, frequency, duration and the extent of reassurance called for.
  • a score of 0 is assigned if the patient is placid and there is only fleeting inner tension.
  • a score of 2 is assigned if there are occasional feelings of edginess and ill defined discomfort.
  • the score is 4 if there are continuous feelings of inner tension or intermittent panic which the patient can only master with some difficulty.
  • the score is 6 in case of unrelenting dread or anguish and overwhelming panic.
  • the inventors have determined that increases in the score of the MADRS item "inner tension” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item "inner tension” impair mother-child interaction as well as psychological well-being of the mother as assessed by the BIMF.
  • the aggregated score for the MADRS item "inner tension" across all 8 patients was 26 at base line. After 2 hours, it was reduced to 11 which corresponds to an improvement of 15 points or 58%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 20 points or 77%. At day 7 after treatment, it was reduced to 12 which corresponds to an improvement of 14 points or 54%.
  • the aggregated score for the MADRS item "inner tension" across all 4 patients was 13 at base line. After 2 hours, it was reduced to 2 which corresponds to an improvement of 11 points or 85%. At day 1 after treatment, it was reduced to 3 which corresponds to an improvement of 10 points or 77%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 8 points or 62%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of inner tension.
  • An improvement in inner tension is reflected by at least an improvement in the score of the MADRS item inner tension about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in inner tension as reflected by at least 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.
  • An improvement in inner tension as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of inner tension achieved by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • the MADRS item “lassitude” represents a difficulty getting started or slowness initiating and performing everyday activities.
  • a score of 0 means that there is hardly any difficulty in getting started and no sluggishness.
  • a score of 2 is assigned if the patient has difficulties in starting activities.
  • a score of 4 means difficulties in starting simple routine activities which are carried out with effort.
  • a score of 6 is assigned in case of complete lassitude, the patient being unable to do anything without help.
  • the inventors have determined that increases in the score of the MADRS item “lassitude” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “lassitude” impair infant care, self-care, psychological well-being, management and adjustment.
  • the aggregated score for the MADRS item “lassitude” across all 8 patients was 27 at base line. After 2 hours, it was reduced to 10 which corresponds to an improvement of 17 points or 63%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 22 points or 81 %. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 24 points or 89%.
  • the aggregated score for the MADRS item “lassitude” across all 4 patients was 16 at base line. After 2 hours, it was reduced to 10 which corresponds to an improvement of 6 points or 38%. At day 1 after treatment, it was reduced to 0 which corresponds to an improvement of 16 points or 100%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 13 points or 81 %.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of lassitude.
  • An improvement in lassitude is reflected by at least an improvement in the score of the MADRS item lassitude about 2 hours; on day 1 , for instance, after 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.
  • CGI-S - Severity
  • CGI- S Clinical Global Impression - Severity
  • PKI-I - Improvement
  • An improvement in lassitude as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of lassitude achieved by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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. Since lassitude also affects other aspects of PPD, the inventors conclude that the observed improvement in the “lassitude” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item “inability to feel” represents the subjective experience of reduced interest in the surroundings, or activities that normally give pleasure. The ability to react with adequate emotion to circumstances or people is reduced.
  • a score of 0 indicates normal interest in the surroundings and in other people, a score of 2 reduced ability to enjoy usual interests.
  • a score of 4 is assigned in case of a loss of interest in the surroundings and a loss of feelings for friends and acquaintances.
  • a score of 6 reflects the experience of being emotionally paralysed, inability to feel anger, grief or pleasure and a complete or even painful failure to feel for close relatives and friends.
  • the inventors have determined that increases in the score of the MADRS item “inability to feel” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “inability to feel” impair mother-child interaction and psychological well-being.
  • the aggregated score for the MADRS item “inability to feel” across all 8 patients was 36 at base line. After 2 hours, it was reduced to 12 which corresponds to an improvement of 24 points or 67%. At day 1 after treatment, it was reduced to 2 which corresponds to an improvement of 34 points or 94%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 30 points or 83%.
  • the aggregated score for the MADRS item “inability to feel” across all 4 patients was 16 at base line. After 2 hours, it was reduced to 9 which corresponds to an improvement of 7 points or 44%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 15 points or 94%. At day 7 after treatment, it was reduced to 1 which corresponds to an improvement of 15 points or 94%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of inability to feel.
  • An improvement in inability to feel is reflected by at least an improvement in the score of the MADRS item inability to feel about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in inability to feel as reflected by at least 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.
  • An improvement in inability to feel as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of inability to feel by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.13
  • the inventors conclude that the observed improvement in the "inability to feel" item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item "concentration difficulties” represents difficulties in collecting one's thoughts mounting to incapacitating lack of concentration.
  • the score is 0 if the patient has no difficulties in concentrating.
  • the score is 2 in case of occasional difficulties in collecting one's thoughts.
  • a score of 4 is assigned in case of difficulties in concentrating and sustaining thought which reduces ability to read or hold a conversation.
  • the score is 6 if the patient is unable to read or converse without great difficulty.
  • the inventors have determined that increases in the score of the MADRS item "concentration difficulties" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item "concentration difficulties” impair infant care as well as management.
  • the aggregated score for the MADRS item "concentration difficulties" across all 8 patients was 30 at base line. After 2 hours, it was reduced to 11 which corresponds to an improvement of 19 points or 63%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 29 points or 97%. At day 7 after treatment, it was reduced to 9 which corresponds to an improvement of 21 points or 70%.
  • the aggregated score for the MADRS item "concentration difficulties" across all 4 patients was 16 at base line. After 2 hours, it was reduced to 7 which corresponds to an improvement of 9 points or 56%. At day 1 after treatment, it was reduced to 2 which corresponds to an improvement of 14 points or 88%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 13 points or 81%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of concentration difficulties.
  • An improvement in concentration difficulties is reflected by at least an improvement in the score of the MADRS item concentration difficulties about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in concentration difficulties as reflected by at least 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.
  • An improvement in concentration difficulties as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of concentration difficulties by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score. This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 7; on day 14; and/or on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • pessimistic thoughts represents thoughts of guilt, inferiority, self- reproach, sinfulness, remorse and ruin.
  • a score of 0 is assigned if there are no pessimistic thoughts.
  • the score is 2 in case of fluctuating ideas of failure, self-reproach or self-depreciation.
  • a score means persistent self-accusations, or definite but still rational ideas of guilt or sin as well as the patient being increasingly pessimistic about the future.
  • a score of 6 is assigned in case of delusions of ruin, remorse or unredeemable sin and self-accusations which are unrealistic and unshakable.
  • the inventors have determined that increases in the score of the MADRS item "pessimistic thoughts" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “pessimistic thoughts” impair psychological wellbeing, social support and management.
  • the aggregated score for the MADRS item “pessimistic thoughts” across all 8 patients was 28 at base line. After 2 hours, it was reduced to 7 which corresponds to an improvement of 21 points or 75%. At day 1 after treatment, it was reduced to 4 which corresponds to an improvement of 24 points or 86%. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 25 points or 89%.
  • the aggregated score for the MADRS item “pessimistic thoughts” across all 4 patients was 16 at base line. After 2 hours, it was reduced to 8 which corresponds to an improvement of 8 points or 50%. At day 1 after treatment, it was reduced to 7 which corresponds to an improvement of 9 points or 56%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 8 points or 50%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of pessimistic thoughts.
  • An improvement in pessimistic thoughts is reflected by at least an improvement in the score of the MADRS item pessimistic thoughts about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in pessimistic thoughts as reflected by at least 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.
  • An improvement in pessimistic thoughts as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of pessimistic thoughts by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • pessimistic thoughts also affects other aspects of PPD, the inventors conclude that the observed improvement in the “pessimistic thoughts” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the MADRS item “reduced sleep” represents the experience of reduced duration or depth of sleep compared to the subject’s own normal pattern when well.
  • a score of 0 is assigned when the subject sleeps as usual.
  • a score of 2 reflects slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep.
  • a score of 4 means that sleep is reduced or broken by at least two hours.
  • a score of 6 means less than two or three hours sleep.
  • the inventors have determined that increases in the score of the MADRS item “reduced sleep” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “reduced sleep” impair self-care, psychological well-being and management.
  • the aggregated score for the MADRS item “reduced sleep” across all 8 patients was 25 at base line.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 12 which corresponds to an improvement of 13 points or 52%.
  • the earliest timepoint for assessing an impact of the treatment on sleep it was reduced to 9 which corresponds to an improvement of 16 points or 64%.
  • the aggregated score for the MADRS item “reduced sleep” across all 4 patients was 12 at base line. At day 1 after treatment, it was reduced to 10 which corresponds to an improvement of 2 points or 17%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 6 points or 50%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of reduced sleep.
  • the reduction or elimination of reduced sleep is reflected by at least an improvement in the score of the MADRS item reduced sleep on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • An improvement in reduced sleep as reflected by at least 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.
  • An improvement in reduced sleep as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of reduced sleep by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 24 hours, and an increased Bl MF score will also be observed on day 1 , for instance, after 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.
  • a further aspect of PPD which can be treated by administration of 5-MeO-DMT, is suicidal ideation.
  • 5-MeO-DMT can be administered to PPD patients to reduce or eliminate suicidal ideation in said patients.
  • “Suicidal thoughts” represents a feeling that life is not worth living, that a natural death would be welcome, having suicidal thoughts, and/or making the preparations for suicide. Suicidal attempts should not in themselves influence the rating for this MADRS item.
  • a score of 0 means that the patient enjoys life.
  • a score of 2 is assigned if the PPD patient is weary of life, and/or has only fleeting suicidal thoughts.
  • a score of 4 means the patient feels they would be better off dead, suicidal thoughts are common and suicide is considered as a possible solution but the patient has no specific plans or intention.
  • a score of 6 is assigned in case the patient has explicit plans for suicide and/or is making active preparations.
  • This MADRS scale item is of particular relevance to suicidal ideation.
  • the inventors have determined that increases in the score of the MADRS item “suicidal thoughts” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the MADRS item “suicidal thoughts” impair self-care, psychological well-being and management.
  • the aggregated score for the MADRS item “suicidal thoughts” across all 8 patients was 11 at base line. After 2 hours, it was reduced to 3 which corresponds to an improvement of 8 points or 73%. At day 1 after treatment, it was reduced to 1 which corresponds to an improvement of 10 points or 91 %. At day 7 after treatment, it was reduced to 3 which corresponds to an improvement of 8 points or 73%.
