THERAPEUTIC COMPOSITIONS COMPRISING DEUTERATED OR PARTIALLY DEUTERATED N,N-DIMETHYLTRYPTAMINE COMPOUNDS

Description

1 / 50 THERAPEUTIC COMPOSITIONS COMPRISING DEUTERATED OR PARTIALLY DEUTERATED N-NIMETHYLTRYPTAMINE COMPOUNDS Separated from BR 112021024333-0, dated 02 / 06 / 2020 FIELD OF THE INVENTION

[0001] The present invention relates to compositions comprising two or more compounds selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and partially deuterated N,N-dimethyltryptamine.

[0002] In particular, the present invention relates to compositions comprising a combination of N,N-dimethyltryptamine and 2% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds selected from α,α-dideutero-N,N-dimethyltryptamine and α,α,β,βtetradeutero-N,N-dimethyltryptamine. Additionally and alternatively, the compositions of the present invention comprise a combination of N,N-dimethyltryptamine and 2% or more by weight of one or more partially deuterated N,N-dimethyltryptamine compounds selected from α,β,βtrideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine, and α-deutero-N,N-dimethyltryptamine. Methods for synthesizing compositions of the present invention are also provided, as well as methods for using such compositions in the treatment of psychiatric or psychocognitive disorders, such as major depressive disorder. BACKGROUND OF THE INVENTION

[0003] Classic psychedelics have shown preclinical and clinical promise in the treatment of psychiatric disorders (Carhart-Harris and Goodwin (2017), The Therapeutic Potential of Psychedelic Drugs: Past, Present and Future, Petition 870260041061, dated 04 / 05 / 2026, page 12 / 71 2 / 50 Neuropsychopharmacology 42, 2105-2113). In particular, psilocybin has demonstrated significant improvement in a number of depression and anxiety assessment scales and randomized double-blind studies (Griffiths et al. (2016), Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomised double-blind trial, Journal of Psychopharmacology 30 (12), 1181-1197).

[0004] N,N-dimethyltryptamine (DMT) is also known to retain therapeutic value as a short-acting psychedelic; however, its duration of action (less than 20 minutes) is so short that it limits effective therapy. Administration protocols have been developed to extend the immersive psychedelic experience of DMT (Gallimore and Strassman (2016), A model for the application of target-controlled intravenous infusion for a prolonged immersive DMT psychedelic experience, Frontiers in Pharmacology, 7:211). However, these protocols present a risk of toxic accumulation in patients who are poor metabolizers of DMT (for a more in-depth discussion see Strassman et al (1994), Dose response study of N,N-dimethyltryptamine in humans, Arch Gen Psychiatry 51, 85).

[0005] α,α,β,β-Tetradeutero-N,N-dimethyltryptamine is known to exhibit a kinetic isotopic effect that confers a significant difference in its in vivo pharmacokinetic profile compared to N,N-dimethyltryptamine. Hydrogen substitution with a deuterium and an sp3 carbon center is known to give rise to a kinetic isotopic effect by virtue of Petition 870260041061, dated 04 / 05 / 2026, page 13 / 71 3 / 50 difference in bond strength between a CH bond and a CD bond. First demonstrated in 1982 (Barker et al. (1982), Comparison of the brain levels of N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine following intraperitoneal injection, Biochemical Pharmacology, 31(15), 2513-2516), the half-life of α,α,β,β-tetradeutero-N,N-dimethyltryptamine in rodent brain is suggestive that administration of α,α,β,β-tetradeutero-N,N-dimethyltryptamine alone would maintain a patient's DMT space for longer than therapeutically essential. SUMMARY OF THE INVENTION

[0006] The present invention is based, in part, on the ability to apply knowledge of the kinetic isotopic effect exhibited by α,α,β,β-tetradeutero-N,N-dimethyltryptamine in order to controllably modify the pharmacokinetic profile of N,N-dimethyltryptamine, thus allowing for more flexible therapeutic application. In particular, by providing compositions of individual drug substances comprising mixtures of N,N-dimethyltryptamine and deuterated N,N-dimethyltryptamine analogs, in particular N,N-dimethyltryptamine comprising at least one deuterium atom in the alpha position (i.e., bonded to the carbon atom to which the dimethylamino mixture is attached) and, according to certain embodiments, one or two deuterium atoms in the beta position, the present invention provides compositions and methods that allow for a single dose well-adjusted to maintain a patient in complete dissociation from the external world, referred to herein as “DMT Space”, for a duration Petition 870260041061, dated 04 / 05 / 2026, page 14 / 71 4 / 50 therapeutically optimized without relying on infusion protocols or combination therapy with monoamine oxidase inhibitors in the clinic. The present invention provides a clinically applicable solution that reduces clinical complexity and increases clinical flexibility in the administration of DMT-assisted psychotherapy.

[0007] Furthermore, we observed a quantifiable relationship between the extent of deuteration, and by proxy the H:D ratio of the incoming reducing agent in synthetic methods disclosed in this document, and the effect on the potentiation of the metabolic half-life of the parent compound. Such a technical effect can be used to quantifiably increase the precision with which compositions comprising pluralities of N,N-dimethyltryptamine compounds (i.e., comprising more than one type of compound selected from N,N-dimethyltryptamine and its deuterated analogues, in particular those deuterated at the alpha position and optionally at the beta position, or pharmaceutically acceptable salts thereof) can be prepared.

[0008] Viewed from a first aspect, therefore, the invention provides a composition comprising two or more compounds selected from N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine, α-protium, α-deutero-N,N-dimethyltryptamine compounds and pharmaceutically acceptable salts of these compounds.

[0009] Viewed from a second aspect, the invention provides a composition that can be obtained by reducing 2-(3-indolyl)N,N-dimethylglyoxalamide with a reducing agent consisting Petition 870260041061, dated 04 / 05 / 2026, page 15 / 71 5 / 50 essentially in up to 90 molar % of lithium aluminum hydride and 10 molar % or more of lithium aluminum deuteride.

[0010] Viewed from a third aspect, the invention provides a composition that can be obtained by reducing 2-(3-indolyl)N,N-dimethylacetamide with a reducing agent consisting essentially of up to 90 molar % by weight of lithium aluminum hydride and 10 molar % or more of lithium aluminum deuteride.

[0011] Viewed from a fourth aspect, the invention provides a pharmaceutical composition comprising a composition as defined in accordance with any one of the first to third aspects in combination with a pharmaceutically acceptable excipient.

[0012] Viewed from a fifth aspect, the invention provides a composition as defined according to any of the first to fourth aspects for use in therapy.

[0013] Viewed from a sixth aspect, the invention provides a composition as defined according to any one of the first to fourth aspects for use in a method of treating a psychocognitive disorder in a patient.

[0014] Viewed from a seventh aspect, the invention provides a method of treating a psychocognitive disorder comprising administering to a patient in need thereof a composition as defined in accordance with any one of the first to fourth aspects.

[0015] Viewed from an eighth aspect, the invention provides the use of a composition as defined according to any one of the first to fourth aspects in the manufacture of a Petition 870260041061, dated 04 / 05 / 2026, p. 16 / 71 6 / 50 medication for use in a treatment method for a psychocognitive disorder in a patient.

[0016] Viewed from a ninth aspect, the invention provides a method of preparing a composition according to any one of the first to third aspects of the invention comprising contacting 2-(3-indolyl)-N,N-dimethylglyoxalamide and / or 2-(3-indolyl)-N,N-dimethylacetamide with a reducing agent consisting essentially of up to 90 molar percent of lithium aluminum hydride and 10 molar percent or more of lithium aluminum deuteride.

[0017] Viewed from a tenth aspect, the invention provides a compound selected from α,β,β-trideutero-N,N-dimethyltryptamine, α,α,β-trideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine, and α-deutero-N,N-dimethyltryptamine.

[0018] Other aspects and embodiments of the present invention will become apparent from the discussion that follows below. BRIEF DESCRIPTION OF THE FIGURES

[0019] Figure 1 shows the predicted pharmacokinetic profile of partially deuterated DMT compared to DMT and fully deuterated DMT. Predicted A) plasma concentration and B) brain tissue concentration, showing the extended half-life of partially deuterated DMT. The shaded area represents the concentrations at the site of effect (>60 ng / ml) that are experienced as complete dissociation from the external world, referred to as the “DMT Space”.

