Medicaments for the treatment of CNS disorders or neurodegenerative disorders, or for the improvement of health and wellbeing

Abstract

Provided herein are compositions, particularly pharmaceutical compositions, comprising racemic and enantiomerically pure mixtures of tetrahydroharmine (THH), R-tetrahydroharmine ((R)-THH), and S-tetrahydroharmine ((S)-THH), and optionally a tryptamine and / or harmala alkaloid, and pharmaceutically acceptable salts thereof. Also provided are uses of the aforementioned compositions, including medical uses. Also provided are methods of preparing the compositions.

Description

[0001] MEDICAMENTS FOR THE TREATMENT OF CNS DISORDERS OR NEURODEGENERATIVE DISORDERS, OR FOR THE IMPROVEMENT OF HEALTH AND WELLBEING

[0002] TECHNICAL FIELD

[0003] The present disclosure relates to pharmaceutical compositions comprising a nonracemic mixture of tetrahydroharmine (THH) and a pharmaceutically acceptable excipient, compositions comprising a nonracemic mixture of tetrahydroharmine (THH) and a tryptamine, and their methods and uses in the treatment of diseases, disorders, or conditions, particularly those related to and / or those responsive to modulation of monoamine oxidase (e.g., MAO-A, MAO-B), serotonin receptors (5-HT2A, 5-HT2C), and / or sigma-1 receptors. BACKGROUND

[0004] The tryptamines are a class of monoamine alkaloids, which share an indole-ethylamine moiety. It is thought that the tryptamines may be useful for the potential treatment of central nervous system (CNS) disorders, including neurodegenerative and psychiatric disorders, and more generally for the improvement of health and wellbeing in otherwise healthy individuals. However, the tryptamines typically have a complex metabolic profile, and as such, possess unpredictable durations of activity. For example, the tryptamine, N,N-dimethyltryptamine (DMT), lacks oral bioactivity when administered alone, or when administered by non-oral routes produces a psychoactive effect that is very brief, typically around 15 minutes, which is too short for sustained therapeutic exposure. Other tryptamines, including 5-MeO-DMT, psilocybin, and lysergic acid diethylamide (LSD), exhibit either short but overly abrupt acute effects or prolonged durations of acute effects extending up to ten hours. These pharmacokinetic extremes, together with the inability to adjust the timing and magnitude of exposure during administration, limit dosing flexibility and clinical optimisation. It is primarily the effects of monoamine oxidase A (MAO-A) that are responsible for the complex metabolic profile of the tryptamines. Indeed, monoamine oxidase A (MAO-A) is the primary enzyme responsible for first-pass oxidative deamination of the tryptamines.

[0005] Tetrahydroharmine (THH) is a p-carboline member of the harmala alkaloid class and has been described in prior literature to weakly inhibit MAO-A, suggesting limited relevance for applications requiring sustained or potent MAO-A modulation. Moreover, prior literature has reported that tetrahydroharmine (THH) shows low receptor affinity and minimal engagement of downstream signalling pathways, leading to the view that tetrahydroharmine(THH) was of limited interest for therapeutic development. Generally, tetrahydroharmine (THH) obtained by synthetic routes is produced in racemic form, whereas tetrahydroharmine (THH) isolated from natural plant sources, or present in traditional preparations, occurs only as a scalemic mixture of its two enantiomers, R-THH and S-THH.

[0006] Banisteriopsis caapi (B. caapi) is the only known natural source that contains pharmacologically meaningful quantities of tetrahydroharmine (THH). However, the ability to obtain enantiomerically pure (R)-THH and / or (S)-THH from B. caapi remains unpredictable, and material produced from traditional preparations contains tetrahydroharmine (THH) in partially racemised and compositionally unstable forms that are unsuitable for pharmaceutical use, thereby limiting their suitability for clinical development.

[0007] SUMMARY

[0008] The subject matter of the present disclosure is predicated in part on the surprising discovery that compositions comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and optionally a tryptamine, or a pharmaceutically acceptable salt thereof, provide advantageous methods of treating diseases, disorders, or conditions.

[0009] In some embodiments, it has been surprisingly found that the individual enantiomers of tetrahydroharmine (THH), being (R)-THH and (S)-THH, particularly when obtained at high enantiomeric purity, may exhibit differentiated and / or superior pharmacological and / or pharmacokinetic properties compared with racemic THH.

[0010] That is, unexpectedly, R-tetrahydroharmine (R-THH) and S-tetrahydroharmine (S-THH), at high enantiomeric purity, demonstrate distinct and previously unrecognised pharmacological properties that lend themselves to the specific combinations and therapeutic applications described herein. First, both enantiomers have been found to exhibit approximately two-fold greater monoamine oxidase A (MAO-A) inhibitory potency compared with racemic tetrahydroharmine (THH), which, in some embodiments, may provide effective tryptamine bioavailability at lower tetrahydroharmine (THH) doses in the compositions and formulations described herein. Second, the enantiomers have been found to exhibit markedly different brain-to-plasma partitioning characteristics, with S-THH demonstrating approximately two-fold greater central nervous system penetration than R-THH, thereby, in some embodiments, supporting enantiomer-specific selection for the route-specific formulations and dosing methods described herein. Third, the enantiomers exhibit distinct receptor interaction profiles, with R-THH showing preferential sigma-1 receptor binding andS-THH demonstrating enhanced 5-HT2C receptor affinity in some embodiments, which may provide mechanistic bases for the indication-specific therapeutic applications described herein. These surprising and advantageous findings, culminating in combined pharmacological differentiations, may, in some embodiments, provide the specific enantiomer compositions, ratios, formulations, and therapeutic methods as described herein.

[0011] Accordingly, in one aspect, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. It has been surprisingly found that such pharmaceutical compositions may potentiate and / or modify the pharmacokinetics and / or pharmacodynamics of a co-administered tryptamine (e.g., DMT). It therefore follows that, in some embodiments, the pharmaceutical composition described herein, is formulated for co-administration with a tryptamine. In some embodiments, the pharmaceutical composition further comprises an additional harmala alkaloid, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional harmala alkaloid is harmine (HME), or a pharmaceutically acceptable salt thereof. In some embodiments, the additional harmala alkaloid is harmaline (HML), or a pharmaceutically acceptable salt thereof.

[0012] In a further aspect, there is provided a composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a tryptamine, or a pharmaceutically acceptable salt thereof. It has been surprisingly found that such compositions may potentiate and / or modify the pharmacokinetics and / or pharmacodynamics of the tryptamine. In some embodiments, the tryptamine is N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises an additional harmala alkaloid, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional harmala alkaloid is harmine (HME), or a pharmaceutically acceptable salt thereof. In some embodiments, the additional harmala alkaloid is harmaline (HML), or a pharmaceutically acceptable salt thereof.

[0013] In a further aspect, there is provided a method of treating a disease, disorder, or condition in a subject, comprising administering the pharmaceutical composition, as described herein, or the composition, as described herein.

[0014] In a further aspect, there is provided use of the pharmaceutical composition, as described herein, or the composition, as described herein, in the manufacture of a medicament for the treatment of a disease, disorder, or condition.In a further aspect, there is provided the pharmaceutical composition, as described herein, or the composition, as described herein, for use in the treatment of a disease, disorder, or condition.

[0015] In a further aspect, there is provided the use of the pharmaceutical composition, as described herein, or the composition, as described herein, in the treatment of a disease, disorder, or condition.

[0016] In some embodiments, the disease, disorder, or condition is responsive to one or more of modulation of Serotonin receptor (5-HT2A) activity; and / or modulation of Serotonin receptor (5-HT2c) activity; and / or modulation of activity at a Serotonin receptor other than 5-HT2Aand 5-HT2c; and / or modulation of activity at a Sigma-1 receptor; and / or modulation of activity at a Dopamine receptor; and / or modulation of activity at an Adrenergic receptor; and / or inhibition of a monoamine oxidase (MAOs); and / or modulation of a monoamine transporter (DAT, SERT and / or NET); and / or enhancement of neuroplasticity.

[0017] In one embodiment, the disease, disorder, or condition is responsive to inhibition of a monoamine oxidase (MAO) (e.g., MAO-A).

[0018] The method of treatment may provide one or more advantages in relation to treating the subject, such as, for example, the ability to tailor the duration of action of the tryptamine.

[0019] It will be appreciated that other aspects, embodiments, and examples of the pharmaceutical compositions, compositions, methods, or uses, are further described herein.

[0020] BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is an SEM image of racemic THH HCI sample at 490* magnification, showing needle-like crystalline particles distributed along fracture lines, with individual particle lengths measuring approximately 35 pm.

[0022] Figure 2 is an SEM image of R-THH- hemifumarate sample at 490* magnification, showing dense, irregularly packed clusters with a distinct layered morphology.

[0023] Figure 3 is an SEM image of S-THH- hemifumarate sample at 1000* magnification, showing compact, plate-like particles forming dense, layered agglomerates with an average particle size of approximately 40 pm.Figure 4 is a schematic depicting the process for conversion of racemic THH into R-THH and S-THH, as well as the process for subsequent racemisation of R-THH or S-THH, to racemic THH in the presence of a strong acid (HCI).

[0024] Figure 5 is tabulated stability data for the formation of R-THH and S-THH hemifumarate salts, demonstrating that the fumarate salts do not undergo racemisation.

[0025] Figure 6 is a dose-response curve showing percentage inhibition of monoamine oxidase MAO-A relative to concentration of rac-THH HCI, vs. Clorgyline (MAO-A inhibitor).

[0026] Figure 7 is a dose-response curve showing percentage inhibition of monoamine oxidase MAO-A relative to concentration of R-THH Hemifumarate, vs. Clorgyline (MAO-A inhibitor).

[0027] Figure 8 is a dose-response curve showing percentage inhibition of monoamine oxidase MAO-A relative to concentration of S-THH Hemifumarate, vs. Clorgyline (MAO-A inhibitor).

[0028] Figure 9 is a dose-response curve showing percentage inhibition of 1 Serotonin (5-Hydroxytryptamine) 5-HT2C relative to concentration of rac-THH HCI, vs. RE 102221.

[0029] Figure 10 is a dose-response curve showing percentage inhibition of 1 Sigma o1 relative to concentration of rac-THH HCI, vs. Haloperidol.

[0030] Figure 11 is a dose -response curve showing percentage inhibition of 1 Serotonin (5-Hydroxytryptamine) 5-HT2C relative to concentration of R-THH Hemifumarate, vs. RE 102221.

[0031] Figure 12 is a dose-response curve showing percentage inhibition of 1 Sigma o1 relative to concentration of R-THH Hemifumarate, vs. Haloperidol.

[0032] Figure 13 is a dose-response curve showing percentage inhibition of 1 Serotonin (5-Hydroxytryptamine) 5-HT2C relative to concentration of S-THH Hemifumarate, vs. RE 102221.

[0033] Figure 14 is a dose-response curve showing percentage inhibition of 1 Sigma o1 relative to concentration of S-THH Hemifumarate, vs. Haloperidol.

[0034] Figure 15 is an FT-IR spectrum of a powder blend formulation comprising Harmine HCI (9.30%), R-THH hemifumarate (9.86%), and DMT hemifumarate (5.03%) with lactosemonohydrate (Supertab® 11SD, 61.00%), Avicel PH 102 (11.83%), colloidal silica (2.01%), and magnesium stearate (0.99%).

[0035] Figure 16 shows preparation of B. caapi, Nuevo Ola vines for extraction.

[0036] Figure 17 shows B. caapi extraction protocol.

[0037] Figure 18 shows a representative Chromatogram, racemic mix of THH.

[0038] Figure 19 shows chiral HPLC spectrum of D326- 109-02, B. caapi, variety: caupuri MeOH extract (ambient temperature overnight).

[0039] DETAILED DESCRIPTION

[0040] General Definitions

[0041] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent pharmaceutical compositions, compositions, methods, and uses, are clearly within the scope of the disclosure, as described herein.

[0042] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.

[0043] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, biochemistry, medicinal chemistry, microbiology and the like).

[0044] As used herein, the term “and / or”, e.g., “X and / or Y”, shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning, e.g., A and / or B includes the options i) A, ii) B, or iii) A and B.

[0045] As used herein, the term “about”, unless stated to the contrary, refers to + / - 20%, typically + / - 10%, typically + / - 5%, of the designated value.

[0046] As used herein, the terms “a”, “an”, and “the” include both singular and plural aspects, unless the context clearly indicates otherwise.It is to be appreciated that certain features that are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination.

[0047] Throughout the present specification, various aspects and components of the disclosure can be presented in a range format. The range format is included for convenience and should not be interpreted as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range, unless specifically indicated. For example, description of a range such as from 1 to 5 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 5, from 3 to 5 etc., as well as individual and partial numbers within the recited range, for example, 1, 2, 3, 4, 5, 5.5 and 6, unless where integers are required or implicit from context. This applies regardless of the breadth of the disclosed range. Where specific values are required, these will be indicated in the specification.

[0048] Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0049] Throughout the specification the phrase “consisting of’ will be understood to mean the elements, integers or steps listed and no others.

[0050] It will be clearly understood that, should a citation / publication be referred to herein, this reference does not constitute an admission that the document forms part of the common general knowledge in the art in the United States, Australia, or in any other country.

[0051] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. In case of conflict, the present specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.As used herein, the term “subject”, or variations thereof, refers to any organism susceptible to a disease, disorder, or condition. For example, the subject may be a mammal, primate, livestock (e.g., sheep, cow, horse, pig), companion animal (e.g., dog, cat), or laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster). In one example, the subject is a mammal. In one example, the subject is a human.

[0052] As used herein, the terms “treatment” and “treating”, or variations thereof, include alleviation of a symptom associated with a specific disease, disorder, or condition, and includes eliminating a symptom associated with the disease, disorder, or condition.

[0053] As used herein, the term “prevention”, and variations thereof, includes the reduction in likelihood of developing a symptom (i.e., reduced incidence) associated with a specific disease, disorder, or condition, and includes the prevention of developing a symptom associated with a specific, disease, disorder or condition, and includes preventing the onset or duration of a symptom associated with the disease, disorder, or condition.

[0054] As would be appreciated by the person skilled in the art, the pharmaceutical composition and compositions described herein may be administered so as to provide at least one component (e.g., the nonracemic mixture of tetrahydroharmine (THH) and / or the tryptamine) of the pharmaceutical composition or composition in a therapeutically effective amount. The term “therapeutically effective amount”, as used herein, refers to the pharmaceutical composition, as described herein, or composition, as described herein, being administered in an amount sufficient to treat or prevent, as defined herein, one or more of the symptoms of the disease, disorder, or condition. In one embodiment, the term “therapeutically effective amount” refers to the amount of a component of the pharmaceutical composition or composition. In one embodiment, the term “therapeutically effective amount” refers to the nonracemic mixture of tetrahydroharmine (THH) present in the pharmaceutical composition or composition. In one embodiment, the term “therapeutically effective amount” refers to the tryptamine present in the composition. In one embodiment, the term “therapeutically affective amount” refers to both the nonracemic mixture of tetrahydroharmine (THH) and tryptamine present in the composition (i.e., both the nonracemic mixture of the tetrahydroharmine (THH) and the tryptamine are each present in a therapeutically effective amount). Accordingly, where more than one therapeutic agent is used in composition, a “therapeutically effective amount” of each therapeutic agent can refer to an amount of the therapeutic agent that would be therapeutically effective when used on its own or may refer to a reduced amount that is therapeutically effective by virtue of its combination with the additional therapeutic agent.As used herein, the term “pharmaceutically acceptable salt”, or like terms, refer to pharmaceutically acceptable organic or inorganic salts. It will be appreciated that any reference to “salt” herein can include “pharmaceutically acceptable salts”. Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, isonicotinate, lactate, salicylate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate) salts. Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D-glucamine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di-or triethanolamine. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion, or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions. It will also be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport.

[0055] In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, acetate, mesylate, tosylate, camsylate fumarate and hemifumarate. In some embodiments the pharmaceutically acceptable salt is a hydrochloride or hemifumarate salt of THH. In one example, the THH is provided as a hydrochloride salt.

[0056] Those skilled in the art of organic and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. As used herein, the terms “pharmaceutically acceptable solvate” and “solvate” refer to an association of one or moresolvent molecules and a therapeutic agent. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropyl alcohol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, isopropyl acetate, acetic acid, and ethanolamine. It will be understood that the present disclosure encompasses solvated forms, including hydrates, of the therapeutic agents.

[0057] As used herein, the term “free base” refers to the neutral, unprotonated form of a basic compound, as opposed to its protonated salt form. In a pharmaceutical context the free base is the parent compound without association with an acid.

[0058] As used herein, the terms “pharmaceutically acceptable excipient” and “excipient” refer to an ingredient in the dosage form that is not medicinally active. The person skilled in the art will appreciate that a pharmaceutically acceptable excipient may be included in a dosage form to optimise any one or more of the properties of the dosage form.

[0059] As used herein, the terms “pharmaceutically acceptable diluent” and “diluent” refer to a pharmacologically inert substance that is suitable for administration to a subject, and which may dilute a therapeutic agent in the dosage form.

[0060] As used herein, the terms “pharmaceutically acceptable carrier” and “carrier” refer to a pharmacologically inert substance that is suitable for administration to a subject, and which may facilitate the delivery of the therapeutic agent.

[0061] It will be appreciated that compounds (e.g., therapeutic agents) may contain chiral (asymmetric) centres, or the molecule as a whole may be chiral. As used herein, the term “stereoisomer” refers to compounds (e.g., therapeutic agents) having the same molecular formula and sequence of bonded atoms (i.e., atom connectivity), but differ in the three-dimensional orientations of their atoms in space. As used herein, the term “enantiomers” refers to two compounds that are stereoisomers in that they are non-superimposable mirror images of one another. Relevant stereocenters may be denoted with (R)- or (S)-configuration. In some embodiments, the enantiomer is of (R)-configuration (i.e., the (R) enantiomer). In some embodiments, the enantiomer is of (S)-configuration (i.e., the (S) enantiomer).

[0062] As used herein, the term “racemic”, including when used in the context of a racemic mixture, refers to a mixture of two enantiomers of a single chiral compound, wherein the two enantiomers are present in equal proportions. That is, a racemic mixture has the two enantiomers present in a 1:1 ratio. It will be appreciated by the person skilled in the art thata racemic mixture is optically inactive because the equal and opposite optical rotations of the two enantiomers are counterbalanced.

[0063] As used herein, the term “nonracemic”, including when used in the context of a nonracemic mixture, refers to a mixture of enantiomers of a single chiral compound, wherein the two enantiomers are present in unequal proportions. That is, a nonracemic mixture is enriched in one enantiomer relative to the other. The degree of enrichment can vary from slight excess to near enantiomeric purity. The term “nonracemic” may be used interchangeably with the term “scalemic”.

[0064] As used herein, the term “enantiomeric excess”, which may be denoted as “ee”, refers to a quantitative measure of the relative abundance of one enantiomer over the other enantiomer in a mixture of two enantiomers. It is calculated as the absolute difference between the mole fraction or percentage of each enantiomer, typically expressed as a percentage. In one example, a racemic mixture, having equal amounts of each enantiomer (i.e., equal amount of the (R) enantiomer and the (S) enantiomer), has an enantiomeric excess (ee) of 0%. In one example, a mixture consisting entirely of one enantiomer (e.g., the (R) enantiomer) has an enantiomeric excess (ee) of 100%. In one example, a mixture containing 70% of one enantiomer (e.g., the (R) enantiomer) and 30% of the other enantiomer (e.g., the (S) enantiomer) has an enantiomeric excess (ee) of 40%. It will be appreciated that a nonracemic mixture, or scalemic mixture, has an enantiomeric excess (ee) of greater than 0%.

[0065] Pharmaceutical Compositions and Compositions

[0066] The subject matter of the present disclosure is predicated in part on the surprising discovery that pharmaceutical compositions comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, may potentiate and / or modify the pharmacokinetics and / or pharmacodynamics of a co-administered tryptamine.

[0067] In some embodiments, pharmaceutical compositions comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, may provide enhanced monoamine oxidase A (MAO-A) inhibition and / or distinct receptor interaction profiles compared with racemic THH, and thereby may potently modulate the pharmacokinetics and / or pharmacodynamics of a co-administered tryptamine, such as N,N dimethyltryptamine.In one aspect, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0068] In some embodiments, the pharmaceutical composition further comprises a tryptamine, or pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and a tryptamine, or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the pharmaceutical composition further comprises N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof. That is, the tryptamine is N,N-dimethyltryptamine (DMT). Accordingly, in some embodiments, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the pharmaceutical composition further comprises N,N-dimethyltryptamine (DMT) as a salt selected from the group consisting of hydrochloride, hemifumarate, camsylate, and fumarate. In one example, the N,N-dimethyltryptamine (DMT) is a hemifumarate salt. Accordingly, in some embodiments, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and N,N-dimethyltryptamine as the hemifumarate salt.

[0071] In a further aspect, there is provided a composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a tryptamine, or a pharmaceutically acceptable salt thereof.

[0072] The person skilled in the art will appreciate that tetrahydroharmine (THH), also known as 7-methoxy-1,2,3,4-tetrahydroharman, is a harmala alkaloid compound having the chemical structure depicted below.

[0073]

[0074] Tetrahydroharmine (THH).

[0075] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, or at least about 99.9%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 90%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 95%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 96%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 97%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 98%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 99%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 99.5%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of at least about 99.9%.

[0076] In some embodiments, it has been surprisingly found that compositions comprising (R)-THH or (S)-THH, particularly in high enantiomeric excess, such as, for example, at least about 95 percent ee or at least about 98 percent ee, exhibit greater monoamine oxidase A (MAO-A) inhibitory potency and / or enhanced receptor selectivity, relative to racemic THH when evaluated under the same experimental conditions. Such high purity enantiomeric compositions may provide increased ability to modulate the pharmacokinetic and / or pharmacodynamic profile of a co-administered tryptamine, including, for example, the magnitude and / or duration of its central exposure.

[0077] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of between about 50% and about 100%, between about 75% and about 100%, between about 90% and about 100%, between about 95% and about 100%, between about 98% and about 100%, or between about 99% and about 100%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of between about 75% and about 100%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of between about 90% and about 100%. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of between about 95% and about 100%.In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 50%, about 60%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, about 99.9%, or about 100%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 95%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 96%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 97%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 98%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 99%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 99.5%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 99.9%. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of about 100%.

[0078] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof. That is, the nonracemic mixture is enriched in (R)-THH, and (R)-THH is present in an amount in excess of (S)-THH (i.e., ratio of greater than 1:1).

[0079] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof. That is, the nonracemic mixture is enriched in (S)-THH, and (S)-THH is present in an amount in excess of (R)-THH (i.e., ratio of greater than 1:1).

[0080] In some embodiments, and as discussed herein, it may be advantageous to have either of the (R)-THH or (S)-THH enantiomers present in enantiomeric excess (ee) in the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof.

[0081] It will be appreciated that, in some embodiments wherein the nonracemic mixture of tetrahydroharmine (THH) has a relatively higher enantiomer excess (ee), compared to a nonracemic mixture of tetrahydroharmine (THH) having a relatively lower enantiomeric excess (ee), the composition comprises a higher ratio of either the (R)- or (S)-enantiomer of tetrahydroharmine (THH) compared to the other enantiomer of tetrahydroharmine (THH). Having a higher ratio of a particular enantiomer of tetrahydroharmine (THH), relative to theother enantiomer, may, in some embodiments, provide an advantage insofar that any properties of the composition (e.g., pharmacokinetic properties), may be attenuated by having such a higher ratio, or proportion, of the particular enantiomer. That is, having an enantiomeric excess (ee) of, for example, 90%, may be advantageous to having an enantiomer excess (ee) of, for example, 40%, of a particular enantiomer.

[0082] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) comprises (R)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 75%, at least about a 90%, at least about a 95%, at least about a 99%, at least about a 99.5%, or at least about a 99.9% enantiomeric excess (ee). In one example, the nonracemic mixture of tetrahydroharmine (THH) comprises (R)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 95% enantiomeric excess (ee). In one example, the nonracemic mixture of tetrahydroharmine (THH) comprises (R)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 97% enantiomeric excess (ee). In one example, the nonracemic mixture of tetrahydroharmine (THH) comprises (R)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

[0083] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) comprises (S)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 75%, at least about a 90%, at least about a 95%, at least about a 99%, at least about a 99.5%, or at least about a 99.9% enantiomeric excess (ee). In one example, the nonracemic mixture of tetrahydroharmine (THH) comprises (S)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 95% enantiomeric excess (ee). In one example, the nonracemic mixture of tetrahydroharmine (THH) comprises (S)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 97% enantiomeric excess (ee). In one example, the nonracemic mixture of tetrahydroharmine (THH) comprises (S)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

[0084] It will be appreciated that the tetrahydroharmine (THH) may be provided in the pharmaceutical composition, or composition, in the form of a pharmaceutically acceptable salt. Pharmaceutical salts include those described herein. In some embodiments, the pharmaceutically acceptable salt of tetrahydroharmine (THH) is selected from the group consisting of hydrochloride, hemifumarate, camsylate, and fumarate. In some embodiments, the pharmaceutically acceptable salt of tetrahydroharmine (THH) is selected from the group consisting of hemifumarate and camsylate. In some embodiments, the pharmaceuticallyacceptable salt of tetrahydroharmine (THH) is selected from the group consisting of hemifumarate and fumarate. In one example, the pharmaceutically acceptable salt of tetrahydroharmine (THH) is hemifumarate. In one example, the pharmaceutically acceptable salt of tetrahydroharmine (THH) is camsylate. In one example, the pharmaceutically acceptable salt of tetrahydroharmine (THH) is fumarate.

[0085] Accordingly, in some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess of (R)-THH of at least about 99%, and the (R)-THH is present as a pharmaceutically acceptable salt selected from the group consisting of hydrochloride, hemifumarate, camsylate, and fumarate. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess of (R)-THH of at least about 99%, and the (R)-THH is present as a hemifumarate salt.

[0086] Similarly, in some embodiments, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess of (S)-THH of at least about 99%, and the (S)-THH is present as a pharmaceutically acceptable salt selected from the group consisting of hydrochloride, hemifumarate, camsylate, and fumarate. In one example, the nonracemic mixture of tetrahydroharmine (THH) has an enantiomeric excess of (S)-THH of at least about 99%, and the (S)-THH is present as a hemifumarate salt.

[0087] Particularly relevant to embodiments wherein the composition comprises a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a tryptamine, or pharmaceutically acceptable salt thereof, as described herein, the person skilled in the art will appreciate that a “tryptamine” is an indolamine metabolite of the essential amino acid, tryptophan. A tryptamine includes tryptamine perse, also referred to as 2-(1H-indol-3-yl)ethan-1 -amine and indolethylamine and indolylethylamine, having the chemical structure depicted below.

[0088]

[0089] Tryptamine.