  • the aggregated score for the MADRS item “suicidal thoughts” across all 4 patients was 8 at base line. After 2 hours, it was reduced to 3 which corresponds to an improvement of 5 points or 63%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 3 points or 38%. At day 7 after treatment, it was reduced to 7 which corresponds to an improvement of 1 point or 13%.
  • the treatment of a PPD patient suffering from suicidal ideation reduces or eliminates the suicidal ideation.
  • the reduction or elimination of suicidal ideation is reflected by at least an improvement in the score of the MADRS item suicidal thoughts about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI-S Clinical Global Impression - Severity
  • CGI-S Clinical Global Impression - Severity
  • An improvement in suicidal ideation as assessed by at least 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.
  • An improvement in suicidal ideation as assessed by a reduction of the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of suicidal thoughts by treating a PPD patient does not only lead to a reduction in the MADRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • suicidal thoughts also affects other aspects of PPD, the inventors conclude that the observed improvement in the “suicidal thoughts” item on the MADRS will additionally contribute to an overall improvement in maternal functioning.
  • the BPRS item “emotional withdrawal” relates to a deficiency in the patient’s ability to relate emotionally during the interview situation. Possible scores are:
  • Emotional contact not present much of the interview because subject does not elaborate responses, fails to make eye contact, doesn’t seem to care if interviewer is listening, or may be preoccupied with psychotic material.
  • the inventors have determined that increases in the score of the BPRS item “emotional withdrawal” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item “emotional withdrawal” impair psychological well-being, mother-child interaction and social support.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of emotional withdrawal.
  • the reduction or elimination of emotional withdrawal is reflected by at least an improvement in the score of the BPRS item emotional withdrawal about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in emotional withdrawal as reflected by at least 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.
  • An improvement in emotional withdrawal as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of emotional withdrawal by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the BIMF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • the BPRS item "blunted affect” relates to a restricted range in emotional expressiveness of face, voice, and gestures as well as a marked indifference or flatness even when discussing distressing topics. Possible scores are:
  • Emotional range is noticeably diminished, patient doesn't show emotion, smile, or react to distressing topics except infrequently.
  • Voice tone is monotonous or there is noticeable decrease in spontaneous movements. Displays of emotion or gestures are usually followed by a return to flattened affect.
  • the inventors have determined that increases in the score of the BPRS item "blunted affect” have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item "blunted affect” impair psychological well-being and motherchild interaction. Conversely, improvements regarding this BPRS item lead to improvements in maternal functioning, in particular in the BIMF functional domains psychological well-being and/or mother-child interaction.
  • the aggregated score for the BPRS item "blunted affect" was 15 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 4 points or 27%. At day 1 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%. At day 7 after treatment, it was reduced to 8 which corresponds to an improvement of 7 points or 47%.
  • the aggregated score for the BPRS item "blunted affect" was 11 at base line. After 3 hours, it was reduced to 8 which corresponds to an improvement of 3 points or 27%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 5 points or 45%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 6 points or 55%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of blunted affect.
  • the reduction or elimination of blunted affect is reflected by at least an improvement in the score of the BPRS item blunted affect about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in blunted affect as reflected by at least 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.
  • An improvement in blunted affect as reflected by a reduction in the CGI-S score or by at least a score of “much improved” in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of blunted affect by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the Bl MF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • blunted affect also affects other aspects of PPD, the inventors conclude that the observed improvement in the “blunted affect” item on the BPRS will additionally contribute to an overall improvement in maternal functioning.
  • the BPRS item “guilt feelings” relates to over concern or remorse for past behavior. Possible scores are:
  • the aggregated score for the BPRS item “guilt feelings” across all 8 patients was 34 at base line. After 3 hours, it was reduced to 14 which corresponds to an improvement of 20 points or 59%. At day 1 after treatment, it was reduced to 11 which corresponds to an improvement of 23 points or 68%. At day 7 after treatment, it was reduced to 10 which corresponds to an improvement of 24 points or 71%.
  • the aggregated score for the BPRS item “guilt feelings” across all 4 patients was 18 at base line. After 3 hours, it was reduced to 9 which corresponds to an improvement of 9 points or 50%. At day 1 after treatment, it was reduced to 5 which corresponds to an improvement of 13 points or 72%. At day 7 after treatment, it was reduced to 5 which corresponds to an improvement of 13 points or 72%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of guilt feelings.
  • the reduction or elimination of guilt feelings is reflected by at least an improvement in the score of the BPRS item guilt feelings about 2 hours; on day 1 , for instance, after 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI- S Clinical Global Impression - Severity
  • An improvement in guilt feelings as reflected by at least 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.
  • An improvement in guilt feelings as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of guilt feelings by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the Bl MF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • the BPRS item "anxiety” relates to reported apprehension, tension, fear, panic or worry. Possible scores are:
  • 5 Moderately Severe. Frequent, but not daily, periods of anxiety with autonomic accompaniment or some areas of functioning are disrupted by anxiety or worry. 6 - Severe. Anxiety with autonomic accompaniment daily but not persisting throughout the day or many areas of functioning are disrupted by anxiety or constant worry.
  • the inventors have determined that increases in the score of the BPRS item "anxiety" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item "anxiety” impair psychological wellbeing, social support and management.
  • the aggregated score for the BPRS item "anxiety" across all 8 patients was 37 at base line. After 3 hours, it was reduced to 19 which corresponds to an improvement of 18 points or 49%. At day 1 after treatment, it was reduced to 16 which corresponds to an improvement of 21 points or 57%. At day 7 after treatment, it was reduced to 17 which corresponds to an improvement of 20 points or 54%.
  • the aggregated score for the BPRS item "anxiety" across all 4 patients was 25 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 14 points or 56%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 19 points or 76%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 19 points or 76%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of anxiety.
  • the reduction or elimination of anxiety is reflected by at least an improvement in the score of the BPRS item anxiety about 2 hours; on day 1 , for instance, after 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.
  • CGI-S - Severity
  • CGI- S Clinical Global Impression - Severity
  • PKI-I - Improvement
  • An improvement in anxiety as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of anxiety by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the Bl MF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • the BPRS item “tension” relates to observable physical and motor manifestations of tension, "nervousness,” and agitation. Possible scores are
  • the inventors have determined that increases in the score of the BPRS item "tension" have negative impacts on both aspects of maternal functioning (maternal competence relating to interactions with the infant(s) as well as maternal self-care). Increased scores in the BPRS item "tension” impair mother-child interaction and psychological wellbeing.
  • the aggregated score for the BPRS item "tension" across all 8 patients was 16 at base line. After 3 hours, it was reduced to 11 which corresponds to an improvement of 5 points or 31 %. At day 1 after treatment, it was reduced to 11 which corresponds to an improvement of 5 points or 31 %. At day 7 after treatment, it was reduced to 10 which corresponds to an improvement of 6 points or 38%.
  • the aggregated score for the BPRS item "tension" across all 4 patients was 14 at base line. After 3 hours, it was reduced to 9 which corresponds to an improvement of 5 points or 36%. At day 1 after treatment, it was reduced to 6 which corresponds to an improvement of 8 points or 57%. At day 7 after treatment, it was reduced to 6 which corresponds to an improvement of 8 points or 57%.
  • 5-MeO-DMT can be used to treat PPD patients to achieve a reduction or elimination of tension.
  • the reduction or elimination of tension is reflected by at least an improvement in the score of the BPRS item tension about 2 hours; on day 1 , for instance, after 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.
  • CGI-S - Severity
  • CGI- S Clinical Global Impression - Severity
  • PKI-I - Improvement
  • An improvement in tension as reflected by a reduction in the CGI-S score or by at least a score of "much improved" in the CGI-I score or the PGI-I score, preferably persists 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.
  • the inventors furthermore conclude that a reduction or elimination of tension by treating a PPD patient does not only lead to a reduction in the BPRS total score, but also to an improvement in maternal functioning, as reflected by an increase in the Bl MF score.
  • This improvement will be achieved rapidly, namely within about 2 hours, and an increased BIMF score will also be observed on day 1 , for instance, after 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.
  • Improvements in one or more aspects of PPD will also lead to overall improvements.
  • treatment leads to a remission.
  • a remission of depressive symptoms may be reflected by a MADRS score equal to or less than 10 and occurs not later than about 2 hours; occurs on day 1 , for instance, after 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.
  • a remission of depressive symptoms may be reflected by a HAM-D score equal to or less than 7 and occurs not later than about 2 hours; occurs on day 1 , for instance, after 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.
  • Improvements in maternal functioning include improvements in the functional domain of self-care. For instance, improvements in the MADRS items lassitude and/or reduced sleep lead to an increase in the BIMF scale scores reflecting self-care.
  • the improvement of the cumulative score of the BIMF scale items reflecting self-care is preferably at least 10 %, more preferably at least 20 %.
  • Improvements in maternal functioning include improvements in the functional domain of infant care. For instance, improvements in the MADRS items lassitude and/or concentration difficulties lead to an increase in the BIMF scale scores reflecting infant care.
  • the improvement of the cumulative score of the BIMF scale items reflecting self-care is preferably at least 15 %, more preferably at least 25 %.
  • Improvements in maternal functioning include improvements in the functional domain of mother-child interaction. For instance, improvements in the MADRS items inability to feel and inner tension lead to an increase in the Bl MF scale scores reflecting mother-child interaction.
  • the improvement of the cumulative score of the BIMF scale items reflecting mother-child interaction is preferably at least 5 %, more preferably at least 15 %
  • Improvements in maternal functioning include improvements in the functional domain of psychological well-being. For instance, improvements in the MADRS items lassitude, pessimistic thoughts, inability to feel, inner tension and/or reduced sleep lead to an increase in the BIMF scale scores reflecting psychological well-being.
  • the improvement of the cumulative score of the BIMF scale items reflecting psychological well-being is preferably at least 25 %, more preferably at least 35 %.
  • Improvements in maternal functioning include improvements in the functional domain of social support. For instance, improvements in the MADRS item pessimistic thoughts leads to an increase in the Bl MF scale scores reflecting social support.
  • the improvement of the cumulative score of the BIMF scale items reflecting social support is preferably at least 10 %, more preferably at least 20 %
  • Improvements in maternal functioning include improvements in the functional domain of management. For instance, improvements in the MADRS items lassitude, pessimistic thoughts and/or concentration difficulties lead to an increase in the Bl MF scale scores reflecting management.