[0020] Figure 2 plots the in vitro half-life calculation for DMT and 6 deuterate-containing compositions described in Example 4. A) Linear regression analysis. The r2 value for the half-life Petition 870260041061, dated 04 / 05 / 2026, page 17 / 71 7 / 50 half-life is 0.754; where the slope was found to be significantly different from zero, p=0.01. B) Half-life of deuterated analogs as a percentage change from DMT (non-deuterated) (dashed line).

[0021] Figure 3, in vitro clearance for DMT and 6 deuterium-containing compositions described in Example 4. A) Linear Regression Analysis. The r2 value for intrinsic clearance is 0.7648; where the slope was found to be significantly different from zero, p=0.01. B) Intrinsic clearance of deuterated analogs as a percentage change from DMT (non-deuterated) (dashed line). DETAILED DESCRIPTION OF THE INVENTION

[0022] Throughout this specification, one or more aspects of the invention may be combined with one or more features described in the specification to define distinct embodiments of the invention.

[0023] References in this document to a singular form of a noun include the plural form of the noun, and vice versa, unless the context states otherwise.

[0024] Throughout this specification, the word comprises, or variations such as comprised or comprising, shall be understood as implying the inclusion of a stated element, whole or in part, or group of elements, whole or in part, but not the exclusion of any other element, whole or in part, or group of elements, whole or in part.

[0025] The present invention provides a composition comprising two or more compounds selected from compounds of N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine, α-protium, α-deutero-N,N- Petition 870260041061, dated 04 / 05 / 2026, page 18 / 71 8 / 50 dimethyltryptamine and pharmaceutically acceptable salts of these compounds.

[0026] A deuterium atom is a hydrogen atom with an additional neutron.

[0027] Frequently in this document, the terms α,α-dideutero-N,N-dimethyltryptamine compounds and α-protium, α-deutero-N,N-dimethyltryptamine compounds are referred to as deuterated (or fully deuterated) N,N-dimethyltryptamine and partially deuterated N,N-dimethyltryptamine, respectively. A deuterated (or fully deuterated) N,N-dimethyltryptamine thus refers strictly to an N,N-dimethyltryptamine compound with both protons in the α-position substituted with deuterium atoms. The term partially deuterated N,N-dimethyltryptamine refers strictly to an N,N-dimethyltryptamine compound in which one of the two protons in the α-position is substituted with a deuterium atom.A deuterated N,N-dimethyltryptamine compound of the present invention is any N,N-dimethyltryptamine compound substituted with two deuterium atoms in the α-position, and a partially deuterated N,N-dimethyltryptamine compound of the present invention is any N,N-dimethyltryptamine compound with one hydrogen atom and one deuterium atom in the α-position.

[0028] Consequently, the invention provides a composition comprising two or more compounds selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine, and partially deuterated N,N-dimethyltryptamine, which is a composition comprising a combination of N,N Petition 870260041061, dated 04 / 05 / 2026, page 19 / 71 9 / 50 dimethyltryptamine and one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds.

[0029] N,N-dimethyltryptamine and all its deuterated analogues freely form addition salts with anionic counter-ions. Throughout the specification, an N,N-dimethyltryptamine compound (in particular N,N-dimethyltryptamine compounds, α,α-dideutero-N,N-dimethyltryptamine compounds and α-protium, α-deutero-N,N-dimethyltryptamine compounds) also refers to any pharmaceutically acceptable salt, for example, the fumarate salt.

[0030] Normally, acidic reagents can be used to prepare salts, in particular pharmaceutically acceptable salts, of N,N-dimethyltryptamine compounds. Examples of suitable acidic reagents are selected from the group consisting of fumaric acid, hydrochloric acid, tartaric acid, citric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, lactic acid, tartaric acid and gluconic acid. Frequently, when in the form of salts, N,N-dimethyltryptamine compounds, in particular as the compounds of the invention, in the compositions of the invention or otherwise used in accordance with the various aspects of the present invention, and embodiments thereof, are fumarate, hydrochloride, tartrate or citrate salts, in particular fumarate salts.

[0031] The compounds present in the composition of the first aspect of the invention, and indeed those of the second and third (and others, as appropriate) aspects of the invention, may thus be present as N,N-dimethyltryptamine compounds, in particular N,N-dimethyltryptamine N,N Petition 870260041061, dated 04 / 05 / 2026, page 20 / 71 10 / 50 deuterated or partially deuterated dimethyltryptamine as defined in this document, in the form of a salt or free base (such as the salts described in this document), optionally as solvates (e.g., hydrates) thereof.

[0032] According to particular embodiments of the invention, α,α-dideutero-N,N-dimethyltryptamine compounds (fully deuterated compounds) comprise 0, 1 or 2 deuterium atoms in the β position, but, apart from the presence of 2, 3 or 4 deuterium atoms, are identical to N,N-dimethyltryptamine compounds. According to these particular embodiments and other particular embodiments of the invention, α-protio-α-deutero-N,N-dimethyltryptamine compounds (partially deuterated compounds) may also comprise 0, 1 or 2 deuterium atoms in the β position, but apart from the presence of 1, 2 or 3 deuterium atoms, are identical to N,N-dimethyltryptamine compounds. The six fully deuterated and partially deuterated compounds according to these particular embodiments of the invention are Petition 870260041061, dated 04 / 05 / 2026, page 21 / 71 11 / 50

[0033] In preferred embodiments of the first aspect, the composition comprises 2% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 5% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 10% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 15% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 20% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds.In preferred embodiments of the first aspect, the composition comprises 25% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 30% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of... Petition 870260041061, dated 04 / 05 / 2026, page 22 / 71 12 / 50 First aspect, the composition comprises 50% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 60% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises 75% or more by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises up to 90% by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises up to 95% by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds.In preferred embodiments of the first aspect, the composition comprises up to 96% by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises up to 97% by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. In preferred embodiments of the first aspect, the composition comprises up to 98% by weight of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds.

[0034] Consequently, it will be understood from the foregoing that, according to particular embodiments of the first aspect of the invention, in particular those embodiments discussed in the following eight paragraphs, the composition comprises between Petition 870260041061, dated 04 / 05 / 2026, page 23 / 71 13 / 50 2% and 90%, 2% and 95%, 2% and 96%, 2% and 97%, 2% and 98%, for example between 5% and 90%, 5% and 95%, 5% and 96%, 5% and 97%, 5% and 98%; 10% and 90%, 10% and 95%, 10% and 96%, 10% and 97%, 10% and 98%; 15% and 90%, 15% and 95%, 15% and 96%, 15% and 97%, 15% and 98%; 20% and 90%, 20% and 95%, 20% and 96%, 20% and 97%, 20% and 98%; 25% and 90%, 25% and 95%, 25% and 96%, 25% and 97%, 25% and 98%; 30% and 90%, 30% and 95%, 30% and 96%, 30% and 97%, 30% and 98%; 50% and 90%, 50% and 95%, 50% and 96%, 50% and 97%, 50% and 98%; 60% and 90%, 60% and 95%, 60% and 96%, 60% and 97%, 60% and 98%; or 75% and 90%, 75% and 95%, 75% and 96%, 75% and 97%, 75% and 98%, by weight, of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds.

[0035] In embodiments of the first aspect, the composition comprises a combination of N,N-dimethyltryptamine compounds and one or more deuterated N,N-dimethyltryptamines selected from α,α-dideutero-N,N-dimethyltryptamine, α,α,β-trideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine, for example a combination of N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine, a combination of N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine or a combination of N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine.

[0036] In preferred embodiments of the first aspect, the composition comprises a combination of N,N-dimethyltryptamine and 2% or more by weight of one or more compounds and deuterated N,N-dimethyltryptamine selected from α,α-dideutero-N,N-dimethyltryptamine and α,α,β,βtetradeutero-N,N-dimethyltryptamine. Petition 870260041061, dated 04 / 05 / 2026, page 24 / 71 14 / 50

[0037] In other embodiments of the first aspect, the composition comprises a combination of N,N-dimethyltryptamine and 2% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds selected from α,α-dideutero-N,N-dimethyltryptamine, α,α,β-trideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine.

[0038] In preferred embodiments of the first aspect, the composition comprises 2% or more by weight of α,α,β,βtetradeutero-N,N-dimethyltryptamine.

[0039] In certain embodiments of the first aspect, the composition comprises 2% or more by weight of α,α,β,βtetradeutero-N,N-dimethyltryptamine and 2% or more by weight of α,α-dideutero-N,N-dimethyltryptamine.

[0040] It will be understood that, whenever a composition comprises 2% or more by weight of one or more deuterated N,N-dimethyltryptamine compounds, such compositions may comprise up to 95% by weight of one or more deuterated N,N-dimethyltryptamine compounds, or up to 96% by weight, up to 97% by weight, or up to 98% by weight.