[0090] A “tryptamine”, as used herein, also encompasses compounds sharing the indole-ethylamine moiety of tryptamine. Such tryptamine compounds include, but are not limited to,N,N-dimethyltryptamine (DMT), also referred to as dimethyltryptamine, having the structure depicted below.

[0091]

[0092] N,N-dimethyltryptamine (DMT).

[0093] A “tryptamine”, as used herein, includes not only the classical tryptamine compounds possessing the indole-ethylamine moiety, but also the family of cyclised tryptamines known as “lysergamides”, which includes, for example, LSD and related compounds. The term “tryptamine” is considered to include analogues such as isotopologues, including deuterated isotopologues. One example of a preferred tryptamine is N,N-dimethyltryptamine (DMT) and pharmaceutically acceptable salts and / or isotopologues thereof.

[0094] In the context of the present disclosure, a “tryptamine” does not include the family of cyclised tryptamines referred to as “P-carbolines”, which includes harmala alkaloids such as, for example, the harmala alkaloids, including tetrahydroharmine (THH). In some embodiments, the additional tryptamine does not include tetrahydroharmine (THH).

[0095] In the context of the present disclosure, other tryptamine compounds include derivatives of N,N-dimethyltryptamine (DMT). Derivatives of N,N-dimethyltryptamine include, but are not limited to, 4-, 5-, 6-, 7-substituted derivatives, and combinations thereof (e.g., 4,5-substituted derivatives). Examples include, but are not limited to, 5-bromo-DMT, 5-chloro-DMT, 5-ethoxy-DMT, 5-ethyl-DMT, 5-fluoro-DMT, 5-hydroxy-DMT, 5-methoxy-DMT, 5-nitro-DMT, 6-bromo-DMT, and 7-bromo-DMT. In some embodiments, the tryptamine is selected from the group consisting of N,N-dimethyltryptamine (DMT) and derivatives thereof. In one example, the tryptamine is N,N-dimethyltryptamine (DMT), ora pharmaceutically acceptable salt and / or isotopologue (e.g., deuterated isotopologue) thereof.

[0096] Accordingly, in some embodiments, there is provided a composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

[0097] It will be appreciated that the tryptamine may be provided in the pharmaceutical composition, or composition, in the form of a pharmaceutically acceptable salt.Pharmaceutical salts include those described herein. In some embodiments, the pharmaceutically acceptable salt of the tryptamine is selected from the group consisting of hydrochloride, hemifumarate, camsylate, succinate, and fumarate. In some embodiments, the pharmaceutically acceptable salt of the tryptamine is selected from the group consisting of hemifumarate and camsylate. In some embodiments, the pharmaceutically acceptable salt of the tryptamine is selected from the group consisting of hemifumarate and fumarate. In one example, the pharmaceutically acceptable salt of the tryptamine is hemifumarate. In one example, the pharmaceutically acceptable salt of the tryptamine is camsylate. In one example, the pharmaceutically acceptable salt of the tryptamine is succinate. In one example, the pharmaceutically acceptable salt of the tryptamine is fumarate.

[0098] In some embodiments, the tryptamine is N,N-dimethyltryptamine (DMT), and the pharmaceutically acceptable salt of N,N-dimethyltryptamine (DMT) is selected from the group consisting of hydrochloride, hemifumarate, camsylate, succinate, and fumarate. In some embodiments, the tryptamine is N,N-dimethyltryptamine (DMT), and the pharmaceutically acceptable salt of N,N-dimethyltryptamine (DMT) is selected from the group consisting of hemifumarate and camsylate. In some embodiments, the tryptamine is N,N-dimethyltryptamine (DMT), and the pharmaceutically acceptable salt of N,N-dimethyltryptamine (DMT) is selected from the group consisting of hemifumarate and fumarate. In one example, the tryptamine is N,N-dimethyltryptamine (DMT), and the pharmaceutically acceptable salt of N,N-dimethyltryptamine (DMT) is hemifumarate. In one example, the tryptamine is N,N-dimethyltryptamine (DMT), and the pharmaceutically acceptable salt of N,N-dimethyltryptamine (DMT) is succinate. In one example, the tryptamine is N,N-dimethyltryptamine (DMT), and the pharmaceutically acceptable salt of N,N-dimethyltryptamine (DMT) is fumarate.

[0099] It will be appreciated that a weight ratio (w / w), as used in the context of this disclosure, may be based on the weight of the free base form of each component. It will also be appreciated that, alternatively, the weight ratio (w / w) may be based on the weight of the salt form of each component. It will also be appreciated that, alternatively again, the weight ratio (w / w) may be based on the weight of the free base equivalent of the salt form of each component. Regardless, it will be understood that each component is in the same form, that is free base form to free base form, salt form to salt form, or free base equivalent of the salt form to free base equivalent of the salt form. In one example, the weight ratio (w / w) of the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine is based on the free base form of each. In one example, the weight ratio (w / w) of the nonracemic mixture oftetrahydroharmine (THH) and the tryptamine is based on the salt form of each. In one example, the weight ratio (w / w) of the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine is based on the free base equivalent of the salt form of each. Unless specifically stated, the weight ratio (w / w) referred to throughout this disclosure may relate to any of the above-mentioned basis.

[0100] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of between about 1:10 and about 10: 1 , between about 1:9 and about 9:1, between about 1:8 and about 8:1, between about 1:7 and about 7:1, between about 1:6 and about 6:1, between about 1:5 and about 5:1, between about 1:4 and about 4:1, between about 1:3 and about 3:1, or between about 1:2 and about 2:1. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of between about 1:10 and about 10:1, between about 1:5 and about 5:1, between about 1:3 and about 3:1, or between about 1:2 and about 2:1. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of between about 5:1 and about 1:5. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of between about 4:1 and about 1:4. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of between about 3:1 and about 1:3. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of between about 2:1 and about 1:2.

[0101] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of at least about 2:1, at least about 3:1, at least about 4: 1 , at least about 5: 1 , at least about 6: 1 , at least about 7: 1 , at least about 8: 1 , at least about 9:1, or at least about 10:1. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of at least about 2:1, at least about 3:1, or at least about 4:1. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of at least about 3:1.

[0102] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the tryptamine are present in a weight ratio (w / w) of about 3: 1.In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of between about 1 :10 and about 10:1, between about 1:9 and about 9:1, between about 1:8 and about 8:1, between about 1 :7 and about 7:1, between about 1 :6 and about 6: 1 , between about 1 :5 and about 5: 1 , between about 1:4 and about 4:1, between about 1:3 and about 3:1, or between about 1:2 and about 2:1. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of between about 1:10 and about 10: 1 , between about 1 :5 and about 5: 1 , between about 1 :3 and about 3: 1 , or between about 1:2 and about 2:1. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of between about 5:1 and about 1:5. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of between about 4:1 and about 1:4. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of between about 3:1 and about 1:3. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of between about 2:1 and about 1 :2.

[0103] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of at least about 2:1, at least about 3:1, at least about 4:1, at least about 5:1, at least about 6:1, at least about 7:1, at least about 8:1, at least about 9:1, or at least about 10:1. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of at least about 2:1 , at least about 3:1 , or at least about 4:1. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of at least about 3:1.

[0104] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1. In one example, the nonracemic mixture of tetrahydroharmine (THH) and N,N-dimethyltryptamine (DMT) are present in a weight ratio (w / w) of about 3:1.

[0105] It has been surprisingly found that, in some embodiments, the weight ratio (w / w) of the nonracemic mixture of tetrahydroharmine (THH) to the tryptamine, for example, N,N-dimethyltryptamine (DMT), may be selected so as to influence the expected duration of action of the tryptamine. In some embodiments, the greater monoamine oxidase A (MAO-A)inhibitory potency of tetrahydroharmine (THH) mixtures enriched with an enantiomer (e.g., 95% enantiomeric excess (ee)) may provide a mechanistic basis for providing a longer tryptamine effect at higher tetrahydroharmine (THH) to tryptamine weight ratios, relative to administration of the tryptamine without tetrahydroharmine (THH). Conversely, lower tetrahydroharmine (THH) to tryptamine weight ratios may, in some embodiments, produce a shorter or more baseline-like duration of action, recognising that the baseline duration will depend on the particular tryptamine and route of administration and may, in some embodiments, be minimal or absent. This ability to potentially modulate expected exposure of the tryptamine may be advantageous in the methods and uses described herein.

[0106] In some embodiments, the pharmaceutical composition, as described herein, or the composition, as described herein, may further comprise an additional harmala alkaloid, or pharmaceutically acceptable salt thereof.

[0107] Accordingly, in some embodiments, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, and an additional harmala alkaloid, or pharmaceutically acceptable salt thereof.

[0108] In some embodiments, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, a tryptamine, or pharmaceutically acceptable salt thereof, and an additional harmala alkaloid, or pharmaceutically acceptable excipient thereof.

[0109] In some embodiments, there is provided a pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient, N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof, and an additional harmala alkaloid, or pharmaceutically acceptable excipient thereof.

[0110] In some embodiments, there is provided a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, a tryptamine, or pharmaceutically acceptable salt thereof, and an additional harmala alkaloid, or pharmaceutically acceptable salt thereof.

[0111] In some embodiments, there is provided a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt thereof, and an additional harmala alkaloid, or pharmaceutically acceptable salt thereof.As discussed herein, it will be appreciated that the harmala alkaloids are a group of P-carboline alkaloids that primarily have monoamine oxidase activity (i.e., monoamine oxidase inhibitory activity). As discussed herein, tetrahydroharmine (THH) belongs to the class of harmala alkaloids. Accordingly, in some embodiments, an “additional harmala alkaloid” will be taken to mean a harmala alkaloid other than tetrahydroharmine (THH). In some embodiments, the additional harmala alkaloid is selected from the group consisting of harmine (HME), harmaline (HML), harmalol, harmalan, 6-methoxyharman (isoharmine), harmine acid methyl ester, harminilic acid, harmanamide, norharmane, norharman, acetylnorharmine, and pharmaceutically acceptable salts thereof. In some embodiments, the additional harmala alkaloid is selected from the group consisting of harmine (HME), harmaline (HML), and pharmaceutically acceptable salts thereof. In one example, the additional harmala alkaloid is harmine (HME), or a pharmaceutically acceptable salt thereof. In one example, the additional harmala alkaloid is harmaline (HML), or a pharmaceutically acceptable salt thereof.

[0112] Accordingly, in some embodiments, there is provided a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, a tryptamine, or a pharmaceutically acceptable salt thereof, and an additional harmala alkaloid, or pharmaceutically acceptable salt thereof, selected from the group consisting of harmine (HME), harmaline (HML), and pharmaceutically acceptable salts thereof. In some embodiments, there is provided a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, a tryptamine, or a pharmaceutically acceptable salt thereof, and harmine (HME), or pharmaceutically acceptable salt thereof. In some embodiments, there is provided a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, a tryptamine, or a pharmaceutically acceptable salt thereof, and harmaline (HML), or pharmaceutically acceptable salt thereof.

[0113] In some embodiments, there is provided a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt thereof, and an additional harmala alkaloid selected from the group consisting of harmine (HME), harmaline (HML), and pharmaceutically acceptable salts thereof. In some embodiments, there is provided a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and harmine (HME), or pharmaceutically acceptable salt thereof. In some embodiments, there is provided a composition comprising a nonracemic mixture of atetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and harmaline (HML), or pharmaceutically acceptable salt thereof.

[0114] In some embodiments, the additional harmala alkaloid is provided as a pharmaceutically acceptable salt. In one example, the pharmaceutically acceptable salt is a hydrochloride. In one example, the additional harmala alkaloid is harmine hydrochloride. In one example, the additional harmala alkaloid is harmaline hydrochloride.

[0115] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the additional harmala alkaloid (e.g., harmine, harmaline, or pharmaceutically acceptable salts thereof) are present in a weight ratio (w / w) of between about 1:10 and about 10:1, between about 1:9 and about 9:1, between about 1:8 and about 8:1, between about 1:7 and about 7:1, between about 1:6 and about 6:1, between about 1:5 and about 5:1, between about 1:4 and about 4:1, between about 1:3 and about 3:1, between about 1:2 and about 2:1. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the additional harmala alkaloid (e.g., harmine, harmaline, or pharmaceutically acceptable salts thereof) are present in a weight ratio (w / w) of between about 1:10 and about 10: 1. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the additional harmala alkaloid (e.g., harmine, harmaline, or pharmaceutically acceptable salts thereof) are present in a weight ratio (w / w) of between about 1 :2 and about 2:1.

[0116] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the additional harmala alkaloid (e.g., harmine, harmaline, or pharmaceutically acceptable salts thereof) are present in a weight ratio (w / w) of at least about 1:10, at least about 1:9, at least about 1:8, at least about 1:7, at least about 1:6, at least about 1:5, at least about 1:4, at least about 1:3, or at least about 1:2. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the additional harmala alkaloid (e.g., harmine, harmaline, or pharmaceutically acceptable salts thereof) are present in a weight ratio (w / w) of at least about 1:2.

[0117] In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) and the additional harmala alkaloid (e.g., harmine, harmaline, or pharmaceutically acceptable salts thereof) are present in a weight ratio (w / w) of about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1. In one example, the nonracemic mixture of tetrahydroharmine (THH) and the additional harmala alkaloid (e.g., harmine, harmaline, or pharmaceutically acceptable salts thereof) are present in a weight ratio (w / w) of about 1:1.In some embodiments, there is provided a pharmaceutical composition comprising: a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0118] a pharmaceutically acceptable excipient; and

[0119] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

[0120] In some embodiments, there is provided a pharmaceutical composition comprising: a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0121] a pharmaceutically acceptable excipient; and

[0122] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

[0123] In some embodiments, there is provided a pharmaceutical composition comprising: a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0124] a pharmaceutically acceptable excipient;

[0125] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0126] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0127] In some embodiments, there is provided a pharmaceutical composition comprising: a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0128] a pharmaceutically acceptable excipient;

[0129] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0130] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0131] In some embodiments, there is provided a pharmaceutical composition comprising: a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0132] a pharmaceutically acceptable excipient;

[0133] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0134] In some embodiments, there is provided a pharmaceutical composition comprising:a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0135] a pharmaceutically acceptable excipient;

[0136] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0137] In some embodiments, there is provided a pharmaceutical composition comprising: (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0138] a pharmaceutically acceptable excipient; and

[0139] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

[0140] In some embodiments, there is provided a pharmaceutical composition comprising: (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0141] a pharmaceutically acceptable excipient; and

[0142] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

[0143] In some embodiments, there is provided a pharmaceutical composition comprising: (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0144] a pharmaceutically acceptable excipient;

[0145] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0146] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0147] In some embodiments, there is provided a pharmaceutical composition comprising: (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0148] a pharmaceutically acceptable excipient;

[0149] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0150] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0151] In some embodiments, there is provided a pharmaceutical composition comprising: (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;a pharmaceutically acceptable excipient;

[0152] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0153] In some embodiments, there is provided a pharmaceutical composition comprising: (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0154] a pharmaceutically acceptable excipient;

[0155] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0156] In some embodiments, there is provided a unit dosage form comprising:

[0157] (R)-THH hemifumarate having an enantiomeric excess (ee) of greater than 96%, optionally greater than 98% (ee), at between about 15 mg to about 25 mg THH equivalent;

[0158] N,N-dimethyltryptamine (DMT) hemifumarate at between about 7 to about 13 mg DMT equivalent;

[0159] harmine hydrochloride, at between about 13 to about 21 mg harmine equivalent; and optionally, a pharmaceutically acceptable excipient.

[0160] In some embodiments, there is provided a unit dosage form comprising:

[0161] (R)-THH hemifumarate having an enantiomeric excess (ee) of greater than 96%, optionally greater than 98% (ee), at about 21 mg THH equivalent;

[0162] N,N-dimethyltryptamine (DMT) hemifumarate at about 10 mg DMT equivalent; and harmine hydrochloride, at about 17 mg harmine equivalent; and

[0163] optionally, a pharmaceutically acceptable excipient.

[0164] In some embodiments, there is provided a pharmaceutical composition comprising: (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0165] a pharmaceutically acceptable excipient; and

[0166] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

[0167] In some embodiments, there is provided a pharmaceutical composition comprising: (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0168] a pharmaceutically acceptable excipient; andN,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

[0169] In some embodiments, there is provided a pharmaceutical composition comprising: (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0170] a pharmaceutically acceptable excipient;

[0171] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0172] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0173] In some embodiments, there is provided a pharmaceutical composition comprising: (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0174] a pharmaceutically acceptable excipient;

[0175] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0176] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0177] In some embodiments, there is provided a pharmaceutical composition comprising: (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0178] a pharmaceutically acceptable excipient;

[0179] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0180] In some embodiments, there is provided a pharmaceutical composition comprising: (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0181] a pharmaceutically acceptable excipient;

[0182] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0183] In some embodiments, there is provided a composition comprising:

[0184] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0185] a tryptamine, or pharmaceutically acceptable salt thereof; andan additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0186] In some embodiments, there is provided a composition comprising:

[0187] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0188] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0189] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0190] In some embodiments, there is provided a composition comprising:

[0191] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0192] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0193] In some embodiments, there is provided a composition comprising:

[0194] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0195] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0196] In some embodiments, there is provided a composition comprising:

[0197] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0198] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0199] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0200] In some embodiments, there is provided a composition comprising:

[0201] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0202] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0203] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.In some embodiments, there is provided a composition comprising:

[0204] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0205] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0206] In some embodiments, there is provided a composition comprising:

[0207] a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0208] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0209] In some embodiments, there is provided a composition comprising:

[0210] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0211] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0212] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0213] In some embodiments, there is provided a composition comprising:

[0214] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0215] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0216] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0217] In some embodiments, there is provided a composition comprising:

[0218] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0219] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0220] In some embodiments, there is provided a composition comprising:

[0221] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0222] In some embodiments, there is provided a composition comprising:

[0223] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0224] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0225] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0226] In some embodiments, there is provided a composition comprising:

[0227] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0228] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0229] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0230] In some embodiments, there is provided a composition comprising:

[0231] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0232] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0233] In some embodiments, there is provided a composition comprising:

[0234] (R)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0235] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0236] In some embodiments, there is provided a composition comprising:

[0237] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0238] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0239] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.In some embodiments, there is provided a composition comprising:

[0240] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0241] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0242] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0243] In some embodiments, there is provided a composition comprising:

[0244] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0245] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0246] In some embodiments, there is provided a composition comprising:

[0247] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0248] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0249] In some embodiments, there is provided a composition comprising:

[0250] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;

[0251] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0252] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0253] In some embodiments, there is provided a composition comprising:

[0254] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0255] a tryptamine, or pharmaceutically acceptable salt thereof; and

[0256] an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0257] In some embodiments, there is provided a composition comprising:

[0258] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 95%;N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0259] In some embodiments, there is provided a composition comprising:

[0260] (S)-THH, or a pharmaceutically acceptable salt thereof, having an enantiomeric excess (ee) of at least about 99%;

[0261] N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof; and an additional harmala alkaloid (e.g., harmine, harmaline), or pharmaceutically acceptable salt thereof.

[0262] The pharmaceutical compositions and compositions, as described herein, may comprise the nonracemic mixture of tetrahydroharmine (THH) in a particular solid form. Similarly, the pharmaceutical composition and compositions, as described herein, may be manufactured on the basis of the nonracemic mixture of tetrahydroharmine (THH) having been in a particular solid form. In some embodiments, the nonracemic mixture of tetrahydroharmine (THH) is provided as a solid form. In one example, the nonracemic mixture of tetrahydroharmine (THH) is provided as a crystalline form.

[0263] The different enantiomers of tetrahydroharmine (THH) may possess different physical characteristics (i.e., morphology). Such differences in physical characteristics may be identifiable through scanning electron microscopy (SEM), as would be appreciated by the person skilled in the art.

[0264] In some embodiments, the (R)-THH is the hemifumarate salt, and is a crystalline solid form. In some embodiments, the (R)-THH is the hemifumarate salt, and is in a highly crystalline solid form. In some embodiments, the (R)-THH is the hemifumarate salt, and has a particle size of at least about 50 pm, at least about 75 pm, at least about 100 pm, at least about 125 pm, at least about 130 pm, at last about 135 pm, at least about 140 pm, at least about 145 pm, or at least about 150 pm in width. In some embodiments, the (R)-THH is the hemifumarate salt, and has a particle size of between about 50 pm and about 500 pm, between about 100 pm and about 300 pm, between about 125 pm and about 200 pm, or between about 140 pm and about 160 pm in width. In some embodiments, the (R)-THH is the hemifumarate salt, and has a particle size of about 100 pm, about 110 pm, about 120 pm, about 130 pm, about 140 pm, or about 150 pm in width. In one example, the (R)-THH is the hemifumarate salt, and has a particle size of about 150 pm. In one example, the (R)-THH is the hemifumarate salt, and has a particle size of about 149 pm in width.In some embodiments, the (S)-THH is the hemifumarate salt, and is a crystalline solid form. In some embodiments, the (S)-THH is the hemifumarate salt, and is in a loosely crystalline solid form. In some embodiments, the (S)-THH is the hemifumarate salt, and has a particle size of at least about 1 pm, at least about 10 pm, at least about 20 pm, at least about 30 pm, at least about 35 pm, at last about 40 pm, at least about 41 pm, at least about 42 pm, or at least about 43 pm in width. In some embodiments, the (R)-THH is the hemifumarate salt, and has a particle size of between about 1 pm and about 100 pm, between about 20 pm and about 75 pm, between about 30 pm and about 50 pm, or between about 40 pm and about 50 pm in width. In some embodiments, the (R)-THH is the hemifumarate salt, and has a particle size of about 10 pm, about 20 pm, about 30 pm, about 40 pm, about 43 pm, or about 45 pm in width. In one example, the (R)-THH is the hemifumarate salt, and has a particle size of about 45 pm. In one example, the (R)-THH is the hemifumarate salt, and has a particle size of about 44 pm in width. In one example, the (R)-THH is the hemifumarate salt, and has a particle size of about 43 pm in width.

[0265] In some embodiments, there is provided a pharmaceutical composition comprising the composition, as described herein, and a pharmaceutically acceptable excipient.

[0266] Single Enantiomeric Compositions and Preparation of Harmala Alkaloid

[0267] There is a tendency for THH to be synthetically prepared in its racemic form or as a scalemic mixture of its two enantiomers, R-THH and S-THH. In its natural form (e.g. in the Ayahuasca vine), or where it has been extracted for consumption as a tea for traditional ceremonial purposes, it also exists as a scalemic mixture. Such racemic / scalemic combination may be problematic when used in pharmaceutical drugs, due to a potentially different pharmacological profile of each enantiomer. The synthetic development of singleenantiomer drugs may therefore be beneficial due to the potential difference in therapeutic efficacy and / or safety. Purified single enantiomer compounds, for example, R-THH or S-THH, may be able to optimise the therapeutic profile by selecting the single enantiomer (either the (R) or (S)) that targets preferred receptors or pathways, thereby improving efficacy and minimising adverse or off-target effects.

[0268] Accordingly, in some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting monoamine oxidase A (MAO-A) activity, wherein said composition includes purified R-THH or a pharmaceutically acceptable salt thereof.In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting MAO-A activity, wherein said composition includes purified S-THH or a pharmaceutically acceptable salt thereof.

[0269] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Sigma o1 activity, wherein said composition includes purified R-THH or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Sigma o1 activity, wherein said composition includes purified S-THH or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Serotonin (5-Hydroxytryptamine) 5-HT2Cactivity, wherein said composition includes purified R-THH or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Serotonin (5-Hydroxytryptamine) 5-HT2Cactivity, wherein said composition includes purified S-THH or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the purified R-THH may be in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, acetate, mesylate, tosylate, camsylate, fumarate, and hemifumarate. In some embodiments, the pharmaceutically acceptable salt of purified R-THH is the fumarate salt or the hemifumarate salt. In one example, the pharmaceutically acceptable salt of purified R-THH is hemifumarate.

[0274] In some embodiments, the S-THH may be in the form of a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, acetate, mesylate, tosylate, camsylate, fumarate, and hemifumarate. In some embodiments, the pharmaceutically acceptable salt of purified S-THH is the fumarate salt or the hemifumarate salt. In one example, the pharmaceutically acceptable salt of purified S-THH is hemifumarate.

[0275] In some embodiments, the use of a hemifumarate salt or a HCI salt of R-THH may offer increased stability over R-THH as the free base form. This may provide theadvantageous use of R-THH hemifumarate or R-THH HCI in a composition, particularly a pharmaceutical composition.

[0276] Further, in some embodiments, the use of a hemifumarate salt or a HCI salt of S-THH may offer increased stability over S-THH as the free base form. This may provide the advantageous use of S-THH hemifumarate or R-THH HCI in a composition, particularly a pharmaceutical composition.

[0277] Further, in some embodiments, the use of a hemifumarate salt of R-THH may offer increased stability over R-THH as the free base form. The hemifumarate salt of R-THH or hemifumarate salt of purified R-THH may also offer the benefit of remaining as the (R) enantiomer (i.e. it is likely to not convert back to the racemate) when placed in an acidic and / or elevated temperature environment, such as the stomach. This may provide the advantageous use of R-THH hemifumarate or R-THH in a composition, particularly a pharmaceutical composition.

[0278] In some embodiments, there is provided the use of purified R-THH, purified S-THH, R-THH hemifumarate, S-THH hemifumarate, R-THH fumarate, or S-THH fumarate in a composition, particularly a pharmaceutical composition.

[0279] In some embodiments, the pharmaceutical composition may include one or more pharmaceutically acceptable excipients selected from the group consisting of diluents, lubricants, glidants, disintegrants, binders, coating, sweetener, and flavouring, or any combination thereof.

[0280] In some embodiments, the pharmaceutical composition may optionally include one or more further alkaloids, said further alkaloid being selected from the group consisting of harmine, harmaline, and DMT.

[0281] In some embodiments, the pharmaceutical composition is a solid dosage form. In some embodiments, the dosage form is an oral dosage form. In some embodiments, the oral dosage form may is a tablet, a capsule, or a solution.

[0282] In some embodiments, there is provided the use of purified R-THH, purified S-THH, R-THH hemifumarate, S-THH hemifumarate, R-THH fumarate, or S-THH fumarate in a composition, particularly a pharmaceutical composition, wherein the composition treats, ameliorates, or prevents a psychological disorder, neurological disorder, an inflammatory disorder, or provides other therapeutic effects.The term ‘psychological disorder’ as used herein, refers to one or more condition(s) wherein a pattern of behavioural, psychological, or physical symptoms impact multiple areas of life. For example, such psychological disorders may include, but are not limited to, attention deficit hyperactivity disorder, bipolar disorder, borderline personality disorder, chronic or persistent pain or inflammation (e.g., fibromyalgia, rheumatologic pain, and headache), depression, an eating disorder or obesity, generalised anxiety disorder, insomnia, mixed anxiety, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, schizophrenia or other severe mental illness (e.g., schizoaffective disorder, manic depressive disorder, or autism), social phobia or other specific phobias (e.g., animals, heights, blood, needles, or public speaking), and substance and alcohol use disorders.