  • the improvement of the cumulative score of the Bl MF scale items reflecting management is preferably at least 20 %, more preferably at least 30 %
  • Improvements in maternal functioning include improvements in the functional domain of adjustment. For instance, improvements in the MADRS item lassitude leads to an increase in the BIMF scale scores reflecting adjustment.
  • the improvement of the cumulative score of the BIMF scale items reflecting adjustment is preferably at least 5 %, more preferably at least 15 %
  • the improvement in maternal functioning relates to one or more, in particular two or more functional domains according to the Barkin Index of Maternal Functioning (BIMF) selected from self-care, infant care, mother-child interaction, psychological wellbeing of the mother, social support, management, and adjustment.
  • BIMF Barkin Index of Maternal Functioning
  • the Bl MF total score is improved by 10 % or more, preferably by 20 % or more.
  • Breastfeeding is the process of feeding human breast milk to a child. Breastfeeding includes feeding milk directly from the breast, as well as feeding the child with breast milk previously pumped and then bottle fed.
  • breastfeeding patients may be confronted with a situation where a decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy.
  • this decision will have a negative impact on maternal functioning and in particular compromise the functional domains mother-child interaction and psychological well-being.
  • the present invention also addresses the need for treating a mental or nervous system disorder in a breastfeeding mother without substantial interruption of breastfeeding.
  • breastfeeding can be resumed shortly after the treatment.
  • the inventors have investigated pharmacokinetic properties and metabolization of 5- MeO-DMT in an effort to determine from which point in time onwards after administration of 5-MeO-DMT or of a pharmaceutically acceptable salt breastfeeding is possible without exposing the suckling child to any relevant risk.
  • breast milk was obtained from a breastfeeding patient treated with 5-MeO- DMT for PPD.
  • a breastfeeding patient suffering from PPD received a dose of 6 mg 5-MeO-DMT and, after 1 hour, a further dose of 12 mg 5-MeO-DMT.
  • 5-MeO-DMT As regards the administered compound, 5-MeO-DMT, itself, absorption and distribution are rapid, with maximum concentrations and pharmacological effects observed during and immediately after dosing, for example, by inhalation.
  • Plasma protein binding is low (13-23 %).
  • the patient data obtained confirm the fast decrease of the 5-MeO-DMT concentration in breast milk (see Example 12). Measurement after 24 hours did not detect any 5-MeO- DMT.
  • RID Relative Infant Dose
  • the exposure of the infant can be determined.
  • a published estimate for daily intake of breast milk as a function of infant weight is 150 ml/kg/day.
  • an infant of 5 kg is fed three times over 24 hours, receiving 250 ml breast milk each time.
  • a 5-MeO-DMT concentration of 2167.0 pg/ml (the value determined at 1 hour) is assumed, for the second feed of 560.6 pg/ml (the value determined at 2.5 hours), and for the third feed of 42.1 pg/ml (the value determined at 8.5 hours).
  • the total exposure of the infant (Daily Infant Dosage, DID) is 692425 pg 5-MeO-DMT/day (0.000692425 mg/day), which value corresponds to 0.000138485 mg/kg/day.
  • the total dose is 18 mg (6 mg as the first dose and 12 mg as the second dose according to the uptitration scheme applied).
  • the amount actually delivered to the patient may be lower than the indicated dose, a calculation of the RID is also carried out assuming that the actually delivered amount is only 50 % of the indicated dose so that any a potential underestimation of the infant exposure is avoided.
  • RIDs Assuming a standard maternal weight of 60 kg, RIDs of 0.092 % (based on 9 mg as the maternal exposure) to 0.046 % (based on 18 mg as the maternal exposure) are obtained.
  • the accepted threshold for "low risk" RID is 10%. It is clear from the calculated value that the 5-MeO-DMT RID is significantly below this threshold.
  • Metabolites as listed in the above table are formed via three different pathways.
  • reaction is catalysed by monoamine oxidase A (MAO-A).
  • the secondary amine, the primary amine and the aldehyde were not identified which indicates that they are not present at any time in a significant concentration.
  • the aldehyde intermediate metabolite undergoes 2 separate biotransformations in human liver hepatocytes. It is either oxidised to 5-methoxyindole acetic acid (5-MIAA) or reduced to 5-methoxyindole-3-ethanol.
  • 5-MIAA 5-methoxyindole acetic acid
  • Both resulting metabolites are endogenous substances and are formed in the human body, for instance, during synthesis and metabolism of melatonin and serotonin (see e.g. Biochemistry of the Pineal. Chapter 3. in Melatonin and the Mammalian Pineal Gland. Arendt J (Ed.) Chapman & Hall, 1995; Slominski R and Slominski AT. Synthesis and Metabolism of Melatonin in the Skin and Retinal Pigment Epithelium. Chapter 3. in Melatonin in the Promotion of Health. Watson RR (Ed.) CRC Press 2012).
  • 5-MIAA has been identified as the major human metabolite.
  • 5-MIAA is considered to be a final metabolite of 5-MeO-DMT.
  • 5-MIAA shows relatively low plasma binding of -50% (mean fraction unbound (Fu); see the example section). It remains in circulation subject to renal clearance.
  • the 5-MIAA urine concentration determined after 2.5 hours of 12 980 501 pg/ml (about 12.98 mg/l) demonstrates that most of the 5-MIAA formed will be rapidly excreted.
  • 5-MIAA is rapid, pharmacokinetic data for healthy volunteers as well as for PPD patients indicate that small amounts of 5-MeO-DMT (corresponding to less than 10 % Cmax) may still be present after about 1 hour. In consequence, 5-MIAA will in fact be formed over some period of time after administration of 5- MeO-DMT.
  • 5-MIAA is a weak acid, which will be present in plasma in ionized form, which reduces the tendency of the compound to enter into breast milk.
  • a 5-MIAA concentration of 13945.2 pg/ml (the value determined at 1 hour) is assumed, for the second feed of 13240.9 pg/ml (the value determined at 2.5 hours), and for the third feed of 359.4 pg/ml (the value determined at 8.5 hours).
  • the total exposure of the infant (DID) is 0.00688638 mg 5-MIAA/day, which value corresponds to 0.00137728 mg/kg/day.
  • the maternal exposure to 5-MIAA can be estimated based on the amount of 5-MeO- DMT administered and the proportion of 5-MeO-DMT converted into 5-MIAA.
  • the mixture contains about 60 % 5- MIAA after 2 hours. Since metabolization is not complete, the actual proportion of 5- MeO-DMT converted into 5-MIAA will be higher. It can be assumed that more than 60 % up to close to 100 % of 5-MeO-DMT will be converted into 5-MIAA as the final metabolite, which is then excreted.
  • a total dose of 18 mg 5-MeO-DMT leads to between 10.15 mg 5-MIAA (60 % conversion) and 16.92 mg 5-MIAA (100 % conversion). Assuming as above that the delivered amount of 5-MeO-DMT is only 9 mg, between 5.08 mg 5-MIAA (60 % conversion) and 8.46 mg 5-MIAA (100 % conversion) is formed.
  • the maternal exposure will be between 0.085 mg/kg/day and 0.282 mg/kg/day. This leads to an estimate for the RID of between 0.49 % and 1 .62 %.
  • the accepted threshold for "low risk” RID is 10%, and it is clear from the calculated values, which represent conservative estimates, that the 5-MIAA RID is significantly below this threshold.
  • the risk profile for 5-MIAA is low considering not just the sub-threshold daily RID value but the fact that the compound is endogenously formed as a metabolite of certain naturally occurring tryptophane derivatives, such as serotonin.
  • a further metabolite identified, bufotenine, is the result of O-demethylation, which is catalysed by CYP2D6.
  • the metabolized formed is then subject to glucuronidation, which is catalysed by UGT:
  • Bufotenine glucuronide cannot bind to receptors and does not exert any effect. Moreover, its concentration is so low that it was not detected in the hepatocyte assay. Bufotenine glucuronide is further converted to 5-hydroxyindole acetic acid:
  • 5-hydroxyindole acetic acid is an endogenous substance, for instance, it occurs in the metabolism of melatonin and serotonin (references as above). Since the O-demethylation pathway of 5-MeO-DMT only plays a minor role and leads to a primary metabolite, bufotenine, which is rapidly cleared from the plasma and the further metabolization leads to compounds present only in very low concentration and ultimately to a metabolite that is also part of endogenous metabolic pathways, the inventors determined that the O-demethylation of 5-MeO-DMT does not involve metabolites that would require imposing a limitation regarding breastfeeding.
  • the third metabolic pathway involves N-oxidation:
  • 5-MeO-DMT-N-oxide was deemed to be non-genotoxic in line with the negative in vitro genotoxicity assessment of the parent molecule.
  • the compound is water soluble and subject to rapid excretion, as confirmed by observations in the rat (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).
  • breast feeding can be resumed shortly after the treatment with 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the treated mother may be advised to temporarily cease breastfeeding, for instance, for a certain time period or until a certain event.
  • Ceasing breastfeeding means that the infant is neither directly fed from the breast nor fed with breastmilk pumped when breastfeeding is discouraged.
  • Bottle feeding breastmilk obtained beforehand is, however, possible. It is the timepoint at which the breastmilk is expressed (and not when the child is fed) that is determinative.
  • the mother is advised to temporarily cease breastfeeding only for the period of the actual treatment, for instance, until the Clinical Assessment of Discharge Readiness (CADR) indicates discharge readiness.
  • CARA Clinical Assessment of Discharge Readiness
  • the Clinical Assessment of Discharge Readiness is carried out to determine that there are no clinical obstacles preventing the patient from returning home.
  • Discharge readiness according to the CADR requires finding that any adverse events are resolved or, if not resolved, are not preventing discharge; that the patient is fully orientated; that the patient has no hallucinations or perception distortions; that the patient is alert (responds readily to name spoken in normal tone; (Modified Observer’s Assessment of Alertness I Sedation scored as 5); that the vital signs are without clinically significant changes compared to baseline; and that the patient is discharge ready in the opinion of the treating physician.
  • the CADR may be administered about 1 hour after administration of the last dose.
  • a licensed professional may perform their own discharge readiness assessment on the basis of relevant factors such as patient vital signs and/or alertness/seda- tion.