[0041] In preferred embodiments of the first aspect, the composition comprises or additionally comprises, for example also comprises, one or more partially deuterated N,N-dimethyltryptamines selected from α,β,β-trideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine, and α-deutero-N,N-dimethyltryptamine. Preferably, the partially deuterated N,N-dimethyltryptamine compound is α-deutero-N,N-dimethyltryptamine. Petition 870260041061, dated 04 / 05 / 2026, page 25 / 71 15 / 50

[0042] In preferred embodiments, one or more partially deuterated N,N-dimethyltryptamine compounds comprise up to 50% by weight of the total composition.

[0043] According to other preferred embodiments of the first aspect of the invention, the composition comprises up to 50% by weight, based on the total weight of the composition, of one or more compounds selected from α,α-dideutero-N,N-dimethyltryptamine compounds, α-protium compounds, α-dideutero-N,N-dimethyltryptamine and pharmaceutically acceptable salts thereof. It will be understood that, in such embodiments, such compositions may comprise 2% or more by weight, for example 5% or more, 10% or more, 15% or more, 20% or more, 25% or more or 30% or more, based on the total composition, of said one or more compounds.

[0044] Typically, the compositions of the invention comprise N,N-dimethyltryptamine.

[0045] According to specific embodiments, the compositions of the present invention, including all embodiments described herein, including but not limited to embodiments comprising N,N-dimethyltryptamine, consist essentially of two or more N,N-dimethyltryptamine compounds (i.e., compounds selected from N,N-dimethyltryptamine and its deuterated analogues, in particular those deuterated at the alpha and optionally beta positions, or pharmaceutically acceptable salts thereof). By composition consisting essentially of two or more N,N-dimethyltryptamine compounds, it is understood that the composition may comprise additional components (other than those Petition 870260041061, dated 04 / 05 / 2026, page 26 / 71 16 / 50 N,N-dimethyltryptamine compounds), but the presence of these additional components will not materially affect the essential characteristics of the composition. In particular, compositions consisting essentially of N,N-dimethyltryptamine compounds will not comprise material amounts of other pharmaceutically active substances (i.e., material amounts of other drug substances).

[0046] Even more typically, the compositions of the present invention, including all embodiments described herein, including but not limited to embodiments comprising N,N-dimethyltryptamine, consist of two or more N,N-dimethyltryptamine compounds.

[0047] The composition of the present invention may comprise from 2% to 98% by weight of N,N-dimethyltryptamine, and preferably from 5% to 95% by weight of N,N-dimethyltryptamine. The preferred compositions of the present The invention comprises 10% to 90% by weight of N,N-dimethyltryptamine, or 15% to 85% by weight of N,N-dimethyltryptamine, or 20% to 80% by weight of N,N-dimethyltryptamine, or 25% to 75% by weight of N,N-dimethyltryptamine, or 30% to 70% by weight of N,N-dimethyltryptamine, or 40% to 60% by weight of N,N- dimethyltryptamine.

[0048] The composition of the present invention preferably comprises from 5% to 95% by weight of a deuterated N,N-dimethyltryptamine compound selected from α,α-dideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine. Petition 870260041061, dated 04 / 05 / 2026, page 27 / 71 17 / 50

[0049] The second aspect of the invention provides a composition that can be obtained by reducing 2-(3-indolyl)-N,N-dimethylglyoxalamide with a reducing agent consisting essentially of up to 90 molar aluminum lithium hydride and 10 molar or more aluminum lithium deuteride; and the third aspect provides a composition that can be obtained by reducing 2-(3-indolyl)-N,N-dimethylacetamide with a reducing agent consisting essentially of up to 90 molar aluminum lithium hydride and 10 molar or more aluminum lithium deuteride. In both aspects, the reducing agent can be dissolved or suspended in a liquid medium. Typically, due to its strong reactivity with water and protective solvents such as alcohols, although available in solid (powder) form, lithium aluminum hydride (or deuteride) is frequently handled in dry aprotic solvents, such as ethers, often under an inert atmosphere.Those experienced in the matter are well aware of such precautions and appropriate protocols.

[0050] It will be understood that the invention thus provides a composition that can be obtained by reducing a composition comprising one or more 2-(3-indolyl)-N,N-dimethylglyoxalamide and 2-(3-indolyl)-N,N-dimethylacetamide with a reducing agent consisting essentially of up to 90 molar aluminum lithium hydride and 10 molar or more aluminum lithium deuteride, optionally dissolved or suspended in a liquid medium. The invention also provides a composition obtained by such reduction or, more generally, obtained by a reduction according to the second or third aspect of the invention. Petition 870260041061, dated 04 / 05 / 2026, page 28 / 71 18 / 50

[0051] It should also be understood that the quantities of N,N-dimethyltryptamine compounds described in this document with specific reference to the composition of the first aspect of the invention may be applied mutatis mutandis to the compositions of the second and third aspects of the invention.

[0052] Preferably, the reducing agent described in this document, for example according to the second, third and ninth aspects of the present invention, but also as described in the immediately preceding paragraph, consists essentially of 85 molar % lithium aluminum hydride and 15 molar % lithium aluminum deuteride, or consists essentially of 80 molar aluminum lithium hydride and 20 molar aluminum lithium deuteride, or consists essentially of 25% molar lithium aluminum hydride and 75% molar lithium aluminum deuteride, or essentially consists of 30% molar lithium aluminum hydride and 70% molar lithium aluminum deuteride, or essentially consists of 65% molar lithium aluminum hydride and 35% molar lithium aluminum deuteride, or essentially consists of 60% molar lithium aluminum hydride and 40% molar lithium aluminum deuteride, or essentially consists of 55% molar lithium aluminum hydride and 45% molar lithium aluminum deuteride, or essentially consists of 50% molar lithium aluminum hydride and 50 molar lithium aluminum deuteride, or consists essentially of 45 molar lithium aluminum hydride and 55 molar aluminum lithium deuteride, or consisting essentially of 40 molar lithium aluminum hydride by weight and 60 molar aluminum lithium deuteride, or consisting essentially of 35 molar aluminum hydride Petition 870260041061, dated 04 / 05 / 2026, page 29 / 71 19 / 50 and lithium and 65% molar Lithium aluminum deuteride, or consists essentially of 30% molar lithium aluminum hydride and 70% molar lithium aluminum deuteride, or consists essentially of 25% molar lithium aluminum hydride and 75% molar lithium aluminum deuteride, or consists essentially of 20% molar lithium aluminum hydride and 80% molar lithium aluminum deuteride, or consists essentially of 15% molar by weight of lithium aluminum.

[0053] According to particular embodiments, stating that the reducing agent consists essentially of lithium aluminum hydride and lithium aluminum deuteride means that the reducing agent may comprise additional components, but that the presence of these components will not materially affect the essential characteristics of the reducing agent (in particular stability and reducing propensity).

[0054] According to the fourth aspect of the invention, a pharmaceutical composition is provided comprising a composition as defined in accordance with the first to third aspects of the invention, in combination with a pharmaceutically acceptable excipient.

[0055] The pharmaceutical composition of the invention comprises a composition of the invention (according to any one of its first to third aspects) in combination with one or more pharmaceutically acceptable excipients. Suitable pharmaceutical compositions may be prepared by a person skilled in the art, with examples of pharmaceutically acceptable excipients including, but not limited to, those described in Gennaro et al., Remmington: The Petition 870260041061, dated 04 / 05 / 2026, page 30 / 71 20 / 50 Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000 (specifically part 5: pharmaceutical manufacturing). Suitable excipients are also described in Handbook of Pharmaceutical Excipients, 2nd Edition; Editors A. Wade and P.J. Weller, American Pharmaceutical Association, Washington, The Pharmaceutical Press, London, 1994.

[0056] The pharmaceutical compositions of the invention can be compressed into solid dosage units, such as tablets, or processed into capsules or suppositories. Using pharmaceutically suitable liquids, the compounds can also be prepared in the form of a solution, suspension, emulsion, or as a spray. To make dosage units, including tablets, the use of conventional additives, such as fillers, colorants, polymeric binders, and the like, is contemplated. In general, any pharmaceutically acceptable additive can be used.

[0057] Suitable fillers with which the pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose and derivatives thereof, and the like, or mixtures thereof used in appropriate amounts.For parenteral administration, aqueous suspensions, isotonic saline solutions, and sterile injectable solutions containing pharmaceutically acceptable dispersing and / or emollient agents, such as propylene glycol or butylene glycol, may be used.