[0283] The term ‘neurological disorder’, as used herein, refers to a condition characterized by a structural, biochemical, or electrical abnormality in the brain, spinal cord, or nerves. For example, a neurological disorder may include, but is not limited to, headaches and migraines, stroke, seizures, Parkinson’s Disease, dementia, Alzheimer’s Disease, epilepsy, aphasia, multiple sclerosis, concussion, and neck and lower back pain.

[0284] The term ‘inflammatory disorder’, as used herein, refers to a condition characterized by acute or prolonged inflammation subsequent to an autoimmune disorder (e.g., rheumatoid arthritis, lupus, psoriasis, ankylosing spondylitis, or type I diabetes), the disease process of a co-morbidity (e.g., Alzheimer’s disease, asthma, cancer, heart disease, or type 2 diabetes), or from a contributing lifestyle factor (e.g., excessive alcohol consumption, obesity or an elevated body mass index (BMI), chronic stress, excessive strenuous exercise, or habitual smoking).

[0285] The term ‘therapeutic effects’ as used herein, refers to effects that contribute positively to the overall health, quality of life, or mental state of an individual. These benefits may include, but are not limited to, mood enhancement, cognitive function improvement, increased self-awareness, stress reduction, better sleep quality, general discomfort alleviation, enhancement of life satisfaction, contentment, or resilience against daily stresses.

[0286] In some embodiments, there is provided a method for using purified R-THH, purified S-THH, R-THH fumarate, S-THH fumarate, R-THH hemifumarate, or S-THH hemifumarate, prepared according to the methods as hereinbefore described, in a composition, particularly a pharmaceutical composition.

[0287] Accordingly, in some embodiments, there is provided a composition, preferably a pharmaceutical composition, including purified R-THH, purified S-THH, R-THH fumarate, S-THH fumarate, R-THH hemifumarate, or S-THH hemifumarate, prepared according to the methods as herein described.

[0288] In some embodiments, there is provided a method for using purified R-THH, purified S-THH, R-THH fumarate, S-THH fumarate, R-THH hemifumarate, or S-THH hemifumarate, prepared according to the methods as herein described, in a composition, particularly a pharmaceutical composition.

[0289] Accordingly, in some embodiments, there is provided a composition, preferably a pharmaceutical composition, including purified R-THH, purified S-THH, R-THH fumarate, S-THH fumarate, R-THH hemifumarate, or S-THH hemifumarate, prepared according to the methods as herein described.

[0290] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting monoamine oxidase A (MAO-A) activity, wherein said composition includes purified R-THH or a pharmaceutically acceptable salt thereof, and optionally, harmine.

[0291] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting MAO-A activity, wherein said composition includes purified S-THH or a pharmaceutically acceptable salt thereof, and optionally, harmine.

[0292] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Sigma o1 activity, wherein said composition includes purified R-THH or a pharmaceutically acceptable salt thereof, and optionally DMT.

[0293] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Sigma o1 activity, wherein said composition includes purified S-THH or a pharmaceutically acceptable salt thereof, and optionally DMT.

[0294] Ayahuasca (a combination of harmine, harmaline and THH) may potentiate the psychoactive effect of DMT by blocking the enzyme MAO. MAO inhibitors in various forms can be used to treat a range of psychiatric disorders, including different forms of depressive disorders.

[0295] Potential targets for the development of drugs to treat depressive and cognitive disorders also include the Sigma 1 receptors (e.g. Sigma o1) and the serotonin receptors (e.g. Serotonin (5-Hydroxytryptamine) 5-HT2C). It is understood that these receptors may play an important role in the regulation of monoamine transmission, and thus thepathophysiology of a range of psychiatric disorders including depressive disorders. Surprisingly, it has been found that the enantiomers of THH (R-THH and S-THH) exhibit significant MAO-A, Sigma o1, and / or Serotonin 5-HT2C inhibition. Furthermore, it has been surprisingly found that these effects are reported to be occurring differentially between the enantiomers of THH.

[0296] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Serotonin (5-Hydroxytryptamine) 5-HT2C activity, wherein said composition includes purified R-THH or a pharmaceutically acceptable salt thereof, and optionally, DMT.

[0297] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, for selectively inhibiting Serotonin (5-Hydroxytryptamine) 5-HT2c activity, wherein said composition includes purified S-THH or a pharmaceutically acceptable salt thereof, and optionally, DMT.

[0298] In some embodiments, there is provided a method for treating a psychological disorder including administering to a patient an effective amount of a compound that selectively inhibits MAO-A, Serotonin (5-Hydroxytryptamine) 5-HT2C activity, or Sigma o1 activity.

[0299] In some embodiments, the compound may selectively inhibit one or more of MAO-A, Serotonin (5-Hydroxytryptamine) 5-HT2C activity, or Sigma o1 activity.

[0300] In some embodiments, the compound may be selected from the group consisting of purified R-THH, purified S-THH, R-THH fumarate, S-THH fumarate, R-THH hemifumarate, and S-THH hemifumarate.

[0301] In some embodiments, there is provided a composition, preferably a pharmaceutical composition, including purified R-THH and purified S-THH. In some embodiments, purified R-THH to purified S-THH may be present in a composition in a weight / weight ratio of about 0:100, about 0.5:100, about 1:100, about 1:20, about 1:19, about 1:18, about 1:17, about 1:16, about 1:15, about 1:14, about 1:13, about 1:12, about 1:11, about 1:10, about 1:9, about 1 :8, about 1 :7, about 1 :6, about 1 :5, about 1 :4, about 1 :3, about 1 :2, or about 1:1.

[0302] In some embodiments, purified S-THH to purified R-THH may be present in a composition in a weight / weight ratio of about 0: 100, about 0.5: 100, about 1 : 100, about 1 :20, about 1:19, about 1:18, about 1:17, about 1:16, about 1:15, about 1:14, about 1:13, about 1:12, about 1:11, about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4,about 1:3, about 1:2 or about 1:1. In some embodiments, purified R-THH and purified S-THH are present in the composition in the form of a pharmaceutically acceptable salt. In one example, purified R-THH and purified S-THH are present in the composition as hemifumarate salts.

[0303] In some embodiments, there is provided a method for preparing racemic THH, including the steps of:

[0304] contacting THH with water to provide a mixture;

[0305] cooling the mixture;

[0306] contacting the mixture with potassium hydroxide,

[0307] stirring the mixture at a temperature and for a time period sufficient to provide a precipitate;

[0308] separating the precipitate from the mixture to provide racemic THH.

[0309] In one example, the mixture is cooled to a temperature below approximately 15 °C. In one example, the mixture is cooled to a temperature below approximately 10 °C. In one example, the mixture is cooled to a temperature between approximately 3 °C and approximately 8 °C. In one example, the mixture is cooled to a temperature of approximately 5 °C.

[0310] In some embodiments, potassium hydroxide is added to the cooled solution incrementally. In some embodiments, the temperature of the cooled solution is increased to approximately room temperature after the addition of sodium hydroxide. In some embodiments, the resulting reaction mixture is stirred for at least approximately 6 hours, at least approximately 8 hours, or at least approximately 10 hours.

[0311] In some embodiments, there is provided a method for preparing (1 R)-7-M ethoxy- 1-methyl-2,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole((1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (hereinafter, ‘R-THH(-)-CSA’), the method including the steps of:

[0312] contacting racemic THH with an alcohol solvent to provide a mixture; heating the mixture;

[0313] contacting the mixture with L-(-)-camphor-10-sulphonic acid, wherein the mixture is stirred at a temperature and for a time period sufficient to provide a precipitate; separating the precipitate from the mixture to provide isolated R-THH (-)-CSA.

[0314] In some embodiments, the racemic THH is synthesised from a hydrochloride salt of THH.In some embodiments, the mixture is heated to a temperature of at least approximately 60 °C. In some embodiments, the mixture is heated to a temperature with the range of approximately 60 °C to approximately 80 °C. In some embodiments, the mixture is heated to a temperature within the range of approximately 70 °C to approximately 80 °C. In one example, the mixture is heated to a temperature of approximately 75 °C.

[0315] In some embodiments, the mixture is stirred at room temperature for at least approximately 10 hours. In some embodiments, the mixture is stirred at room temperature for at least approximately 12 hours. In some embodiments, the mixture is stirred at room temperature for at least approximately 15 hours. In one example, the mixture is stirred at room temperature for approximately 17 hours.

[0316] In some embodiments, the method may further include purifying R-THH-(-)-CSA, wherein the steps of purification include dissolving R-THH-(-)-CSA in an alcohol solvent and recrystalizing to provide purified R-THH-(-)-CSA. In one example, the alcohol solvent is ethanol.

[0317] By ‘purified R-THH-(-)-CSA’, in the context of R-THH-(-)-CSA, it is meant that the R-THH-(-)-CSA is substantially free of other compounds. In some embodiments, ‘purified R-THH-(-)-CSA’ is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, ‘purified R-THH-(-)-CSA’ is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98% pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0318] By ‘purified R-THH-(-)-CSA’, in the context of enantiomeric excess, it is meant that the R-THH-(-)-CSA is substantially free of other enantiomers. In some embodiments, ‘purified R-THH-(-)-CSA’, in the context of enantiomeric excess, is at least approximately 70%ee, at least approximately 75%ee, at least approximately 80%ee, or at least approximately 85%ee. In some embodiments, purified R-THH-(-)-CSA is at least approximately 90%ee, at least approximately 91%ee, at least approximately 92%ee. In some embodiments, purified R-THH-(-)-CSA, in the context of enantiomeric excess, is at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, or at least approximately 99%ee.

[0319] R-THH-(-)-CSA may be in the form of a solid, a liquid, an oil or a viscous liquid, and is likely to contain impurities.Purified R-THH-(-)-CSA may be in the form of a solid, a liquid, an oil or a viscous liquid.

[0320] In some embodiments, there is provided a method for preparing (R)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (herein after, ‘R-THH’), including the steps of:

[0321] contacting R-THH-(-)-CSA with water to provide a mixture;

[0322] contacting the mixture with an alcohol solvent;

[0323] contacting the mixture with potassium hydroxide,

[0324] heating the mixture;

[0325] cooling the mixture for a time period sufficient to provide a precipitate separating the precipitate from the mixture to provide purified R-THH.

[0326] In one example, potassium hydroxide is added incrementally.

[0327] In some embodiments, the mixture is heated to a temperature of at least approximately 50 °C. In some embodiments, the mixture is heated to a temperature of at least approximately 55 °C. In one example, the mixture is heated to a temperature within the range of approximately 55 °C and approximately 65 °C. In one example, the mixture is heated to a temperature of approximately 60 °C. In some embodiments, the heated mixture is stirred for at least approximately 15 minutes, including, for example, at least approximately 30 minutes.

[0328] In some embodiments, the mixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below approximately 10°C, for example, cooled to a temperature between approximately 2 °C and approximately 8 °C. In one example, the mixture is cooled for at least approximately 1 hour. In some embodiments, the mixture is cooled for at least approximately 2 hours, for example, at least approximately 3 hours.

[0329] The term ‘purified R-THH’, in the context of R-THH, is taken to mean that the R-THH is substantially free of other compounds. In some embodiments, ‘purified R-THH’ is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, purified R-THH is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98% pure, at least approximately 99% pure, or at least approximately 99.5% pure.The term ‘purified R-THH’, in the context of enantiomeric excess, is taken to mean that the R-THH is substantially free of other enantiomers. In some embodiments, purified R-THH, in the context of enantiomeric excess, is at least approximately 70%ee, at least approximately 75%ee, at least approximately 80%ee, or at least approximately 85%ee. In some embodiments, purified R-THH is at least approximately 90%ee, at least approximately 91%ee, or at least approximately 92%ee. In some embodiments, purified R-THH, in the context of enantiomeric excess, is at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, or at least approximately 99%ee.

[0330] In some embodiments, R-THH includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of R-THH. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of R-THH. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In one example, NMT 1% w / w and not less than 0.01% w / w.

[0331] In some embodiments, there is provided a method for preparing (S)-7-methoxy-1-methyl-2,3,4,9-tetrahydro-1 H-pyrido[3,4-b]indole((1 R)-7,7-dimethyl -2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate, (herein after ‘S-THH-(-)-CSA’) including the steps of:

[0332] contacting racemic THH with an alcohol solvent to provide a mixture; heating the mixture;

[0333] contacting the mixture with L(-)-camphor-10-sulphonic acid, wherein the mixture is stirred at a temperature and for a time period sufficient to provide a precipitate; removing the precipitate from the mixture;

[0334] separating S-THH-(-)-CSA from the mixture to provide isolated S-THH-(-)-CSA.

[0335] In some embodiments, the racemic THH is synthesised from a hydrochloride salt of THH.

[0336] In some embodiments, the mixture is heated to a temperature of above approximately 60° C. In some embodiments, the mixture is heated to a temperature within the range of approximately 65 °C to approximately 75 °C. In some embodiments, the mixture is heated to a temperature within the range of approximately 70 °C and approximately 75 °C. In one example, the mixture is heated to a temperature of approximately 72 °C.In some embodiments, the mixture is stirred for at least approximately 10 hours. In some embodiments, the mixture is stirred for at least approximately 12 hours, or at least approximately 15 hours. In some embodiments, the mixture is stirred between approximately 15 hours and approximately 17 hours.

[0337] In some embodiments, the method further comprises purifying S-THH-(-)-CSA, wherein the steps of purification comprise dissolving S-THH-(-)-CSA in an alcohol solvent and recrystalizing to provide purified S-THH-(-)-CSA. In one example, the alcohol solvent is ethanol.

[0338] The term ‘purified S-THH-(-)-CSA’, in the context of S-THH-(-)-CSA, is taken to mean that the S-THH-(-)-CSA is substantially free of other compounds. In some embodiments, ‘purified S-THH-(-)-CSA’ is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, ‘purified S-THH-(-)-CSA’ is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98% pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0339] The term ‘purified S-THH-(-)-CSA’, in the context of enantiomeric excess, is taken to mean that the S-THH-(-)-CSA is substantially free of other enantiomers. In some embodiments, purified S-THH-(-)-CSA, in the context of enantiomeric excess, is at least approximately 70%ee, at least approximately 75%ee, at least approximately 80% ee, or at least approximately 85%ee. In some embodiments, purified S-THH-(-)-CSA is at least approximately 90%ee, at least approximately 91%ee, or at least approximately 92%ee. In some embodiments, purified S-THH-(-)-CSA, in the context of enantiomeric excess, is at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, or at least approximately 99%ee.

[0340] S-THH-(-)-CSA may be in the form of a solid, a liquid, an oil or a viscous liquid, and is likely to contain impurities.

[0341] Purified S-THH-(-)-CSA may be in the form of a solid, a liquid, an oil or a viscous liquid.

[0342] In some embodiments, there is provided a method for preparing (S)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (herein after, ‘S-THH’), including the steps of:contacting S-THH-(-)-CSA with water to provide a mixture;

[0343] heating the mixture;

[0344] contacting the mixture with an alcohol solvent;

[0345] contacting the mixture with potassium hydroxide,

[0346] cooling the mixture for a time period sufficient to provide a precipitate separating the precipitate from the mixture to provide purified S-THH.

[0347] In some embodiments, the mixture is heated to a temperature of above approximately 50 °C. In some embodiments, the mixture is heated to a temperature of above approximately 55 °C. In some embodiments, the mixture is heated to a temperature of between approximately 55 °C and approximately 65 °C. In one example, the mixture is heated to a temperature of approximately 60 °C.

[0348] In some embodiments, potassium hydroxide is added incrementally.

[0349] In some embodiments, the mixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below approximately 10 °C, for example, to a temperature between approximately 2 °C and approximately 8 °C. In some embodiments, the mixture is cooled for at least approximately 10 hours. In some embodiments, the mixture is cooled for at least approximately 12 hours. In some embodiments, the mixture is cooled for between approximately 15 hours and approximately 19 hours. In one example, the mixture is cooled for approximately 17 hours.

[0350] The term ‘purified S-THH’, as used in the context of S-THH, is taken to mean that the S-THH is substantially free of other compounds. In some embodiments, ‘purified S-THH’ is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, purified S-THH is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98% pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0351] The term ‘purified S-THH’, as used in the context of enantiomeric excess, is taken to mean that the S-THH is substantially free of other enantiomers. In some embodiments, purified S-THH, in the context of enantiomeric excess, is at least approximately 70%ee, least approximately 75%ee, at least approximately 80%ee, or at least approximately 85%ee. In some embodiments, purified S-THH is at least approximately 90%ee, at least approximately 91%ee, or at least approximately 92%ee. In some embodiments, purified S-THH, in thecontext of enantiomeric excess, is at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, at least approximately 99%ee, at least approximately 99.5%ee, or at least approximately 100%ee.

[0352] In some embodiments, S-THH includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of S-THH. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of S-THH. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0353] In some embodiments, there is provided a method for preparing (1S)-7-Methoxy-1-methyl-2,4a,9,9a-tetrahydro-1 H-pyrido[3,4-b]indole ((1 S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (hereinafter, ‘S-THH. (+)-CSA’). including the steps of:

[0354] contacting S-THH with an alcohol solvent to provide a mixture;

[0355] heating the mixture;

[0356] contacting the mixture with D-(+)-camphor-10-sulphonic acid, wherein the mixture is stirred at a temperature and for a time period sufficient to provide a precipitate;

[0357] separating the precipitate from the mixture to provide isolated S-THH-(+)-CSA.

[0358] In some embodiments, the mixture is heated to a temperature of at least approximately 60 °C. In some embodiments, the mixture is heated to a temperature of at least approximately 65 °C. In some embodiments, the mixture is heated to a temperature of between approximately 70 °C and approximately 80 °C. In one example, the mixture is heated to a temperature of approximately 75 °C.

[0359] In some embodiments, the mixture is stirred at room temperature for at least approximately 2 hours. In some embodiments, the mixture is stirred at room temperature for at least approximately 3 hours. In one example, the mixture is stirred at room temperature for at least approximately 4 hours.

[0360] In some embodiments, the method further comprises purifying S-THH-(+)-CSA, wherein the steps of purifying comprise dissolving S-THH-(+)-CSA in an aqueous alcohol solvent and recrystalizing to provide purified S-THH-(+)-CSA. In some embodiments, theaqueous alcohol solvent is a solvent mixture of ethanol and water. In one example, the aqueous alcohol solvent is approximately 1:1 ethanol / water.

[0361] S-THH-(+)-CSA may be in the form of a solid, a liquid, an oil or a viscous liquid, and is likely to contain impurities.

[0362] The term ‘purified S-THH-(+)-CSA’, in the context of S-THH-(+)-CSA, is taken to mean that the S-THH-(+)-CSA’ is substantially free of other compounds. In some embodiments, purified S-THH-(+)-CSA is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, purified S-THH-(+)-CSA is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98 % pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0363] The term ‘purified S-THH-(+)-CSA’, in the context of enantiomeric excess, is taken to mean that the S-THH-(+)-CSA is substantially free of other enantiomers. In some embodiments, purified S-THH-(+)-CSA, in the context of enantiomeric excess, is at least approximately 50%ee, at least approximately 55%ee, at least approximately 60% ee, or at least approximately 65%ee. In some embodiments, purified S-THH-(+)-CSA is at least approximately 70%ee, at least approximately 76%ee, or at least approximately 75%ee. In these embodiments, purified S-THH-(+)-CSA, in the context of enantiomeric excess, is at least approximately 80%ee, at least approximately 85%ee, at least approximately 90%ee, at least approximately 91%ee, at least approximately 92%ee, at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, or at least approximately 96%ee.

[0364] Purified S-THH-(+)-CSA may be in the form of a solid, a liquid, an oil or a viscous liquid.

[0365] In some embodiments, there is provided a method for preparing (S)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (herein after ‘S-THH’), including the steps of:

[0366] contacting S-THH-(+)-CSA with water to provide a mixture;

[0367] heating the mixture;

[0368] contacting the mixture with an alcohol solvent;

[0369] contacting potassium hydroxide with the mixture;

[0370] cooling the mixture for a time period sufficient to provide a precipitate; separating the precipitate from the mixture to provide purified S-THH.In some embodiments, potassium hydroxide is added incrementally.

[0371] In some embodiments, the mixture is heated to a temperature of at least approximately 50 °C. In some embodiments, the mixture is heated to a temperature of at least approximately 55 °C. In some embodiments, the mixture is heated to a temperature with the range of approximately 55 °C and approximately 65 °C. In one example, the mixture is heated to approximately 60 °C. In some embodiments, the heated mixture is stirred for at least approximately 15 minutes, including, for example, stirred for at least approximately 30 minutes.

[0372] In some embodiments, the mixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below approximately 10 °C, or between approximately 2 °C and approximately 8 °C. In some embodiments, the mixture is cooled for at least approximately 1 hour. In some embodiments, the mixture is cooled for at least approximately 2 hours, including, for example, at least approximately 3 hours.

[0373] The term ‘purified S-THH’, in the context of S-THH, is taken to mean that the S-THH is substantially free of other compounds. In some embodiments, ‘purified S-THH’ is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, purified S-THH is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98 % pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0374] In some embodiments, the method described herein may further include the steps of preparing a pharmaceutically acceptable salt of purified S-THH. The pharmaceutically acceptable salt of S-THH is selected from the group consisting of hydrochloride, acetate, mesylate, tosylate, camsylate, fumarate, and hemifumarate. In one example, the method described herein further includes the steps of preparing a hydrochloride or hemifumarate salt from purified S-THH.

[0375] The term ‘purified S-THH’, in the context of enantiomeric excess, is taken to mean that the S-THH is substantially free of other enantiomers. In some embodiments, purified S-THH, in the context of enantiomeric excess, is at least approximately 70%ee, at least approximately 80%ee, at least approximately 82%ee, or at least approximately 84%ee. In some embodiments, purified S-THH is at least approximately 86%ee, at least approximately 88%ee, or at least approximately 90%ee. In some embodiments, purified S-THH, in thecontext of enantiomeric excess, is at least approximately 92%ee, at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, at least approximately 99%ee, or at least approximately 100%ee.

[0376] In some embodiments, S-THH includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of S-THH. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of S-THH. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0377] In some embodiments, there is provided a method for preparing a hemifumarate salt of S-THH including the steps of:

[0378] dissolving S-THH in an alcohol solvent to provide a mixture, wherein the mixture is heated at a temperature sufficient to facilitate dissolution;

[0379] adding fumaric acid to the mixture to provide an admixture;

[0380] cooing the admixture for a time sufficient to precipitate the hemifumarate salt; separation the precipitate from the admixture to provide hemifumarate salt of S- THH.

[0381] In some embodiments, the mixture is heated under reflux.

[0382] In some embodiments, fumaric acid is added to the mixture incrementally.

[0383] In some embodiments, the admixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below approximately 10 °C, or between approximately 2 °C and approximately 8 °C. In some embodiments, the mixture is cooled for at least approximately 10 hours. In some embodiments, the mixture is cooled for at least approximately 15 hours. In some embodiments, the mixture is cooled for between approximately 15 hours and approximately 25 hours. In some embodiments, the mixture is cooled for at least approximately 19 hours.

[0384] In some embodiments, the hemifumarate salt of S-THH is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, the hemifumarate salt of S-THH is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure,at least approximately 98 % pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0385] In some embodiments, S-THH hemifumarate is substantially free of other enantiomers. In some embodiments, S-THH hemifumarate, in the context of enantiomeric excess, is at least approximately 70%ee, at least approximately 75%ee, at least approximately 80%ee, or at least approximately 82%ee. In some embodiments, purified S-THH hemifumarate is at least approximately 84%ee, at least approximately 86%ee, or at least approximately 88%ee. In some embodiments, purified S-THH hemifumarate, in the context of enantiomeric excess, is at least approximately 90%ee, at least approximately 91%ee, at least approximately 92%ee, at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, or at least approximately 98%ee.

[0386] In some embodiments, hemifumarate salt of S-THH contains less than approximately 20% water by weight. In some embodiments, the hemifumarate salt of S-THH contains less than approximately 15% water by weight, or less than approximately 12% water by weight. In one example, the hemifumarate salt of S-THH contains less than approximately 10% water by weight.

[0387] In some embodiments, S-THH hemifumarate includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of S-THH hemifumarate. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of S-THH hemifumarate. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0388] In some embodiments, there is provided a method for preparing a fumarate salt of S-THH including the steps of:

[0389] dissolving S-THH in an alcohol solvent to provide a mixture, wherein the mixture is heated at a temperature sufficient to facilitate dissolution;

[0390] adding fumaric acid to the mixture to provide an admixture;

[0391] cooing the admixture for a time sufficient to precipitate the fumarate salt; separation the precipitate from the admixture to provide fumarate salt of S-THH.

[0392] In some embodiments, the mixture is heated under reflux.In some embodiments, fumaric acid is added to the mixture incrementally.

[0393] In some embodiments, the admixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below approximately 10 °C, or between approximately 2 °C and approximately 8 °C. In some embodiments, the mixture is cooled for at least approximately 10 hours. In some embodiments, the mixture is cooled for at least approximately 15 hours, or between approximately 15 hours and approximately 25 hours. In one example, the mixture is cooled for at least approximately 19 hours.

[0394] In some embodiments, the precipitate is separated from the admixture using filtration, for example, vacuum filtration. In one example, after filtration, the precipitate is dried.

[0395] In some embodiments, the fumarate salt of S-THH is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, the fumarate salt of S-THH is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98% pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0396] In some embodiments, S-THH fumarate is substantially free of other enantiomers. In some embodiments, S-THH fumarate, in the context of enantiomeric excess, is at least approximately 70%ee, at least approximately 75%ee, at least approximately 80%ee, or at least approximately 82%ee. In some embodiments, purified S-THH fumarate is at least approximately 84%ee, at least approximately 86%ee, or at least approximately 88%ee. In some embodiments, purified S-THH fumarate, in the context of enantiomeric excess, is at least approximately 90%ee, may be at least approximately 91%ee, may be at least approximately 92%ee, may be at least approximately 93%ee, may be at least approximately 94%ee, may be at least approximately 95%ee, may be at least approximately 96%ee, may be at least approximately 97%ee or may be at least approximately 98%ee.

[0397] In some embodiments, fumarate salt of S-THH contains less than approximately 20% water by weight. In some embodiments, the fumarate salt of S-THH contains less than approximately 15% water by weight, or less than approximately 12% water by weight. In one example, the fumarate salt of S-THH contains less than approximately 10% water by weight.

[0398] In some embodiments, S-THH fumarate includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than(NLT) 0.01% w / w, relative to the amount of S-THH fumarate. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of S-THH fumarate. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0399] In some embodiments, there is provided a method for preparing (R)-7-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole ((1 S)-7,7-di methyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (hereinafter, ‘R-THH-(+)-CSA’), including the steps of:

[0400] contacting racemic THH with an alcohol solvent to provide a mixture; heating the mixture;

[0401] contacting the mixture with D-(+)-camphor-10-sulphonic acid, wherein the mixture is stirred at a temperature and for a time period sufficient to provide a precipitate;

[0402] removing the precipitate from the mixture;

[0403] separating R-THH-(+)-CSA from the mixture to provide isolated R-THH-(+)-CSA.