  • the patient may be advised not to recommence breastfeeding before the later of discharge and 6 hours after the last dose; preferably the later of discharge and 3 hours after the last dose; more preferably the later of discharge and 2 hours after the last dose; in particular the later of discharge and 1 hour after the last dose. It is also possible to wait longer until resuming breastfeeding, for instance, until the concentrations of 5-MeO-DMT and/or its metabolites in a breastmilk sample fall below certain thresholds.
  • breastfeeding may be temporarily ceased until the 5-MeO-DMT concentration in a breastmilk sample falls below 2000 pg/ml, 500 pg/ml or 75 pg/ml and/or until the 5-MIAA concentration in breastmilk falls below 14000 pg/ml, 2000 pg/ml or 75 pg/ml.
  • breastmilk may be pumped and discarded until the concentrations of 5- MeO-DMT and/or 5-MIAA fall below the indicated levels.
  • breastfeeding may be temporarily ceased for a fixed period, for instance, based on clinical experience regarding concentrations of 5-MeO-DMT and/or its metabolites in breastmilk.
  • the patient is advised to cease breastfeeding until 48 hours after receiving the last dose of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the patient is preferably advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof, more preferably until 12 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 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 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the concentration of 5-MeO-DMT and/or 5-MIAA in breast milk is as low as possible, in order to avoid any relevant risk on the suckling child. Any relevant risk on the suckling child can be avoided, if any expressed breast milk is discarded as long as the concentrations of 5-MeO-DMT and/or 5-MIAA in breast milk exceed predetermined thresholds or breastfeeding is only resumed when the 5-MeO-DMT concentration and/or the 5-MIAA concentration in breast milk is below a predetermined threshold.
  • the threshold for 5-MeO-DMT in breast milk is as low as possible.
  • the threshold for 5-MIAA in breast milk is as low as possible.
  • the threshold for both, 5-MeO-DMT and 5- MIAA, in breast milk is as low as possible.
  • the Delivered Infant Dose (DID) for 5-MeO-DMT and/or 5-MIAA should be kept as low as possible.
  • the DID for 5-MeO-DMT is kept as low as possible.
  • the DID for 5-MIAA is kept as low as possible.
  • the DID for both, 5-MeO-DMT and 5-MIAA is kept as low as possible.
  • DID for 5-MeO-DMT and/or 5-MIAA of the invention are as follows: In order to achieve the above DID, breastfeeding needs adaption. This adaptation is selected from an appropriate time point for resumption of breastfeeding, an appropriate number of feeds during the first 24 hours after resumption of breastfeeding, by pumping and discarding breastmilk for an appropriate period of time or by a combination of these measures.
  • the Relative Infant Dose (RID) for 5-MeO-DMT and/or 5-MIAA The Relative Infant Dose (RID) for 5-MeO-DMT and/or 5-MIAA
  • the Relative Infant Dose (RID) for 5-MeO-DMT and/or 5-MIAA should be as low as possible.
  • the RID for 5-MeO-DMT is kept as low as possible.
  • the RID for 5-MIAA is kept as low as possible.
  • the RID for both, 5-MeO-DMT and 5-MIAA is kept as low as possible.
  • RID for 5-MeO-DMT and/or 5-MIAA of the invention are as follows:
  • DID and the RID for 5-MeO-DMT and/or 5-MIAA are relevant aspects of the present invention. While each individual aspect is relevant as such, in a preferred embodiment of the invention both aspects, the DID for 5-MeO-DMT and/or 5-MIAA and the RID for 5-MeO-DMT and/or 5-MIAA, should be considered in combination. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MeO-DMT and the RID for 5-MeO-DMT are combined.
  • the DID and the RID for 5-MeO-DMT is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MIAA and the RID for 5-MIAA are combined.
  • the DID and the RID for 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MeO-DMT and the RID for 5-MIAA are combined.
  • the DID for 5-MeO-DMT and the RID for 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the RID for 5-MeO-DMT and the DID for 5-MIAA are combined.
  • the RID for 5-MeO-DMT and the DID for 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention.
  • the DID for 5-MeO-DMT and 5-MIAA and the RID for 5-MeO-DMT and 5-MIAA are combined.
  • the DID for 5-MeO- DMT and 5-MIAA and the RID for 5-MeO-DMT and 5-MIAA is kept as low as possible. Relevant DID and relevant RID that can be combined are provided in the present invention. Modes of Administration
  • 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 assure a rapid onset of action.
  • a most preferred route of administration is administration by inhalation.
  • the inhalation of the therapeutically effective amount of 5-MeO-DMT occurs within a single breath.
  • 5-MeO-DMT can be employed as a neat substance or in the form of a formulation for nasal administration, examples of which are known in the art.
  • 5-MeO-DMT can be employed as a pharmaceutically acceptable salt, preferably the hydrobromide salt, or in the form of a formulation of a pharmaceutically acceptable salt, preferable the hydrobromide salt. Examples of appropriate devices are known in the art.
  • Buccal administration or sublingual administration can also rely on a pharmaceutically acceptable salt of 5-MeO-DMT, preferable the hydrobromide salt, as such or in the form of formulations, for instance, tablets, films, sprays, creams, as generally known in the art.
  • a pharmaceutically acceptable salt of 5-MeO-DMT preferable the hydrobromide salt, as such or in the form of formulations, for instance, tablets, films, sprays, creams, as generally known in the art.
  • an aerosol comprises (a) a pharmaceutically acceptable gas; (b) aerosol particles of 5-methoxy-N,N-dimethyltryp- tamine (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 of about 1.3 mg/l to about 10 mg/l, in particular of about 2 mg/l to about 9 mg/l.
  • the pharmaceutically acceptable gas is preferably air.
  • the aerosol particles preferably contain less than 1 wt% impurities, in particular less than 0.5 wt% impurities. They furthermore preferably contain less than 0.5 wt% 5-MeO-DMT degradation products, in particular less than 0.2 wt% 5-MeO-DMT degradation products resulting from a chemical modification of 5-MeO-DMT as a result of a chemical reaction during aerosol formation.
  • the aerosol essentially consists of (a) air; (b) aerosol particles of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • the aerosol particles preferably contain 5-MeO-DMT in the form of the free base.
  • the aerosol is preferably characterized by a mass median aerodynamic diameter of less than 3 pm and more than 0.1 pm, in particular by a mass median aerodynamic diameter of less than 2 pm and more than 0.1 pm.
  • the aerosol may be formed 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 over the thin layer of 5-MeO-DMT to produce aerosol particles.
  • the thin layer may have a thickness of less than about 10 pm, in particular less than about 7.5 pm. It may have a thickness in the range of about 0.1 pm to about 10 pm, in particular in the range of about 0.3 pm to about 7.5 pm.
  • the thin layer of 5-MeO-DMT, configured on a solid support may be exposed to thermal energy via the air passing over the thin layer.
  • the thin layer of 5-MeO-DMT, configured on a solid support may be exposed to thermal energy via the solid support.
  • the air passing over the thin layer may have a temperature in the range of about 180°C to about 260°C.
  • the air passing over the thin layer may in particular have a temperature of about 210°C and pass over the thin layer at a rate of about 12 l/min for a duration of about 15 seconds.
  • the aerosol particles may be contained in a volume of equal 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. It is preferably delivered to a patient via a single inhalation.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided in a form suitable for inhalation in a medical context.
  • 5-MeO-DMT and pharmaceutically acceptable salts are provided thereof in the form of aerosols. These aerosols have a suitable aerosol particle mass density so that a therapeutically effective dose of the aerosol can be administered to a patient via a single inhalation.
  • Aerosols useful in the present invention can be formed using thermal energy.
  • thermal energy When using thermal energy to form an aerosol of a compound, it is very difficult to predict which conditions are suitable for safe, efficient and predictable aerosol ization, in particular if the aerosol is to be used for systemic delivery of that compound to a patient via the lungs.
  • Relevant variables in this context include a) the dose of the compound, b) the morphological state in which that compound is made available for aerosolization (e.g. in crystal form, or in form as a thin layer), 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 create the aerosol (defined by flow rate and duration of air flow).
  • compositions and methods described herein are for safe, efficient and predictable systemic delivery of 5-MeO-DMT or a pharmaceutically acceptable salt thereof to a patient through inhalation.
  • Safe means that the aerosol particles should contain only a very small amount of impurities and 5-MeO-DMT degradation products
  • efficient means that the dosage is aerosolized to a defined extent and preferably almost completely or completely, that the aerosol has desirable physical properties for delivery of the 5-MeO- DMT or a pharmaceutically acceptable salt thereof systemically via the lungs mainly via absorption in the pulmonary alveoli, and that the aerosol can be inhaled by the patient in a single inhalation (i.e., within one deep breath), and “predictable” means that there should be almost no or no variability in the amount of degradation products, in the extent of aerosolization, and in the physical properties of the aerosol.
  • a suitable aerosol can be achieved by a) providing the therapeutically effective amounts of 5-MeO-DMT as a thin layer, on a solid support, b) exposing the thin 5-MeO-DMT layer to elevated controlled temperatures for a short duration of time, and c) providing a controlled amount of air so that an aerosol is formed.
  • a composition for delivery of a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by a) exposing a thin layer of 5-MeO- DMT, configured on a solid support, to thermal energy, and b) passing air over the thin layer of 5-MeO-DMT; wherein said aerosol has one or more of the following features: 1) it contains aerosol particles which are characterized by a mass median aerodynamic diameter of less than 3 micron, 2) it contains aerosol particles which are characterized by less than 1 % wt impurities and less than 0.5% 5-MeO-DMT degradation products, 3) it can be delivered to a patient via a single inhalation.
  • the generation of aerosol particles characterized by a mass median aerodynamic diameter of less than 3 microns, with less than 1% wt impurities and less than 0.5% wt 5- MeO-DMT drug degradation products, in an aerosol volume which can be delivered to a patient via a single inhalation, is achieved by defining a) the dosage amount of 5-MeO- DMT contained in the thin layer of 5-MeO-DMT, b) the thickness of the thin layer of the 5-MeO-DMT, c) the thermal energy to which the thin layer of 5-MeO-DMT is exposed (defined by temperature and duration of exposure), and d) the total amount of the air which passes over the thin layer of 5-MeO-DMT (defined by airflow rate and duration of airflow).
  • the thin layer of 5-MeO-DMT is exposed to thermal energy via the air passing over the thin layer, in which case that air is heated.