[0058] The invention also provides a pharmaceutical composition of the invention, in combination with suitable packaging material. Petition 870260041061, dated 04 / 05 / 2026, page 31 / 71 21 / 50 for the composition, the packaging material, including instructions for use of the pharmaceutical composition.

[0059] The compositions of the invention are useful in therapy and can be administered to a patient as needed. As used in this document, the term patient preferably refers to a human patient, but may also refer to a domestic mammal. The term does not cover laboratory mammals.

[0060] According to the sixth aspect of the invention, a composition as defined according to any one of the first to fourth aspects is provided for use in a method of treating a psychocognitive disorder in a patient. The seventh aspect of the invention provides a method of treating a psychocognitive disorder comprising administering to a patient in need thereof a composition as defined according to any one of the first to fourth aspects, and the eighth aspect provides the use of a composition as defined according to any one of the first to fourth aspects in the manufacture of a medicament for use in a method of treating a psychocognitive disorder in a patient.

[0061] As used in this document, the term psychocognitive disorder encompasses psychiatric disorders that may be associated with one or more cognitive disorders. As used in this document, the term psychiatric disorder is a clinically significant syndrome or behavioral or psychological pattern occurring in an individual that is associated with current distress (e.g., a painful symptom) or impairment (i.e., deficiency in one or more). Petition 870260041061, dated 04 / 05 / 2026, page 32 / 71 22 / 50 important areas of functioning) or with a significantly increased risk of suffering death, pain, disability, or a significant loss of freedom.

[0062] The diagnostic criteria for psychiatric and psychocognitive disorders referred to in this document are provided in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the contents of which are incorporated into this document by reference.

[0063] As used in this document, the term “obsessive-compulsive disorder” is defined by the presence of obsessions or compulsions, but commonly both. Symptoms can cause significant functional impairment and / or distress. An obsession is defined as an unwanted, intrusive thought, image, or impulse that repeatedly enters a person’s mind. Compulsions are repetitive behaviors or mental acts that a person feels compelled to perform. Typically, obsessive-compulsive disorder (OCD) manifests as one or more obsessions that lead to the adoption of a compulsion. For example, an obsession with germs may lead to a compulsion to clean. A compulsion may be overt and observable by others, such as checking if a door is locked, or a hidden mental act that cannot be observed, such as repeating a certain phrase in one’s mind.

[0064] As used in this document, the term "depressive disorder" includes major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, and terminal depression. Petition 870260041061, dated 04 / 05 / 2026, page 33 / 71 23 / 50

[0065] As used in this document, the term “Major Depressive Disorder” (MDD, also referred to as major depression or clinical depression) is defined as the presence of five or more of the following symptoms over a period of two weeks or more (also referred to in this document as a “major depressive episode”), for most of the day, nearly every day: • Depressed mood, such as feeling sad, empty, or tearful (in children and adolescents, depressed mood may appear as constant irritability); • Reduced interest in, or lack of pleasure in, all or most activities; • Significant weight loss when not dieting, weight gain, or decreased or increased appetite (in children, failure to gain weight as expected); • Insomnia or increased desire to sleep; • Restlessness or sluggish behavior that can be observed by other people; • Fatigue or loss of energy; • feelings of worthlessness or excessive or inappropriate guilt; • Difficulty making decisions or difficulty thinking or concentrating; • recurring thoughts of death or suicide, or attempted suicide. Petition 870260041061, dated 04 / 05 / 2026, page 34 / 71 24 / 50

[0066] At least one of the symptoms must be a depressed mood or a loss of interest or pleasure.

[0067] Persistent depressive disorder, also known as dysthymia, is defined as a patient exhibiting the following two characteristics: A. Has a depressed mood most of the time, nearly every day, for at least two years. Children and adolescents may have an irritable mood, and the timeframe is at least one year. B. While depressed, a person experiences at least two of the following symptoms: • Overeating or lack of appetite. • Sleeping too much or having difficulty sleeping. • Fatigue, lack of energy. • Low self-esteem. • Difficulty concentrating or making decisions.

[0068] As used in this document, the term “treatment-resistant depression” describes MDD that fails to achieve an adequate response to appropriate treatment with standard care therapy.

[0069] As used in this document, “bipolar disorder, also known as manic-depressive illness, is a disorder that causes unusual changes in mood, energy, activity levels, and the ability to perform daily tasks.

[0070] There are two defined subcategories of bipolar disorder; all of them involve clear changes in mood, energy, and activity levels. These mood states vary Petition 870260041061, dated 04 / 05 / 2026, page 35 / 71 25 / 50 of periods of extremely “up, exultant, and energized” behavior (known as manic episodes, and defined further below) to very sad, “down, or hopeless” periods (known as depressive episodes). Less severe manic periods are known as hypomanic episodes.

[0071] Bipolar I Disorder — defined by manic episodes lasting at least 7 days, or by manic symptoms that are so severe that the person requires immediate hospital care. Depressive episodes also typically occur, usually lasting at least 2 weeks. Depressive episodes with mixed features (having both depressive and manic symptoms at the same time) are also possible.

[0072] Bipolar II Disorder — defined by a pattern of depressive episodes and hypomanic episodes, but not the fully developed manic episodes described above.

[0073] As used in this document, “bipolar depression is defined as an individual who is experiencing depressive symptoms with a prior or coexisting episode of manic symptoms, but does not meet the clinical criteria for bipolar disorder.

[0074] As used in this document, the term “anxiety disorder” includes generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

[0075] “Generalized Anxiety Disorder (GAD) as used in this document means a chronic disorder characterized by long-lasting anxiety that is not focused on any object or Petition 870260041061, dated 04 / 05 / 2026, pp. 36 / 71 26 / 50 situation. Those who suffer from GAD experience persistent, nonspecific fear and worry, and become excessively concerned about everyday matters. GAD is characterized by chronic excessive worry accompanied by three or more of the following symptoms: restlessness, fatigue, concentration problems, irritability, muscle tension, and sleep disturbance.

[0076] A phobia is defined as a persistent fear of an object or situation that the affected person will do anything to avoid, usually disproportionate to the actual danger presented. If the feared object or situation cannot be entirely avoided, the affected person will endure it with marked distress and significant interference in social or occupational activities.

[0077] A patient suffering from panic disorder is defined as one who experiences one or more brief attacks (also referred to as a panic attack) of intense terror and apprehension, often marked by trembling, confusion, dizziness, nausea, and / or difficulty breathing. A panic attack is defined as a fear or discomfort that arises abruptly and peaks in less than ten minutes.

[0078] Social anxiety disorder is defined as an intense fear and avoidance of negative public scrutiny, public embarrassment, humiliation, or social interaction. Social anxiety often manifests as specific physical symptoms, including blushing, sweating, and difficulty speaking.

[0079] Post-traumatic stress disorder (PTSD) is an anxiety disorder that results from a traumatic experience. Petition 870260041061, dated 04 / 05 / 2026, pp. 37 / 71 27 / 50 Post-traumatic stress can result from an extreme situation, such as combat, natural disaster, rape, hostage situations, child abuse, bullying, or even a serious accident. Common symptoms include hypervigilance, flashbacks, avoidance behaviors, anxiety, anger, and depression.

[0080] As used in this document, the term "substance abuse" means a patterned use of a drug in which the user consumes the substance in amounts or by methods that are harmful to themselves or others.

[0081] As used in this document, the term "avolition disorder" refers to a disorder that includes, as a symptom, decreased motivation to initiate and perform purposeful, self-directed activities.

[0082] In preferred embodiments of the sixth to eighth aspects of the present invention, the psychocognitive disorder is selected from (i) an obsessive-compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse, and (v) an avolition disorder.

[0083] According to particular embodiments of the sixth to eighth aspects of the present invention, depressive disorder is major depressive disorder. According to even more particular embodiments, major depressive disorder is treatment-resistant major depressive disorder.

[0084] Compositions comprising partially deuterated N,N-dimethyltryptamine compounds of the present invention can be synthesized following the schemes of Petition 870260041061, dated 04 / 05 / 2026, pp. 38 / 71 28 / 50 reaction (synthetic schemes) provided in Scheme 1 and Scheme 2 below. The chemistry represented in the schemes was reported by PE Morris and C Chiao (Journal of Labelled Compounds And Radiopharmaceuticals, Vol. XXXIII, No. 6, 455465 (1993)). Compositions comprising partially deuterated N,N-dimethyltryptamine compounds of the present invention can also be synthesized following the synthesis scheme represented in Scheme 3 and Example 4 below.

