Antioxidant salts of psilocin

Abstract

The present application provides a compound having improved stability against oxidation, compared to psilocin and previously known psilocin salts, and having sufficient biological activity to enable a therapeutic effect. The compound of the present application is a salt of psilocin wherein the salt comprises, as the counterion, a carboxylate-containing compound of Formula (I) Also provided are compositions of the psilocin salt and methods of use thereof in the treatment of a disease or condition, or treating one or more symptoms of the disease or condition, by administering the salt of psilocin, wherein the disease or condition is a neurological injury, a neurodegenerative disease, an inflammatory condition, chronic pain, or a psychological condition.

Description

ANTIOXIDANT SALTS OF PSILOCINCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims priority to U.S. Provisional Application No. 63 / 779,545, filed March 28, 2025, the contents of which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION

[0002] The present application pertains to the field of psilocin salts. More particularly, the present application relates to pharmaceutically acceptable, antioxidant salts of psilocin and methods of manufacture and therapeutic uses thereof.BACKGROUND

[0003] Psilocin (4-hydroxy-N,N-dimethyltryptamine) is a psychoactive compound which is naturally-occurring, and can be isolated from psilocybin mushrooms. Psilocybin is a phosphate ester of psilocin and is also found in psilocybin mushrooms. Psilocybin is rapidly dephosphorylated in vivo, to form psilocin, which is the psychoactive compound. Research into the therapeutic benefits of psilocybin and its active metabolite, psilocin, has led to the use of these psychoactives for the treatment of a variety of conditions including drug dependence, anxiety, depression, PTSD, eating disorders, and chronic pain.

[0004] Both psilocin and psilocybin have limited stability in aqueous solutions and such solutions rapidly degrade on exposure to light. Moreover, the active agent, psilocin, has a relatively low solubility in aqueous media, which limits its ability to be used in, for example a dosage form suitable for intravenous or subcutaneous injection.

[0005] Classic psychedelics, which are serotonergic hallucinogens, like psilocin, have been shown in multiple lines of research to potentially induce therapeutic changes in people with a variety of psychiatric conditions. However, naturally occurring psilocin is only found in relatively small amounts in the psilocybin mushrooms (Tyls et al. EuropeanNeuropsychopharmacology 201424 (3): 342-356). For this reason and because of the relative instability of psilocin, most research has focused on the prodrug, psilocybin.

[0006] Published studies have shown psilocin exposure (through psilocybin administration) to result in significant improvement in symptoms of anxiety, depression, and substance use disorders. Further, psilocin's clinical safety has been extensively studied in adult populations, both as a single agent and as a component of an adjunctive treatment. Psilocin is most commonly administered as psilocybin capsules through oral administration and has been assessed in open-label and double-blind, controlled trials. Dosing regimens for psilocybin have ranged from 0.014 mg / kg to 0.6 mg / kg (which roughly correspond to dose ranges of 7 pg / kg - .32 mg / kg of psilocin based on estimated dose-normalized bioavailability of 52.7% from (F. Hasler et al. Pharmaceutica Acta Helvetiae 199772(3), 175-184), administered either as a single dose, or multiple escalating doses weeks apart.

[0007] U.S. Patent No. 11,312,684 discloses psilocin benzoate and psilocin succinate salts to be preferred salt forms for producing a pharmaceutical composition with superior shelf- life stability, and resistance to oxidative degradation. Stability for up to three weeks is disclosed for some of their salts.

[0008] U.S. Patent No. 12,102,616 discloses psilocin mucate salt as a form of psilocin that is stable and potentially provides anti-anxiolytic effects, without hallucinogenic effects, following administration.

[0009] There remains a need for alternative psilocin salts, esters and conjugates and formulations thereof with improved stability, in particular, with resistance to oxidative degradation, as compared to psilocin.

[0010] The above information is provided for the purpose of making known information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should be construed, that any of the preceding information constitutes prior art against the present invention.SUMMARY OF THE INVENTION

[0011] An object of the present application is to provide salts of psilocin prepared with acids that are known to have antioxidant properties, and compositions and uses thereof. It is an aim of the present application, amongst others, to provide a compound, composition, use and method that addresses at least one disadvantage of the prior art, whether identified here or elsewhere, or to provide an alternative to existing compounds, compositions, uses or methods. For instance, it may be an aim of the present application to provide a compound, or class of compounds, having improved stability against oxidation compared to psilocin and previously known salts, and having sufficient biological activity to enable a therapeutic effect.