  • the heated air passing over the thin layer may have a temperature in the range of about 180°C to about 260°C.
  • the air passing over the thin layer may in particular have a temperature of about 210°C.
  • the thin layer of 5-MeO-DMT is exposed to thermal energy via the solid support, in which case the air passing over the thin layer is not heated, but the solid support is heated.
  • the heated solid support may have a temperature in the range of about 180°C to about 420°C.
  • the 5-MeO-DMT used for formation of the thin layer, on the solid support is highly pure, with a purity of at least 99%, preferably at least 99.5%.
  • the dosage amount of 5-MeO-DMT contained in the thin layer of 5-MeO-DMT, configured on the solid support is from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg.
  • Useful specific amounts are, e.g., 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 e.g. about 6 mg, about 12 mg, and about 18 mg.
  • Solid supports on which 5-MeO-DMT or a pharmaceutically acceptable salt thereof is provided, can have a variety of shapes. Examples of such shapes include, without limitation, cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mm thickness and virtually any shape permeated by small (e.g., less than 1.0 mm-sized) pores. Preferably, solid supports provide a large surface to volume ratio (e.g., greater than 100 per meter) and a large surface to mass ratio (e.g., greater than 1 cm 2 per gram).
  • a solid support of one shape can also be transformed into another shape with different properties.
  • a flat sheet of 0.25 mm thickness has a surface to volume ratio of approximately 8,000 per meter. Rolling the sheet into a hollow cylinder of 1 cm diameter produces a support that retains the high surface to mass ratio of the original sheet but has a lower surface to volume ratio (about 400 per meter).
  • a number of different materials are used to construct the solid supports. Classes of such materials include, without limitation, metals, inorganic materials, carbonaceous materials and polymers. The following are examples of the material classes: aluminum, silver, gold, stainless steel, copper and tungsten; silica, glass, silicon and alumina; graphite, porous carbons, carbon yarns and carbon felts; polytetrafluoroethylene and polyethylene glycol. Combinations of materials and coated variants of materials are used as well. Where aluminum is used as a solid support, aluminum foil is a suitable material. Examples of silica, alumina and silicon based materials include amphorous silica S-5631 (Sigma, St.
  • BCR171 an alumina of defined surface area greater than 2 m 2 /g from Aldrich, St. Louis, Mo.
  • silicon wafer as used in the semiconductor industry. Carbon yams and felts are available from American Kynol, Inc., New York, N.Y.
  • the thickness of the thin layer of the 5-MeO-DMT, configured on the solid support is less than about 10 pm, in particular less than about 7.5 pm. It may have a thickness in the range of about 0.1 pm to about 10 pm, in particular in the range of 0.3 pm to 7.5 pm.
  • the total amount of the air passing over the thin layer of 5-MeO-DMT is defined by a flow rate of between about 6 liters per minute and about 40 liters per minute, preferable between about 8 liters per minute and about 16 liters per minute and the duration of airflow is chosen so that the total volume of aerosol does not exceed about 3 liters, preferably is between about 1 liter and 3 liters, such as between 2 liters and 3 liters.
  • the duration of airflow should be less than about 30 seconds.
  • a useful specific airflow rate and duration is about 12 liters per minute and about 15 seconds, leading to an aerosol volume of about 3 liters.
  • Another useful specific airflow rate and duration is 10 liters per minute and about 15 seconds, leading to leading to an aerosol volume of about 2.5 liters.
  • Another useful specific airflow rate and duration is 8 liters per minute and about 15 seconds, leading to leading to an aerosol volume of about 2 liters.
  • Another useful specific airflow rate and duration is 10 liters per minute and about 12 seconds, leading to leading to an aerosol volume of about 2 liters.
  • the aerosol formation rate is greater than 0.1 mg/sec.
  • the aerosol has an aerosol particle mass density of about 0.5 mg/l to about 18 mg/l, such as of about 0.5 mg/l to about 12.5 mg/l, preferably of about 1.3 mg/l to about 10 mg/l, in particular of about 2 mg/l to about 9 mg/l.
  • the 5-MeO-DMT aerosol particles are characterized by a mass median aerodynamic diameter of less than 3 micron and more than 0.1 micron, preferably of less than 2.5 micron and more than 0.1 micron, most preferably of less than 2 micron and more than 0.1 micron.
  • the 5-MeO-DMT aerosol particles are characterized by less than 1% wt impurities, preferably by less than 0.5% wt impurities.
  • the 5-MeO-DMT aerosol particles are characterized by less than 0.5% wt 5-MeO-DMT degradation products, preferably by less than 0.2% wt 5-MeO-DMT degradation products.
  • a composition for delivery of a therapeutically effective amount of 5-MeO-DMT may comprise an aerosol, wherein the aerosol is formed by a) exposing a dosage amount of 12 mg 5-MeO-DMT, configured as a thin layer of less than 5 micron thickness on a solid support, to a temperature of 210° C via passing heated air over the thin layer for a duration of 15 seconds; wherein said aerosol has one or more of the following features: 1) it contains aerosol particles which are characterized by a mass median aerodynamic diameter of less than 3 micron, 2) it contains aerosol particles which are 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.
  • a skilled person knowing the aerosol characteristics and the aerosolization conditions defined in the present invention, can identify suitable vaporization devices or systems, which lead to the required aerosol characteristics.
  • suitable vaporization devices or systems include e.g. the Volcano Medic Vaporization System with the associated dosing capsules with drip pad (Storz & Bickel, Germany; as disclosed in e.g. 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; as disclosed e.g. in US 7,458,374 B2, US 9,370,629 B2 and US 9,687,487 B2).
  • the aerosol generated may be collected in a balloon and inhaled by the patient from the balloon.
  • the present invention also provides dose ranges, particular doses as well as dosing regimens (administration schemes).
  • the invention is in part based on the inventor's conclusion that the occurrence of a peak psychedelic experience during the acute phase after administration of 5-MeO-DMT is driving its therapeutic benefit in patients suffering from PPD, in particular one or more of the aspects defined above, either in a causal relationship or at least as a surrogate behavioural marker for the underlying unknown therapeutic mechanism. Consequently, achieving peak experiences more rapidly, in a larger proportion of patients and with better reproducibility in an individual patient, compared with previously tested psychedelic agents and dosing regimens, will lead to a better therapeutic profile.
  • the present invention also relies on the short duration of action of 5-MeO-DMT and the absence of relevant tolerance (i.e., the absence of diminished or no psychedelic effects after re-administration), as a basis for enabling a dosing regimen with frequent re-administrations (such as more than once daily, or daily), which are designed to increase the rate of occurrence of peak experiences, thereby increasing the therapeutic benefit.
  • Such repeat administrations within short time also allow an intraindividual doseoptimization which reduces the risk of overdosing, which may otherwise lead to somatic side effects, such as the serotonin syndrome, negative psychic reactions, such as flashbacks of the experience at later timepoints, induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state (so- called "white-outs").
  • somatic side effects such as the serotonin syndrome
  • negative psychic reactions such as flashbacks of the experience at later timepoints
  • induction of mania or hypomania or to less meaningful psychedelic experiences with few or no memories of the altered state so- called "white-outs”
  • the 5- MeO-DMT is administered as a monotherapy, i.e., the patient does not receive any other treatment for PPD or symptoms associated with PPD.
  • the dosage amount of 5-MeO-DMT administered to a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation is in the range of about 1 mg to about 25 mg, or any amount of range therein, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg and most preferred from about 4 mg to about 12 mg.
  • Useful specific amounts are e.g. 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.
  • Patients may also be treated with an equimolar dose of a pharmaceutically acceptable salt of 5-MeO-DMT, such as the hydrobromide salt.
  • a pharmaceutically acceptable salt of 5-MeO-DMT such as the hydrobromide salt.
  • the improved methods for the treatment of a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the occurrence of a clinical response not later than about 2 hours after administration of 5-MeO-DMT.
  • the improved methods for the treatment of a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the persistence of a clinical response, including a clinical response which occurred not 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.
  • the improved methods for the treatment of a patient, as defined herein, diagnosed with postpartum depression, including a treatment-resistant form of this disorder, and including this disorder associated with suicidal ideation, with a therapeutically effective amount of 5-MeO-DMT comprise the administration of more than a single dose of 5-MeO-DMT.
  • this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 2 to 7 administrations, with not less than about 1 hour and not more than about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
  • this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 24 hours between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
  • this more than a single dose of 5-MeO-DMT is administered to a patient in one or more treatment blocks, each block consisting of 1 to 3 administrations, with about 1 to 4 hours, preferably 1 to 2 hours, between each administration within each treatment block, and not less than about 6 days between the end of one treatment block and the start of the next treatment block.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each of the administrations and in each of the treatment blocks is constant for that individual patient and is selected from about 1 mg to about 25 mg, preferably from about 2 mg to about 20 mg, more preferably from about 4 mg to about 20 mg and most preferred from about 4 mg to about 12 mg.
  • Useful specific amounts are e.g. 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 dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 20 mg being reached or all administrations within that treatment block being administered.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration within each treatment block, and then increases with each subsequent administration within each treatment block until the earlier of 20 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects.
  • the dosage amount 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 dosage amount of the prior administration. For example, if the dosage amount of the first administration was 6 mg and the dosage amount increase is 6 mg, unless one of the previously mentioned stopping criteria has been reached, then the dosage amount of the second administration will be 12 mg. Preferably, the dosage amount for the third administration will be 18 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient in each treatment block is selected from about 2 mg to about 8 mg for the first administration, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 8 mg to about 14 mg for the second administration, and from about 14 mg to about 20 mg for the third administration.
  • Useful specific amounts for the first, second and third administration are e.g. about 6 mg, about 12 mg, and about 18 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of the first treatment block, and then increases with each subsequent administration within that first treatment block until the earlier of 20 mg being reached or all administrations within that treatment block being administered or the patient having experienced a peak psychedelic experience or the supervising physician having decided that further dose increases are inappropriate based on observed side effects, with that highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks. For example, if the highest dosage in the first treatment block was 18 mg because the patient experienced a peak psychedelic experience at that dose, then the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks will be 18 mg.