[0404] In some embodiments, the racemic THH is synthesised from a hydrochloride salt of THH.

[0405] In some embodiments, the mixture is heated to a temperature of above approximately 50 °C. In some embodiments, the mixture is heated to a temperature of above approximately 55 °C. In some embodiments, the mixture is heated to a temperature within the range of approximately 55 °C and approximately 65 °C. In one example, the mixture is heated to a temperature of approximately 60 °C.

[0406] In some embodiments, the mixture is stirred at room temperature for at least approximately 10 hours. In some embodiments, the mixture is stirred at room temperature for at least approximately 12 hours, or at least approximately 15 hours. In some embodiments, the mixture is stirred at room temperature for at least approximately 17 hours.

[0407] In some embodiments, the method further comprises purifying R-THH-(+)-CSA, wherein the steps of purifying comprise dissolving R-THH-(+)-CSA in an alcohol solvent and recrystalizing to provide purified R-THH-(+)-CSA. In one example, the alcohol solvent is ethanol.In some embodiments, R-THH-(+)-CSA is in the form of a solid, a liquid, an oil or a viscous liquid, and is likely to contain impurities.

[0408] The term ‘purified R-THH-(+)-CSA’, in the context of R-THH-(+)-CSA, is taken to mean that the R-THH-(+)-CSA is substantially free of other compounds. In some embodiments, ‘purified R-THH-(+)-CSA’ is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, purified R-THH-(+)-CSA is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98 % pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0409] The term ‘purified R-THH-(+)-CSA’, in the context of enantiomeric excess, is taken to mean that the R-THH-(+)-CSA is substantially free of other enantiomers. In some embodiments, R-THH-(+)-CSA, in the context of enantiomeric excess, is at least approximately 60%ee, at least approximately 65%ee, at least approximately 68%ee, or at least approximately 70%ee. In some embodiments, R-THH-(+)-CSA is at least approximately 71%ee, at least approximately 72%ee, or at least approximately 73%ee. In some embodiments, R-THH-(+)-CSA, in the context of enantiomeric excess, is at least approximately 74%ee, at least approximately 75%ee, at least approximately 76%ee at least approximately 77%ee, at least approximately 78%ee, at least approximately 79%ee, at least approximately 80%ee, at least approximately 81%ee, or at least approximately 82%ee.

[0410] In some embodiments, purified R-THH-(+)-CSA is in the form of a solid, a liquid, an oil, or a viscous liquid

[0411] In some embodiments, there is provided a method for preparing R-THH, including the steps of:

[0412] contacting R-THH-(+)-CSA with water to provide a mixture;

[0413] heating the mixture;

[0414] contacting the mixture with an alcohol;

[0415] contacting the mixture with potassium hydroxide, wherein the mixture is stirred at a temperature and for a time period sufficient to provide a precipitate; separating the precipitate from the mixture to provide R-THH.

[0416] In some embodiments, the mixture is heated to a temperature of above approximately 50 °C. In some embodiments, the mixture is heated to a temperature of above approximately55 °C. In some embodiments, the mixture is heated to within the range of approximately 55 °C and approximately 65 °C. In one example, the mixture is heated to approximately 60 °C.

[0417] In some embodiments, the potassium hydroxide is added to the mixture incrementally.

[0418] In some embodiments, the mixture is stirred at room temperature for at least approximately 10 hours. In some embodiments, the mixture is stirred at room temperature for at least approximately 12 hours, or at least approximately 15 hours. In one example, the mixture is stirred at room temperature for approximately 17 hours.

[0419] In some embodiments, R-THH is substantially free of other enantiomers. In some embodiments, R-THH, in the context of enantiomeric excess, is at least approximately 60%ee, at least approximately 65%ee, at least approximately 68%ee, or at least approximately 70%ee. In some embodiments, R-THH is at least approximately 71%ee, at least approximately 72%ee, or at least approximately 73%ee. In some embodiments, R-THH, in the context of enantiomeric excess, at least approximately 74%ee, at least approximately 75%ee, at least approximately 76%ee, at least approximately 77%ee, at least approximately 78%ee, at least approximately 79%ee, at least approximately 80%ee, at least approximately 81%ee, or at least approximately 82%ee.

[0420] In some embodiments, R-THH includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of R-THH. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of R-THH. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0421] In some embodiments, there is provided a method for preparing R-THH-(-)-CSA, including the steps of:

[0422] contacting R-THH with an alcohol solvent to provide a mixture;

[0423] heating the mixture;

[0424] contacting the mixture with L-(-)-camphor-10-sulphonic acid, wherein the mixture is stirred at a temperature and for a time period sufficient to provide a precipitate; separating the precipitate from the mixture to provide isolated R-THH-(-)-CSA.

[0425] In some embodiments, the mixture is heated to a temperature of above approximately 50 °C. In some embodiments, the mixture is heated to a temperature of above approximately 55 °C, or to a temperature of approximately 60 °C. In some embodiments, the mixture isheated to a temperature of between approximately 60 °C and approximately 70 °C. In some embodiments, the mixture is heated to a temperature of approximately 65 °C, approximately 66 °C, or approximately 67 °C.

[0426] In some embodiments, the mixture is stirred at room temperature for at least approximately 2 hours. In some embodiments, the mixture is stirred at room temperature for at least approximately 3 hours, or at least approximately 4 hours. In some embodiments, the mixture is stirred at room temperature for between approximately 4 hours and approximately 6 hours. In some embodiments, the mixture is stirred at room temperature for approximately 4.5 hours, approximately 5 hours, approximately 5.5 hours, or approximately 6 hours.

[0427] In some embodiments, the method further comprises purifying R-THH-(-)-CSA, wherein the steps of purifying comprise dissolving R-THH-(-)-CSA in an alcohol solvent and recrystalizing to provide purified R-THH-(-)-CSA. In one example, the alcohol solvent is ethanol.

[0428] In some embodiments, there is provided a method for preparing R-THH, including the steps of:

[0429] contacting R-THH-(-)-CSA with water to provide a mixture;

[0430] heating the mixture;

[0431] contacting the mixture with an alcohol solvent;

[0432] contacting the mixture with potassium hydroxide,

[0433] cooling the mixture for a time period sufficient to provide a precipitate; separating the precipitate from the mixture to provide purified R-THH

[0434] In some embodiments, the mixture is heated to a temperature of at least approximately 50 °C. In some embodiments, the mixture is heated to a temperature of at least approximately 55 °C. In some embodiments, the mixture is heated to a temperature of between approximately 55 °C and approximately 65 °C. In some embodiments, the mixture is heated to a temperature of approximately 58 °C, approximately 60 °C, or approximately 62 °C.

[0435] In some embodiments, the potassium hydroxide is added to the mixture incrementally.

[0436] In some embodiments, the mixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below 10 °C, or between approximately 2 °C and approximately 8 °C. In some embodiments, the mixture is cooled for at least approximately 1 hour. In some embodiments, the mixture is cooled for at leastapproximately 2 hours, or for between approximately 3 hours and approximately 4 hours. In one example, the mixture is cooled for approximately 3.5 hours.

[0437] In some embodiments, R-THH is substantially free of other enantiomers. In some embodiments, R-THH, in the context of enantiomeric excess, is at least approximately 75%ee, at least approximately 80%ee, at least approximately 82%ee, or at least approximately 84%ee. In some embodiments, R-THH is at least approximately 86%ee, at least approximately 88%ee, or at least approximately 90%ee. In some embodiments, R-THH, in the context of enantiomeric excess, is at least approximately 91 %ee, at least approximately 92%ee, at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, or at least approximately 99%ee.

[0438] In some embodiments, the method described herein may further comprise the steps of preparing a pharmaceutically acceptable salt of purified R-THH. The pharmaceutically acceptable salt of R-THH may be selected from the group consisting of hydrochloride, acetate, mesylate, tosylate, camsylate, fumarate, and hemifumarate. In some embodiments, the method described herein further includes the steps of preparing a hydrochloride or hemifumarate salt from purified R-THH.

[0439] In some embodiments, R-THH includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of R-THH. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of R-THH. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0440] In some embodiments, there is provided a method for preparing a hemifumarate salt of R-THH including the steps of:

[0441] dissolving R-THH in an alcohol solvent to provide a solution, wherein the solution is heated at a temperature sufficient to facilitate dissolution;

[0442] adding fumaric acid to the solution to provide an admixture,

[0443] cooing the solution for a time sufficing to precipitate the hemifumarate salt; separating the precipitate from the admixture to provide hemifumarate salt of R- THH.

[0444] In some embodiments, the mixture is heated under reflux.In some embodiments, fumaric acid is added to the mixture incrementally.

[0445] In some embodiments, the admixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below approximately 10 °C, or between approximately 2 °C and approximately 8 °C. In some embodiments, the mixture is cooled for at least approximately 10 hours. In some embodiments, the mixture is cooled for at least approximately 15 hours, or cooled for between approximately 15 hours and approximately 25 hours. In one example, the mixture is cooled for approximately 19 hours.

[0446] In some embodiments, the hemifumarate salt of R-THH is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, the hemifumarate salt of R-THH is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98 % pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0447] In some embodiments, the hemifumarate salt of R-THH is substantially free of other enantiomers. In some embodiments, hemifumarate salt of R-THH, in the context of enantiomeric excess, is at least approximately 75%ee, at least approximately 80%ee, at least approximately 82%ee, or at least approximately 84%ee. In some embodiments, hemifumarate salt of R-THH is at least approximately 86%ee, at least approximately 88%ee, or at least approximately 90%ee. In some embodiments, hemifumarate salt of R-THH, in the context of enantiomeric excess, is at least approximately 91%ee, at least approximately 92%ee, at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, or at least approximately 99%ee.

[0448] In some embodiments, hemifumarate salt of R-THH contains less than approximately 20% water by weight. In some embodiments, the hemifumarate salt of R-THH contains less than approximately 15% water by weight, or less than approximately 12% water by weight. In some embodiments, the hemifumarate salt of R-THH contains less than approximately 10% water by weight.

[0449] In some embodiments, R-THH hemifumarate includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of R-THH hemifumarate. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w,relative to the amount of R-THH hemifumarate. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0450] In some embodiments, there is provided a method for preparing a fumarate salt of R-THH including the steps of:

[0451] dissolving R-THH in an alcohol solvent to provide a solution, wherein the solution is heated at a temperature sufficient to facilitate dissolution;

[0452] adding fumaric acid to the solution to provide an admixture,

[0453] cooing the solution for a time sufficing to precipitate the fumarate salt; separating the precipitate from the admixture to provide fumarate salt of R-THH.

[0454] In some embodiments, the mixture is heated under reflux.

[0455] In some embodiments, fumaric acid is added to the mixture incrementally.

[0456] In some embodiments, the admixture is cooled to a temperature below approximately 15 °C. In some embodiments, the mixture is cooled to a temperature below approximately 10 °C, or between approximately 2 °C and approximately 8 °C. In some embodiments, the mixture is cooled for at least approximately 10 hours. In some embodiments, the mixture is cooled for at least approximately 15 hours, or for between approximately 15 hours and approximately 25 hours. In some embodiments, the mixture is cooled for approximately 19 hours.

[0457] In some embodiments, the fumarate salt of R-THH is at least approximately 50% pure, at least approximately 60% pure, at least approximately 70% pure, or at least approximately 80% pure. In some embodiments, the fumarate salt of R-THH is at least approximately 90% pure, at least approximately 95% pure, at least approximately 97% pure, at least approximately 98 % pure, at least approximately 99% pure, or at least approximately 99.5% pure.

[0458] In some embodiments, the fumarate salt of R-THH is substantially free of other enantiomers. In some embodiments, the fumarate salt of R-THH, in the context of enantiomeric excess, is at least approximately 75%ee, at least approximately 80%ee, at least approximately 82%ee, or at least approximately 84%ee. In some embodiments, the fumarate salt of R-THH is at least approximately 86%ee, at least approximately 88%ee, or at least approximately 90%ee. In some embodiments, fumarate salt of R-THH, in the context of enantiomeric excess, at least approximately 91%ee, at least approximately 92%ee, at leastapproximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, or at least approximately 99%ee.

[0459] In some embodiments, the fumarate salt of R-THH contains less than approximately 20% water by weight. In some embodiments, the fumarate salt of R-THH contains less than approximately 15% water by weight, or less than approximately 12% water. In some embodiments, the fumarate salt of R-THH contains less than approximately 10% water by weight.

[0460] In some embodiments, R-THH fumarate includes impurities. In some embodiments, the impurities are present in an amount of not more than (NMT) 10% w / w and not less than (NLT) 0.01% w / w, relative to the amount of R-THH fumarate. In some embodiments, the impurities are present in an amount of NMT 8% w / w and NLT 0.01% w / w, relative to the amount of R-THH fumarate. In some embodiments, NMT 6% w / w and NLT 0.01% w / w. In some embodiments, NMT 4% w / w and NLT 0.01% w / w. In some embodiments, NMT 1% w / w and not less than 0.01% w / w.

[0461] In some embodiments, of the methods described herein, the precipitate is separated from the mixture using filtration, for example, vacuum filtration. In one example, the precipitate after filtration is dried.

[0462] In some embodiments, of the methods described herein, the term ‘alcohol solvent’ as used herein, refers to any solvent containing an alcohol functional group, being -OH. In some embodiments, the alcohol solvent is selected from the group consisting of heptane, isopropanol, ethanol, hexane, methanol, and a combination thereof. In one example, the alcohol solvent is ethanol. In one example, the alcohol solvent is isopropanol. In one example, the alcohol solvent is methanol.

[0463] In some embodiments, the alcohol solvent is selected from the group consisting of isopropanol, ethanol, methanol, and a combination thereof.

[0464] In some embodiments, of the methods described herein, impurities are present in an amount of at least approximately 0.01% w / w. In some embodiments, impurities are present in an amount of at least approximately 1% w / w, at least approximately 2% w / w, or at least approximately 4% w / w. In some embodiments, impurities are present in an amount of at least approximately 0.01% w / w, at least approximately 0.05% w / w, at least approximately 0.1% w / w, at least approximately 0.2% w / w, at least approximately 0.3% w / w, at leastapproximately 0.4% w / w, at least approximately 0.5% w / w, at least approximately 0.7% w / w, at least approximately 1% w / w, at least approximately 2% w / w, at least approximately 3% w / w, at least approximately 4% w / w, at least approximately 5% w / w, at least approximately 6% w / w, at least approximately 7% w / w, at least approximately 8% w / w, or at least approximately 9% w / w.

[0465] In some embodiments, of the methods described herein, impurities are present in an amount of at most approximately 10% w / w, at most approximately 8% w / w, at more approximately 6% w / w, or at most approximately 4% w / w. In some embodiments, impurities are present in an amount of at most approximately 10% w / w, at most approximately 9% w / w, at most approximately 8% w / w, at most approximately 7% w / w, at most approximately 6% w / w, at most approximately 5% w / w, at most approximately 4% w / w, at most approximately 3.5% w / w, at most approximately 3% w / w, at most approximately 2.5% w / w, at most approximately 2% w / w, at most approximately 1.5% w / w, at most approximately 1% w / w, at most approximately 0.75% w / w, at most approximately 0.5% w / w, at most approximately 0.1% w / w, or at most approximately 0.01% w / w.

[0466] In some embodiments, of the methods described herein, impurities are present in an amount of approximately 0.01% w / w, approximately 0.05% w / w, approximately 1% w / w, approximately 1.5% w / w, approximately 2% w / w, approximately 2.5% w / w, approximately 3% w / w, approximately 4% w / w, approximately 5% w / w, approximately 6% w / w, approximately 7% w / w, approximately 8% w / w, approximately 9% w / w, or approximately 10% w / w.

[0467] The impurities may be derived from a by-product of the method. For example, the compound S-THH may be present in the composition in an amount of between approximately 0.05% w / w and approximately 1% w / w, relative to the amount of R-THH. Similarly, for example, the compound R-THH may be present in the composition in an amount of between approximately 0.05% w / w and approximately 1% w / w, relative to the amount of S-THH.

[0468] In some embodiments, there is provided racemic THH, R-THH(-)-CSA, purified R-THH-(-)-CSA, purified R-THH, S-THH-(-)-CSA, purified S-THH, S-THH-(+)-CSA, purified S-THH-(+)-CSA, R-THH-(+)-CSA, purified R-THH-(+)-CSA, R-THH, or R-THH-(-)-CSA, prepared according to the methods as hereinbefore described.

[0469] In some embodiments, there is provided a compound selected from the group consisting of racemic THH, R-THH(-)-CSA, purified R-THH-(-)-CSA, purified R-THH, S-THH-(-)-CSA, purified S-THH, S-THH-(+)-CSA, purified S-THH-(+)-CSA, R-THH-(+)-CSA, purified R-THH-(+)-CSA, R-THH, and R-THH-(-)-CSA, said compound prepared according to themethods as hereinbefore described, and wherein said compound has a purity of at least approximately 50%, at least approximately 60%, at least approximately 70%, at least approximately 80%, at least approximately 90%, at least approximately 95%, at least approximately 97%, at least approximately 98%, at least approximately 99%, or at least approximately 99.5% pure.

[0470] In some embodiments, there is provided R-THH hemifumarate, S-THH hemifumarate, R-THH fumarate, or S-THH fumarate, prepared according to the methods as hereinbefore described.

[0471] Accordingly, in some embodiments, there is provided R-THH hemifumarate or S-THH hemifumarate prepared according to methods as hereinbefore described and having a purity of at least approximately 50 %, at least approximately 60 %, at least approximately 70%, at least approximately 80%, at least approximately 90%, at least approximately 95%, at least approximately 97%, at least approximately 98%, at least approximately 99%, or at least approximately 99.5% pure.

[0472] Accordingly, in some embodiments, there is provided R-THH, R-THH hemifumarate, S-THH or S-THH hemifumarate prepared according to methods as hereinbefore described having enantiomeric excess at least approximately 75%ee, at least approximately 80%ee, at least approximately 82%ee, or at least approximately 84%ee. In some embodiments, hemifumarate salt of R-THH is at least approximately 86%ee, at least approximately 88%ee, or at least approximately 90%ee. In some embodiments, hemifumarate salt of R-THH, in the context of enantiomeric excess, is at least approximately 91%ee, at least approximately 92%ee, at least approximately 93%ee, at least approximately 94%ee, at least approximately 95%ee, at least approximately 96%ee, at least approximately 97%ee, at least approximately 98%ee, or at least approximately 99%ee.

[0473] Methods and Uses

[0474] As discussed herein, the subject matter of the present disclosure is predicated in part on the surprising discovery that the pharmaceutical compositions, described herein, and compositions, described herein, may be particularly advantageous in methods of treating various diseases, disorders, and conditions, and related uses, via administration of the pharmaceutical composition or composition.

[0475] The advantages may be particularly realised upon co-administration of a tryptamine. In the instance of the pharmaceutical composition, as described herein, wherein the tryptamine is not co-formulated in the broadest embodiment of the pharmaceuticalcomposition, it will be understood that tryptamine may be co-administered in the methods and uses, described herein.

[0476] As used herein, the term “co-administration” refers to the administration of two or more active agents to a subject in a manner that allows their therapeutic and / or pharmacological effects to overlap. Co-administration includes both simultaneous administration (e.g., in a single dosage form or administration at the same time) and sequential administration (e.g., separate dosage forms or administration at different times), provided that the agents are administered within a time frame such that their therapeutic and / or pharmacological effects overlap (i.e., are concurrent or complementary). In one example, co-administration is simultaneous administration. In one example, co-administration is sequential administration. The term “co-administration” encompasses both administration by the same route or by different routes.

[0477] In embodiments relating to the pharmaceutical composition, as described herein, the pharmaceutical composition may comprise the nonracemic mixture of the tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, and the tryptamine, or pharmaceutically acceptable salt thereof, may be provided in a single composition, and therefore, in such embodiments, are co-administered.

[0478] In embodiments relating to the pharmaceutical composition, as described herein, the pharmaceutical composition may comprise the nonracemic mixture of the tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, and not the tryptamine, or pharmaceutically acceptable salt thereof. In such embodiments, the tryptamine, or pharmaceutically acceptable salt thereof, may be co-administered by virtue of administration of a further composition comprising the tryptamine, or pharmaceutically acceptable salt thereof. Accordingly, in one example, the pharmaceutical composition, as described herein, and a tryptamine, or pharmaceutically acceptable salt thereof, are co-administered. Accordingly, in some embodiments, the pharmaceutical composition, described herein, is formulated for co-administration with a tryptamine, or pharmaceutically acceptable salt thereof.

[0479] In embodiments relating to the composition, as described herein, it will be appreciated that the nonracemic mixture of the tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, and the tryptamine, or pharmaceutically acceptable salt thereof, are provided in a single composition, and therefore, in such embodiments, are co-administered. It also remains possible for one or more further tryptamines to be co-administered by virtue ofadministration of one or more further composition comprising the one or more further tryptamines, or a pharmaceutically acceptable salt thereof. Accordingly, in some embodiments, the composition, as described herein, is formulated for co-administration with one or more further tryptamines, or pharmaceutically acceptable salt thereof.

[0480] The nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, may possess therapeutic efficacy insofar that it may exhibit activity at any one or more of several pharmacologically relevant targets. Such pharmacologically relevant targets may include, for example, serotonin receptors (e.g., 5-HT2A, 5-HT2C), sigma-1 receptors, dopamine receptors, adrenergic receptors, monoamine oxidases (e.g., MAO-A, MAO-B), and monoamine transporters (e.g., DAT, SERT, NET). Additional effects in enhancing neuroplasticity may also be observed.

[0481] Without wishing to be limiting or to be bound by theory, it is believed that compositions and pharmaceutical compositions disclosed herein enable advantageous receptor pathway stacking. The tryptamine, such as DMT, can provide useful 5-HT2A / 2C agonism and / or sigma-1 activation and / or neuroplasticity enhancement. When desired, this can be combined with (R)-THH of a selected enantiomeric purity and this may provide for additional sigma-1 engagement and / or creation of amplified neuroprotective and reward-circuit effects valuable for substance use disorders. Alternatively, when desired this can be combined with (S)-THH of a selected enantiomeric purity and this may provide for enhanced 5-HT2C activity and / or amplification of appetite regulation and / or impulse control, thereby relevant for eating disorders and stimulant addiction. Further MAO-A inhibition by either THH enantiomer may extend these receptor interactions temporally. This creates synergistic multi-target profiles unachievable with single compound therapy, enabling precision matching of receptor pathway combinations to specific clinical indications.

[0482] Accordingly, in a further aspect, there is provided a method of treating of a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is responsive to one or more of:

[0483] modulation of Serotonin receptor (5-HT2A) activity; and / or

[0484] modulation of Serotonin receptor (5-HT2c) activity; and / or

[0485] modulation of sigma-1 receptor activity; and / or

[0486] modulation of activity at a Serotonin receptor other than 5-HT2Aand 5-HT2B; and / or modulation of activity at a Dopamine receptor; and / or

[0487] modulation of activity at an Adrenergic receptor; and / or

[0488] inhibition of a monoamine oxidase (MAOs); and / ormodulation of a monoamine transporter (DAT, SERT and / or NET); and / or enhancement of neuroplasticity;

[0489] comprising administering the pharmaceutical composition, or composition, as described herein, to the subject.

[0490] In some embodiments, the disease, disorder, or condition is responsive to monoamine oxidase (MAO) modulation. In one example, the disease, disorder, or condition is responsive to monoamine oxidase (MAO) inhibition. In one example, the monoamine oxidase is monoamine oxidase A (MAO-A). In one example, the monoamine oxidase is monoamine oxidase B (MAO-B).

[0491] Accordingly, in some embodiments, there is provided a method of treating a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is responsive to monoamine oxidase (e.g., MAO-A, MOA-B) inhibition.

[0492] In some embodiments, the disease, disorder, or condition is associated with the central nervous system, the peripheral nervous system, or both the central nervous system and the peripheral nervous system. In one example, the disease, disorder, or condition is associated with the central nervous system. In one example, the disease, disorder, or condition is associated with the peripheral nervous system. In one example, the disease disorder, or condition is associated with the central nervous system and the peripheral nervous system.

[0493] It will be appreciated that such disease, disorders, or conditions are not necessarily exclusively associated to either of the central or peripheral nervous systems. However, it will also be appreciated that some particular disease, disorder, or conditions may be more dominated by effects associated with either of the central nervous system or peripheral nervous system. In one example, the disease, disorder, or condition is predominantly associated with the central nervous system. In one example, the disease, disorder, or condition is predominantly associated with the peripheral nervous system.

[0494] As discussed herein, the pharmaceutical composition or composition comprises nonracemic tetrahydroharmine (THH). It therefore follows that in some embodiments, the pharmaceutical composition or composition comprises (R)-THH in enantiomeric excess (ee). Similarly, it follows that in some embodiments, the pharmaceutical composition or composition comprises (S)-THH in enantiomeric excess (ee).It has been surprisingly found that particular enantiomers of tetrahydroharmine (THH), namely the (R)- or (S)-enantiomer, demonstrate different pharmacokinetic properties that may advantageously, ultimately render the particular enantiomer as particularly useful in the treatment of a disease, disorder, or condition.

[0495] In some embodiments, when administered as a single agent, it has been observed that (S)-THH provides greater central nervous system exposure of the THH molecule than (R)-THH under equivalent dosing conditions, whereas (R)-THH exhibits relatively higher peripheral exposure in this monotherapy context.

[0496] Therefore, in some embodiments, there is provided a method of treating a disease, disorder, or condition associated predominantly with the central nervous system, comprising administering the pharmaceutical composition, or composition, as described herein, wherein (S)-THH is present in enantiomeric excess. In monotherapy contexts, (S)-THH may provide greater central exposure of the tetrahydroharmine (THH) molecule than (R)-THH under equivalent dosing conditions.

[0497] Accordingly, in some embodiments, there is provided a method of treating a disease, disorder, or condition in which increased central exposure of a co-administered tryptamine is desirable, comprising administering the pharmaceutical composition, or composition, as described herein, wherein (R)-THH is present in enantiomeric excess.

[0498] In some embodiments, where attenuated central exposure of the co-administered tryptamine or enhanced 5 HT2C receptor signalling is therapeutically desirable, there is provided a method comprising administering the pharmaceutical composition, or composition, as described herein, wherein (S)-THH is present in enantiomeric excess.

[0499] Accordingly, in some embodiments, (S)-THH may be selected in combination therapy where attenuation of central tryptamine exposure or preferential engagement of 5-HT2C signalling is desirable, including in settings in which a more moderated intensity of the tryptamine effect is clinically advantageous.