[0085] The relative proportions of N,N-dimethyltryptamine as opposed to deuterated N,N-dimethyltryptamine compounds and partially deuterated N,N-dimethyltryptamine compounds can be controlled by varying the ratio of lithium aluminum hydride and lithium aluminum deuteride in the reducing agent. The relative proportions can be further varied by adding one or more of N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine to the compositions described above in this document.

[0086] A particular advantage of the present invention, in particular but not limited to the compositions obtained according to its second and third aspects and the method of its ninth aspect, is that the reductions described according to these aspects of the invention allow particularly high purities to be obtained without the need for subsequent chromatographic purification (e.g., column chromatography), thus increasing the efficiency with which the compositions of the invention can be prepared. Furthermore, the ability to avoid the use of chromatography to achieve high purities makes the increase in Petition 870260041061, dated 04 / 05 / 2026, pp. 39 / 71 29 / 50 scale is more efficient and therefore offers better cost-effectiveness.

[0087] The identification of the compositions resulting from the reduction step in Schemes 1 and 2 (which represent particular embodiments of the second and third aspects of the invention) can be achieved, if desired, by chromatographic separation of the components of the mixtures by conventional means available to specialists in combination with spectroscopic and / or mass spectrometric analysis. OH O / VA SOCl2 in Et2O J o 2 2 í -78°CH NM O / J ° Co H Scheme 1 OH / -¾ SOCL in Et2O / c 2 í γ -78°CH NM / Ό Co H Scheme 2 Cl NMe2 O / O / NHMe2 in Et2O \\ / 0 ____________ / o Co Co Η H e2 μι / n NMe2 H / D .H / D / 11 / r, LiAIH4 LiAID4 in Et2O, / 0 ^H^CL^— r Co H Cl NMe2 / ---¾. NHMe2 in Et2O Γ / O________2 2 / O Co Co Η H le2 NMe2 LiAIH4 LiAID4in Et2O, ^--eH / DCH2CL2 J Η / β r Co \^^NH Petition 870260041061, dated 04 / 05 / 2026, pp. 40 / 71 30 / 50

[0088] Alternative compositions of the present invention can be obtained by mixing N,N-dimethyltryptamine, obtained by Scheme 1 or Scheme 2, when the reducing agent is exclusively lithium aluminum hydride, with a deuterated N,N-dimethyltryptamine compound obtained from Scheme 1 or Scheme 2 when the reducing agent is exclusively lithium aluminum deuteride.

[0089] The compositions described above in this document may be further modified by the addition of one or more deuterated or partially deuterated N,N-dimethyltryptamine compounds. Stocks of such deuterated or partially deuterated N,N-dimethyltryptamine compounds may be obtained, for example, from the chromatographic separation described above. In this way, for example, the compounds of the tenth aspect of the invention may be obtained. According to particular embodiments of the tenth aspect, the compound is selected from α,β,β-trideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine, and α-deutero-N,N-dimethyltryptamine.

[0090] Although the identification of the compositions resulting from the reduction described in this document can be achieved by chromatographic separation of the components of the mixtures, in combination with spectroscopic and / or mass spectrometric analysis, a particular benefit of the present invention is that, according to particular embodiments, there may be no need to do so. This is because, in addition to the purities achievable according to the present invention, as alluded to above, we recognize that there is a quantifiable relationship between the extent of deuteration (or in other words, the Petition 870260041061, dated 04 / 05 / 2026, pp. 41 / 71 31 / 50 quantification or proportion of deuterium in the N,N-dimethyltryptamine compounds in the compositions of the present invention) and the metabolic half-life of the resulting composition. The extent of deuteration can be controlled by the amount of deuterium-containing reducing agent used in the method of the invention, through which (according to particular embodiments) the compositions of the invention can be obtained, and thus the control exercised, in a predictable way, over the potentiation of the metabolic half-life of the parent compound (non-deuterated N,N-dimethyltryptamine).

[0091] In particular, as detailed in Example 4 and reported in Figures 2 and 3, we demonstrate that increasing the deuterium enrichment at the α-carbon of N,N-dimethyltryptamine increases metabolic stability, leading to a decrease in clearance and a longer half-life. There is a linear relationship between molecular weight and half-life, particularly when the reducing agent used to produce the deuterium-enriched N,N-dimethyltryptamine compositions of this invention comprises LiAlH4 and LiAlD4 in a ratio between about 1:2.5 and about 2.5:1.

[0092] These types of compositions constitute specific embodiments of the first aspect of the invention. According to these specific embodiments, the composition essentially consists of a mixture of N,N-dimethyltryptamine and one or both of α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine, the composition optionally being in the form of a pharmaceutically acceptable salt, characterized by: the average molecular weight of N,N-dimethyltryptamine, α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N Petition 870260041061, dated 04 / 05 / 2026, pp. 42 / 71 The concentrations of 32 / 50 dimethyltryptamine present in the composition range from 188.28 to 190.28.

[0093] As used in this document, average molecular weight means the weighted average of the molecular weights of N,N-dimethyltryptamine and one or both of α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine, as measured by an appropriate mass spectroscopic technique, for example LC-MS SIM (selected ion monitoring), ignoring any weight contribution from the formation of pharmaceutically acceptable salts, where applicable.

[0094] It will be understood that the provision of compositions with such specific average molecular weights can be achieved by those skilled in the art through the teachings described in this document, in particular by adjusting the relative proportions of lithium aluminum hydride and lithium aluminum deuteride in the reductions described in this document.

[0095] In this context, stating that the composition consists essentially of a mixture of N,N-dimethyltryptamine and one or both of α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine means that the composition may comprise additional components to these, but the presence of such additional components will not materially affect the essential characteristics of the composition. In particular, the composition will not comprise material quantities of other pharmaceutically active compounds, including other N,N-dimethyltryptamine compounds. Thus, material quantities of other N,N-dimethyltryptamine compounds Petition 870260041061, dated 04 / 05 / 2026, pp. 43 / 71 33 / 50 deuterated, in particular β-deutero-N,N-dimethyltryptamine and β,β-dideutero-N,N-dimethyltryptamine compounds, such as β-deutero-N,N-dimethyltryptamine and β,β-dideutero-N,N-dimethyltryptamine compounds and β-deutero-N,N-dimethyltryptamine and β,β-dideutero-N,N-dimethyltryptamine compounds having respectively one or two deuterium atoms in place of hydrogen atoms in the α-position not present in the compositions of such embodiments.

[0096] In other words, and put alternatively, the compositions according to these specific embodiments constitute a drug substance comprising a biologically active ingredient consisting essentially of a mixture of N,N-dimethyltryptamine and one or more of α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine, characterized in that: the biologically active ingredient having an average molecular weight of 188.28 to 190.28 and in which the drug substance is optionally in the form of a pharmaceutically acceptable salt.

[0097] It will be understood that the compositions according to these specific embodiments comprise one or more of α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine in amounts greater than those found in isotopically unenriched N,N-dimethyltryptamine. It will also be understood that the greater the proportion of α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine in these specific embodiments, the greater the average molecular weight of the composition.

[0098] According to more specific concretizations, the average molecular weight of N,N-dimethyltryptamine, α-deutero-N,N-Dimethyltryptamine, α-deutero-N,N-Dimethyltryptamine, 870260041061, dated 04 / 05 / 2026, page 44 / 71 The concentration of 34 / 50 dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine present in the composition is 188.9 to 189.7, for example 188.90 to 189.70.

[0099] According to even more specific embodiments of the specific embodiments described in this document, including compositions in which the average molecular weight of N,N-dimethyltryptamine, α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine present in the composition is from 188.9 to 189.7, for example 188.90 to 189.70, the composition is optionally in the form of a pharmaceutically acceptable salt, whereby it will be understood that N,N-dimethyltryptamine, α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine present in the composition are present in the form of a pharmaceutically acceptable salt. Such salts may be as described elsewhere in this document and, according to even more specific embodiments, the composition is in the form of a fumarate salt.

[00100] Each patent and non-patent referenced in this document is incorporated by reference in its entirety, as if the entire content of each reference were set forth in this document in its entirety.