  • the dosage amount of the 5-MeO-DMT administered to an individual patient is selected from about 2 mg to about 8 mg for the first administration of the first treatment block, and then increased, unless the patient has already experienced a peak psychedelic experience within that treatment block or the supervising physician has decided that further dose increases are inappropriate based on observed side effects, to a dosage selected from about 8 mg to about 14 mg for the second administration of the first treatment block, and from about 14 mg to about 20 mg for the third administration of the first treatment block, with the highest dosage in that first treatment block being used as the dosage for all subsequent treatment blocks and administrations within those subsequent treatment blocks.
  • Useful specific amounts for the first, second and third administration in the first treatment block are e.g. about 6 mg, about 12 mg, and about 18 mg.
  • a pharmaceutically acceptable salt of 5-MeO-DMT can also be used in all of the above dosing regimen, and that the appropriate weight amounts of a salt to be administered can be calculated from the stated weight amounts of the free base, assuming that equimolar amounts are used.
  • 5-MeO-DMT is preferably not administered together with a MAO inhibitor.
  • the occurrence of a "peak psychedelic experience" in a patient can be identified through achievement of at least 60% of the maximum possible score in each of the four subscales (mystical, positive mood, transcendence of time and space, and ineffability) of the 30- item revised Mystical Experience Questionnaire (M EQ-30) (as described in Barrett FS, J Psychopharmacol. 2015;29(11):1182-90).
  • the occurrence of a "peak psychedelic experience" in a patient can also be identified through achievement of at least 60% of the maximum possible score of 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).
  • OBN Oceanic Boundlessness
  • ASC Altered States of Consciousness
  • the occurrence of a "peak psychedelic experience" in a patient is preferably identified through achievement of a score of at least 75 in the Peak Experience Scale (PES) Total Score, also referred to as the Peak Psychedelic Experience Questionnaire (PPEQ), which averages answers scored by the patient from 0 to 100 for the following three questions: 1. How intense was the experience; 2. To what extent did you lose control; 3. How profound (i.e. deep and significant) was the experience?
  • PES Peak Experience Scale
  • PPEQ Peak Psychedelic Experience Questionnaire
  • 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).
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspect 1 wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or more.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • HAM-D 17-item Hamilton Depression Rating Scale
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 4, wherein the patient is diagnosed with a treatment-resistant form of postpartum depression.
  • BIMF Barkin Index of Maternal Functioning
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered in a first dosage amount for a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a dosage amount higher than the previous administration unless the patient experiences a peak psychedelic experience.
  • OBN Oceanic Boundlessness
  • ASC Altered States of Consciousness
  • PES Peak Experience Scale
  • PES Peak Experience Scale
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 18 to 20, wherein the dosage amount of 5-MeO-DMT or a pharmaceutically acceptable salt to be administered to the patient is inhaled with a single breath.
  • 5-MeO-DMT for use as in aspects 18 to 21 , wherein the 5-MeO-DMT is used in the form of the free base.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 22, wherein a clinical response, as reflected by a reduction 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.
  • CGI-S Clinical Global Impression - Severity
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 25, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 26, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 27, wherein a clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 28, wherein a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 29, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 30, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, occurs on day 1 , for instance, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 31 , wherein the clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 32, wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 33, wherein the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 34, wherein the clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 35, wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 36, wherein the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 37, wherein the clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 38, wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 39, wherein the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) or a pharmaceutically acceptable salt thereof for use in any of aspects 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in aspects 1 to 45, wherein the treatment improves maternal functioning.
  • BIMF Barkin Index of Maternal Functioning
  • 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).
  • PPD postpartum depression
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in item 1 wherein the patient has a Montgomery-Asberg Depression Rating Scale (MADRS) score of 20 or more or a 17-item Hamilton Depression Rating Scale (HAM-D) score of 16 or more.
  • MADRS Montgomery-Asberg Depression Rating Scale
  • HAM-D 17-item Hamilton Depression Rating Scale
  • BIMF Barkin Index of Maternal Functioning
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 8, wherein the 5-MeO-DMT or salt thereof is administered at a dose or in a dosage regimen that causes the patient to experience a peak psychedelic experience.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 9, wherein a dosage of about 4 mg to about 20 mg 5-MeO-DMT is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 9, wherein a dosage of about 6 mg; or of about 12 mg; or of about 18 mg is administered, or wherein equimolar amounts of the pharmaceutically acceptable salt are administered instead of 5-MeO-DMT.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 10, wherein the 5-MeO-DMT or salt thereof is administered in a first dosage amount for a first administration; and the 5-MeO-DMT or salt thereof is administered in zero to six subsequent administrations; wherein each subsequent administration uses a dosage amount higher than the previous administration unless the patient experiences a peak psychedelic experience.
  • OBN Oceanic Boundlessness
  • ASC Altered States of Consciousness
  • PES Peak Experience Scale
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 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.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 18 to 20, wherein the dosage amount of 5-MeO-DMT or a pharmaceutically acceptable salt to be administered to the patient is inhaled with a single breath.
  • 5-MeO-DMT for use as in items 18 to 21 , wherein the 5-MeO-DMT is used in the form of the free base.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 22, wherein a clinical response, as reflected by a reduction 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.
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 23, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, occurs on day 1 , for instance, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 24, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 25, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 26, wherein a clinical response, as reflected by a reduction in the Clinical Global Impression - Severity (CGI-S) score, persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • CGI-S Clinical Global Impression - Severity
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 27, wherein a clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 28, wherein a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 29, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, occurs not later than about 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 30, wherein a remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, occurs on day 1 , for instance, about 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 31 , wherein the clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 6 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 32, wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 33, wherein the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, on day 7 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • a MADRS score equal to or less than 10
  • a HAM-D score equal to or less than 7
  • the clinical response as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 14 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 35, wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 36, wherein the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, on day 14 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 37, wherein the clinical response, as assessed by at least 50% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, persists until at least 28 days after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 38, wherein there is a clinical response, as assessed by at least 75% improvement of the MADRS or HAM-D score, compared to the respective score prior to treatment, on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 39, wherein the patient is in remission of depressive symptoms, as assessed by a MADRS score equal to or less than 10, or a HAM-D score equal to or less than 7, on day 28 after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of items 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 48 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of items 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 24 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of items 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 6 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of items 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 3 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-Methoxy-N,N-dimethyltryptamine or a pharmaceutically acceptable salt thereof for use in any of items 1 to 40, wherein the patient is a breastfeeding mother who is advised to discontinue breastfeeding until 2 hours after the last administration of 5-MeO-DMT or a pharmaceutically acceptable salt thereof.
  • 5-MeO-DMT or a pharmaceutically acceptable salt thereof for use as in items 1 to 45, wherein the treatment improves maternal functioning.
  • BIMF Barkin Index of Maternal Functioning
  • Step 1 A stock solution of 5-MeO-DMT free base in 100% ethanol is prepared in a volumetric flask, so that the target dosage of 5-MeO-DMT free base to be administered via inhalation to the volunteer or patient is contained in a solution volume of 200 pl.
  • Typical target dosages are from 1 mg to 25 mg 5-MeO-DMT.
  • 90 mg of 5-MeO-DMT will be dissolved in 100% ethanol for a final solution volume of 1 ml. Aliquots of the stock solution can then be stored in vials until further use.
  • Step 2 200 pl of the solution is transferred to a dosing capsule containing the drip pad (Storz & Bickel, Germany), and then the dosing capsule is closed with its lid.
  • Step 3 The dosing capsule filled with the 5-MeO-DMT ethanol solution is transferred to the filling chamber of a first Volcano Medic Vaporizer, which has been pre-heated with the temperature set at 55°C. Then the airflow of the vaporizer is switched on for 60 seconds at the pre-set rate of about 12 l/min. The heated air will flow through the dosing capsule, allowing the ethanol to evaporate, with the target dosage of 5-MeO-DMT being left in the capsule, as a thin layer covering the stainless-steel wire mesh. Accurate preparation of the dosing capsule can be confirmed by demonstrating that the final weight increase of the capsule compared to the weight of the empty capsule is about equal to the target dosage of 5-MeO-DMT.
  • Step 4 The prepared dosing capsule is removed from the filling chamber. It is then transferred to the filling chamber of a second Volcano Medic Vaporizer, which has been preheated with the temperature set at 210°C and the airflow on for at least 5 minutes and then turned off immediately prior to transfer.
  • An inhalation balloon with a valve (Storz & Bickel, Germany) is mounted on the socket of the filling chamber, the filling chamber is closed tightly and immediately afterwards the airflow is switched on for exactly 15 seconds at the pre-set flow rate of about 12 1/min, and then turned off. This will allow the full dose of 5-MeO-DMT to aerosolize and be distributed in approximately 3 liters of air in the inhalation balloon.
  • Step 5 The balloon is then disconnected from the filling chamber, which automatically closes the valve. After attachment of the mouthpiece to the balloon, the aerosol is ready for immediate administration to the volunteer or patient.
  • Step 6 To prepare for the administration, the patient is asked to initially perform 1-2 deep inhalations with full exhalations, ending this sequence with a deep exhalation. Then, with the mouthpiece firmly held against the lips, the full and complete volume of the inhalation balloon is inhaled in one inhalation, holding the breath for 10 ( ⁇ 2.5) seconds, followed by a normal exhalation. After completing the inhalation procedure, the patient will be instructed to lie down.
  • 5-MeO-DMT HBr was prepared on a 100mg scale. 5-MeO-DMT free base was combined with isopropyl acetate (10 vols), and the resulting solution of 5-MeO-DMT was heated to 50°C. HBr was charged (1 M in ethanol, 1eq) in one single aliquot. The mixture was held at temperature and equilibrated for 3 hours.
  • the salt has a melting point of 174°C and is characterized by an X-ray diffraction pattern comprising peaks at 14.5°2e ⁇ 0.2°2e; 16.7°2e ⁇ 0.2°2e; 17.0°2e ⁇ 0.2°2e; 2O.6°20 ⁇ O.2°20; 2O.7°20 ⁇ O.2°20; 21.4°20 ⁇ O.2°20; 24.2 o 2e ⁇ 0.2°2d; 24.8 o 2e ⁇ 0.2°2d; 25.3°20 ⁇ O.2°20; 27.4°20 ⁇ O.2°20; measured using Cu Ka radiation.