[0012] In accordance with an aspect of the present application, there is provided a salt of psilocin wherein the salt comprises, as the counterion, a carboxylate-containing compound of Formula IO'Rwherein:each of R1, R2, and R3is independently H, OH, methyl, t-butyl, or OCH3, wherein at least one of R1, R2, and R3is OH,each of R4and R5is H or methyl,A is absent, CH=CH, CH2-CH2, or CH2.

[0013] In one embodiment, the psilocin salt includes a counterion of formula I that includes at least one hydroxyl having an O-H bond dissociation energy (BDE) of less than 90 Kcal / mol or in the range of from about 75 kcal / mol to about 90 kcal / mol. In some examples,the counterion of formula I includes at least one hydroxyl having an O-H BDE in the range of 75-85 kcal / mol.

[0014] In one embodiment, there is provided a salt of psilocin wherein the salt comprises, as the counterion, a carboxylate-containing compound of Formula lawherein each of R1, R2, R3, R4, and R5are defined as above in relation to the counterion of Formula I. For example, the carboxylate-containing counterion compound can be:In a preferred embodiment, the carboxylate-containing counterion is syringate.

[0015] In some embodiments there is provided a salt of psilocin wherein the salt comprises, as the counterion, a carboxylate-containing compound of Formula lbwherein each of R1, R2, R3, R4, and R5are defined as above in relation to the counterion of Formula I. For example, the carboxylate-containing counterion compound can be:In a preferred embodiment, the carboxylate-containing counterion is isoferulate or caffeate.

[0016] In some embodiments there is provided a salt of psilocin wherein the salt comprises, as the counterion, a carboxylate-containing compound of Formula IcIcwherein each of R1, R2, R3, R4, and R5are defined as above in relation to the counterion of Formula I. For example, the carboxylate-containing counterion compound can be:

[0017] In some embodiments there is provided a salt of psilocin wherein the salt comprises, as the counterion, a carboxylate-containing compound of Formula Idwherein each of R1, R2, R3, R4, and R5are defined as above in relation to the counterion of Formula I. For example, the carboxylate-containing counterion compound can be:In some embodiments, the compound provides a dual therapeutic effect based on therapeutic properties of psilocin and therapeutic properties of the counterion.

[0018] In another aspect of the present application, there is provided a pharmaceutical composition comprising the salt of psilocin, as described herein, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable additive or excipient selected from the group consisting of antioxidants, preservatives, buffering agents, fillers, binders, sweetening agents, colouring agents, chelating agents, disintegrants, coating agents, anti-adherents, lubricants, glidants, surface acting agents, humectants, viscosity imparting agents, diluents and cosolvents. In some embodiments, the composition comprises at least one antioxidant agent that is ascorbate, pyruvate, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), calcium stearate, citrate, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate, vitamin E (a-tocopherol), resveratrol, sodium edetate, or a combination of two or more thereof. The pharmaceutical composition can be useful in the treatment of a disease or condition in a subject in need thereof, wherein the disease or condition is a neurological injury, a neurodegenerative disease, an inflammatory condition, chronic pain, or a psychological condition, or in the treatment of one or more symptoms of the disease or condition.

[0019] In accordance with another aspect of the present application, there is provided a method of treating a disease or condition in a subject in need thereof, or treating one or more symptoms of the disease or condition, the method comprising administering to the subject the salt of psilocin as described herein, or a pharmaceutical composition comprising the salt of psilocin, wherein the salt of psilocin is administered in an amount sufficient to treat the disease or condition, wherein the disease or condition is a neurological injury, a neurodegenerative disease, an inflammatory condition, chronic pain, or a psychological condition.DETAILED DESCRIPTION

[0020] Definitions

[0021] Unless defined otherwise, 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 invention belongs.

[0022] As used in the specification and claims, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0023] The term "comprising", as used herein, will be understood to mean that the list following is non-exhaustive and may or may not include any other additional suitable items, for example one or more further feature(s), component(s) and / or ingredient(s) as appropriate.

[0024] Reference throughout this specification to "one embodiment," "an embodiment," "another embodiment," "a particular embodiment," "a related embodiment," "a certain embodiment," "an additional embodiment," or "a further embodiment" or combinations thereof means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the foregoing phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0025] The term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B", "A or B", "A", and "B".