[00101] The invention can be better understood with reference to the following non-limiting clauses and examples: 1. A composition comprising two or more compounds selected from N,N-dimethyltryptamine, deuterated N,N-dimethyltryptamine and partially deuterated N,N-dimethyltryptamine. 2. The composition of clause 1 comprising a combination of N,N-dimethyltryptamine and 2% or more by weight of one or more Petition 870260041061, dated 04 / 05 / 2026, pp. 45 / 71 35 / 50 deuterated or partially deuterated N,N-dimethyltryptamine compound, characterized in that: a deuterated N,N-dimethyltryptamine compound is substituted by two deuterium atoms in the α position and a partially deuterated N,N-dimethyltryptamine compound is an N,N-dimethyltryptamine compound with one hydrogen atom and one deuterium atom in the α position. 3. The composition of clause 1 or 2 characterized by: the deuterated N,N-dimethyltryptamine compound being selected from α,α-dideutero-N,N-dimethyltryptamine and α,α,β,βtetradeutero-N,N-dimethyltryptamine. 4. The composition of clause 3 comprising 2% or more by weight of α,α,β,β-tetradeutero-N,N-dimethyltryptamine. 5. The composition of clause 3 or 4 comprising 2% or more by weight of α,α-dideutero-N,N-dimethyltryptamine. 6. The composition of any of clauses 1 to 5 comprising one or more partially deuterated N,N-dimethyltryptamine compounds selected from α,β,β-trideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine and α-deutero-N,N-dimethyltryptamine. 7. The composition of clause 6 is characterized by: the partially deuterated N,N-dimethyltryptamine compound being α-deutero-N,N-dimethyltryptamine. 8. The composition of any of clauses 1 to 7 characterized by: one or more partially deuterated N,N-dimethyltryptamine compounds comprising up to 50% by weight of the total composition. 9. The composition of any of clauses 1 to 8 comprising from 5% to 95% by weight of N,N-dimethyltryptamine. Petition 870260041061, dated 04 / 05 / 2026, pp. 46 / 71 36 / 50 10. The composition of any of clauses 1 to 9 comprising from 5% to 95% by weight of a deuterated N,N-dimethyltryptamine compound selected from α,α-dideutero-N,N-dimethyltryptamine and α,α,β,β-tetradeutero-N,N-dimethyltryptamine. 11. A composition obtained by reducing 2-(3-indolyl)N,N-dimethylglyoxalamide with a reducing agent consisting essentially of up to 90% by weight of lithium aluminum hydride and 10% or more of lithium aluminum deuteride. 12. A composition that can be obtained by reducing 2(3-indolyl)-N,N-dimethylacetamide with a reducing agent consisting essentially of up to 90% by weight of lithium aluminum hydride and 10% or more of lithium aluminum deuteride. 13. Composition of any of clauses 1 to 12 for use in the treatment of a psychiatric or psychocognitive disorder in a patient. 14. Composition for use in accordance with clause 13 characterized by: the psychiatric or psychocognitive disorder being selected from (i) an obsessive-compulsive disorder, (ii) a depressive disorder, (iii) an anxiety disorder, (iv) substance abuse and (v) an avolition disorder. 15. A compound selected from α,β,β-trideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine, and α-deutero-N,N-dimethyltryptamine. EXAMPLES Example 1: Petition 870260041061, dated 04 / 05 / 2026, pp. 47 / 71 37 / 50

[00102] 2-(3-indolyl)-N,N-dimethylacetamide is synthesized as described in Morris and Chiao (1993), Journal of labelled compounds and radiopharmaceuticals, Vol. XXXIII, No. 6. 0.063 g LiAlH4 and 0.278 g LiAlD4 (molar ratio 20:80 of LiAlH4:LiAlD4) are suspended in 25 ml dry Et2O with magnetic stirring. 0.785 g of 2-(3-indolyl)-N,N-dimethylacetamide is dissolved in 300 ml and slowly added to the stirred suspension. The reagents are heated under reflux for 3 hours, then cooled in an ice bath and quenched dropwise with water. The resulting mixture is filtered, dried, and the solvents removed under vacuum to yield approximately 0.5 g of a composition consisting of 3 molar N,N-dimethyltryptamine, 28 molar α-deutero-N,N-dimethyltryptamine, and 69 molar α,α-dideutero-N,N-dimethyltryptamine. Example 2:

[00103] 0.173g LiAlH4 and 0.156g LiAlD4 (molar ratio 55:45 of LiAlH4:LiAlD4) are suspended in 25 ml dry Et2O with magnetic stirring. 0.785g of 2-(3-indolyl)-N,N-dimethylacetamide is dissolved in 300 ml and slowly added to the stirred suspension. The reagents are heated under reflux for 3 hours, then cooled in an ice bath and quenched dropwise with water. The resulting mixture is filtered, dried, and the solvents removed under vacuum to yield approximately 0.5 g of a composition consisting of 24 molar % N,N-dimethyltryptamine, 50 molar % α-deutero-N,N-dimethyltryptamine, and 26 molar % α,α-dideutero-N,N-dimethyltryptamine. Example 3: Petition 870260041061, dated 04 / 05 / 2026, pp. 48 / 71 38 / 50

[00104] 0.293g L1AIH4 and 0.035g L1AID4 (molar ratio 90:10 of LiAlH4:LiAlD4) are suspended in 25 ml dry Et2O with magnetic stirring. 0.785 g of 2-(3-indolyl)-N,N-dimethylacetamide is dissolved in 300 ml and slowly added to the stirred suspension. The reagents are heated under reflux for 3 hours, then cooled in an ice bath and quenched dropwise with water. The resulting mixture is filtered, dried, and the solvents removed under vacuum, to yield approximately 0.5 g of a composition consisting of 76 mol% N,N-dimethyltryptamine, 22 mol% α-deutero-N,N-dimethyltryptamine and 2 mol% α,α-dideutero-N,N-dimethyltryptamine. Example 4: Use of hepatocytes to assess clearance in relation to DMT.

[00105] In vitro determination of intrinsic clearance is a valuable model for predicting in vivo hepatic clearance. The liver is the main organ of drug metabolism in the body, containing both phase I and phase II drug-metabolizing enzymes, which are present in the intact cell. Sample Synthesis

[00106] 220.9 g of N,N-DMT (as free base) was prepared as N,N-DMT fumarate, using the chemistry depicted in Scheme 3. An additional 4–6 g of six partially deuterated mixtures were also produced using modified conditions. Petition 870260041061, dated 04 / 05 / 2026, pp. 49 / 71 39 / 50 Stage 3 EtOH Fumaric acid Mol Weight: 304.34 Scheme 3 DMT synthesis Stage 1: coupling of indole-3-acetic acid and dimethylamine

[00107] For a container of 51 under N2 was loaded indole 3-Acetic acid (257.0 g, 1.467 mol), hydroxybenzotriazole (HOBt, ~20% wet) (297.3 g, 1.760 mol) and dichloromethane (2313 ml) were added to give a milky white suspension. l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 337.5 g, 1.760 mol) was then added in portions over 5 minutes at 16-22 °C. The reaction mixture was stirred for 2 hours at room temperature before 2M dimethylamine in T&E (1100 ml, 2.200 mol) was added dropwise over 20 minutes at 20-30 °C. The resulting solution was stirred at room temperature for 1 hour where HPLC indicated 1.1%. Petition 870260041061, dated 04 / 05 / 2026, pages 50 / 71 40 / 50 indole-3-acetic acid and 98.1% target product referred to as Stage 1). The reaction mixture was then charged with 10% K2CO3 (1285 ml) and stirred for 5 minutes. The layers were separated, and the superaqueous layer extracted with dichloromethane (643 ml x 2). The organic extracts were combined and washed with saturated brine (643 ml). The organic extracts were then dried with MgSO4, filtered, and concentrated in vacuo at 45°C. This yielded 303.1 g of crude Stage 1 as a whitish sticky solid. The crude material was then subjected to a paste in tert-butyl methyl ether (TBME, 2570 ml) at 50°C for 2 hours before being cooled to room temperature, filtered, and washed with TBME (514 ml x 2). The filter cake was then dried in vacuum at 50°C to provide Stage 1, 266.2 g (yield=90%) as a whitish solid with a purity of 98.5% by HPLC and >95% by NMR. Stage 2: DMT Preparation For a 5 l vessel under N2, Stage 1 (272.5 g, 1.347 mol) and tetrahydrofuran (THF, 1363 ml) were charged to give a whitish suspension. 2.4 M LiAlH4 in THF (505.3 ml, 1.213 mol) was then charged dropwise for 35 minutes at 20-56°C to give an amber solution. The solution was heated to 60°C for 2 hours where HPLC indicated Stage 1 ND, target product support referred to as Stage 2 (92.5%), Impurity 1 (2.6%), Impurity 2 (1.9%). The complete reaction mixture was cooled to room temperature and then charged with a 25% (aq) Rochelle salts solution (2725 ml) dropwise for 30 minutes at 20-30°C. The resulting milky white suspension was left to stir at 20-25°C for 1 hour after Petition 870260041061, dated 04 / 05 / 2026, pp. 51 / 71 41 / 50 where the layers were separated, the upper organic layer was washed with saturated brine (681 ml). The organic layer was then dried over MgSO4, filtered and concentrated in vacuo at 45°C. The resulting crude oil was subjected to an ethanol azeotrope (545 ml x 2). This provided 234.6 g (yield = 92%) of Stage 2 with a purity of 95.0% by HPLC and >95% by NMR. Stage 3a (i)-(iii): Preparation of DMT Fumarate Seed Crystals

[00108] (i) Stage 2 (100 mg) was carried over into 8 volumes of isopropyl acetate and heated to 50°C before loading fumaric acid (1 equivalent) as a solution in ethanol. The vial was then left to mature at 50°C for 1 hour before being cooled to room temperature and shaken overnight, resulting in a white suspension. The solids were isolated by filtration and dried for 4 hours at 50°C to give 161 mg of the product (yield > 99%). Purity by HPLC was determined to be 99.5% and by NMR to be > 95%.