  • Hippocampus was homogenised in ice-cold 0.25 M sucrose (1 :30 w/v) using a motor driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris were removed by centrifugation at 1 ,000g for 10 minutes. The supernatant was stored on ice and the pellet re-homogenised in 0.25 M sucrose (1 :15 w/v) and centrifuged at 750g for 10 minutes. The supernatants were combined and diluted in ice-cold membrane preparation buffer, (1 :100 w/v) using a tight-fitting glass/Teflon homogeniser (12 strokes, 800 rpm) and centrifuged at 20,500 g for 10 minutes.
  • the pellet was resuspended in ice-cold membrane preparation buffer and incubated at 37°C for 10 minutes before being centrifuged at 20,500 g for 10 minutes.
  • the pellet was resuspended and centrifuged a final time to wash the tissue (20,500 x g for 10 mins).
  • the resulting pellet was then resuspended in ice-cold assay buffer at a tissue concentration equivalent to 3.125 mg wet weight of tis- sue/ml. All centrifugations were carried out at 4°C.
  • the membrane preparation buffer consisted of 50 mM Tris-HCI, pH 7.7, 4 mM CaCh and 0.1 % ascorbic acid.
  • the assay buffer consisted of 50 mM Tris, pH 7.7, 4 mM CaCh, 0.1 % ascorbic acid and 10 pM Pargyline.
  • hippocampal membranes 400 pl; equivalent 1.25 mg wet weight tissue/tube
  • 50 pl of 0.075 - 9.6 nM [ 3 H]8-OH-DPAT 50 pl of assay buffer (total binding) or 50 pl of 1 pM WAY 100635 (non-specific binding) at 25°C for 30 minutes.
  • the wash buffer consisted of 50 mM Tris, pH 7.7.
  • hippocampal membranes 400 pl; equivalent 1.25 mg wet weight tissue/tube
  • 50 pl of 0.6 nM [ 3 H]8-OH-DPAT 50 pl of assay buffer (total binding) or 50 pl of 1 pM WAY 100635 (non-specific binding) or 50 pl of one of the test compounds in one of ten concentrations between 1 and 10000 nM at 25°C for 30 minutes.
  • Membrane bound radioactivity was recovered by filtration under vacuum through Skatron 11731 filters, pre-soaked in 0.5% polyethylenimine (PEI) using a Skatron cell harvester. Filters were rapidly washed with ice-cold wash buffer (wash setting 0,9,9) and radioactivity determined by liquid scintillation counting (1 ml Packard MV Gold scintillator).
  • PEI polyethylenimine
  • the concentration of compound required to inhibit 50% of specific binding (IC50) and the Hill Slope were calculated by using non-linear regression.
  • the Kj was calculated using the one-site binding model allowing for ligand depletion.
  • Frontal cortex was homogenised in ice-cold 0.25 M sucrose (1 :30 w/v) using a motor driven Teflon pestle (12 strokes at 120 rpm). Myelin and cell debris was removed by centrifugation at 1 ,000g for 10 minutes. The supernatant was stored on ice and the pellet re-homogenised in 0.25 M sucrose (1 :15 w/v) and centrifuged at 750g for 10 minutes.
  • the supernatants were combined and diluted in ice-cold 50 mM Tris-HCI assay buffer, pH 7.4 (1 :100 w/v), homogenised using a tight-fitting glass/Teflon homogeniser (12 strokes, 800 rpm) and centrifuged at 20,500 g for 10 minutes. The pellet was centrifuged a further two times to wash the tissue (20,500 x g for 10 mins). The resulting pellet was then resuspended in ice-cold 50 mM Tris-HCI assay buffer, pH 7.4 at a tissue concentration equivalent to 10 mg wet weight of tissue/ml. All centrifugations were carried out at 4°C.
  • frontal cortical membranes 400 pl; equivalent to 4 mg wet weight of tissue/tube
  • 50 pl of 0.00625 - 0.8 nM [ 3 H]MDL- 100,907 50 pl of assay buffer or 50 pl of 10 pM ketanserin (non-specific binding) at 25°C for 60 minutes.
  • the assay and wash buffer consisted of 50 mM Tris-HCI buffer pH 7.4.
  • frontal cortical membranes 400 pl; equivalent 4 mg wet weight tissue/tube
  • 50 pl of 0.1 nM [3H]MDL-100,907 was incubated with 50 pl of 0.1 nM [3H]MDL-100,907 and either 50 pl of assay buffer (total binding) or 50 pl of 10 pM ketanserin (non-specific binding) or 50 pl of one of the test compounds in one of ten concentrations between 1 and 10000 nM at 25°C for 60 minutes.
  • Membrane bound radioactivity was recovered and determined as above. Data analysis was also as above.
  • the dissociation constant (Kd value) of [ 3 H]8-OH-DPAT for 5-HT1A receptors in hippocampal membranes from post-mortem human brain tissue was determined for each of the three donors.
  • the dissociation constants (Kd values) obtained were 0.51 , 0.28 and 0.52 nM, respectively.
  • the dissociation constant (Kd values) of [ 3 H]MDL-100,907 for 5-HT2A receptors in frontal cortical membranes from post-mortem human brain tissue was determined for each of the three donors.
  • the dissociation constants (Kd values) obtained were 0.11 , 0.08 and 0.08 nM, respectively.
  • Part B was an open-label, single-arm Phase 2 trial applying an individualized dosing regimen with intrapatient dose escalation with 5-MeO-DMT.
  • the primary endpoint of Part A was to assess the safety and tolerability of single dosing of 5-MeO-DMT in patients with TRD.
  • the primary endpoint of Part B was to assess the effects on the severity of depression, as assessed by the proportion of patients in remission on day seven after dosing, defined as a MADRS total score of less than or equal to 10.
  • Part B 7 of 8 patients (87.5%) experienced at least one ADR. All ADRs resolved spontaneously. No SAEs were reported.
  • the primary endpoint was met with seven of eight patients (87.5%) achieving a MADRS remission on day seven (p ⁇ 0.0001).
  • the mean MADRS change from baseline at day seven was 24.4 (76%).
  • Table 3-C Scores recorded against relevant MADRS and BPRS items for patients as- signed to 12mg dosing regimen.
  • 5-MeO-DMT concentrations were determined using LC-MS/MS.
  • PK parameters were generated by algebraic analysis of the concentration versus time plots for each individual. The analysis was carried out using the software Phoenix WinNonlin 6.3.
  • Table 4 below shows median percentage plasma concentrations relative to Cmax as determined for the time points indicated.
  • 5-MeO-DMT did not induce mutation in four histidine-requiring bacterial strains (TA98, TA100, TA1535 and TA1537) of Salmonella typhimurium, and one tryptophan-requiring strain (WP2 uvrA pKM101) of Escherichia coli. These conditions included treatments at concentrations up to 5000 pg/plate (the maximum recommended concentration according to current regulatory guidelines), in the absence and in the presence of a rat liver metabolic activation system (S-9).
  • 5-MeO-DMT was incubated at a nominal concentration of 1 pM and 10 pM with human hepatocytes in suspension in Leibovitz L-15 medium (1 x 106 cells/mL).
  • a standard stock solution of 5-MeO-DMT was prepared in ethanol at 20 mM and was further diluted with Leibovitz L-15 medium to a concentration of 2 mM.
  • the 2 mM stock solution was diluted with Leibovitz L-15 medium to a concentration of 20 pM or 2 pM.
  • An aliquot (250 pL) of the 20 pM and 2 pM test substance formulations was added to each hepatocyte incubation sample (250 pL), as appropriate, so that the final test substance concentration in the incubations was 10 pM or 1 pM, respectively, and incubations contained less than 1 % (v/v) solvent.
  • Incubations were performed at ca. 37°C in a shaking water bath (total incubation volume 0.5 mL). For 1 pM, 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 pM, incubations were terminated after 0, 10, 30, 60 and 120 minutes, by the addition of ice-cold acetonitrile containing internal standard (1 pg/mL Psilocin-d10).
  • the samples were vortex mixed and centrifuged at ca 13,000 rpm for 10 minutes at room temperature. Following centrifugation, the protein-free supernatants were removed for analysis.
  • Blank control incubations were carried out with Leibovitz L-15 medium in place of the test substance. No cells control samples were performed with Leibovitz L-15 medium in place of hepatocytes. Aliquots of the blank control samples were taken at 120 minutes, while no cells control samples were taken at 0, 30 and 120 for 1 pM incubations and at 0 and 120 minutes for 10 pM incubations.
  • Suitable chromatographic conditions were developed to retain the parent compound and give a suitable chromatographic response.
  • the 0, 30 and 120-minute incubation samples generated following incubation of 5-MeO-DMT at 10 pM were analysed using reverse phase LC-MS analysis to generate high and low energy mass spectra (MSE).
  • MSE mass spectra
  • Prior to sample analysis a 100 pL aliquot of each sample was evaporated to near dryness under a steady stream of nitrogen at room temperature, and subsequently reconstituted in 50 pL of mobile phase A (0.1 % formic acid in water).
  • Each sample (0, 30 and 120-minute, 10 pM) was analysed using accurate mass LC-MS to determine relative levels of parent compound at each time-point, and determine the profile of metabolites formed. Appropriate blank and control samples were also analysed.
  • the 10 and 60-minute, 10 pM incubation samples were not analysed and were stored at -80°C (nominal).
  • Results obtained are summarized in the above table 1 .
  • Example 10 Metabolic stability for 5-Methoxy lndole-3-Acetic Acid (5-MIAA) and 5-Methoxytryptophol in a human hepatocyte co-culture model
  • the metabolic stability of 5-MIAA and 5-methoxytryptophol was investigated in a Hprel co-culture assay with human hepatocytes (Hprel HumanPoolTM, primary hepatic co-cul- ture model from Visikol Inc.).
  • the incubations were performed using 1 and 10 pM initial concentrations and sampling at 0, 1 , 2, 4, 8, 24, 48, and 72 hours (h) time points.
  • the samples were analysed using UPLC/QE-orbitrap-MS.
  • the predicted hepatic extraction ratios were 2% for 5-MIAA and 67% 5-methoxytryp- tophol.
  • the single-arm, open-label clinical trial will involve 15 adult female patients with clinically diagnosed postpartum depression (PPD).
  • PPD postpartum depression
  • the patients will receive a single-day individualized 5-MeO-DMT dosing regimen via inhalation after vaporization.
  • the patients will receive up to three doses of 5-MeO-DMT on Day 0: 6 mg, 12 mg, and 18 mg.