[0026] "Compound" as the term is used herein, refers to and encompasses the chemical compound itself, either named or represented by structure, and salt form(s) thereof, whether explicitly stated or not, unless context makes clear that such salt forms are to be excluded. The term "compound" further encompasses solvate forms of the compound, in which solvent is noncovalently associated with the compound or is reversibly associated covalently with the compound, as when a carbonyl group of the compound is hydrated to form a gem-diol. Solvate forms include those of the compound itself and its salt form(s) and are inclusive of hemisolvates, monosolvates, disolvates, including hydrates; and when a compound can be associated with two or more solvent molecules, the two or more solvent molecules may be the same or different.

[0027] In some instances, a compound of the invention will include an explicit reference to one or more of the above forms, e.g., salts and solvates, which does not implyany solid state form of the compound; however, this reference is for emphasis only, and is not to be construed as excluding any other of the forms as identified above. Furthermore, when explicit reference to a salt and / or solvate form of a compound is not made, that omission is not to be construed as excluding the salt and / or solvate form(s) of the compound unless the context makes clear that such salt and / or solvate forms are to be excluded.

[0028] The phrase "salt thereof" as the phrase is used herein, refers to a salt form of a compound. A salt form of a compound is of one or more internal salt forms and / or involves the inclusion of a counterion. The counterion in a salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge on the parent compound. A salt form of a compound has one or more than one charged atom in its structure. In instances where multiple charged atoms are part of the salt form, multiple counter ions and / or multiple charged counter ions may be present. Hence, a salt form of a compound typically has one or more charged atoms corresponding to those of the non-salt form of the compound and one or more counterions. In some aspects, the non-salt form of a compound contains at least one amino group or other basic moiety, and accordingly in the presence of an acid, an acid addition salt with the basic moiety is obtained.

[0029] As used herein, the phrase, "pharmaceutically acceptable salt", denotes any pharmaceutically acceptable salt of such compound, or any other adduct or derivative which, upon administration to a patient, is capable of providing (directly or indirectly) a compound as otherwise described herein, or a metabolite or residue thereof.

[0030] A pharmaceutically acceptable salt is a salt form of a compound that is suitable for administration to a subject as described herein.

[0031] The term "stable", as used herein to reference compounds, refers to compounds that possess stability sufficient to allow manufacture and that maintain the integrity for a sufficient period of time to be detected and preferably for a sufficient period of time to be useful for the therapeutic purposes detailed herein. The term "oxidative stability", as used herein, refers to a compound's resistance to degradation, breakdown or loss of therapeutic activity due to oxidation.

[0032] The term "bond dissociation energy" or "BDE", as used herein, refers to a measure of the strength of a chemical bond, defined as the standard enthalpy change when a bond is cleaved by homolysis to give radical species. In the context of the present application, BDE refers particularly to the O-H bond dissociation energy of phenolic hydroxyl groups in the counterions of Formula I.

[0033] The term "antioxidant", as used herein, refers to a substance that inhibits or prevents oxidation, particularly the oxidation of other molecules. In the context of the present application, an antioxidant counterion is a counterion comprising at least one phenolic hydroxyl group.

[0034] The terms "treating", "treatment" and "therapy" are used herein to refer to curative therapy, prophylactic therapy, palliative therapy and preventative therapy. Thus, in the context of the present disclosure the term "treating" encompasses curing, ameliorating or tempering the severity of a medical condition or one or more of its associated symptoms.

[0035] The terms "therapeutically effective amount" or "pharmacologically effective amount" or "effective amount" refer to an amount of an agent sufficient to produce a desired therapeutic or pharmacological effect in the subject being treated. The terms are synonymous and are intended to qualify the amount of each agent that will achieve the goal of improvement in disease severity and / or the frequency of incidence over treatment of each agent by itself while preferably avoiding or minimising adverse side effects, including side effects typically associated with other therapies. Those skilled in the art can determine an effective dose using information and routine methods known in the art.