[0500] Accordingly, in some embodiments, there is provided a method of treating a disease, disorder, or condition associated predominantly with the central nervous system, comprising administering the pharmaceutical composition, or composition, as described herein, wherein (S)-THH is present in enantiomeric excess.In some embodiments, there is provided a method of treating a disease, disorder, or condition in which relatively greater peripheral exposure of the tryptamine molecule, or enhanced sigma 1 receptor activity, is desirable, comprising administering the pharmaceutical composition, or composition, as described herein, wherein (R)-THH is present in enantiomeric excess.

[0501] Therefore, in some embodiments, there is provided a method of treating a disease, disorder, or condition associated (predominantly) with the central nervous system, comprising administering the pharmaceutical composition, or composition, as described herein, wherein (S)-THH is in enantiomeric excess (ee). In some embodiments, there is provided a method of treating a disease, disorder, or condition associated (predominantly) with the peripheral nervous system, comprising administering the pharmaceutical composition, or composition, as described herein, wherein (R)-THH is in enantiomeric excess (ee).

[0502] As a result of the different preference for central versus peripheral partitioning, systemic inhibition of monoamine oxidase (e.g., MAO-A, MAO-B) may be modulated, therefore modulating the activity of the tryptamine. It has been surprisingly found that the pharmaceutical compositions and compositions described herein, wherein (S)-THH is in enantiomeric excess (ee), provide higher relative central nervous system partitioning compared to peripheral nervous system partitioning, when compared to administration of a comparable amount of (R)-THH. In the same way, it has been surprisingly found that the pharmaceutical compositions and compositions described herein, wherein (R)-THH is in enantiomeric excess (ee), provide higher relative peripheral nervous system partitioning when compared to administration of a comparable amount of (S)-THH.

[0503] In monotherapy contexts, the extent of central versus peripheral exposure of tetrahydroharmine may vary according to which enantiomer is present in excess. For example, a composition comprising a nonracemic mixture of tetrahydroharmine in which (S)-THH is present in high enantiomeric excess, such as at least about 98 percent ee, may provide greater central exposure of the THH molecule than a corresponding composition in which (R)-THH is present in high enantiomeric excess, such as at least about 98 percent ee, under otherwise equivalent monotherapy dosing conditions. Conversely, compositions comprising (R)-THH in high enantiomeric excess, such as at least about 98 percent ee, may provide relatively greater peripheral exposure of the THH molecule when administered alone.In monotherapy settings, differences in THH distribution may contribute to differences in the location and extent of monoamine oxidase inhibition and may therefore influence the resulting pharmacological profile. In some embodiments, (S)-THH provides greater central exposure than (R)-THH when administered alone, whereas (R)-THH provides relatively greater peripheral exposure under equivalent monotherapy conditions.lt is therefore foreseeable that the extent of partitioning in the central or peripheral nervous system may be affected by the enantiomer excess (ee) of the nonracemic mixture of tetrahydroharmine (THH). For example, a composition comprising the nonracemic mixture of tetrahydroharmine (THH) in an enantiomeric excess (ee), being predominantly (S)-THH, of greater than about 95%, will have greater central nervous system partitioning than the corresponding composition comprising the nonracemic mixture of tetrahydroharmine (THH) in an enantiomeric excess (ee), being predominantly (R)-THH, of greater than about 95%. Conversely, a composition comprising the nonracemic mixture of tetrahydroharmine (THH) in an enantiomeric excess (ee), being predominantly (R)-THH, of greater than about 95%, will have greater peripheral nervous system partitioning than the corresponding composition comprising the nonracemic mixture of tetrahydroharmine in an enantiomeric excess (ee), being predominantly (S)-THH, of greater than about 95%.

[0504] As a result of the different levels of central nervous system and peripheral nervous system partitioning of (R)-THH and (S)-THH, it is foreseeable that the pharmaceutical compositions, and compositions, as described herein, may be modified so as to affect this partitioning, affect the level and location of inhibition of monoamine oxidase, and ultimately affect the duration of action of the co-administered tryptamine (e.g., DMT) in each system. This shortening or lengthening of duration of activity of the co-administered tryptamine may be relative to administration of the corresponding tryptamine alone.

[0505] In some embodiments, (R)-THH has a lower central nervous system partitioning than (S)-tetrahydroharmine (THH). In some embodiments, (S)-THH has a higher central nervous system partitioning than (R)-THH.

[0506] Selection of the route of administration can provide for an additional layer of control based upon this knowledge of preferential (R)- 1 (S)-THH partitioning. It will be appreciated that with intranasal and / or IV delivery of the tryptamine, such as DMT, the greater central nervous system (e.g. brain) partitioning of co-administered (S)-THH will provide for stronger central MAO-A inhibition, thereby extending psychedelic duration despite lower peripheral inhibition. If the tryptamine, such as DMT, is to be delivered orally then (R)-THH's more balanced distribution profile (i.e. more partitioning to the peripheral nervous system than for (S)-THHbut still with companying central nervous system distribution albeit to a lesser extent) provides superior hepatic protection enabling better systemic bioavailability when co-administered. It will be appreciated that this allows the preferred approach of tryptamine administration route to be selected, along with appropriate non-racemic tetrahydroharmine composition to target clinically desired outcomes based upon tryptamine system / organ targeting and accompanying optimal MAO-A inhibition. As discussed previously, additional therapeutic control can also be achieved by selection of the ratio of non-racemic tetrahydroharmine to tryptamine to tailor duration of action. Such levels of fine control and optimisation have not previously been achievable in the design of co-formulated tryptamine and MAO-A inhibitor therapy until the present disclosure.

[0507] In some embodiments, the disease, disorder, or condition is understood to be associated with synergistic sigma-1 receptor modulation (e.g., wherein the tetrahydroharmine (THH) and / or tryptamine provide coordinated sigma-1 chaperone activation). In some embodiments, the disease, disorder, or condition is selected from the group consisting of major depressive disorder (MDD), substance use disorders involving disrupted reward processing or maladaptive motivational states, prolonged grief disorder, chronic pain conditions with neuropathic components, inflammatory and neuroimmune disorders with central nervous system involvement, neurodegenerative disorders including those associated with agitation, apathy or cognitive decline, post-traumatic stress disorder and trauma-related conditions characterised by hyperarousal, intrusive symptoms or affective dysregulation, and cognitive impairment or executive dysfunction in neuropsychiatric disorders.

[0508] In one example, the disease, disorder, or condition is major depressive disorder (MDD). In one example, the disease, disorder, or condition is a substance use disorders involving disrupted reward processing or maladaptive motivational states. In one example, the disease, disorder, or condition is prolonged grief disorder. In one example, the disease, disorder, or condition is a chronic pain conditions with neuropathic components. In one example, the disease, disorder, or condition is an inflammatory or neuroimmune disorder with central nervous system involvement. In one example, the disease, disorder, or condition is a neurodegenerative disorder associated with agitation, apathy or cognitive decline. In one example, the disease, disorder, or condition is post-traumatic stress disorder or trauma-related conditions characterised by hyperarousal, intrusive symptoms or affective dysregulation. In one example, the disease, disorder, or condition is cognitive impairment or executive dysfunction in a neuropsychiatric disorder.In embodiments where the disease, disorder, or condition is understood to be associated with synergistic sigma-1 receptor modulation, co-administration of (R)-THH and a tryptamine (e.g., N,N-dimethyltryptamine) may be advantageous. Accordingly, in some embodiments, there is provided a method of treating a disease, disorder, or condition selected from the group consisting of (MDD), substance use disorders involving disrupted reward processing or maladaptive motivational states, prolonged grief disorder, chronic pain conditions with neuropathic components, inflammatory and neuroimmune disorders with central nervous system involvement, neurodegenerative disorders including those associated with agitation, apathy or cognitive decline, post-traumatic stress disorder and trauma-related conditions characterised by hyperarousal, intrusive symptoms or affective dysregulation, and cognitive impairment or executive dysfunction in neuropsychiatric disorders, comprising administering the pharmaceutical composition, or composition, as described herein, wherein the (R)-THH is in enantiomeric excess (ee), preferably at least about 90%, at least about 95% or at least about 99% enantiomeric excess (ee).

[0509] In some embodiments, the disease, disorder, or condition is understood to be associated with complementary serotonin modulation (e.g., wherein the tryptamine provides 5-HT2A receptor agonism and / or the tetrahydroharmine (THH) contributes 5-HT2C partial agonism). In some embodiments, the disease, disorder, or condition is selected from the group consisting of substance use disorders (including stimulant and alcohol use disorders); , post-traumatic stress disorder (PTSD), agitation (e.g., associated with Alzheimer’s disease, dementia, autism spectrum disorder (ASD)), eating disorders and appetite dysregulation, acute substance withdrawal, mood apathy in neurodegenerative diseases (e.g., associated with Alzheimer’s disease, dementia), anxiety and stress-related conditions characterised by excessive fear, tension or dysregulated arousal, and depressive disorders. In one example, the disease, disorder, or condition is substance use disorder. In one example, the disease, disorder, or condition is post-traumatic stress disorder (PTSD). In one example, the disease, disorder, or condition is agitation (e.g., associated with Alzheimer’s disease, dementia, autism spectrum disorder (ASD)). In one example, the disease, disorder, or condition is an eating disorder. In one example, the disease, disorder, or condition is acute substance withdrawal. In one example, the disease, disorder, or condition is mood apathy (e.g., associated with Alzheimer’s disease, dementia). In one example, the disease, disorder, or condition is an impulse control disorder. In one example, the disease, disorder, or condition is an anxiety and stress-related condition. In one example, the disease, disorder, or condition is depressive disorder substance withdrawal.In embodiments where the disease, disorder, or condition is understood to be associated with complementary serotonin modulation, co-administration of (S)-THH and a tryptamine (e.g., N,N-dimethyltryptamine) may be advantageous. Accordingly, in some embodiments, there is provided a method of treating a disease, disorder, or condition selected from the group consisting of substance use disorders (including stimulant and alcohol use disorders), post-traumatic stress disorder (PTSD), agitation (e.g., associated with Alzheimer’s disease, dementia, autism spectrum disorder (ASD)), eating disorders and appetite dysregulation, acute substance withdrawal, mood apathy in neurodegenerative diseases (e.g., associated with Alzheimer’s disease, dementia), anxiety and stress-related conditions characterised by excessive fear, tension or dysregulated arousal, and depressive disorders, comprising administering the pharmaceutical composition, or composition, as described herein, wherein the (S)-THH is in enantiomeric excess (ee), preferably at least about 90%, at least about 95% or at least about 99% enantiomeric excess (ee).

[0510] It has further been surprisingly found that, in some embodiments, administration of the pharmaceutical composition, or composition, as described herein, may provide for the ability to adjust the pharmacokinetics and / or pharmacodynamics of a co-administered tryptamine (e.g., N,N-dimethyltryptamine). In this way, in some embodiments, it may be possible to influence the efficacy profile of the tryptamine (e.g., N,N-dimethyltryptamine), by altering the central or peripheral nervous system partitioning (as described above), and / or by modulating the expected therapeutic duration of the tryptamine (e.g., N,N-dimethyltryptamine).

[0511] It has been surprisingly found that nonracemic compositions and pharmaceutical compositions of tetrahydroharmine (THH) as described herein are significantly more potent in terms of their MAO inhibition than racemic compositions of tetrahydroharmine (THH). Particularly, those compositions and pharmaceutical compositions comprising (R)-THH or (S)-THH at greater than 95% enantiomeric excess (ee) have been found to be significantly more potent MAO inhibitors than racemic tetrahydroharmine (THH). This allows such high purity enantiomeric compositions and pharmaceutical compositions to display greater ability for modulation of the duration of action of a tryptamine, such as DMT. It has also been surprisingly found that the weight ratio (w / w) of the tryptamine, or pharmaceutically acceptable salt thereof, to the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, may be selected so as to influence the expected duration of activity of the tryptamine, based on the enhanced monoamine oxidase A (MAO-A) inhibitory potency of the nonracemic tetrahydroharmine (THH) mixture, in enantiomericexcess (ee) of at least about 95%. In contrast, racemic tetrahydroharmine (THH) exhibits markedly weaker monoamine oxidase A (MAO-A) inhibition. In one example, a lower weight ratio (w / w) of tryptamine to the nonracemic mixture of tetrahydroharmine (THH) is expected to be associated with a longer duration of action of the tryptamine. In one example, a higher weight ratio (w / w) of tryptamine to the nonracemic mixture of tetrahydroharmine (THH) is expected to be associated with a shorter duration of action of the tryptamine. As discussed above, the expected duration of action of the tryptamine may depend on the route of administration and the tissue in which tryptamine activity is being measured, and may display a non-linear response to changes in the tetrahydroharmine (THH) to tryptamine ratio.

[0512] In some embodiments, administration of the composition, as described herein, provides extended duration of activity of the tryptamine, or pharmaceutically acceptable salt thereof, compared to administration of the tryptamine, or pharmaceutically acceptable salt, alone. In some embodiments, administration of the composition, as described herein, provides extended duration of activity of N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof, compared to administration of N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt, alone. It will be appreciated that “duration of activity” refers to the time period in which the active agent is therapeutically effective (also referred to as “therapeutic exposure”).

[0513] In some embodiments, administration of the composition described herein provides an extended duration of activity of the tryptamine, or a pharmaceutically acceptable salt thereof, compared with administration of the tryptamine alone. In vivo pharmacokinetic studies demonstrate that co administration of nonracemic tetrahydroharmine with N,N dimethyltryptamine results in markedly increased systemic exposure and prolonged systemic persistence of DMT relative to DMT administered alone, particularly at higher tetrahydroharmine doses. These increases in exposure are consistent with an extended period of therapeutic activity of the tryptamine. The term ‘duration of activity’ refers to the period during which the active agent is present at concentrations sufficient to exert a therapeutic effect.ln some embodiments, the administration of the composition, as described herein, provides extended duration of activity of the tryptamine, or pharmaceutically acceptable salt thereof, compared to administration of the tryptamine, or pharmaceutically acceptable salt, alone, of at least about 1.1 -fold, at least about 1.2-fold, at least about 1.25-fold, at least about 1.3-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, or at least about 5-fold. In some embodiments, the administration of the composition, as described herein, provides extended duration of activity of N,N-dimethyltryptamine, orpharmaceutically acceptable salt thereof, compared to administration of N,N-dimethyltryptamine, or pharmaceutically acceptable salt, alone, of at least about 1.1 -fold, at least about 1.2-fold, at least about 1.25-fold, at least about 1.3-fold, at least about 1.5-fold, at least about 2-fold, at least about 3-fold, or at least about 5-fold.

[0514] As a result of the extended duration of activity of the tryptamine, or pharmaceutically acceptable salt thereof, compared to administration of the tryptamine, or pharmaceutically acceptable salt, alone, in some embodiments, administration provides a therapeutic exposure of the tryptamine of at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, at least about 60 minutes, at least about 90 minutes, at least about 120 minutes, at least about 240 minutes, at least about 360 minutes, at least about 480 minutes, or at least about 540 minutes. In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of the tryptamine of between about 10 minutes and about 120 minutes, between about 20 minutes about 90 minutes, or between about 30 minutes and about 60 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of the tryptamine of between about 30 minutes and about 60 minutes. In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of the tryptamine of about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, or about 60 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of the tryptamine of about 30 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of the tryptamine of about 40 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of the tryptamine of about 50 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of the tryptamine of about 60 minutes.

[0515] In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of N,N-dimethyltryptamine (DMT) of at least about 5 minutes, at least about 10 minutes, at least about 20 minutes, at least about 30 minutes, at least about 40 minutes, at least about 50 minutes, or at least about 60 minutes. In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeuticexposure of N,N-dimethyltryptamine (DMT) of between about 10 minutes and about 120 minutes, between about 20 minutes about 90 minutes, or between about 30 minutes and about 60 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of N,N-dimethyltryptamine (DMT) of between about 30 minutes and about 60 minutes. In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of N,N-dimethyltryptamine (DMT) of about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, or about 60 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of N,N-dimethyltryptamine (DMT) of about 30 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of N,N-dimethyltryptamine (DMT) of about 40 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of N,N-dimethyltryptamine (DMT) of about 50 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of N,N-dimethyltryptamine (DMT) of about 60 minutes.

[0516] In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of Psilocybin of at least about 60 minutes, at least about 90 minutes, at least about 120 minutes, at least about 240 minutes, at least about 360 minutes, at least about 480 minutes, or at least about 540 minutes. In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of Psilocybin of between about 120 minutes and about 600 minutes, between about 180 minutes about 540 minutes, or between about 240 minutes and about 480 minutes. In one example, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of Psilocybin of between about 120 minutes and about 600 minutes. In some embodiments, administration of the pharmaceutical composition or composition, as described herein, provides a therapeutic exposure of Psilocybin of about 180 minutes, about 240 minutes, about 360 minutes, about 420 minutes, about 480 minutes, or about 540 minutes.

[0517] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof,comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in therapeutic exposure of the tryptamine compared to administration of the tryptamine alone of at least about 1.1 -fold, about 1.2-fold, about 1.25-fold, about 1.3-fold, about 1.5-fold, about 2-fold, about 3-fold, or about 5-fold.

[0518] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in therapeutic exposure of the tryptamine compared to administration of the tryptamine alone of at least about 1.1 -fold, about 1.2-fold, about 1.25-fold, about 1.3-fold, about 1.5-fold, about 2-fold, about 3-fold, or about 5-fold.

[0519] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in the half-life (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, at least about 1.50-fold, at least about 1.60-fold, at least about 2.0-fold, or at least about 2.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in the half-life (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of at least about 1.20-fold.

[0520] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in the half-life (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of about 1.10-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, about 1.50-fold, about 1.60-fold, about 2.0-fold, or about 2.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess(ee) of at least about 95%, administration of the composition provides an increase in the halflife (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of about 1.20-fold.

[0521] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in the half-life (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, at least about 1.50-fold, at least about 1.60-fold, at least about 2.0-fold, or at least about 2.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in the half-life (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of at least about 1.20-fold.

[0522] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in the half-life (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of about 1.10-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, about 1.50-fold, about 1.60-fold, about 2.0-fold, or about 2.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in the halflife (ti / 2) (hours, h) of co-administered tryptamine (e.g., DMT) of about 1.20-fold.

[0523] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of at least about 1.05-fold, at least about 1.10-fold, at least about 1.15-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof,comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold.

[0524] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of about 1.05-fold, about 1.10-fold, about 1.15-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of about 1.10-fold.

[0525] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of at least about 1.05-fold, at least about 1.10-fold, at least about 1.15-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold.

[0526] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of about 1.05-fold, about 1.10-fold, about 1.15-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the methoddescribed herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides reduction in the clearance rate (CL) (mL / min / kg) of co-administered tryptamine (e.g., DMT) of about 1.10-fold.

[0527] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of at least about 1.05-fold, at least about 1.10-fold, at least about 1.15-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold.

[0528] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of about 1.05-fold, about 1.10-fold, about 1.15-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of about 1.10-fold.

[0529] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of at least about 1.05-fold, atleast about 1.10-fold, at least about 1.15-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold.

[0530] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of about 1.05-fold, about 1.10-fold, about 1.15-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides an increase in plasma accumulation (AUCiast) (h.ng / mL) of co-administered tryptamine (e.g., DMT) of about 1.10-fold.

[0531] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of at least about 1.05-fold, at least about 1.10-fold, at least about 1.15-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold.

[0532] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of about 1.05-fold, about 1.10-fold, about 1.15-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of about 1.10-fold.

[0533] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of at least about 1.05-fold, at least about 1.10-fold, at least about 1.15-fold, at least about 1.20-fold, at least about 1.30-fold, at least about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of at least about 1.10-fold.

[0534] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of about 1.05-fold, about 1.10-fold, about 1.15-fold, about 1.20-fold, about 1.30-fold, about 1.40-fold, or at least about 1.50-fold, when compared to administration of the tryptamine alone. In one example, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about 95%, administration of the composition provides a reduced elimination rate constant (Az) (1 / h) of co-administered tryptamine (e.g., DMT) of about 1.10-fold.

[0535] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess (ee) of at least about95%, the (R)-THH has a reduced brain to plasma ratio of partitioning compared to an equivalent (S)-THH composition. In some embodiments, in the method described herein, where the nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (R)-tetrahydroharmine (R-THH) in an enantiomeric excess of at least about 95%, or at least about 98%, the (R) tetrahydroharmine (R-THH) provides lower central nervous system exposure of the tetrahydroharmine (THH) molecule relative to peripheral exposure when administered as a single agent, compared with an equivalent composition comprising (S)-tetrahydroharmine (S-THH).

[0536] In some embodiments, in the method described herein, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine (S-THH) in an enantiomeric excess (ee) of at least about 95%, the S-THH has a increased brain to plasma ratio of partitioning compared to an equivalent (R)-THH composition. In some embodiments, in the method described herein, where the nonracemic mixture of tetrahydroharmine, or a pharmaceutically acceptable salt thereof, comprises (S)-tetrahydroharmine in an enantiomeric excess of at least about 95%, or at least about 9%, the (S)-tetrahydroharmine (S-THH) provides greater central nervous system exposure of the tetrahydroharmine (THH) molecule when administered as a single agent, relative to an equivalent composition comprising (R)-tetrahydroharmine (R-THH).

[0537] In some embodiments, in the method described herein, wherein the weight ratio (w / w) of the nonracemic mixture of the tetrahydroharmine (THH) to the tryptamine is increased, the area under the curve (AUG) of the tryptamine is increased relative to delivery of the tryptamine alone. In some embodiments, the increase in area under the curve (AUG) does not materially increase the maximum plasma concentration (Cmax) of the tryptamine. In some embodiments, the increase in area under the curve (AUG) is achieved with no more than a modest change in the maximum plasma concentration (Cmax) of the tryptamine.

[0538] In some embodiments, in the method described herein, wherein the weight ratio (w / w) of the nonracemic mixture of the tetrahydroharmine (THH) to N,N-dimethyltryptamine (DMT) is increased, the area under the curve (AUC) of the N,N-dimethyltryptamine (DMT) is increased relative to delivery of the N,N-dimethyltryptamine (DMT) alone. In some embodiments, the increase in area under the curve (AUC) does not materially increase the maximum plasma concentration (Cmax) of N,N-dimethyltryptamine (DMT).

[0539] In a further aspect, there is provided use of the pharmaceutical composition or composition, as described herein, in the manufacture of a medicament for the treatment of a disease, disorder, or condition, as described herein.In a further aspect, there is provided the pharmaceutical composition or composition, as described herein, for use in the treatment of a disease, disorder, or condition as described herein.

[0540] In a further aspect, there is provided use of the pharmaceutical composition or composition, as described herein, in the treatment of a disease, disorder, or condition as described herein.

[0541] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a pharmaceutical composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the disease, disorder, or condition is responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0542] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a pharmaceutical composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the disease, disorder, or condition is responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0543] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a pharmaceutical composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the disease, disorder, or condition is selected from the group consisting of (MDD), substance use disorders involving disrupted reward processing or maladaptive motivational states, prolonged grief disorder, chronic pain conditions with neuropathic components, inflammatory and neuroimmune disorders with central nervous system involvement, neurodegenerative disorders including those associated with agitation, apathy or cognitive decline, post-traumatic stress disorder and trauma-related conditions characterised by hyperarousal, intrusive symptoms or affective dysregulation, and cognitive impairment or executive dysfunction in neuropsychiatric disorders.

[0544] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a pharmaceutical composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a pharmaceutical composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the disease, disorder, or condition is selected from the group consisting of substance use disorders (including stimulant and alcohol use disorders), post-traumatic stress disorder (PTSD), agitation (e.g., associated with Alzheimer’s disease, dementia, autism spectrum disorder (ASD)), eating disorders and appetite dysregulation, acute substance withdrawal, mood apathy in neurodegenerative diseases (e.g., associated with Alzheimer’s disease, dementia), anxiety and stress-related conditions characterised by excessive fear, tension or dysregulated arousal, and depressive disorders.

[0545] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0546] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0547] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition is selected from the group consisting of (MDD), substance use disorders involving disrupted reward processing or maladaptive motivational states, prolonged grief disorder, chronic pain conditions with neuropathic components, inflammatory and neuroimmune disorders with central nervous system involvement, neurodegenerative disorders including those associated with agitation, apathy or cognitive decline, post-traumatic stress disorder and trauma-related conditions characterised by hyperarousal, intrusive symptoms or affective dysregulation, and cognitive impairment or executive dysfunction in neuropsychiatric disorders.In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0548] In some embodiments, there is provided a method of treating a disease, disorder, or condition, comprising administering a composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, wherein the disease, disorder, or condition selected from the group consisting of substance use disorders (including stimulant and alcohol use disorders), post-traumatic stress disorder (PTSD), agitation (e.g., associated with Alzheimer’s disease, dementia, autism spectrum disorder (ASD)), eating disorders and appetite dysregulation, acute substance withdrawal, mood apathy in neurodegenerative diseases (e.g., associated with Alzheimer’s disease, dementia), anxiety and stress-related conditions characterised by excessive fear, tension or dysregulated arousal, and depressive disorders..

[0549] In some embodiments, there is provided the use of a pharmaceutical composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0550] In some embodiments, there is provided the use of a pharmaceutical composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0551] In some embodiments, there is provided the use of a pharmaceutical composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disease, disorder, or condition is selected from the group consisting of major depressive disorder (MDD), substance use disorders involving disrupted reward processing or maladaptive motivational states, prolonged grief disorder, chronic pain conditions with neuropathic components, inflammatory and neuroimmune disorders with central nervous system involvement, neurodegenerative disorders including thoseassociated with agitation, apathy or cognitive decline, post-traumatic stress disorder and trauma-related conditions characterised by hyperarousal, intrusive symptoms or affective dysregulation, and cognitive impairment or executive dysfunction in neuropsychiatric disorders.

[0552] In some embodiments, there is provided the use of a pharmaceutical composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0553] In some embodiments, there is provided the use of a pharmaceutical composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, in the manufacture of a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of substance use disorders (including stimulant and alcohol use disorders), post-traumatic stress disorder (PTSD), agitation (e.g., associated with Alzheimer’s disease, dementia, autism spectrum disorder (ASD)), eating disorders and appetite dysregulation, acute substance withdrawal, mood apathy in neurodegenerative diseases (e.g., associated with Alzheimer’s disease, dementia), anxiety and stress-related conditions characterised by excessive fear, tension or dysregulated arousal, and depressive disorders.

[0554] In some embodiments, there is provided the use of a composition comprising a nonracemic mixture of a tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0555] In some embodiments, there is provided the use of a composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0556] In some embodiments, there is provided the use of a composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition is selectedfrom the group consisting of major depressive disorder (MDD), substance use disorders involving disrupted reward processing or maladaptive motivational states, prolonged grief disorder, chronic pain conditions with neuropathic components, inflammatory and neuroimmune disorders with central nervous system involvement, neurodegenerative disorders including those associated with agitation, apathy or cognitive decline, post-traumatic stress disorder and trauma-related conditions characterised by hyperarousal, intrusive symptoms or affective dysregulation, and cognitive impairment or executive dysfunction in neuropsychiatric disorders.