[00109] (ii) Replacing isopropyl acetate with isopropyl alcohol in method (i) yielded a white suspension after overnight stirring. The solids were isolated by filtration and dried for 4 hours at 50°C to give 168 mg of product (yield > 99%). Purity by HPLC was determined to be 99.8% and by NMR to be > 95%.

[00110] Replacing isopropyl acetate with tetrahydrofuran in method (i) yielded a white suspension after overnight agitation. The solids were Petition 870260041061, dated 04 / 05 / 2026, pp. 52 / 71 42 / 50 isolates were filtered and dried for 4 hours at 50°C to provide 161 mg of product (yield > 99%). Purity by HPLC was determined to be 99.4% and by NMR to be > 95%.

[00111] X-ray powder diffraction analysis showed that the products of each of methods 9i) to(iii) were the same, which was labeled Standard A. Stage 3b: Preparation of DMT fumarate

[00112] A 5 l flanged flask under N2 was loaded with fumaric acid (152.7 g, 1.315 mol) and Stage 2 (248.2 g, 1.315 mol) as a solution in ethanol (2928 ml). The mixture was heated to 75 °C to give a dark brown solution. The solution was filtered by polishing into a preheated (80 °C) 5 l jacketed container. The solution was then cooled to 70 °C and seeded with Standard A (0.1% by weight). The seed was allowed to mature for 30 minutes before cooling to 0 °C at a rate of 5 °C / hour. After stirring for an additional 4 hours at 0 °C, the batch was filtered and washed with cold ethanol (496 ml x 2) and then dried at 50 °C overnight. This yielded 312.4 g (yield=78%) of Stage 3 with a purity of 99.9% by HPLC and >95% by NMR. XRPD: Standard A. Synthesis of Deuterated Mixtures of DMT Compounds

[00113] A modified synthesis in Stage 2 using solid LiAlH4 / LiAlD4 mixtures was adopted, using 1.8 equivalents of LiAlH4 / LiAlD4 versus 0.9 equivalents using the process described above for non-deuterated DMT.

[00114] Six deuteration reactions were performed. Petition 870260041061, dated 04 / 05 / 2026, pp. 53 / 71 43 / 50 Representative Synthesis of a Deuterated Mixture (using 1:1 LiAlH4:LiAlD4) of DMT Compounds

[00115] A 3-necked flask under N2 was loaded with LiAlH4 (1.013 g, 26.7 mmol), LiAlD4 (1.120 g, 26.7 mmol) and THF (100 ml). The resulting suspension was stirred for minutes before Stage 1 (6 g, 29.666 mmol) was loaded in portions over 15 minutes at 20-40°C. The reaction mixture was then heated to reflux (66°C) for hours, at which point HPLC indicated no remaining in Stage 1. The mixture was cooled to 0°C and quenched with 25% Rochelle salts (aq) (120 ml) for 30 minutes at <30°C. The resulting milky suspension was stirred for 1 hour and then allowed to separate. The lower aqueous layer was removed and the upper organic layer washed with saturated brine (30 ml). The organics were then dried over MgSO4, filtered, and concentrated in vacuo. This yielded 4.3 g of crude material. The crude product was then returned to ethanol (52 ml) and charged with fumaric acid (2.66 g, 22.917 mmol) before heating to 75°C.The resulting solution was left to cool to room temperature overnight before further cooling to 0-5 °C for 1 hour. The solids were isolated by filtration and washed with cold ethanol (6.5 ml x 2). The filtered cake was dried at 50 °C overnight to provide 5.7 g (yield = 63%) of product with a purity of 99.9% by HPLC and >95% by NMR. Evaluation of the Extent of Deuteration

[00116] This was achieved by LCMS-SIM Single Ion Monitoring (SIM), the analysis provided a separate ion count for each mass for the three Petition 870260041061, dated 04 / 05 / 2026, pp. 54 / 71 44 / 50 compounds of deuterated N,N-dimethyltryptamine (N,N-dimethyltryptamine (D0), α-deutero-N,N-dimethyltryptamine (D1) and α,α-dideutero-N,N-dimethyltryptamine (D2)) were collected at the retention time for N,N-dimethyltryptamine. The percentage of each component was then calculated from these ion counts.

[00117] For example, %D0 = [D0 / (D0 + D1 + D2)] x 100. HPLC parameters System: Agilent 1100 / 1200 series liquid chromatography or equivalent. Column: Triart Fenil; 150 x 4.6 mm particle size 3.0 μm (Ex: YMC, Number of parts: TPH12S03-1546PTH) Mobile Phase A: Water: Trifluoroacetic Acid (100:0.05%) Mobile Phase B: Acetonitrile: Trifluoroacetic Acid (100:0.05%) Gradient: Time %A %B 0 95 5 13 62 38 26 5 95 30.5 5 95 31 95 5 Flow Rate: 1.0 ml / Downtime: 31 minutes Running time: 4 minutes Injection volume: Wash bottle: 5 pl: N / A Column temperature: 30°C combined Wavelength: 200 nm (4 nm) Reference: N / A Mass Spectrometry Parameters System: Agilent 6100 Series Quadrupole LC-MS or equivalent Drying Gas Flow Rate: 12.0 l / min Petition 870260041061, dated 04 / 05 / 2026, pages 55 / 71 45 / 50 Drying gas temperature: 350°C Nebulizer Pressure: 35 psig Shredder: 110 Gain: 1.00 Cpd RT RRT Concent. Diluent Detection Mass D0 10.64 1.00 0.30 mg / ml CH3CN:H2O (50:50) (+) YES 189.1 0 m / z D1 10.64 1.00 0.30 mg / ml CH3CN:H2O (50:50) (+) YES 190.1 0 m / z D2 10.54 1.00 0.30 mg / ml CH3CN:H2O (50:50) (+) YES 191.1 0 m / z The MS-SIM range is the target mass ± 0.1 m / z The data for the six deuterated reactions are tabulated in Table 1 below: Mixture No. (LiAlH4:LiAlD4 Ratio) Input (Stage 1) Stage 3 Output (yield) Purity by HPLC Purity by NMR Deuteration % of D1 D2 1 (SPL026) (0:1) 5g 5.3g (65%) 99.7% >95% 0.7% 2.7% 96.6% 2 (1:1) 6g 5.699g (63%) 99.9% >95% 30.0% 48.3% 21.7% 3 (1:2) 5g 4.206g (52%) 99.9% >95% 16.5% 4 6.8% 36.8% 4 (1:3) 5g 5.558g (68%) 99.8% >95% 9.3% 41.5% 49.2% 5 (2:1) 5g 4.218g (52%) 99.9% >95% 47.5% 41.3% 11.2% Petition 870260041061, dated 04 / 05 / 2026, pp. 56 / 71 46 / 50 6 (3:1) 5g 5.0g (62%) 99.4% >95% 57.5 35.3% 7.4%

[0156] In vitro intrinsic clearance of DMT (SPL026) and 6 mixtures of deuterated compounds

[0157] Determining intrinsic clearance in vitro is a valuable model for predicting hepatic clearance in vivo. The liver is the primary organ for drug metabolism in the body, containing both phase I and phase II drug-metabolizing enzymes, which are present in the intact cell. Objective

[0158] To use human hepatocytes to evaluate the intrinsic clearance in vitro of a deuterated DMT analogue mixture relative to DMT. Experiment Description

[0159] Pooled human hepatocytes (mixed genera) from 10 donors (0.545 million cells / ml) were used to investigate intrinsic in vitro clearance of DMT and 6 deuterated analogues.