[0036] A "pharmaceutical carrier, diluent or excipient" includes, but is not limited to, any physiological buffered (i.e., about pH 6.0 to 7.4) medium comprising a suitable water-soluble organic carrier, conventional solvents, dispersion media, fillers, solid carriers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents.Suitable water-soluble organic carriers include, but are not limited to, saline, dextrose, corn oil, dimethylsulfoxide, and gelatin capsules. Other conventional additives include lactose, mannitol, corn starch, potato starch, binders such as microcrystalline cellulose, cellulosederivatives such as hydroxypropylmethylcellulose, acacia, gelatins, disintegrators such as sodium carboxymethylcellulose, and lubricants such as talc or magnesium stearate.

[0037] "Subject" includes any human or non-human mammal. Thus, in addition to being useful for human treatment, the compounds of the present invention may also be useful for veterinary treatment of mammals, including companion animals and farm animals, such as, but not limited to dogs, cats, horses, cows, sheep, and pigs. In preferred embodiments the subject is a human.

[0038] In the context of this specification the term "administering" and variations of that term including "administer" and "administration", includes contacting, applying, delivering or providing a compound or composition of the invention to a subject by any appropriate means.

[0039] The present application is directed to antioxidant salts of psilocin in which the counterion is selected based on its antioxidant properties. The psilocin salt of the present application comprises as the counterion, a carboxylate-containing compound of Formula Iwherein:each of R1, R2, and R3is independently H, OH, methyl, t-butyl, or OCH3, wherein at least one of R1, R2, and R3is OH,each of R4and R5is H or methyl, andA is absent, CH=CH, CH2-CH2, or CH2.

[0040] As described above, U.S. Patent No. 11,312,684 discloses psilocin benzoate and suggests that it is useful in preparing a pharmaceutical composition with superior shelf-life stability and resistance to oxidative degradation in comparison to the free-base form of psilocin. However, while the stability of the psilocin benzoate compositions disclosed in U.S.11,312,684 was improved over compositions of the free-base form of psilocin, oxidative degradation was still observed, as illustrated, for example, by the colour changes of buffered solutions over time (Example 1 of U.S. 11,312,684).

[0041] The present inventor has surprisingly identified a subset of counterions that provide oxidative stability to psilocin salts thereof. The counterions are derived from benzoic acid derivatives having the following structure of Formula I:wherein:each of R1, R2, and R3is independently H, OH, methyl, t-butyl, or OCH3, wherein at least one of R1, R2, and R3is OH,each of R4and R5is H or methyl, andA is absent, CH=CH, CH2-CH2, or CH2.

[0042] These counterions are characterised by low O-H bond dissociation energies, as determined by density functional theory (DFT) based methods (e.g., J.S. Wright et al., J. Am. Chem. Soc. 1997, 119, 18, 4245-4252) and the antioxidant activities of the corresponding acids. Preferably, the counterions are derived from known natural product acids. Most are sold commercially, alone or as part of mixtures in natural health products. These counterions are further selected to have no or minimal toxicity, such that their inclusion in a pharmaceutical composition, at the concentrations required for therapeutic effect of the psilocin, would not cause toxicity issues in the subject to which the composition is administered.

[0043] Counterions of Formula I include at least one hydroxyl group, either para or meta to the carboxylate-containing group. These counterions have been found to provide improved oxidative stability over benzoate as the counterion in a psilocin salt, due to the presence of at least one phenolic O-H bond having a low (i.e., less than 90 Kcal / mol) bond dissociation energy.

[0044] The bond-dissociation energy (BDE), is a measure of the strength of a chemical bond A-B. It can be defined as the standard enthalpy change when A-B is cleaved by homolysis to give fragments A and B, which are usually radical species. The BDE of a particular bond type is affected by the chemical context of the bond within a molecule -different moieties positioned nearby on the molecule will have differing effects on the BDE of a particular bond. For example, the BDE of the O-H bond in water and phenol are 111 kcal / mol and 89 kcal / mol, respectively. The lower O-H BDE in phenol relative to water or typical aliphatic alcohols is due to resonance stabilization of the phenoxy radical.Substituents in a phenol affect the O-H BDE via resonance, electronic, and hydrogen bonding effects as shown below.

[0045] The counterions of Formula I are characterized by at least one O-H group having a bond dissociation energy (BDE) of less than 90 Kcal / mol. In some embodiments, the counterions of Formula I have at least one OH group having a BDE in the 75-90 kcal / mol range, or the 75-85 kcal / mol range. Ions having the lowest BDEs have the highest antioxidant properties. The BDE values disclosed in the table above are representative of the counterions within Formula I and can be used by one of ordinary skill in the art to predict the relative antioxidant activity of any counterion falling within Formula I. BDE values for counterions not expressly listed can be calculated using DFT-based methods as described in J.S. Wright et al., J. Am. Chem. Soc. 1997, 119, 18, 4245-4252, or estimated based on the known effects of substituents on phenolic O-H BDE as described herein.