[0557] In some embodiments, there is provided the use of a composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition responsive to monoamine oxidase (e.g., MAO-A) inhibition.

[0558] In some embodiments, there is provided the use of a composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine (e.g., N,N-dimethyltryptamine), or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease, disorder, or condition selected from the group consisting of substance use disorders (including stimulant and alcohol use disorders), post-traumatic stress disorder (PTSD), agitation (e.g., associated with Alzheimer’s disease, dementia, autism spectrum disorder (ASD)), eating disorders and appetite dysregulation, acute substance withdrawal, mood apathy in neurodegenerative diseases (e.g., associated with Alzheimer’s disease, dementia), anxiety and stress-related conditions characterised by excessive fear, tension or dysregulated arousal, and depressive disorders.

[0559] It will be appreciated that the pharmaceutical composition and composition, as described herein, may be administered to a subject via any suitable means, including, for example, oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular), inhalation (including fine particle dusts or mists that may be generated by means of various types of metered dose pressurised aerosols), intranasal (including liquid spray, mist, or dry powder nasal delivery systems), nebulisers or insufflators, rectal, intraperitoneal and topical (including dermal, transdermal, buccal, sublingual, and intraocular), although the most suitable route may depend upon, for example, the condition and disorder of the recipient.In some embodiments, the pharmaceutical composition or composition, as described herein, is administered via oral administration, inhalation administration, intranasal administration, intravenous administration, or intramuscular administration. In one example, the pharmaceutical composition or composition, as described herein, is administered via oral administration. In one example, the pharmaceutical composition or composition, as described herein, is administered via inhalation administration. In one example, the pharmaceutical composition or composition, as described herein, is administered via intravenous administration. In one example, the pharmaceutical composition or composition, as described herein, is administered via intramuscular administration. In one example, the pharmaceutical composition or composition, as described herein, is administered via intranasal administration. In one example, the pharmaceutical composition or composition, as described herein, is administered via intramuscular administration.

[0560] It therefore follows that the pharmaceutical composition or composition, as described herein, may be formulated for administration via a particular route. In some embodiments, the pharmaceutical composition or composition, as described herein, is formulated for oral administration. For example, the pharmaceutical composition or composition, as described herein, may be formulated as discrete units such as capsules, cachets, pills, or tablets, each comprising a predetermined amount of the pharmaceutical composition or composition; as a powder or granules, as a solution or a suspension in an aqueous liquid or non-aqueous liquid, for example as elixirs, tinctures, sus-pensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

[0561] It will be appreciated that a tablet may be made for example by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active, or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored, and may be formulated so as to provide slow or controlled release of the pharmaceutical composition or composition, as described herein. The pharmaceutical composition or composition, as described herein, for example, may be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising one or more pharmaceutically acceptableexcipients, or otherwise, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.

[0562] It will be appreciated that oral administration includes suspensions which may contain, for example, a pharmaceutically acceptable excipient. Examples include microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavouring agents such as those well known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate, calcium sulfate, sorbitol, glucose and / or lactose and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants such as those known in the art. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Disintegrators include without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. A pharmaceutical composition or composition, as described herein, may also be delivered through the oral cavity by sublingual and / or buccal administration. Moulded tablets, compressed tablets, or freeze-dried tablets are exemplary forms that may be used. Exemplary compositions include those comprising fast dissolving diluents such as mannitol, lactose, sucrose and / or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as cellulose (avicel) or polyethylene glycols (PEGs). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxyl propyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer, and agents to control release such as polyacrylic copolymer. Such formulations can also include permeation enhancers to improve mucosal uptake such as, for example, alkylsaccharides such as dodecyl maltoside, bile salt derivatives, medium-chain surfactants, and chitosan or chitosan derivatives that transiently increase epithelial permeability. Lubricants, glidants, flavours, colouring agents, and stabilisers may also be added for ease of fabrication and use. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodi-um chloride, and the like. For oral administration in liquid form, the pharmaceutical composition or composition, as described herein, can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.

[0563] In some embodiments, the pharmaceutical composition or composition, as described herein, is formulated for parenteral delivery. Formulations for parenteral administrationinclude aqueous and non-aqueous sterile injections solutions which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier, for example saline or water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1.3-butanediol, water, Ringer’s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and sus-pending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.

[0564] The pharmaceutical compositions and compositions, as described herein, may also include polymeric excipients / additives or carriers, e.g., polyvinylpyrrolidones, derivatised celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch (HES), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-p-cyclodextrin and sulfobutylether-p-cyclodextrin), polyethylene glycols, and pectin. The pharmaceutical compositions and compositions, as described herein, may further include diluents, buffers, citrate, trehalose, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants), inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and / or additives suitable for use in the pharmaceutical compositions and compositions, as described herein, are listed in "Remington: The Science & Practice of Pharmacy", 19. sup. th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference", 52. sup. nd ed., Medical Economics, Montvale, N.J. (1998), and in "Handbook of Pharmaceutical Excipients", Third Ed., Ed. A. H. Kibbe, Pharmaceutical Press, 2000.

[0565] In some embodiments, the pharmaceutical composition or composition, as described herein, is formulated for inhalation administration. In some embodiments, the pharmaceuticalcomposition or composition, as described herein, is formulated for intravenous administration. In some embodiments, the pharmaceutical composition or composition, as described herein, is formulated for intramuscular administration. In some embodiments, the pharmaceutical composition or composition, as described herein, is formulated for intranasal administration.

[0566] If administered intravenously, an infusion of the pharmaceutical composition or composition, as described herein, over a period of time may be used, for example. Furthermore, the pharmaceutical composition or composition, as described herein, may be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

[0567] In some embodiments, the route of administration for a composition comprising purified (R)-tetrahydroharmine (R-THH) or purified (S)-tetrahydroharmine (S-THH_) is selected in view of any one of (i) the desired balance of central versus peripheral exposure of the tetrahydroharmine (THH) molecule, (ii) the distinct receptor interaction profiles exhibited by the enantiomers, including preferential sigma-1 receptor activation by (R)-THH and enhanced 5-HT2C receptor activation by (S)-THH, and / or (iii) the required degree of central and peripheral monoamine oxidase A (MAO-A) inhibition under the intended dosing conditions. These considerations may apply to monotherapy (i.e., administration of tetrahydroharmine (THH) without a co-administered tryptamine) or combination therapy comprising tetrahydroharmine (THH) together with a tryptamine.

[0568] In further embodiments, the route of administration is selected independently of the choice of enantiomer. In some embodiments, either (R)-THH or (S)-THH may be delivered orally or non-orally, in monotherapy or combination therapy, according to the intended therapeutic objective, including modulation of MAO-A inhibition profile, sigma-1 receptor activity, 5-HT2C activation, or the desired balance of central and peripheral exposure of THH or of a co-administered tryptamine.

[0569] In some embodiments, there may be preferred routes of administration for the pharmaceutical composition or composition, as described herein, based upon the preferential partitioning of the (R)-THH and (S)-THH previously described. For example, a composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, may be delivered orally based upon (R)-THH's more balanced central and peripheralsystem distribution maintaining sustained hepatic and intestinal MAO-A inhibition throughout absorption. This means it is more effective at protecting a tryptamine during first-pass metabolism. Higher plasma levels of the (R)-THH provide robust peripheral protection enabling oral bioavailability, whilst adequate brain penetration extends therapeutic duration. The more sustained plasma level acts as continuous reservoir replenishing tryptamine to the brain over 3-5 hours, essential for the oral route's gradual absorption kinetics.

[0570] In some embodiments, a composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, may be delivered non-orally (including by the intranasal, inhaled and IV routes) based upon (S)-THH's greater central to peripheral partitioning which maximizes central nervous system MAO-A inhibition where the tryptamine accumulates post-absorption, so extending psychedelic duration through direct brain protection. Since these non-oral routes bypass hepatic first-pass metabolism, peripheral MAO inhibition is largely unnecessary. Preferential brain delivery provides CNS-selective effects with minimal peripheral side effects, reduced nausea, cardiovascular effects, and tyramine sensitivity, potentially creating safer psychedelic experiences ideal for outpatient settings.

[0571] In some embodiments, a composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine may be delivered orally based upon (R)-THH's more balanced central and peripheral system distribution maintaining sustained hepatic and intestinal MAO-A inhibition throughout absorption.

[0572] In some embodiments, a composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and a tryptamine may be delivered non-orally (including by the IN and IV routes) based upon (S)-THH's greater central to peripheral partitioning.

[0573] In some embodiments, a composition comprising an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and N,N-dimethyltryptamine (DMT) may be delivered orally based upon (R)-THH's more balanced central and peripheral system distribution maintaining sustained hepatic and intestinal MAO-A inhibition throughout absorption.

[0574] In some embodiments, a composition comprising an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and N,N-dimethyltryptamine (DMT) may be delivered non-orally (including by the IN and IV routes) based upon (S)-THH's greater central to peripheral partitioning.It will be appreciated that the pharmaceutical composition or composition, as described herein, may be administered in any suitable dosage regimen.

[0575] The amount of the pharmaceutical composition or composition, as described herein, that is required to achieve a therapeutic effect will, of course, vary with the particular active agent, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject being treated, and the renal and hepatic function of the subject, and the particular condition, disorder or disease being treated, as well as its severity. An ordinary skilled physician or clinician can readily determine and prescribe the effective amount of the active agent required to treat the disease, disorder, or condition.

[0576] Dosages of pharmaceutical composition or composition, as described herein, when used in the methods and uses described herein, will range between, for example, about 0.01 mg per kg of body weight per day (mg / kg / day) to about 1000 mg / kg / day. This particular dosage may define any one of the active agents in the pharmaceutical composition or composition, as described herein, for example, the nonracemic mixture of tetrahydroharmine (THH) or the tryptamine or the harmala alkaloid, or pharmaceutically acceptable salts thereof. In some embodiments, the dosage of the pharmaceutical composition or composition, as described herein, is between about 0.01 and 1000, 0.1 and 500, 0.1 and 100, 1 and 50 mg / kg / day. In some embodiments, the dosage of the pharmaceutical composition or composition, as described herein, is between about 0.01 and 1000 mg / kg / day. In some embodiments, the dosage of the pharmaceutical composition or composition, as described herein, is between about 0.1 and 100 mg / kg / day. In some embodiments, the dosage of the pharmaceutical composition or composition, as described herein, is greater than about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, 1000 mg / kg / day. In some embodiments, the dosage of the pharmaceutical composition or composition, as described herein, is greater than about 0.01 mg / kg / day. In some embodiments, the dosage of the pharmaceutical composition or composition, as described herein, is less than about 5000, 1000, 75, 50, 20, 10, 1, 0.1 mg / kg / day. In some embodiments, the dosage of pharmaceutical composition or composition, as described herein, is less than about 1000 mg / kg / day.

[0577] The pharmaceutical composition or composition, as described herein, may, for example, be administered as a single daily dose, or otherwise the total daily dosage may be administered in divided doses of two, three, or four times daily. In some embodiments, the pharmaceutical composition or composition, as described herein, may be dosed lessfrequently than once per day, for example once per two days, three days, four days, five days, six days, or once per week.

[0578] In some embodiments, the pharmaceutical composition or composition, as described herein, is administered as a single dose or as multiple doses. In one example, the pharmaceutical composition or composition, as described herein, is administered as a single dose. In one example, the pharmaceutical composition or composition, as described herein, is administered as multiple doses. In one example, the pharmaceutical composition or composition, as described herein, is administered as multiple doses of approximately equal dosages. In some embodiments, the pharmaceutical composition or composition, as described herein, is administered as two, three, four, five, six, seven, eight, nine, or ten, approximately equal dosages. In one example, the pharmaceutical composition or composition, as described herein, is administered as three approximately equal dosages.

[0579] In some embodiments, the pharmaceutical composition or composition, as described herein, is administered as multiple doses at relevant intervals. The intervals (i.e. , time period between administration of one dose and the next), may be approximately equal. In one example, the pharmaceutical composition or composition, as described herein, is administered as multiple doses, wherein the multiple doses are administered in an approximately equal interval. In some embodiments, the interval is at least about 1 minute, at least about 2 minutes, at least about 3 minutes, at least about 5 minutes, at least about 10 minutes, at least about 15 minutes, at least about 20 minutes, or at least about 30 minutes. In some embodiments, the interval is at least about 1 minute, at least about 5 minutes, or at least about 10 minutes. In one example, the interval is at least about 5 minutes.

[0580] In some embodiments, the interval is between about 1 minute and about 4 hours, between about 2 minutes and about 2 hours, between about 3 minutes and about 1 hour, between about 4 minutes and about 30 minutes, or between about 5 minutes and about 15 minutes. In one example, the interval is between about 5 minutes and about 15 minutes.

[0581] In some embodiments, the interval is about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, or about 30 minutes. In one example, the interval is about 5 minutes. In one example, the interval is about 10 minutes.

[0582] Accordingly, where the pharmaceutical composition or composition, as described herein, is to be administered as three doses wherein the interval is 5 minutes, thepharmaceutical composition or composition, as described herein, is administered at time point 0, 5, and 10 minutes.

[0583] EXAMPLES

[0584] Further features of the present disclosure are more fully described in the following non-limiting Examples. This description is included solely for the purposes of exemplifying the present disclosure. It should not be understood as a restriction on the broad description of the disclosure as set out above.

[0585] Example 1 - Method of preparing racemic THH from Harmaline

[0586] Rac-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (rac-THH)

[0587]

[0588] H)

[0589] Harmaline HCI (2 g) is dissolved in ethanol (7.5 vols) and water (8.75 vols). The formed solution is cooled to between 5 - 10 °C. Sodium Borohydride (0.2 vols) is then added in portions, as a solid. The reaction mixture is then stirred at 5 - 10 °C for NMT 10 minutes, before being stirred at room temperature overnight. The reaction mixture is then quenched by the addition of 2M hydrochloric acid (6.25 vols). The solution is then stirred at room temperature for NMT 10 minutes (pH of solution = 1). The pH of the reaction mixture is then adjusted to 10 by the addition of 25% aqueous ammonia (2.5 vols).

[0590] A white precipitate forms and the resulting suspension is cooled to between 5 - 10 °C. The precipitate is then isolated by vacuum filtration on a glass frit funnel, washed with water (2 x 1.25 vols) and dried under vacuum for NLT 1 hour. Tetrahydroharmine is isolated as a white solid (1.52 g, 87%).

[0591] Example 2 - Method of preparing R-THH camsylate from racemic THH

[0592] (1R)- 7- Methoxy- 1 -methyl-2, 4a, 9, 9a-tetrahydro- 1H-pyrido[ 3, 4-b Jindole ((1R)-7, 7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl) methanesulfonate (R-THH. (-)-CSA)

[0593]

[0594] rac-THH R-THH. (-)-CSA

[0595] Racemic-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (3.00g, 13.8 mmol) was added to a flask to which was added ethanol (70 mL) in portions. The mixture was heated to 75°C after each portion was added resulting in a fine suspension. A solution of L-(-)-camphor-IO-sulfonicacid (3.22 g, 13.9 mmol) in ethanol (15 mL) was added to the reaction at 75°C, which was stirred at ambient temperature 17 h. The mixture was filtered, and the white solid washed with ethanol (30 mL) and dried in the funnel, under vacuum for 17 h. (1R)-7-methoxy-1-methyl-2,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole ((1R)-7,7-dimethyl-2-oxobicyclo[2.2.1] heptan-1-yl)methanesulfonate (R-THH.(-)-CSA) was obtained as a white solid (2.23 g, 36%). HPLC tR (279 nm) 4.72 (99.2%) min. Chiral HPLC tR 12.55 (S-THH 3.7%), 13.71 (R-THH, 96.3%) min, 92.7%ee.

[0596] Ethanol (80 mL) was added in portions to the white solid, heating to 70°C after each addition. The mixture did not completely dissolve. Water (2 mL) was added to give a solution and the stirred for 15 min at 73°C. The solution as allowed to cool to ambient temperature over 6 h, in which time a precipitate was evident. The mixture was filtered and washed with ethanol (30 mL). The filter cake was briefly dried on the filter before being transferred to a vacuum oven (40°C, 50 mbar) for 13 h. (1R)-7-methoxy-1-methyl-2,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole ((1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (R-THH.(-)-CSA) was obtained as a white solid (1.68 g, 79%). HPLC tR (279 nm) 4.74 (99.2%) min. Chiral HPLC tR 12.50 (S-THH 0.4%), 13.71 (R-THH, 99.6%) min, 99.2%ee.

[0597] Example 3 - Method of preparing R-THH from R-THH camsylate

[0598] (R)-7-Methoxy- 1-methyl-2, 3, 4, 9-tetrahydro- 1H-pyrido[3, 4-b]indole (R-TH H)

[0599]

[0600] R-THH. (-)-CSA R-THH(1R)-7-Methoxy-1 -methyl-2, 4a, 9, 9a-tetrahydro-1H-pyrido[3,4-b]indole ((1R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (1.67 g, 3.72 mmol) was suspended in water (33 mL) and ethanol was added to give a solution (2x 10 mL). A solution of potassium hydroxide (0.31 g, 3.40 mmol) in water (6 mL) was added in portions and stirred at 60°C for 0.5 h. The reaction was cooled to 2-8°C for 3 h, the mixture was filtered and washed with water (15 mL). The solid was dried in the funnel under vacuum for 1.5 h then in a vacuum oven (40°C, 50 mbar) for 17 h. (R)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was isolated as a white solid (0.74 g, 92%). HPLC tR (279 nm) 4.75 (100 %) min. Chiral HPLC tR 12.65 (S-THH 0.2%) min, 13.68 (99.8%), 99.6%ee.

[0601] Example 4 - Method of preparing R-THH hemifumarate from R-THH

[0602] (R)-7-Methoxy- 1-methyl-2, 3, 4, 9-tetrahydro- 1H-pyrido[3, 4-b]indole hemifumarate (R-THH hemifumarate)

[0603]

[0604] (R)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (R-THH) (0.10 g, 0.46 mmol) was suspended in isopropanol (5 mL) and heated under reflux until dissolved. Fumaric acid (0.05 g, 0.46 mmoL) was dissolved with heating into isopropanol (3 mL) and added dropwise to amine solution at 60°C. The mixture was heated at reflux for 30 min then stirred at ambient temperature for another 30 min. The mixture was cooled at to 2-8°C for 1.5 h, filtered, washed with isopropanol (2 x 2 mL), dried in the funnel for 30 min, then in the vacuum oven (50°C, 50 mbar) for 4.5 h. (R)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hemifumarate (0.10 g, 79%). HPLC tR (279 nm) 4.71 (99.0%) min. Chiral HPLC tR 12.19 (S-THH 0.29%) min, 13.16 (R-THH 99.7%), 99.4%ee.

[0605] This method may also be adapted to prepare (R)-7-methoxy-1 -methyl-2, 3,4,9-tetrahydro-1H-pyrido[3,4-b]indole fumarate (R-THH fumarate), by adjusting the molar equivalents of Fumaric acid employed in the method accordingly.

[0606] Example 5 - Method of preparing R-THH camsylate from R-THH

[0607] (1R)-7-Methoxy-1 -methyl-2, 4a, 9, 9a-tetrahydro-1H-pyrido[3,4-b]indole ((1R)-7, 7-di methyl-2-oxobicyclo[2.2.1]heptan-1-yl) methanesulfonate (R-THH. (-)-CSA)

[0608]

[0609] (1R)-7-Methoxy-1-methyl-2,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole (1.03 g, 4.78 mmol) was suspended in ethanol (21 mL) and heated to 66°C to give a solution. A solution of L-(-)-camphor-10-sulfonic acid (1.11 g, 4.78 mmol) was added to the ethanol solution causing a precipitate to form. Heating continued for 0.5 h then the mixture was left to cool to room temperature over 5 h. The mixture was filtered, washed with ethanol (8 mL) and dried in the funnel for 1 h. The sample was dried in a vacuum over (40°C, 50 mbar) for 17 h to afford (R-THH. (-)-CSA as a cream powder (1.77 g, 83%). HPLC tR 4.73 (99.3%) min. The solid was recrystallized (ethanol / water) to give a cream solid after drying. (1R)-7-Methoxy-1-methyl-2,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole ((1R)-7,7-dimethyl-2-oxobicyclo[2.2.1] heptan-1-yl)methanesulfonate (R-THH.(-)-CSA (1.24 g, 70%). HPLC tR (279 nm) 4.77 (99.5%) min. Chiral HPLC tR 12.61 (S-THH 0.3%) min, 13.70 (R-THH, 99.6%), 99.3%ee. Example 6 - Method of preparing S-THH camsylate from S-THH

[0610] 1S)-7-Methoxy- 1-methyl-2, 4a, 9, 9a-tetrahydro- 1H-pyrido[3, 4-b]indole ((1S)-7, 7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl) methanesulfonate (S-THH. (+)-CSA)

[0611]

[0612] (1S)-7-Methoxy-1-methyl-2,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole (1.25 g, 5.78 mmol) was suspended in ethanol (25 mL) and heated to 72°C to give a solution. A solution of D-(+)-camphor-10-sulfonic acid (1.34 g, 5.77 mmol) was added to the ethanol solution causing a precipitate to form. Heating continued for 0.5 h then the mixture was left to cool to room temperature over 4 h. The mixture was filtered, washed with ethanol (10 mL) and dried in the funnel for 3 h. The sample was dried in a vacuum oven (40°C, 50 mbar) for 17 h to afford (S-THH. (+)-CSA as a beige powder (2.09 g, 81%). Chiral HPLC tR 12.77 (S-THH,97.7%), 13.80 (R-THH, 2.3%) min, 95.3%ee. The solid was recrystallized (ethanol / water) to give a cream solid after drying. (1 S)-7-methoxy-1 -methyl-2,4a,9,9a-tetrahydro-1 H-pyrido[3,4-b]indole ((1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (S-THH. (+)-CSA (1.49 g, 72%). HPLC tR (279 nm) 4.74 (99.2%) min. Chiral HPLC tR 12.60 (S-THH 100%) min, 100%ee.

[0613] Example 7 - Method of preparing S-THH from S-THH camsylate

[0614] (S)-7-Methoxy- 1-methyl-2,3,4, 9-tetrahydro- 1 H-pyrido[3,4-b]indole (S-TH H)

[0615]

[0616] (1S)-7-Methoxy-1-methyl-2,4a,9,9a-tetrahydro-1H-pyrido[3,4-b]indole ((1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (1.48 g, 3.30 mmol) was suspended in water (30 mL) and ethanol was added to give a solution (2x 10 mL). A solution of potassium hydroxide (0.28 g, 5.00 mmol) in water (5 mL) was added in portions and stirred at 60°C for 0.5 h. The reaction was cooled to 2-8°C for 3 h, the mixture was filtered and washed with water (20 mL). the solid was dried in the funnel under vacuum for 2 h then in a vacuum oven (40°C, 50 mbar) for 17 h. (S)-7-Methoxy-1 -methyl-2, 3,4, 9-tetrahydro-1 Pipy rido[3, 4- b]indole was isolated as a white solid (0.64 g, 90%). HPLC tR(279 nm) 4.76 (99.8%) min. Chiral HPLC tR12.65 (S-THH 100%) min, 100%ee.

[0617] Example 8 - Method of preparing S-THH hemifumarate

[0618] (S)-7-methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hemifumarate (S-THH hemifumarate).

[0619]

[0620] (S)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (0.10 g, 0.46 mmol) was suspended in isopropanol (2 mL) and heated to reflux to dissolve the solid. Fumaric acid (0.05 g, 0.46 mmol) was added to the solution causing and precipitation of material, and heated for 0.5 h, then stirred at ambient temperature for 2.5 h. The solution wascooled to 2-8°C for 19 h. the solid was filtered, washed with isopropanol (2 x2 mL) and dried under vacuum for 0.5 h. The sample was further dried in a vacuum oven (50°C, 50 mbar) for 2.5 h. (S)-7-Methoxy-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole hemifumarate was isolated (0.10 g, 79%). HPLC tR (279 nm) 4.71 (99.2%) min. Chiral HPLC tR 12.16 (S-THH 98.9%) min, 13.02 (R-THH 1.0%), 98.0%ee.

[0621] This method may also be adapted to prepare (S)-7-Methoxy-1 -methyl-2, 3,4,9-tetrahydro-1H-pyrido[3,4-b]indole fumarate (S-THH fumarate), by adjusting the molar equivalents of Fumaric acid employed in the method accordingly.

[0622] Example 9 - SEM analysis of THH

[0623] Salt form appears to have a major influence on the morphology of tetrahydroharmine (THH) particles, as revealed by scanning electron microscopy (SEM). Distinct differences in particle shape, size, and surface features were observed across the hydrochloride salt and the R- and S-hemifumarate salts, highlighting the impact of molecular arrangement and crystallisation conditions on the final solid-state form.

[0624] Needle-shaped particles, sparsely distributed across the surface and highly elongated, were observed in the racemic THH HCI sample (Figure 1). The needles measured approximately 35 pm in length and appeared sharp and crystalline. Prominent substrate cracking was also noted. The physical characteristics of this batch were consistent with poor powder flow and handling challenges typical of acicular materials.

[0625] In contrast, the R-THH- hemifumarate form showed dense, irregularly packed clusters with a layered appearance (Figure 2). Particles exhibited a more complex morphology, with crystalline texture and substantial aggregation. A representative particle measured approximately 149 pm in width. This form appeared highly crystalline and structurally intricate.

[0626] The S-THH- hemifumarate sample presented particles of intermediate size (-43.9 pm), also displaying a layered morphology, but with more open and loosely packed structures (Figure 3). Compared to the R-enantiomer, these particles appeared less dense and slightly more ordered in their arrangement.

[0627] Overall, these findings support the conclusion that THH salt form significantly affects particle morphology, with potential implications for powder flow, compaction, and downstream formulation performance.Example 10 - Stability

[0628] Trials were conducted using shorter reaction times, different solvents and cooler reaction conditions with the objective of preventing racemisation of the THH enantiomers.

[0629] Conditions used for the formation of racemic THH hydrochloride on the individual R-and S-THH enantiomers however resulted in racemised THH products heating at95°C in IPA for 30 min.

[0630] When using the process described in the present specification for hemifumarate salt formation, these conditions did not cause racemisation, even at refluxing conditions as was evident by the product ee of 100%. A second trial (Trial 2) employed much milder conditions of 5°C over 10 min and also achieved this stability (Figures 4 and 5).

[0631] Example 11 - Binding assays and activity of R-THH and S-THH

[0632] The activities of R-THH-(-)-CSA, S-THH-(+)-CSA, R-THH hemifumarate, and S-THH hemifumarate were evaluated in enzyme and radioligand binding assays.