[0160] A concentration of 5 μM was used for all test compounds, as well as sumatriptan, serotonin, and benzylamine controls. This concentration was chosen to maximize the signal-to-noise ratio while keeping it below the Michaelis constant (Km) for the enzyme monoamine oxidase (MAO). Diltiazem and diclofenac controls were used at a laboratory-validated concentration of 1 μM.

[0161] The compounds were mixed with the hepatocyte suspension in a 96-well plate and incubated for Petition 870260041061, dated 04 / 05 / 2026, pages 57 / 71 47 / 50 to 60 minutes at 37 °C. The suspension was stirred continuously. At time point 7, small aliquots were withdrawn, and the concentration of the test compound / mixture was measured by LC-MS / MS. The time points measured were 2, 4, 8, 15, 30, 45 and 60 minutes. The following LC-MS / MS conditions were used for the analysis: Instrument: Thermo TSQ Quantitative with Thermo system Vanquish UPLC Column: Luna Omega 2.1x50 mm 2.6pm Solvent A: H2O + 0.1% formic acid Solvent B: Acetonitrile+ 0.1% formic acid Flow rate: 0.8 ml / min Injection Volume: 1 pl Column Temperature: 65°C Gradient: Time (minutes) Solvent B % 0.00 5.0 0.90 75.0 1.36 99.0 1.36 5.0 1.80 5.0 MS Parameters: Positive ion spray voltage: 4000 V Vaporizer temperature: 450°C Ion transfer tube temperature: 365°C Covering gas: 54 Petition 870260041061, dated 04 / 05 / 2026, pages 58 / 71 48 / 50 Auxiliary gas: 17 Sweeping gas: 1 Wait time: 8 ms MRM transitions: • D0 = mass-to-charge ratio 189.14 > 58.16. • D1 = mass-to-charge ratio 190.14 > 59.17. • D2 = mass-to-charge ratio 191.14 > 60.17.

[0162] MRM transitions were determined from a preliminary analysis of DMT samples that did not contain deuterium for the D0 transition), or high levels of D1 or D2 deuteration (for the D1 and D2 transitions respectively).

[0163] The resulting concentration-time profile was then used to calculate intrinsic clearance (CLint) and half-life (t½). To do this, the MS peak area or MS peak area / IS response of each analyte is plotted on a natural logarithmic scale on the y-axis versus sampling time (minutes) on the x-axis. The slope of this line is the elimination rate constant. This is converted to half-life by ln(2) / slope. Intrinsic clearance is calculated from the slope / elimination rate constant and the formula is CLint = (-1000*slope) / cell density 1E6 / ml, to give units of microliter / min / million cells. Results

[0164] Intrinsic clearance and half-life values ​​were calculated for DMT and the 6 deuterated mixtures described above. These data were weighted depending on the ratio of D0, D1 and D2 to give an overall intrinsic clearance and half-life value for each compound mixture (Table 2). Petition 870260041061, dated 04 / 05 / 2026, pp. 59 / 71 49 / 50 Table 2. In vitro intrinsic clearance and calculated half-life of DMT and 6 deuterated mixtures. Compound Name or Mixture Number (from Table 1) LiAlH4:LiAlD4 Input Ratio Do:Di:D2 Output Ratio Molecular Weight Intrinsic Clearance (pl / min / million cells) Half-life (min) DMT (SPL026) 1:0 100:0:0 188.269 13.77 92.39 1 0:1 0.7:2.7 96.6 190.240 7.15 178.79 2 1:1 30.0: 48.3: 21.7 189.192 10.46 125.80 3 1:2 16.5: 46.8: 36.8 189.669 9.36 140.43 4 1:3 9.3: 41.5: 49.2 189,676 11,14 116,84 5 2:1 47.5: 41.3: 11.2 188,910 10,99 119,61 6 3:1 57.4: 35.3: 7.4 188,961 13,64 95,04

[0165] The data were fitted with a linear model using regression analysis, which revealed that deuterium enrichment in the α-carbon of DMT decreased intrinsic clearance linearly with increasing molecular weight (MW), therefore Petition 870260041061, dated 04 / 05 / 2026, pages 60 / 71 50 / 50 allowing the manufacture of DMT drug substances with half-lives that can be accurately predicted within the identified range.

[0166] Mixture 1, which contains 96.6% D2-DMT, showed the greatest change, with the intrinsic clearance rate nearly halved compared to non-deuterated DMT (Figure 3), and the half-life nearly doubling (Figure 2). The intermediate deuteration mixtures (Mixtures 2 to 5) decreased intrinsic clearance in a manner correlated with molecular weight (Figure 3). Conclusion

[0167] These data demonstrate that increasing the deuterium enrichment at the α-carbon of DMT increases metabolic stability, leading to a decrease in clearance and a longer half-life. There is a linear relationship between MW and half-life, particularly when the reducing agent used to produce the deuterium-containing drug substance enriched with DMT by methods of the present invention comprises LiAlH4 and LiAlD4 in a ratio between 1:2.5 and 2.5:1. Petition 870260041061, dated 04 / 05 / 2026, pages 61 / 71

Claims

1 / 3 CLAIMS 1. Use of a composition comprising: (a) a compound of α,α-dideutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; (b) a compound of α-protio-α-deutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; and (c) N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; wherein the composition comprises 50% or more by weight of the compound of α,α-dideutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and of the compound of α-protio-α-deutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; characterized in that it is for the manufacture of a medicament for the treatment of a psychocognitive disorder in a patient.

2. Use according to claim 1, characterized in that the composition consists essentially of: (a) α,α-dideutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; (b) α-protio, α-deutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; and (c) N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof; wherein the average molecular weight of α-protio, α-deutero-N,N-dimethyltryptamine, α,α-dideutero-N,N-dimethyltryptamine and N,N-dimethyltryptamine, present in the composition, is from 188.90 to 190.

28.

3. Use according to claim 1 or claim 2, characterized in that the composition comprises 60% or more by weight of the compound α,α-dideutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof, and the compound αprotio,α-deutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof. Petition 870260041061, dated 04 / 05 / 2026, pp. 62 / 71 2 / 3 4. Use according to any one of claims 1 to 3, characterized in that the compound α,α-dideutero-N,N-dimethyltryptamine is α,α-dideutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

5. Use according to any one of claims 1, 3 and 4, characterized in that the composition comprises an α-protio, α-deutero-N,N-dimethyltryptamine compound selected from the group consisting of α,β,β-trideutero-N,N-dimethyltryptamine, α,β-dideutero-N,N-dimethyltryptamine and α-protio, α-deutero-N,N-dimethyltryptamine, and pharmaceutically acceptable salts thereof.

6. Use in accordance with any one of claims 1 to 5, characterized in that the composition comprises α-protio, α-deutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

7. Use in accordance with any of claims 1 to 6, characterized in that the compositions have a purity greater than or equal to 99% by HPLC, preferably a purity greater than or equal to 99.9% by HPLC.

8. Use according to any one of claims 1 to 7, characterized in that the compounds α-protio, α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine, and N,N-dimethyltryptamine, are in the form of a pharmaceutically acceptable salt, preferably in that the pharmaceutically acceptable salt is a fumarate salt.

9. Use according to any one of claims 1 to 7, characterized in that the compounds α-protio, α-deutero-N,N-dimethyltryptamine and α,α-dideutero-N,N-dimethyltryptamine, and N,N-dimethyltryptamine, are in the form of a fumarate salt.

10. Use in accordance with any of claims 1 to 9, characterized in that the composition comprises 60% or more by weight of the compound α,α-dideutero-N,N-dimethyltryptamine, or a pharmaceutically acceptable salt thereof.

11. Use according to claim 1, characterized in that the psychocognitive disorder is selected from the group consisting of (i) obsessive-compulsive disorder, (ii) depressive disorder, (iii) anxiety disorder, (iv) substance abuse and (v) avolition disorder.

12. Use according to claim 11, characterized in that the disorder is selected from the group consisting of treatment-resistant depression, major depressive disorder, persistent depressive disorder, bipolar disorder, bipolar depression, terminal depression, generalized anxiety disorder, phobia, panic disorder, social anxiety disorder, and post-traumatic stress disorder.

13. Use according to claim 11, characterized in that the disorder is selected from the group consisting of treatment-resistant depression, major depressive disorder, and generalized anxiety disorder. Petition 870260041061, dated 04 / 05 / 2026, pp. 64 / 71

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