[0046] In some embodiments, the counterion of Formula I comprises a hydroxyl group at the para or meta, but not ortho, position to the carboxylate-containing group, which provides increased antioxidant activity over counterions having a hydroxyl group at a meta position.

[0047] In another embodiment, the counterion of Formula I comprises a hydroxyl group at the para position and a second hydroxyl in one of the meta positions. The presence of the second hydroxyl group increases significantly the antioxidant activity (and lowering of the BDE). This arrangement is particularly favorable and lowers the BDE of the phenolic O-H bond by 9.2 Kcal / mol compared to a hydrogen.

[0048] The presence of a methyl group, and to a lesser extent a methoxy group, adjacent to a hydroxyl group in the counterion of Formula I (i.e., bound to a carbon in the phenyl ring that is next to the carbon in the ring that is bound to the hydroxyl group) also lowers the BDE of the phenolic O-H bond, thereby increasing the antioxidant potency and oxidative stability of the salt. Accordingly, in some embodiments, the counterion of Formula I comprises a methyl or methoxy group adjacent to the phenolic O-H either meta or para to the carboxylate. In contrast, the phenolic O-H BDE is higherthan in phenol itself if the carboxylic acid is ortho to it, as in salicylic acid. The calculated BDEs for a variety of phenolic compounds claimed are shown below:Calculated Phenolic O-H Bond Dissociation Energies in selected antioxidant acids87.1 + 8.1 87.1 + 2.5 87.1 + 2.6 = 95.2 = 89.787.1 + 2.6 - 9.2 87.1 + 2.6-.2.0 87.1 + 2.6 -1.4 87.1 + 2.5 -1.4 = 80.5 =87.7 = 89.3 = 89.287.1 + 2.6 - 9.2 - 9.287-1+ 2.6 -1.4-1.4 87.1 + 2.6 - 2.0 - 2.0 = 72.3 =87 5= 85.787.1 + 2.6 87.1 - 2.0 87.1 - 4.0 = 89.7 = 85.1 = 83.1

[0049] In some embodiments, the carboxylate-containing compound has the structure of Formula la:la

[0050] In non-limited examples of this embodiment, the carboxylate-containing counterion is:

[0051] In other embodiments, the carboxylate-containing compound has the structure of Formula lb:R2lb

[0052] In non-limited examples of this embodiment, the carboxylate-containing counterion is:

[0053] In other embodiments, the carboxylate-containing compound has the structure of Formula Ic:Ic

[0054] In non-limited examples of this embodiment, the carboxylate-containing counterion is:

[0055] In other embodiments, the carboxylate-containing compound has the structure of Formula Id:

[0056] In non-limited examples of this embodiment, the carboxylate-containing counterion is:

[0057] In some embodiments the counterion additionally provides beneficial health effects in addition to those of psilocin. For example, in addition to their antioxidant effect, the following compounds provide additional therapeutic benefits including, but not limited to those indicated below:- caffeic acid and caffeate have anti-inflammatory, and anti-cancer properties;- ferulic acid and ferulate are known to neutralize free radicals, reduce inflammation, reverse signs of aging and have been used in traditional Chinese medicine for treatment of cardiovascular and cerebrovascular diseases and to prevent thrombosis;- isoferulic acid and isoferulate have antidiabetic and antiglycation activities, as well as anti-inflammatory, anti-diabetic, anti-viral, and anticancer properties; and- syringic acid and syringate are reported to provide a therapeutic benefit in treating diabetes, cardiovascular diseases, and inhibiting cancer cell proliferation.Accordingly, selection of the counterion can be made, in part, based on their additional therapeutic effect. The present disclosure therefore provides antioxidant salts of psilocin having dual therapeutic effect based on the therapeutic properties of psilocin and the therapeutic properties of the counterion.

[0058] In some embodiments, the salts of psilocin described herein provide enhanced physical properties, such as solubility, dissolution rate, bioavailability, physical stability, chemical stability, flowability, fractability, or compressibility, in addition to improved oxidative stability, over psilocin in its free-base form. The psilocin salts described herein may be in a crystalline form.