  • the second dose (12 mg) will only be administered if: a. A peak experience (total score of >75) has not been achieved following the 6 mg dose, and b. The 6 mg dose was safe and well-tolerated according to the investigator, c. Any psychoactive effects (PsE) of the prior dose have subsided, and d. Pre-dose vital parameters and forced expiratory volume in one second (FEV1) are in normal range, or if outside of the normal range, are not clinically significant according to the investigator.
  • a third dose (18 mg) will only be administered if: a. A peak experience (total score of >75) has not been achieved following the 12 mg dose, and b. The 12 mg dose was safe and well-tolerated according to the investigator, and c. Any PsE of the prior dose have subsided, and d. Pre-dose vital parameters and forced expiratory volume in one second (FEV1) are in normal range, or if outside of the normal range, are not clinically significant according to the investigator.
  • FEV1 forced expiratory volume in one second
  • the patients will be assessed for a peak psychedelic experience (based on a patient- scored visual analogue scale, the PE scale), sedation, and other endpoints after dosing.
  • a peak psychedelic experience based on a patient- scored visual analogue scale, the PE scale
  • sedation based on a patient- scored visual analogue scale, the PE scale
  • other endpoints after dosing.
  • follow-up visits are planned for Day 1 , and Day 7 after the dosing day.
  • BMI body mass index
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • Has any current or past clinically significant condition e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of hypertensive disorders of pregnancy during pregnancy or in the postnatal period (e.g., gestational hypertension, pre-eclampsia-eclampsia, superimposed pre-eclampsia), uncontrolled diabetes, severe cardiovascular disease, severe hepatic or renal failure, severe brain disorder (including seizure disorder, stroke, dementia, degenerative neurologic diseases, meningitis, encephalitis, and head injury with loss of consciousness) that renders the patient unsuitable for the trial according to the investigator’s judgment. Takes any medication or other substance that renders the patient unsuitable for the trial according to the investigator’s judgment.
  • severe infection e.g., severe infection, pulmonary disease, uncontrolled hypertension, new onset of hypertensive disorders of pregnancy during pregnancy or in the postnatal period (e.g., gestational hypertension, pre-eclampsia-eclampsia,
  • Patient who has a positive pregnancy test at screening or on the pre-test day (Day -1), is pregnant, or plans to become pregnant during the course of the trial and up to 90 days after 5-MeO-DMT dosing. 12. Patients with DSM-5 drug or alcohol use disorder within 6 months prior to screening.
  • the primary objective of the trial is to determine the onset and 7-day durability of anti- depressive effects of a single-day individualized dosing regimen of 6 mg, 12 mg and 18 mg of 5-MeO-DMT in adult, female patients with PPD.
  • Secondary objectives are to determine the anti-depressive effects; the anti-anxiety effects; the effects on maternal behavior; the safety and tolerability; the intensity and duration of psychoactive effects (PsE); the impact on cognitive outcome of a single-day individualized dosing regimen of 6 mg, 12 mg and 18 mg of 5-MeO-DMT in adult, female patients with PPD.
  • An exploratory objective is to determine in breastmilk, blood and urine the amount of 5- MeO-DMT and metabolites, bufotenine and 5-methoxyindole-3-acetic acid (5-MIAA), measured by LC/MS/MS (metabolite identification screening may be performed, as required), following dose administration of a single-day IDR of 6 mg, 12 mg and 18 mg of 5-MeO-DMT in adult, female patients with PPD.
  • 5-MIAA 5-methoxyindole-3-acetic acid
  • the primary endpoint of the study is the evaluation of the anti-depressive effects of 5- MeO-DMT by the change from baseline in MADRS assessed at Day 7.
  • Secondary endpoints include the anti-depressive effects of 5-MeO-DMT evaluated by
  • Duration of the PsE defined as the time from study drug dosing to the time when the PsE have subsided (investigator- and patient-scored), completed 30 to 60 minutes after each dosing.
  • Diagnosis was Major Depressive Disorder without psychotic features, confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2), with peri-partum onset that began no earlier than gestation and no later than the first 4 weeks postpartum.
  • MINI Mini-International Neuropsychiatric Interview
  • the patient was diagnosed with postpartum depression after giving birth to her third child.
  • the patient completed all planned visit days.
  • the inhalation procedure was adequately performed by the patient and was well tolerated with no inhalation-related adverse events.
  • the recorded PES score achieved upon exposure to a nominal dose of 6mg was 17.3. This score indicated the need to proceed to the administration of a subsequent, higher dose of 12mg, per the design of the individualised dosing regimen.
  • the PES score achieved for this dose was 85.7 and, being >75, indicated the occurrence of a peak psychedelic experience and the completion of the IDR for this patient.
  • the patient reported a major improvement in her depressive symptoms as assessed by MADRS at the earliest assessment timepoint of 2 hours after drug administration, with the effect being maintained over time (Table 9).
  • the patient also fulfilled standard criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score equal or less than 10).
  • Diagnosis was Major Depressive Disorder without psychotic features, confirmed by the Mini-International Neuropsychiatric Interview (MINI) (v7.0.2), with peri-partum onset that began no earlier than gestation and no later than the first 4 weeks postpartum.
  • MINI Mini-International Neuropsychiatric Interview
  • the patient completed all planned visit days (here on day 5 instead of day 7).
  • the inhalation procedure was adequately performed by the patient and was well tolerated with no inhalation-related adverse events.
  • the recorded PES score achieved upon exposure to a nominal dose of 6mg was 1 . This score indicated the need to proceed to the administration of a subsequent, higher dose of 12mg, one hour after the first dose, per the design of the individualised dosing regimen.
  • the PES score achieved for this dose was 94.7 and, being >75, indicated the occurrence of a peak psychedelic experience and the completion of the IDR for this patient.
  • the patient reported a major improvement in her depressive symptoms as assessed by MADRS at the earliest assessment timepoint of 2 hours after drug administration, with the effect being maintained over time (Table 12).
  • the patient also fulfilled standard criteria for MADRS response (at least 50% improvement from baseline) and MADRS remission (MADRS total score equal or less than 10).
  • Table 12 MADRS/BPRS scores table
  • 5-MeO-DMT has a significantly improved efficacy profile compared to approved pharmacological therapies for postpartum depression and to all previously tested psychedelic agents, when used according to the present invention.
  • the second patient was lactating, and, per the clinical trial protocol, breastmilk samples were collected pre-dosing and at multiple timepoints after administration of the last dose. These samples were subsequently analysed via LC-MS/MS assay for the detection of 5- MeO-DMT, bufotenine (a primary metabolite of 5-MeO-DMT) and 5-MIAA (a final metabolite of 5-MeO-DMT). Similar analyses were carried out on patient serum and urine samples. The data are summarised in the table below.
  • BLQ Below limit of quantification.
  • the lower limit of quantification is 25pg/ml for both 5- MeO-DMT and 5-MIAA in both serum and breastmilk; it is 25pg/ml in urine for 5-MeO- DMT and 250 pg/ml for 5-MIAA in urine.
  • the data indicate the rapid clearance of 5-MeO-DMT from serum by the first measurement timepoint of 1 hour post last dose, with a concentration of 132.9 pg/ml detected at this point and all subsequent timepoints resulting in concentrations below the lower limit of quantification of the assay. Additionally, endogenous levels of 5-MIAA were confirmed in serum prior to dosing, with highest concentrations detected at the first measurement timepoint (1 hour after dosing) and returning to baseline levels within 1 day.
  • the urine assay data demonstrate the presence of 5-MeO-DMT at concentrations approx, four-fold higher than those detected in serum at 1 hour (indicating already significant excretion by this point), falling off rapidly to undetectable levels after this timepoint, while 5-MIAA levels peak at concentrations approx.

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Abstract

La 5-méthoxy-N,N-diméthyltryptamine (5-MeO-DMT) ou un sel pharmaceutiquement acceptable de celle-ci est utilisée dans le traitement d'une patiente atteinte de dépression post-partum (DPP).
PCT/EP2023/076817 2023-01-30 2023-09-27 5-méthoxy-n,n-diméthyltryptamine pour le traitement de la dépression post-partum Ceased WO2024160390A1 (fr)

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KR1020257028944A KR20250135903A (ko) 2023-01-30 2023-09-27 산후 우울증의 치료를 위한 5-메톡시-n,n-다이메틸트립타민
AU2023426967A AU2023426967A1 (en) 2023-01-30 2023-09-27 5-methoxy-n,n-dimethyltryptamine for the treatment of postpartum depression
CN202380095315.6A CN120813348A (zh) 2023-01-30 2023-09-27 用于治疗产后抑郁的5-甲氧基-n,n-二甲基色胺
EP23782215.0A EP4658265A1 (fr) 2023-01-30 2023-09-27 5-méthoxy-n,n-diméthyltryptamine pour le traitement de la dépression post-partum
IL322429A IL322429A (en) 2023-01-30 2023-09-27 5-Methoxy-N,N-dimethyltryptamine for the treatment of postpartum depression
MX2025008755A MX2025008755A (es) 2023-01-30 2025-07-25 5-metoxi-n,n-dimetiltriptamina para el tratamiento de la depresion postparto

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PCT/EP2023/057883 WO2023186835A1 (fr) 2022-03-27 2023-03-27 Traitement de troubles mentaux
PCT/EP2023/057873 WO2023186826A1 (fr) 2022-03-27 2023-03-27 5-meo-dmt destinée à être utilisée dans le traitement de la dépression post-partum
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PCT/EP2023/076816 Ceased WO2024160389A1 (fr) 2023-01-30 2023-09-27 5-méthoxy-n,n-diméthyltryptamine destinée à être utilisée dans le traitement de troubles mentaux chez des mères allaitantes

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US12264131B2 (en) 2022-08-19 2025-04-01 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
US12275735B2 (en) 2021-01-15 2025-04-15 Beckley Psytech Limited Ergoline analogues

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12275735B2 (en) 2021-01-15 2025-04-15 Beckley Psytech Limited Ergoline analogues
US12264131B2 (en) 2022-08-19 2025-04-01 Beckley Psytech Limited Pharmaceutically acceptable salts and compositions thereof
US12246005B2 (en) 2023-06-13 2025-03-11 Beckley Psytech Limited 5-methoxy-n,n-dimethyltryptamine (5-MeO-DMT) formulations

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AU2023426967A1 (en) 2025-09-18
CN120813348A (zh) 2025-10-17
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