[0633] The R-THH hemifumarate was sourced from batch D326-64-01, which had an enantiomeric excess (ee) of 96.6 percent. The corresponding S-THH hemifumarate was obtained from batch D326-65-01, with an enantiomeric excess (ee) of 97.0 percent. The R-THH camphor sulphonate salt (R-THH-(-)-CSA) was produced as batch D310-138-02 and exhibited an enantiomeric excess (ee) of 99.3 percent. The S-THH camphor sulphonate salt (S-THH-(+)-CSA) was prepared as batch D310-131-01 and had an enantiomeric excess (ee) of 96.2 percent.

[0634] Methods employed in this study were adapted from the scientific literature. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Biochemical assay results for the reference standards are presented as the percent inhibition of specific binding or activity. The methods employed are summarised in Table 1 below:

[0635] Table 1

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[0659] Results

[0660] Biochemical assay results are presented as the percent inhibition of specific binding or activity.

[0661] Dose Finding (DF) for primary assays, the lowest concentration with a significant response as determined by the assays criteria is shown. Where applicable, either the secondary assay results with the lowest dose / concentration meeting the significance criteria, or if inactive, the highest dose / concentration that did not meet the significance criteria is shown.

[0662] Primary screening was completed in duplicate with quantitative data (e.g., IC50 ± SEM, Ki ± SEM and nH) are shown where applicable for individual requested assays. In screening packages, primary screening in duplicate with semi-quantitative data (e.g., estimated IC50, Ki and nH) are shown where applicable (concentration range of 4 log units); available secondary functional assays are carried out (30 mM) and MEC or MIC determined only if active in primary assays >50% at 1 log unit below initial test concentration. Significant responses are presented in Tables 2 and 3, and individual responses are presented in Table 4.

[0663] Table 2

[0664]

[0665] Table 3

[0666]

[0667] * A standard error of the mean is presented where results are based on multiple, independent determinations.

[0668] “N.C. = Not calculated”.

[0669] All the % inhibition is more than 50, unable to calculate IC50, Ki, and nH

[0670] All the % inhibition is less than 50, unable to calculate IC50, Ki, and nH

[0671] Table 4

[0672]

[0673]

[0674] * Batch: Represents compounds tested concurrently in the same assay(s).

[0675] “N.C. = Not calculated”.

[0676] All the % inhibition is more than 50, unable to calculate IC50, Ki, and nH

[0677] All the % inhibition is less than 50, unable to calculate IC50, Ki, and nHDose response data based on the above observed experimental results were generated as shown in Figures 6 to 16.

[0678] The observed data demonstrate that each of the R and S enantiomers of THH exhibits surprisingly and unexpectedly improved inhibition of MAO-A, with R-THH having an IC50 = 0.091 pM, and S-THH having an IC50 = 0.097 pM, compared to racemic THH having an IC50 = 0.18 pM (Table 3), consistent with each separate enantiomer being approximately twice as potent as the racemate.

[0679] The results also indicate that isolating the R-THH and S-THH enantiomers shows a much stronger effect on particular receptors, including Sigma o1 and Serotonin (5-Hydroxytryptamine) 5-HT2C, when compared to the racemic form.

[0680] Example 12 - Blood Brain Barrier (BBB) permeability studies

[0681] A plasma and brain distribution pharmacokinetic (PK) study was performed in male ICR mice following administrations of rac-THH hydrochloride, R-THH hemifumarate and S-THH hemifumarate at 1 mg / kg through intravenous (IV) injection. The brain and plasma samples were parallelly collected at 0.5, 1 and 4 hours (h) after IV injection from three alternative animals at each time point. The detailed study design is shown in ‘Methods’ below.

[0682] The body and brain weights of each animal are reported in the table above. No adverse effects were found through cage-side inspection over 4 h period of blood collection. The exposure levels (in ng / g or ng / mL) of rac-THH hydrochloride, R-THH hemifumarate and S-THH hemifumarate in brain and plasma samples determined by LC-MS / MS in the brain / plasma ratios were also calculated. The values of the lower limit of quantification (LLOQ) in both plasma and brain homogenate samples analysis for rac-THH hydrochloride and R-THH hemifumarate were respectively at 100 and 20 ng / mL, and the exposure level below the 75% of LLOQ (75 and 15 ng / mL) were determined as below the limit of quantification (BLOQ). The values of LLOQ for S-THH hemifumarate analysis in plasma and brain homogenate samples were respectively at 20 and 50 ng / mL, the exposure level below the 75% of LLOQ (15 and 37.5 ng / mL) were determined as BLOQ.

[0683] Materials and Equipment

[0684] 1. Test Substance and Dosing Pattern

[0685] Three test compounds (rac-THH hydrochloride, R-THH hemifumarate and S-THH hemifumarate) were formulated in dimethyl sulfoxide (DMSO) / Solutol® HS15 / phosphatebuffered saline (PBS) (5 / 5 / 90, v / v / v) at 0.2 mg / mL for IV injection with dosing volume of 5 mL / kg. The conversion factors of 1.182, 1.460 and 1.460 were applied to convert the free base concentrations for rac-THH hydrochloride, R-THH hemifumarate and S-THH hemifumarate, respectively. The formulations are summarized as follows in Table 5 (visual observations):

[0686] Table 5

[0687]

[0688] (a) This is based upon visual observation: S: soluble; SS: slight soluble; I: insoluble (suspension or precipitation)

[0689] (b) Y: formula is kept in tube or vial with brown color, or covered with aluminium foil; N: no protection from light

[0690] (c) 4°C: prepared fresh and stored in the refrigerator or kept on ice.

[0691] (d) C. factor: conversion factor

[0692] 2. Animals

[0693] Male ICR mice weighing 30 ± 5 g were provided by BioLASCO Taiwan Co., Ltd.. Animals were acclimated for 3 days prior to use and were confirmed to be in good health. The animals were housed in animal cages with a space allocation of 30 x 19 x 13 cm. All animals were maintained in a controlled temperature (20 - 24°C) and humidity (30% - 70%) environment with 12-h light / dark cycles. Free access to standard lab diet [MFG (Oriental Yeast Co., Ltd., Japan)] and autoclaved tap water were granted. All aspects of this work including housing, experimentation, and animal disposal were performed in general accordance with the “Guide for the Care and Use of Laboratory Animals: Eighth Edition” (National Academies Press, Washington, D.C., 2011) in the AAALAC-accredited laboratory animal facility. In addition, the animal care and use protocol was reviewed and approved by the IACUC at Pharmacology Discovery Services Taiwan, Ltd.

[0694] 3. Chemicals0.9 % NaCI (Saline; Sing-Tong, Taiwan), Acetonitrile (ACN; J. T. Baker®, USA), Dimethyl sulfoxide (DMSO; Honeywell Research Chemicals, USA), Formic acid (FA; Merck, Germany), Losartan (Sigma, USA), Phosphate buffered saline PBS (Sigma, USA) and Solutol® HS15 (BASF, Germany).

[0695] 4. Equipment

[0696] Agilent Poroshell 120 EC-C18 column (2.7 pm, 3.0 x 50 mm; Agilent Technologies, Inc., USA), Animal cage (Allentown, USA), BD® lithium heparin tube (BD®, USA), Centrifuge 5810R (Eppendrof, Germany), Centrifuge tube (50 mL; Labcon, USA), Disposal syringe (1 mL, Terumo Corporation, Japan), Electronic scale (0-1000 g; Tanita Corporation, Japan), Gilson pipettes (# P200 Neo-P10N Micro Pipette; Gilson, France), Goldenrod animal lancet (4 mm, Goldenrod Corporation, USA), LC-MS / MS Triple Quad™ 6500+ (SCIEX, USA), Microcentrifuge tubes 1.5 mL click-cap (Treff AG, Switzerland), Pipette (# P200 Gilson, France), Pipette tips (Costar, USA), Polypropylene 96-well round U-bottom deep well plates and silicone microplate lids (StorPlate-96 U and StorMat-96; PerkinElmer Inc., USA), RAININ pipettes (E4 Multi E12-50XLS+, E12-300XLS, Refurbished Rainin E4™ XLS™ electronic 12 channel pipette, 30-300 pL, E4 Pipette Multi E12-1200XLS+, and EA6-300XLS; RAININ, USA), Stop watch (Casio, China), and Surgical instruments (Klappenecker, Germany).

[0697] Methods

[0698] Table 6: Study Design

[0699]

[0700]

[0701] <

[0702] Plasma Sample Collection from Mice (Parallel Sampling)

[0703] Blood aliquots (-300 pL) were collected via cardiac puncture from three mice into tubes coated with lithium heparin at the specified time points. The tubes were mixed gently and kept on ice and then centrifuged at 2,500 xg for 15 minutes (min) at 4°C, within 1 hour after collections. The plasma samples were then harvested and kept frozen at <-70°C until further processing.

[0704] Brain Sample Collection from Mice

[0705] Following terminal blood collection, mice were decapitated and the whole brains were quickly removed, rinsed with cold saline (0.9% NaCI), blotted with dry gauze and weighed. The brain samples were homogenized in the 0.2 mL of cold PBS, pH 7.4, respectively. The homogenate from each organ samples was then stored at <-70°C until further processing.

[0706] Table 7: Targets for Bioanalysis

[0707]

[0708] Quantitative Bioanalysis (Plasma and Brain Samples)

[0709] The plasma and the brain homogenate samples were processed using ACN precipitation and analyzed by LC-MS / MS. The detailed chromatographic conditions, bioanalytical methods, and acceptance criteria are summarized as follows:

[0710]

[0711] ic Conditions

[0712] Instrument Control No.: LCM-MS-004; LC-MS / MS: Triple Quad™ 6500+; Data Processor: Analyst 1.7; Ionization Mode: Atmospheric pressure chemical ionization (APCI), Negative ions; Scan Mode: Multiple reaction monitoring (MRM); Instrument Response: Peak area ratio; Regression Model: Weighted linear regression by 1 / X2; MRM of Analyte: 199.2 / 184.3 (rac-Tetrahydroharmine hydrochloride); 199.0 / 184.3 (R-tetrahydroharmine hemifumarate); 199.2 / 184.3 (S-tetrahydroharmine hydrochloride,); MRM of Internal Standard (IS): 421.2 / 179.1 (Losartan); Column: Agilent Poroshell 120 EC-C18 column 2.7 pm (3.0 x 50 mm); Column Temperature (°C): 40; Run Time (min): 5.0; Injection Volume (pL): 10.0; Mobile Phase: Mobile Phase A: Water (H2O) / FA= 100 / 0.2 (v / v), Mobile Phase B: ACN / FA=100 / 0.2 (v / v / v).

[0713] Table 8: HPLC Conditions

[0714]

[0715] Bioanalytical methods

[0716] Sample Matrices: Mouse plasma and brain samples; the brain samples were homogenized with 0.2 mL PBS; Standard Ranges: 20 - 2000 ng / mL.

[0717] Pharmacokinetics

[0718] The exposure levels (in ng / g or ng / mL) of rac-THH hydrochloride, R-THH hemifumarate and S-THH hemifumarate in brain and plasma samples were reported. The brain / plasma ratios were also calculated.

[0719] ResultsThe body and brain weights observed are described in Table 9.

[0720] Table 9

[0721]

[0722] The exposure levels (in ng / g or ng / mL) of rac-THH, R-THH and S-THH in mouse brain and plasma samples, are described in Table 10.

[0723] Table 10

[0724]

[0725]

[0726] SD- standard deviation; LLOQ- 20, 50 or 100 ng / mL; BLOQ- below the limit of quantification (15, 37.5 or 75 ng / mL); <75% of LLOQ; SEM- standard error of the mean.Body and brain weights of each animal were respectively recorded before the compound administration and at the study termination. The values of mean ± SEM were reported.

[0727] The cage-side inspection was performed at the time of blood collection for each group of mice tested; mice treated with rac-THH, R-THH and S-THH at each timepoint of 0.5, 1 and 4 hours. No significant findings were observed.

[0728] The exposure levels (in ng / g or ng / mL) of rac-THH, R-THH and S-THH in mouse brain and plasma samples after rac-THH, R-THH and S-THH (1 mg / kg, IV) administrations were analyzed through the LC-MS / MS; the brain / plasma ratios were also calculated (see table above). The values of mean ± SD were reported.

[0729] Adjusted pharmacology calculations

[0730] Summary of 0.5 h time points in brain and plasma concentration studies:

[0731] rac-THH: 709 ng / g (brain concentration), < 75 ng / mL (Plasma concentration), >9.45 (brain to plasma ratio).

[0732] R-THH: 996 ng / g (brain concentration), 142 ng / mL (Plasma concentration), >7.05 (brain to plasma ratio).

[0733] S-THH: 1327 ng / g (brain concentration), 92 ng / mL (Plasma concentration), >14.75 (brain to plasma ratio).

[0734] Considering the limits of quantification, at least at this time point (0.5hr), the data indicates that rac-THH will have a brain-to-plasma ratio of at least 9.45 (since plasma concentration will be less than 75 ng / mL).

[0735] Further discussion

[0736] The following discussion relates to THH enantiomer brain-to-plasma partitioning when administered as a single agent (monotherapy), without a co-administered tryptamine.

[0737] Under monotherapy conditions, the observed results are consistent with (S)-THH providing markedly greater central exposure of the THH molecule than both racemic THH and (R)-THH, whereas (R)-THH exhibits relatively higher plasma concentrations under equivalent dosing conditions. These findings demonstrate distinct distributional profiles for the two enantiomers when administered alone.As (S)-THH affords substantially greater central exposure of THH during monotherapy, it may be advantageous in applications where predominantly central pharmacology is desired, including enhanced central MAO-A inhibition and stronger 5-HT2C receptor activation. By contrast, (R)-THH, which maintains higher plasma exposure than (S)-THH when administered alone, may be selected for monotherapy applications requiring a more balanced distribution between central and peripheral compartments or where sigma-1 receptor activity and peripheral pharmacology are therapeutically relevant.

[0738] The differential brain-to-plasma partitioning observed in monotherapy therefore enables selection of the preferred enantiomer according to the intended therapeutic objective: (S)-THH for monotherapy applications requiring enhanced central nervous system exposure of THH or stronger 5-HT2C engagement, and (R)-THH for applications in which balanced central and peripheral exposure, or enhanced sigma-1 receptor activity, is preferred.

[0739] Example 12B - Blood Brain Barrier (BBB) Combination Studies: THH Enantiomers Coadministered with DMT

[0740] To evaluate the effect of THH enantiomer co-administration on tryptamine brain exposure, a pharmacokinetic study was conducted in male CD-1 mice receiving intravenous (IV) dosing of N,N-dimethyltryptamine (DMT) together with THH enantiomers.

[0741] Methods

[0742] Male CD-1 mice (n = 3 per group per timepoint) received IV co-administration of DMT (2 mg / kg) with either rac-THH, R-THH hemifumarate, or S-THH hemifumarate at two dose levels (1.25 mg / kg and 7.5 mg / kg). Plasma samples were collected at eight timepoints up to 8 h, and brain samples were collected at 0.5 h. Samples were analysed by LC-MS / MS for DMT, THH, and the MAO-A metabolite 3-indoleacetic acid (3-IAA). DMT brain-to-plasma ratios were calculated at 0.5 h.

[0743] Results

[0744] Table 11: Summary of THH and DMT brain concentrations, plasma concentrations, and DMT

[0745]

[0746]

[0747] Further discussion

[0748] Unexpectedly, the brain-to-plasma partitioning profile of tetrahydroharmine (THH) enantiomers differs when co-administered with N,N-dimethyltryptamine (DMT) compared with administration as single agents. Under co-administration conditions, brain concentrations of (R)-THH and (S)-THH converge, indicating that the presence of DMT alters blood-brain barrier handling of the THH enantiomers. These findings contrast with monotherapy results, in which (S)-THH provides substantially greater central exposure of THH than (R)-THH.

[0749] In combination therapy, clear enantioselective differences were observed for DMT itself. Co-administration with (R)-THH provided substantially enhanced central DMT exposure relative to (S)-THH. At the low THH dose (1.25 mg / kg), (R)-THH yielded approximately 25 percent higher DMT brain concentrations and approximately 23 percent higher DMT brain-to-plasma ratios than (S)-THH. At the high THH dose (7.5 mg / kg), (R)-THH provided approximately 22 percent higher DMT brain concentrations and approximately 34 percent higher DMT brain-to-plasma ratios than (S)-THH. Analysis of plasma 3-IAA / DMT ratios demonstrated greater MAO-A inhibition with (R)-THH co-administration, with reductions of approximately 26 percent (low dose)(1.66 vs 2.10) and 23 percent (high dose)(0.93 vs 1.14) relative to (S)-THH at 30 minutes. The reproducibility of these effects across a six-fold THH dose range indicates a robust pharmacological distinction between the enantiomers in combination therapy contexts.

[0750] These findings demonstrate that selection of TH H enantiomer for combination therapy with a tryptamine may be guided by the desired central tryptamine exposure and receptorsignalling profile. (R)-THH may be selected where enhanced central tryptamine exposure orsigma-1-linked modulation is beneficial. Conversely, (S)-THH may be preferred where attenuated central tryptamine exposure or enhanced 5-HT2C receptor activation is desirable, including applications in which serotonergic modulation with less intense psychedelic effects is therapeutically advantageous. Together with the monotherapy findings in Example 12, these results further support enantiomer-specific selection based on the intended therapeutic objective.

[0751] Example 13 - Oral Capsule Compositions / Formulations

[0752] Details of oral capsule formulations are provided in Tables 12 to 21 below:

[0753] Table 12: Freebase:Salt ratios

[0754]

[0755] Table 13

[0756]

[0757] Table 14

[0758]

[0759] Table 15

[0760]

[0761] Table 16

[0762]

[0763] Table 17

[0764]

[0765] Table 18

[0766]

[0767] Table 19

[0768]

[0769] Table 20

[0770]

[0771] Table 21

[0772]

[0773] Each of the oral capsule formulations A and B may be administered as a single oral dose, or alternatively, may be administered via multiple oral doses. For example, the oral capsule formulations may be administered as 1 dose, or as up to 4 concomitantly or sequentially administered doses.

[0774] The weight ratios of tryptamine (particularly DMT) to R-THH or S-THH disclosed in the formulation examples represent optimised compositions for therapeutic applications. Weight ratios ranging from 1:3 to 3:1 (tryptamine:THH) have been found to provide optimal pharmacokinetic profiles balancing MAO inhibition efficacy, duration of effect, and tolerability. Broader ranges of 1 : 10 to 10: 1 encompass formulations suitable for various clinical scenarios including microdosing (lower tryptamine ratios) and intensive therapeutic protocols (higher tryptamine ratios).

[0775] Example 14 - Extraction of THH from B. cappiThree samples (20 cm x 0.5-1 cm D) of Banisteriopsis caapi vines (varieties: Caupuri, Ourinhos and Nuevo Ola detailed below), were prepared (see Figure 16) and extracted according to the process in shown in Figure 17.

[0776] Caupuri is a variety of B. caapi with swollen / enlarged nodes, the vine sections look like a knotted rope and the canes obtained had a diameter of 0.5 cm. The supplier claimed the clones to contain 1.65mg / g THH (tetrahydroharmine): 0.25mg / g Harmaline: 5.54mg / g Harmine.

[0777] Ourinhos varieties in-part a yellow colour to the tea and are more potent than other varieties of B. caapi. The cane supplied were thicker (1 cm diameter) than Caupuri. According to the supplier, it was found to contain: 4mg / gTHH (tetrahydroharmine): 0.81 mg / g Harmaline: 7.15mg / g Harmine.

[0778] Banisteriopsis caapi Nuevo Ola is a strong, vigorous vine originally from Peru. The canes obtained were 1 cm in diameter and more fibrous than the other varieties. The supplier suggested that the Nuevo Ola contained 6.09mg / g THH (tetrahydroharmine): 1.20mg / g Harmaline: 6.28mg / g Harmine.

[0779] Experimental

[0780] The vines were pounded with a mallet then cut into 2-3 cm pieces. The samples (~25 g) were placed in a 250 mL round bottom flask and extracted with refluxing water (100 ml, 2 h, 17 h). Alternatively, the samples (~25 g) were stirred in either ethanol (EtOH), or methanol (MeOH) at ambient temperature (200 mL, 17 h). The extracts were filtered through a funnel using Whatman 3 filter paper and the residue was washed with the extraction solvent (100 mL). Samples were taken from the filtrate and stored at 2-8°C until analysed. The rest of the filtrate was concentrated under reduced pressure; for water extractions (50°C, 100 mbar) and for solvent extractions (30°C, 50-100 mbar). The resulting yellow / brown gums were dried in a vacuum oven (25°C ,50 mbar) for 5-17 h. These samples were made to 10 mg / ml in EtOH, agitated under vortex (2 min), sonicated for 10 min, then placed in a centrifuge (2500 rpm, 10 min). The supernatant was analysed for chiral purity according HPLC with UV detector. Refer to Figure 18 for example chromatograms.

[0781] Reference table for product codes and reaction conditions

[0782]

[0783]

[0784] Enantiomeric ratios of THH samples (detailing scalemic THH)

[0785] The following are enantiomeric ratios of THH samples collected after concentration of the extracts and re-suspended in EtOH, measured by chiral HPLC analysis.

[0786] D326-105-02: (water, 2h): tR: 12.23 (S-THH, 7.5%), 13.29 (R-THH, 92.5%) min. ee=85.0%.

[0787] D326-102-02: (water, 2h): tR: 12.46 (S-THH, 14.8%), 13.36 (R-THH, 85.2%) min. ee=70.4%.

[0788] D326-106-02: (water, 2h): tR: 12.37 (S-THH, 10.8%), 13.38 (R-THH, 89.2%) min. ee=78.4%.

[0789] D326-108-02: (water, 17h): tR: 12.33 (S-THH, 30.6%), 13.30 (R-THH, 69.4%) min. ee=38.8%.

[0790] D326-108-02 (repeat): (water, 17h): tR: 12.47 (S-THH, 30.0%), 13.44 (R-THH, 70.0%) min. ee=40.0%.

[0791] D326-100-02: (water, 17h): tR: 12.46 (S-THH, 29.1%), 13.33 (R-THH, 70.9%) min. ee=41.8%.

[0792] D326-107-02: (water, 17h): tR: 12.29 (S-THH, 30.2%), 13.31 (R-THH, 69.8%) min. ee=39.6%.

[0793] D326-109-02: (MeOH, 17h): tR: 12.31 (S-THH, 2.3%), 13.30 (R-THH, 95.2%) min. ee=92.9%.

[0794] D326-101-02: (MeOH, 17h): tR: 12.33 (S-THH, 7.4%), 13.30 (R-THH, 92.6%) min. ee=85.2%.

[0795] D326-101-02 (repeat): (MeOH, 17h): tR: 12.52 (S-THH, 7.0%), 13.43 (R-THH, 93.0%) min. ee=86.0%.

[0796] D326-113-02: (MeOH, 17h): tR: 12.37 (S-THH, 6.3%), 13.36 (R-THH, 87.9%) min. ee= 81.6%.

[0797] D326-110-02: (EtOH, 17h): tR: 12.30 (S-THH, 3.6%), 13.31 (R-THH, 96.4%) min. ee= 92.8%.

[0798] D326-104-02: (EtOH, 17h): tR: 12.53 (S-THH, 5.8%), 13.42 (R-THH, 94.2%) min. ee=88.4%.

[0799] D326-114-02: (EtOH, 17h): tR: 12.31 (S-THH, 7.3%), 13.29 (R-THH, 92.7%) min. ee=85.4%.

[0800] ResultsConcentrated filtrates were weighed for each species of B. caapi and tested in order to estimate the extraction efficiency of the various conditions used. Mass data for the concentrates showed no real trend aside from B. caapi Nuevo Ola having higher mass yields than the other B. caapi varieties (see table below). Higher weights observed in the water extracts are attributed to the residual water content in those samples.

[0801]

[0802] Chiral HPLC samples were taken at two points during the B. Caapi extractions Samples taken from the concentrated extracts that had been resuspended in ethanol are discussed below.

[0803] The experiments described in entries 1 and 2 in the table below were designed to mimic the traditional method of Ayahuasca preparation, (boiling the material in water to prepare a tea). The experiments described in entries 3-4 of the table below were designed to preserve the natural enantiomeric ratio of the B. caapi vines, acknowledging that the application of heat would likely induce racemisation. The chiral HPLC results of samples that came from the concentrated vine extracts are shown in the table below.

[0804]

[0805] ‘Analysis repeated.

[0806] The THH ee values from the concentrated extract samples that were suspended in EtOH are shown below.

[0807]

[0808]

[0809] A representative chiral HPLC spectrum is shown in Figure 19. S- and R-THH are labelled in the HPLC spectra and show an excess of the R-enantiomer over the S-enantiomer. Other peaks are present in the spectra, most prominently around RT 5.9 min, which are additional compounds present in the B. caapi extracts. According to analytical data from the supplier, these are likely to be harmine and harmaline.

[0810] Discussion

[0811] The chiral analysis of THH from B. caapi vines sampled after concentration of the extracts all showed that the R-THH enantiomer was the prominent form in both traditional and non-traditional extraction conditions.

[0812] The analytical results of the extracts suggests that heating the vines in water (as per traditional Ayahuasca preparations, entries 1 and 2) alters the THH enantiomeric ratio and decreases the enantiomeric excess. The enantiomeric excess decreases with heating over time. The extractions using solvents (non-traditional, entries 3-4) gave enantiomeric ratios where R-THH was most prominent (88-98%).

[0813] After heating at reflux for 17 h, all B. caapi species showed a similar ratio of enantiomers, S=~30% and R=~70%. Further experiments are needed to determine whether this ratio would convert to a racemic mixture with longer heating times.

[0814] For the non-traditional extraction techniques (entries 3-4) the THH enantiomers appeared more stable than for traditional methods of extraction. The R-THH enantiomer was in excess for all the experiments conducted by 82-95%, with more conversion from R-THH to S-THH occurring over time

[0815] Extraction and chiral analysis of three varieties of B. caapi vines suggested the R-THH enantiomer to be predominant and in a scalemic form in the natural state as it was in excess under all conditions tested. Heating in water to mimic traditional methods of Ayahuasca preparation, caused a loss in ee which was time dependent, compared to ee values obtained by extracting the vines using non-traditional solvents to preserve enantiomeric purity. No noted variation in ee was observed between B. caapi species.Example 15 - Inhibition Studies

[0816] Study Objective

[0817] To evaluate, in Radioligand Binding assays, the activity of the test compound(s), rac-THH hydrochloride, R-THH hemifumarate was determined.

[0818] Methods

[0819] Methods employed in this study have been adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained.