[0059] In some embodiments, the psilocin may be in a co-crystalline form with one or more different counterions of Formula I, or with a counterion of Formula I and one or more different counterions selected from any pharmaceutically acceptable salt known in the art. Some of these co-crystals exhibit enhanced solubility or stability.

[0060] In an alternative embodiment, the psilocin salts described herein may be in an amorphous form or mixtures thereof (e.g., mixtures of crystal forms, or mixtures of crystal and amorphous forms).

[0061] Also provided are methods for synthesis of the present psilocin salts comprising combining psilocin with an acid form of the carboxylate counterion of Formula I, in a suitable solvent or solvent mixture. The salt precipitates spontaneously from the mixture or upon cooling of the mixture. It has been surprisingly found that the psilocin salts described herein can be prepared with excellent efficiency. In some embodiments, the psilocin salts are facilely prepared with above 80% yield, and in some instances a yield of about 95%. A variety of solvents, including but not limited to tetrahydrofuran (THF), acetone, ethyl acetate and dichloromethane, are suitable for use in the salt forming reaction. Without wishing to be bound by theory, the general applicability of this synthetic method to counterions of Formula I is believed to arise from the similar pKa values and structural characteristics shared by the carboxylic acid moiety common to all Formula I counterions, which enables consistent salt formation with the basic dimethylamine group of psilocin under the disclosed reaction conditions. The Examples below demonstrate successful salt formation across the full range of structural variations within Formula I, including counterions with different A groups (absent, CH=CH, CH2-CH2, and CH2) and various R-group substitution patterns. One of ordinary skill in the art, guided by the general methods and specific examples disclosed herein, could readily prepare any psilocin salt encompassed by Formula I without undue experimentation.

[0062] In a particular embodiment for preparing the psilocin salts of Formula I, the synthesis is carried out by dissolving psilocin in THF or ethyl acetate, adding a solution of the carboxylic acid counterion in the same or a compatible solvent, and cooling the mixture to approximately -10°C to induce crystallization. This method represents a method for preparing high-purity crystalline salts in good yield. The reaction can be scaled and adapted by one of ordinary skill in the art using routine optimization of solvent volumes, concentrations, and crystallization temperatures.

[0063] Pharmaceutical Compositions

[0064] In another embodiment, the present application provides a pharmaceutical composition comprising the psilocin salts as described herein. The compositions described herein can be formulated for administration, for example, oral, subcutaneous, intravenous, or intramuscular administration using techniques well known in the pharmaceutical arts. In particular embodiments, the pharmaceutical composition is formulated for intravenous administration. One of ordinary skill in the art, using standard pharmaceutical formulation techniques and the guidance provided herein regarding compatible excipients and antioxidants, could readily prepare pharmaceutical compositions comprising any of the psilocin salts of Formula I for any of the disclosed routes of administration without undue experimentation.

[0065] The psilocin salt compositions described herein can comprise a pharmaceutically effective amount of the psilocin salt, in association with one or more pharmaceutically acceptable excipients including carriers, vehicles and diluents. The term "excipient" herein means any substance, not itself a therapeutic agent, used as a diluent, adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a solution for oral, parenteral, intradermal, subcutaneous, or topical application. Excipients can include, by way of illustration and not limitation, diluents, wetting agents, polymers, lubricants, stabilizers, and substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Acceptable excipients include (but are not limited to) stearic acid, magnesium stearate, sodium and calcium salts of phosphoric and sulfuricacids, magnesium carbonate, dextrin, mannitol, sorbitol, lactose, sucrose, starches, gelatin, polymers such as polyvinyl-pyrrolidone, polyvinyl alcohol, and polyethylene glycols, and other pharmaceutically acceptable materials. Examples of excipients and their use is described in Remington's Pharmaceutical Sciences, 20th Edition (Lippincott Williams & Wilkins, 2000). The choice of excipient will, to a large extent, depend on factors such as the mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0066] In some embodiments the psilocin salts provided herein have greater aqueous solubility (solubility in water or saline) than the psilocin free-base form. The improved aqueous solubility of the salt forms relative to free-base psilocin is a well-understood consequence of ionic character and is expected to apply generally to all salts of Formula I, enabling formulation into injectable compositions. The salt forms also provide improved handling characteristics and more precise dosing compared to free-base psilocin.

[0067] The psilocin salts provided herein have improved stability, including oxidative stability, either in solid form or in solution (water or saline) compared to psilocin free-base in solution. In some embodiments the psilocin salts described herein are stable for at least one day, one week, two weeks, one month, two months, three months, four months, five months, six months or at least one year during storage under ambient conditions.

[0068] The improved oxidative stability observed for the psilocin salts of Formula I is believed to be generally applicable across all counterions meeting the structural requirements of Formula I due to the presence of at least one phenolic hydroxyl group having a low O-H bond dissociation energy. Without wishing to be bound by theory, this phenolic hydroxyl group acts as a hydrogen atom donor that can neutralize reactive oxygen species and free radicals before they can oxidize the indole ring of psilocin. The stability data presented in Example 15, demonstrating stability for periods ranging from four months to two years for representative salts spanning different structural classes within Formula I, provides support for the general stability benefits of the claimed compounds. One of ordinary skill in the art having regard to this data, would recognize that other counterions within Formula I having similar or lower O-H BDE values would exhibit comparable or superior oxidative stability.

[0069] While the psilocin salts described herein have improved stability compared to the psilocin free-base form, it is contemplated that the stability can be further improved by formulating the psilocin salts of the present application with one or more excipients to reduce the effects of oxidation. For example, the psilocin salt can be formulated with ascorbate, pyruvate, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), calcium stearate, citrate, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate, vitamin E (a-tocopherol), resveratrol, sodium edetate, or a combination of two or more thereof.

[0070] Pharmaceutical Use

[0071] The present application further provides a psilocin salt as described herein, or a pharmaceutical composition comprising a psilocin salt as described herein, for use in treatment of a disease or condition in a subject in need thereof. For example, the psilocin salt or composition thereof can be used to treat a neurological injury, a neurodegenerative disease, diabetes (for example, diabetes associated with obesity), an inflammatory condition, pain (for example, nociplastic pain or neuropathic pain) including chronic pain, or a psychological condition. The neurological injury can be, for example, a stroke, a traumatic brain injury, or a spinal cord injury. The neurodegenerative disease can be, for example, Alzheimer's disease, Huntington's disease, or Parkinson's disease. The inflammatory condition can be, for example, lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn's disease, multiple sclerosis, septicemia, chronic obstructive pulmonary disease (COPD), or Alzheimer's disease. The chronic pain can be, for example, chronic pain from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, sciatica, or episodic or chronic trigeminal autonomic cephalalgia (e.g., episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), or short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)). The psychological condition can be, for example, post -traumatic stress, attention deficit hyperactivity disorder, anxiety, addiction, depression, compulsion, IBS (irritable bowel syndrome), fibromyalgia, CRPS (complex regional pain syndrome), phantom limb, an eating disorder or compulsive behavior.

[0072] The therapeutic utility of the psilocin salts of the present application for the treatment of the diseases and conditions disclosed herein is supported by extensive published literature demonstrating the efficacy of psilocin (typically administered as the prodrug psilocybin) in treating psychiatric and neurological conditions. See, e.g., Tyls et al., European Neuropsychopharmacology 2014, 24(3): 342-356; Griffiths et al., Journal of Psychopharmacology 2016, 30(12): 1181-1197; and Carhart-Harris et al., Lancet Psychiatry 2016, 3(7): 619-627. Without wishing to be bound by theory, psilocin exerts its therapeutic effects primarily through agonism at serotonin 5-HT2A receptors, which mediates both its psychedelic effects and its neuroplasticity-promoting properties relevant to treating depression, anxiety, and addiction. Since the psilocin salts of the present application liberate psilocin upon administration and dissolution, and one of ordinary skill in the art would understand that the antioxidant counterion does not interfere with the pharmacological activity of psilocin, the therapeutic efficacy established for psilocin extends to the salts disclosed herein.

[0073] While specific in vivo efficacy data is not presented herein for each disease and condition recited, one of ordinary skill in the art would readily appreciate that the psilocin salts of the present application, upon administration, will dissociate to release psilocin, which will exhibit the same pharmacological activity as psilocin administered by other means. The selection of the antioxidant counterion provides improved stability for manufacturing, storage, and formulation purposes, but does not alter the fundamental therapeutic mechanism of psilocin. For counterions having independent therapeutic properties (e.g., caffeic acid's anti-inflammatory effects, ferulic acid's neuroprotective effects), a dual therapeutic benefit may be achieved, although such additional benefits are not required forthe therapeutic utility of the claimed compositions.