[0820] Conditions:

[0821] >

[0822]

[0823] >

[0824]

[0825] Results of inhibition studies for compounds against 5HT2b

[0826] rac-THH hydrochloride, 10 pM (concentration), 83% inhibition

[0827] R-THH hemifumarate, 10 pM (concentration), 53% inhibitionDiscussion

[0828] Far less inhibition of 5HT2b was shown by R-THH enantiomer (53%) vs rac-THH (83%). This is a potential strong safety benefit, for example if used as a stand-alone medicine. This is also important, given that it has an increased relative plasma level vs racemic. It may therefore be safer when used as a medicine.

[0829] Example 16 - In Vivo Pharmacokinetic Studies

[0830] Study Objective

[0831] To evaluate the in vivo effects of racemic, (R)-THH, and (S)-THH, MAO-A inhibition, and DMT pharmacokinetics in mice.

[0832] Methods

[0833] Test articles (TA), TA1-7, were dosed to mice as follows:

[0834] " ""

[0835] <

[0836] "

[0837] "

[0838]

[0839]

[0840] Protocol conditions were as follows:

[0841]

[0842]

[0843] <

[0844] The components of test articles in the study design (freebase equivalent ratios / doses) were as follows:

[0845] &

[0846] <

[0847]

[0848]

[0849] Plasma Sample Collection

[0850] Blood aliquots were collected from mice via facial vein (1st to 2nd time points or 1st time point) or cardiac puncture with isoflurane anesthesia (terminal time point) in tubes coated with lithium heparin, mixed gently, then kept on ice and centrifuged at 2,500 xg for 15 min at 4°C, within 1 h of collection. The plasma was then harvested and kept frozen at <-70°C until further processing.

[0851] Quantitative Analysis of Plasma Samples

[0852] The plasma samples were processed using protein precipitation and analyzed by LC-MS / MS. A plasma calibration curve was generated. Aliquots of drug-free plasma were spiked with the test article at the specified concentration levels. The spiked plasma samples were processed together with the unknown plasma samples using the same procedure. The processed plasma samples were placed into the autosampler until the LC-MS / MS analysis, at which time peak areas were recorded, and the concentrations of test articles in the unknown plasma samples were determined using the respective calibration curve. The reportable linear range of the assay was determined, along with the lower limit of quantitation (LLOQ).Pharmacokinetics

[0853] Plots of plasma concentration of the compounds versus time were constructed. The fundamental pharmacokinetic parameters of each compound after IV administration were obtained from the non-compartmental analysis (NCA) using WinNonlin (best-fit mode).

[0854] Results

[0855] 1. DMT Half-Life (ti / 2)

[0856]

[0857] The results show that TA-4 and TA-6 (high-dose enantiomers, (R)-THH and (S)-THH) afford a significantly longer half-life of DMT (0.469 h and 0.397 h, respectively) compared to racemic THH. This longer half-life of DMT is indicative of slower elimination, evidencing that (R)-THH and (S)-THH inhibition of MAO-A is effective.

[0858] 2. DMT Clearance (CL)

[0859]

[0860] The results show that the enantiomers, (R)-THH and (S)-THH, reduce clearance of DMT to a greater extent than racemic THH. This reduced clearance evidences that the enantiomers, (R)-THH and (S)-THH, are more effective inhibitors of MAO-A than racemic THH.3. DMT AUCiast or AllCmf (Exposure Accumulation)

[0861]

[0862] The results show that both enantiomers, (R)-THH and (S)-THH, result in greater accumulation of DMT in the plasma, compared to racemic THH. This increased accumulation evidences that the enantiomers, (R)-THH and (S)-THH, are more effective inhibitors of MAO-A than racemic THH.

[0863] 4. DMT Az (Elimination Rate Constant)

[0864]

[0865] The results show that high-dose enantiomers show a significantly reduced elimination rate constant of DMT compared to racemic THH. This lower elimination rate constant evidences greater MAO-A inhibition of (R)-THH and (S)-THH compared to racemic THH, as a faster decay of elimination rate is indicative of slower clearance of DMT.

[0866] 5. Summary of DMT Plasma Pharmacokinetic Enhancement by THH Enantiomers versus Racemic THH

[0867]

[0868] Further Discussion

[0869] Unexpectedly, administration of highly enriched THH enantiomers, for example at least about 95 percent enantiomeric excess, results in pharmacokinetic modification of N,N-dimethyltryptamine (DMT). Across both low and high THH doses, the purified enantiomers produced substantially greater enhancements in DMT half-life (ti / 2), systemic exposure, and clearance reduction than racemic THH under otherwise equivalent conditions. The increase in exposure was disproportionately larger than changes observed in peak concentration, indicating a qualitative alteration in DMT disposition rather than a simple additive effect on monoamine oxidase A (MAO-A) inhibition.

[0870] In both plasma and brain, coadministration of high purity enantiomeric THH resulted in stronger suppression of 3-indoleacetic acid formation than racemic THH, demonstrating enhanced systemic and central monoamine oxidase A (MAO-A) inhibition not predictable from racemic p-carboline behaviour. The magnitude of these effects, and their reproducibility across a six-fold THH dose range, further distinguishes the high purity enantiomers from the racemate.

[0871] A further unexpected finding was that the presence of DMT altered the central disposition of high purity THH in a manner not observed with racemic THH. Under combination conditions, the relative differences in THH brain exposure seen in monotherapy did not persist, indicating that purified enantiomers engage in transporter or metabolic interactions that racemic THH does not reveal. These altered interactions are detectable when the enantiomers are administered in substantially pure form.Taken together, these findings establish that high purity enantiomeric THH compositions provide advantageous results that are not achievable with racemic THH, including, significantly, enhanced modulation of DMT pharmacokinetics and extended therapeutic exposure. The results support the use of (R)-THH and (S)-THH compositions for achieving improved pharmacokinetics of a co-administered tryptamine in therapeutic applications.Itemised List of Embodiments (A)

[0872] Item 1. A composition comprising:

[0873] a nonracemic mixture of tetrahydroharmine (THH) having an enantiomeric excess of at least 90%, or pharmaceutically acceptable salt thereof; and

[0874] a tryptamine, or pharmaceutically acceptable salt thereof.

[0875] Item 2. A composition comprising:

[0876] a nonracemic mixture of tetrahydroharmine (THH) having an enantiomeric excess of at least 95%, or pharmaceutically acceptable salt thereof; and

[0877] a tryptamine, or pharmaceutically acceptable salt thereof.

[0878] Item 3. A composition comprising:

[0879] a nonracemic mixture of tetrahydroharmine (THH) having an enantiomeric excess of at least 98%, or pharmaceutically acceptable salt thereof; and

[0880] a tryptamine, or pharmaceutically acceptable salt thereof.

[0881] Item 4. The composition of any one of items 1 to 3, wherein the tryptamine is selected from the group consisting of N,N-dimethyltryptamine (DMT) and derivatives thereof. Item 5. The composition of any one of items 1 to 4, wherein the tryptamine, or pharmaceutically acceptable salt thereof, is N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt thereof.

[0882] Item 6. The composition of item 5, wherein the N,N-dimethyltryptamine (DMT) is present as the hemifumarate salt.

[0883] Item 7. The composition of any one of items 1 to 6, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess of (R)-THH.

[0884] Item 8. The composition of any one of items 1 to 6, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess of (S)-THH.

[0885] Item 9. The composition of any one of items 1 to 6, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises (R)- THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).Item 10. The composition of any one of items 1 to 6, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises (S)- THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

[0886] Item 11. The composition of any one of items 1 to 10, wherein the pharmaceutically acceptable salt of tetrahydroharmine (THH) is selected from the group consisting of hydrochloride, hemifumarate, camsylate, succinate, and fumarate.

[0887] Item 12. The composition of any one of items 1 to 11, wherein the pharmaceutically acceptable salt of tetrahydroharmine (THH) is selected from the group consisting of hemifumarate and camsylate.

[0888] Item 13. The composition of any one of items 1 to 3, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess of (R)-THH of at least about 99%, and wherein the (R)-THH is present as the hemifumarate salt.

[0889] Item 14. The composition of any one of items 1 to 3, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess of (S)-THH of at least about 99%, and wherein the (S)-THH is present as the hemifumarate salt.

[0890] Item 15. The composition of any one of items 1 to 14, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, and the tryptamine, or pharmaceutically acceptable salt thereof, are present in a weight ratio (w / w) of between about 1:10 and about 10:1, between about 1 :5 and about 5:1, between about 1 :3 and about 3: 1 , or between about 1 :2 and about 2: 1.

[0891] Item 16. The composition of any one of items 1 to 15, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, and the tryptamine, or pharmaceutically acceptable salt thereof, are present in a weight ratio (w / w) of between about 1 :3 and about 3:1.

[0892] Item 17. The composition of any one of items 1 to 16, further comprising a harmala alkaloid, or pharmaceutically acceptable salt thereof.

[0893] Item 18. The composition of any one of items 1 to 17, wherein the composition further comprises an additional harmala alkaloid selected from the group consisting of harmine (HME), harmaline (HML), harmalol, harmalan, 6-methoxyharman (isoharmine), harmineacid methyl ester, harminilic acid, harmanamide, norharmane, norharman, acetylnorharmine, and pharmaceutically acceptable salts thereof.

[0894] Item 19. The composition of any one of items 1 to 18, wherein the composition further comprises an additional harmala alkaloid selected from the group consisting of harmine (HME), harmaline (HML), and pharmaceutically acceptable salts thereof.

[0895] Item 20. The composition of any one of items 16 to 19, wherein the additional harmala alkaloid is harmine (HME) hydrochloride.

[0896] Item 21. The composition of any one of items 16 to 19, wherein the additional harmala alkaloid is harmaline (HML) hydrochloride.

[0897] Item 22. The composition of any one of items 17 to 21 , wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, and the additional harmala alkaloid, or pharmaceutically acceptable salt thereof, are present in a weight ratio (w / w) of between about 1:10 and about 10:1, between about 1:5 and about 5: 1 , between about 1 :3 and about 3:1, or between about 1 :2 and about 2:1.

[0898] Item 23. The composition of any one of items 1 to 22, wherein the composition is formulated for oral administration, inhalation administration, intranasal administration, intravenous administration, or intramuscular administration.

[0899] Item 24. The composition of any one of items 1 to 23, wherein the composition is formulated for administration as a single dose or as multiple doses.

[0900] Item 25. The composition of any one of items 1 to 24, wherein the composition is formulated for administration as multiple doses, and wherein the multiple doses are administered in an approximately equivalent dosage amount.

[0901] Item 26. The composition of any one of items 1 to 25, wherein the composition is formulated for administration as multiple doses, and wherein the multiple doses are administered in an approximately equal interval.

[0902] Item 27. The composition of item 26, wherein the interval is at least about 1 minute, at least about 5 minutes, or at least about 10 minutes.

[0903] Item 28. The composition of any one of items 1 to 27, wherein the composition is formulated for administration as three doses, and a dose is administered at time 0 minutes, 5 minutes, and 10 minutes.Item 29. A pharmaceutical composition comprising the composition of any one of items 1 to 28, and a pharmaceutically acceptable excipient.

[0904] Item 30. A method of treating of a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is responsive to one or more of:

[0905] modulation of Serotonin receptor (5-HT2A) activity; and / or

[0906] modulation of Serotonin receptor (5-HT2c) activity; and / or

[0907] modulation of sigma-1 receptor activity; and / or

[0908] modulation of activity at a Serotonin receptor other than 5-HT2Aand 5-HT2c; and / or modulation of activity at a Dopamine receptor; and / or

[0909] modulation of activity at an Adrenergic receptor; and / or

[0910] inhibition of a monoamine oxidase (MAOs); and / or

[0911] modulation of a monoamine transporter (DAT, SERT and / or NET); and / or enhancement of neuroplasticity;

[0912] comprising administering the composition of any one of items 1 to 28, or the pharmaceutical composition of item 29, to the subject.

[0913] Item 31. The method of item 30, wherein the disease, disorder, or condition is responsive to inhibition of a monoamine oxidase (MAO) and / or activation of the sigma-1 receptor and / or 5-HT2C agonism and / or neuroplasticity enhancement.

[0914] Item 32. The method of item 30 or item 31, wherein the monoamine oxidase is monoamine oxidase-A (MAO-A) or monoamine oxidase-B (MOA-B).

[0915] Item 33. The method of any one of items 30 to 32, wherein the disease, disorder, or condition is associated with the central nervous system.

[0916] Item 34. The method of any one of items 30 to 32, wherein the disease, disorder, or condition is associated with the peripheral nervous system.

[0917] Item 35. The method of any one of items 30 to 34, wherein the disease, disorder, or condition is selected from the group consisting of substance use disorders, post- traumatic stress disorder (PTSD), agitation associated with neuropsychiatric or neurodevelopmental disorders, eating disorders, acute substance withdrawal, apathy in neurodegenerative diseases, major depressive disorder (MDD), prolonged grief disorder, and anxiety and stress- related conditions.

[0918] Item 36. The method of any one of items 30 to 35, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, andwherein the disease, disorder, or condition is selected from the group consisting of major depressive disorder (MDD), stimulant use disorder, alcohol use disorder, neurodegenerative disorders, neuropathic pain, and trauma related disorders.

[0919] Item 37. The method of any one of items 30 to 35, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and wherein the disease, disorder, or condition is selected from the group consisting of stimulant use disorder and other substance use disorders, post-traumatic stress disorder (PTSD), agitation, eating disorders, acute substance withdrawal, and apathy or affective dysregulation in neurodegenerative diseases.

[0920] Item 38. The method of any one of items 30 to 35, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises R- tetrahydroharmine (R-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 98%, and wherein the R-THH, or pharmaceutically acceptable salt thereof, has a reduced brain to plasma ratio of partitioning compared to the equivalent (S)-THH mixture.

[0921] Item 39. The method of any one of items 30 to 35, and item 37, wherein the mixture of nonracemic tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, comprises S-tetrahydroharmine (S-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 95%, and wherein the S-THH, or pharmaceutically acceptable salt thereof, has an increased brain to plasma ratio of partitioning compared to the equivalent (R)-THH mixture.

[0922] Item 40. The method of any one of items 30 to 36 and item 38, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess (ee) of (R)-THH, or a pharmaceutically acceptable salt thereof, and wherein the composition or the pharmaceutical composition is delivered orally. Item 41. The method of any one of items 30 to 35 and items 37 and 39, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess (ee) of (S)-THH, or a pharmaceutically acceptable salt thereof, and wherein the composition or the pharmaceutical composition is delivered by the inhaled, intranasal, intravenous, or intramuscular administration routes.

[0923] Item 42. The method of any one of items 30 to 36, 38 and 40, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof,comprises R-tetrahydroharmine (R-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 98%, and wherein the composition or the pharmaceutical composition is delivered orally.

[0924] Item 43. The method of any one of items 30 to 35 and items 37 and 39, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises S-tetrahydroharmine (S-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 95%, and wherein the composition or the pharmaceutical composition is delivered by the inhaled, intranasal, intravenous, or intramuscular administration routes.

[0925] Item 44. A pharmaceutical composition comprising a nonracemic mixture of tetrahydroharmine (THH), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0926] Item 45. The pharmaceutical composition of item 44, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess (ee) of at least about 75%, at least about 90%, or at least about 98%.

[0927] Item 46. The pharmaceutical composition of item 44 or item 45, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess of (R)-THH, or a pharmaceutically acceptable salt thereof.

[0928] Item 47. The pharmaceutical composition of item 44 or item 45, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess of (S)-THH, or a pharmaceutically acceptable salt thereof.

[0929] Item 48. The pharmaceutical composition of item 44 or item 45, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises (R)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

[0930] Item 49. The pharmaceutical composition of item 44 or item 45, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises (S)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).Item 50. The pharmaceutical composition of any one of items 44 to 49, wherein the pharmaceutical composition further comprises a tryptamine, or a pharmaceutically acceptable salt thereof.

[0931] Item 51. The pharmaceutical composition of item 50, wherein the tryptamine, or pharmaceutically acceptable salt thereof, is N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt thereof.

[0932] Item 52. The pharmaceutical composition of any one of items 44 to 51, wherein the pharmaceutical composition further comprises harmine (HME) as a hydrochloride salt. Item 53. The pharmaceutical composition of any one of items 44 to 51 , wherein the pharmaceutical composition further comprises harmaline (HML) as a hydrochloride salt. Item 54. The pharmaceutical composition of any one of items 44 to 53, formulated for co-administration with a tryptamine.

[0933] Item 55. A composition comprising:

[0934] R-tetrahydroharmine (R-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 98%; and

[0935] a N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

[0936] Item 56. A composition comprising:

[0937] S-tetrahydroharmine (S-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 98%; and

[0938] a N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.Itemised List of Embodiments (B)

[0939] Item 1. A composition including purified R-THH or a pharmaceutically acceptable salt thereof.

[0940] Item 2. A composition including purified S-THH or a pharmaceutically acceptable salt thereof.

[0941] Item 3. A composition for selectively inhibiting MAO-A activity, including a compound selected from the group consisting of purified R-THH or a pharmaceutically acceptable salt thereof and purified S-THH or a pharmaceutically acceptable salt thereof.

[0942] Item 4. A composition for selectively inhibiting Sigma o1 activity, including a purified R-THH or a pharmaceutically acceptable salt thereof.

[0943] Item 5. A composition for selectively inhibiting Serotonin (5-Hydroxytryptamine) 5- HT2C activity, wherein said composition includes purified S-THH ora pharmaceutically acceptable salt thereof.

[0944] Item 6. A composition according to any one of items 1 to 5, wherein the pharmaceutically acceptable salt is selected from the group consisting of fumarate, hemifumarate, hydrochloride, mesylate, tosylate, camsylate and acetate.

[0945] Item 7. A composition according to item 6 wherein the pharmaceutically acceptable salt is fumarate or hemifumarate.

[0946] Item 8. A composition according to item 7 wherein the pharmaceutically acceptable salt is hemifumarate.

[0947] Item 9. A composition according to any one of items 1 to 8, wherein the composition includes R-THH or a pharmaceutically acceptable salt thereof, and S-THH or a pharmaceutically acceptable salt thereof, wherein the weight ratio of R-THH and S- THH in the composition is about 0.5:100 to about 1:1.Item 10. A composition according to any one of items 1 to 9, wherein the composition includes S-THH or a pharmaceutically acceptable salt thereof, and, wherein the weight ratio of S-THH to R-THH in the composition is about 1 :20 to about 1:1.

[0948] Item 11. A composition according to any one of items 1 to 10, including one or more pharmaceutically acceptable excipients.

[0949] Item 12. A composition according to any one of items 1 to 11 , wherein the composition is a solid dosage form.

[0950] Item 13. A method of treating, ameliorating, or preventing a psychological disorder in a human in need thereof, said method including administering to said human an effective amount of a composition according to any one of items 1 to 12.

[0951] Item 14. A method for treating a psychological disorder including administering to a patient an effective amount of a compound that selectively inhibits MAO-A.

[0952] Item 15. A method for treating a psychological disorder including administering to a patient an effective amount of a compound that selectively inhibits Sigma o1.

[0953] Item 16. A method for treating a psychological disorder including administering to a patient an effective amount of a compound that selectively inhibits Serotonin (5- Hydroxytryptamine) 5-HT2C.

[0954] Item 17. A method according to any of items 14 to 16, wherein the compound is selected from the group consisting of R-THH, purified S-THH, R-THH fumarate, S- THH fumarate, R-THH hemifumarate and S-THH hemifumarate.

[0955] Item 18. Use of a MAO-A inhibitor in the manufacture of a medicament for the treatment of a psychological disorder in a human.

[0956] Item 19. Use of a Sigma o1 inhibitor in the manufacture of a medicament for the treatment of a psychological disorder in a human.

[0957] Item 20. Use of a Serotonin (5-Hydroxytryptamine) 5-HT2c inhibitor in the manufacture of a medicament for the treatment of a psychological disorder in a human.Item 21. Use, according to any of items 18 to 20, wherein the MAO-A inhibitor is selected from the group consisting of R-THH, purified S-THH, R-THH fumarate, S- THH fumarate, R-THH hemifumarate and S-THH hemifumarate.

[0958] Item 22. A method according to any one of items 13 to 17, or use according to any one of items 16 to 19, wherein the psychological disorder is selected from attention deficit hyperactivity disorder, chronic or persistent pain, depression; eating disorders or obesity, generalised anxiety disorder, mixed anxiety, insomnia, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, social phobia or other specific phobias (e.g., animals, heights, blood, needles, or public speaking), substance or alcohol use disorders, prolonged grief disorder or any combination thereof.

[0959] Item 23. A method for preparing racemic THH, including the steps of:

[0960] contacting THH with water to provide a mixture;

[0961] cooling the mixture;

[0962] contacting the mixture with potassium hydroxide,

[0963] stirring the mixture at a temperature and for a time period sufficient to provide a precipitate;

[0964] separating the precipitate from the mixture to provide racemic THH.

[0965] Item 24. A method for preparing R-THH-(-)-CSA, including the steps of:

[0966] contacting racemic THH with an alcohol solvent to provide a mixture; heating the mixture;

[0967] contacting the mixture with L-(-)-camphor-10-sulphonic acid, wherein the mixture is stirred at a temperature and for a time period sufficient to provide a precipitate;

[0968] separating the precipitate from the mixture to provide isolated R-THH (-)-CSA.

[0969] Item 25. A method of item 24, further including purifying R-THH-(-)-CSA, wherein the steps of purifying include dissolving R-THH-(-)-CSA in an alcohol solvent and recrystalizing to provide purified R-THH-(-)-CSA.

[0970] Item 26. A method for preparing R-THH, including the steps of:

[0971] contacting R-THH-(-)-CSA with water to provide a mixture;

[0972] contacting the mixture with an alcohol solvent;contacting the mixture with potassium hydroxide,

[0973] heating the mixture;

[0974] cooling the mixture for a time period sufficient to provide a precipitate separating the pr...

Claims

1. CLAIMS1. A composition comprising (R)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

2. A composition comprising (S)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

3. A composition comprising:a nonracemic mixture of tetrahydroharmine (THH) having an enantiomeric excess of at least 90%, at least 95%, or at least 98%, or pharmaceutically acceptable salt thereof; and a tryptamine, or pharmaceutically acceptable salt thereof.

4. The composition of claim 3, wherein the tryptamine, or pharmaceutically acceptable salt thereof, is N,N-dimethyltryptamine (DMT), or a pharmaceutically acceptable salt thereof.

5. The composition of claim 3 or claim 4, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises (R)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

6. The composition of claim 3 or claim 4, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, comprises (S)-THH, or a pharmaceutically acceptable salt thereof, having at least about a 99% enantiomeric excess (ee).

7. The composition of any one of claims 3 to 6, wherein the pharmaceutically acceptable salt of tetrahydroharmine (THH) is selected from the group consisting of hemifumarate and camsylate.

8. The composition of any one of claims 3 to 7, wherein the nonracemic mixture of tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, and the tryptamine, or pharmaceutically acceptable salt thereof, are present in a weight ratio (w / w) of between about 1:3 and about 3:1.

9. The composition of any one of claims 3 to 8, further comprising a harmala alkaloid, or pharmaceutically acceptable salt thereof.

10. The composition of any one of claims 3 to 9, wherein the composition further comprises an additional harmala alkaloid selected from the group consisting of harmine (HME), harmaline (HML), and pharmaceutically acceptable salts thereof.

11. The composition of any one of claims 3 to 10, wherein the composition is formulated for oral administration, inhalation administration, intranasal administration, intravenous administration, or intramuscular administration.

12. A pharmaceutical composition comprising the composition of any one of claims 1 to 11, and a pharmaceutically acceptable excipient.

13. A method of treating of a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is responsive to one or more of:modulation of Serotonin receptor (5-HT2A) activity; and / ormodulation of Serotonin receptor (5-HT2c) activity; and / ormodulation of sigma-1 receptor activity; and / ormodulation of activity at a Serotonin receptor other than 5-HT2Aand 5-HT2c; and / or modulation of activity at a Dopamine receptor; and / ormodulation of activity at an Adrenergic receptor; and / orinhibition of a monoamine oxidase (MAOs); and / ormodulation of a monoamine transporter (DAT, SERT and / or NET); and / or enhancement of neuroplasticity;comprising administering the composition of any one of claims 1 to 11, or the pharmaceutical composition of claim 12, to the subject.

14. The method of claim 13, wherein the disease, disorder, or condition is selected from the group consisting of substance use disorders, post-traumatic stress disorder (PTSD), agitation associated with neuropsychiatric or neurodevelopmental disorders, eating disorders, acute substance withdrawal, apathy in neurodegenerative diseases, major depressive disorder (MDD), prolonged grief disorder, and anxiety and stress-related conditions.

15. The method of claim 13 or claim 14, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess (ee) of (R)- THH, or a pharmaceutically acceptable salt thereof, and wherein the disease, disorder, or condition is selected from the group consisting of major depressive disorder (MDD), stimulant use disorder, alcohol use disorder, neurodegenerative disorders, neuropathic pain, and trauma related disorders.

16. The method of claim 13 or claim 14, wherein the mixture of nonracemic tetrahydroharmine (THH), or pharmaceutically acceptable salt thereof, has an enantiomeric excess (ee) of (S)- THH, or a pharmaceutically acceptable salt thereof, and wherein the disease, disorder, or condition is selected from the group consisting of stimulant use disorder and other substance use disorders, post-traumatic stress disorder (PTSD), agitation, eating disorders, acute substance withdrawal, and apathy or affective dysregulation in neurodegenerative diseases.

17. A composition comprising:R-tetrahydroharmine (R-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 98%; anda N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

18. A composition comprising:S-tetrahydroharmine (S-THH), or pharmaceutically acceptable salt thereof, in an enantiomeric excess (ee) of at least about 98%; anda N,N-dimethyltryptamine (DMT), or pharmaceutically acceptable salt thereof.

19. A method for preparing a hemifumarate salt of (S)-THH or (R)-THH including the steps of:dissolving (S)-THH or (R)-THH, respectively, in an alcohol solvent to provide a mixture, wherein the mixture is heated at a temperature sufficient to facilitate dissolution; adding fumaric acid to the mixture to provide an admixture,cooing the admixture for a time sufficient to precipitate the hemifumarate salt; separation of the precipitate from the admixture to provide hemifumarate salt of (S)-THH or (R)-THH, respectively.

20. Use of a composition of any one of claims 1 to 11 , or the pharmaceutical composition of claim 12, in the manufacture of a medicament for the treatment of a disease, disorder, or condition in a subject, wherein the disease, disorder, or condition is responsive to one or more of: modulation of Serotonin receptor (5-HT2A) activity; and / ormodulation of Serotonin receptor (5-HT2C) activity; and / ormodulation of sigma-1 receptor activity; and / ormodulation of activity at a Serotonin receptor other than 5-HT2Aand 5-HT2c; and / or modulation of activity at a Dopamine receptor; and / ormodulation of activity at an Adrenergic receptor; and / orinhibition of a monoamine oxidase (MAOs); and / ormodulation of a monoamine transporter (DAT, SERT and / or NET); and / or enhancement of neuroplasticity.

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