[0074] In some embodiments, the present application provides a method of treating or preventing a disease or condition in a subject comprising administering to the subject the psilocin salt orthe pharmaceutical composition, as described herein.

[0075] In some embodiments, the present application provides use of the psilocin salt or pharmaceutical composition, as described herein, in the manufacture of amedicament for treating or preventing a disease or condition, such as those described above.

[0076] In some embodiments, the present application provides the psilocin salt or the pharmaceutical composition, as described herein, for use in treating or preventing a disease or condition in a subject.

[0077] The dosage of psilocin salt administered can be determined by one of ordinary skill in the art based on known dosing regimens for psilocybin (the prodrug of psilocin) in clinical studies, adjusted as appropriate for the molecular weight of the salt form. As disclosed in the Background, dosing regimens for psilocybin have ranged from 0.014 mg / kg to 0.6 mg / kg, corresponding approximately to psilocin doses of 7 pg / kg to 0.32 mg / kg based on bioavailability conversion. One of ordinary skill in the art could, without undue experimentation, determine appropriate therapeutic doses for the psilocin salts of the present application for any of the disclosed indications using routine dose-finding methodologies known in the art.

[0078] To gain a better understanding of the invention described herein, the following examples are set forth. It should be understood that these examples are for illustrative purposes only. Therefore, they should not limit the scope of this invention in any way.

[0079] The following examples are intended to illustrate the general applicability of the synthetic methods to counterions representing the full structural diversity of Formula I, including counterions where A is absent (Examples 5-9, 12, 14), where A is CH=CH (Examples 1-4), where A is CH2-CH2 (Example 11), and where A is CH2 (Examples 10 and 13). The examples further demonstrate salt formation with counterions having various R-group substitution patterns, including mono-hydroxyl, di-hydroxyl, and tri-hydroxyl substituted counterions, as well as counterions bearing methyl, methoxy, and t-butyl substituents. Together, these examples enable one of ordinary skill in the art to prepare any salt encompassed by the claims without undue experimentation.EXAMPLES

[0080] EXAMPLE 1: 3-Methoxy-4-hydroxycinnamic acid (ferulic acid) salt of psilocinC22H26N2O5: MW = 398

[0081] a) Ferulic, (175 mg), acid dissolved in 4 mL of acetone was added to a solution of 180 mg of psilocin dissolved in 3 ml of acetone. The solution was cooled for 1 h at -10°C and then filtered to yield 192 mg (56%) of a white powder. Melting point 161-162°C.

[0082] b) Ferulic acid 196 mg dissolved in 3 mL of THF was added to 5 mL of THF containing 204 mg of psilocin. The solution was cooled to -10°C for one hour. No precipitate was observed. The solvent was removed under vacuum and residue was taken up in 10 mL of acetone, cooled to -10°C for 1 h, and then filtered to yield 207 mg (54%) of a white powder, mp. 160-161°C.

[0083] XH NMR (400 MHz, in acetone-d6). 6: 7.57 (d, J= 15.6 Hz, 1H), 7.31 ( d, J = 2.0 Hz, 1H, 7.11 (dd, J = 8.4, 2.0 Hz, 1H) 6.96 (s, 1H) 6.86 (t, J = 7.8 Hz, 1H) 6.80 (dd, J = 8.4, 0.4 Hz, 1H) 6.38 (d, J = 16Hz, 1H) 6.35(dd, J = 7.4, 0.5 Hz, 1H) 3.91 (s, 3H), 2.97 (t, J = 5.2Hz, 2H), 2.73 (t, J = 5.2Hz, 2H), 2.36, (s,6H).

[0084] 13C (acetone-d6). 6: 172.2, 152.2, 149.6, 144.6, 127.9, 122.4, 121.33, 121.28, 121.17, 116.0, 113.71, 113.60, 112.5, 205.1 102. 47, 61.8, 55.4, 44.7, 25.0.

[0085] EXAMPLE 2: 3-Hydroxy-4-methoxycinnamic acid (isoferulic acid) salt of psilocinC22H26N2O5. MW= 398

[0086] a) Freshly prepared psilocin, 235 mg, was dissolved in 5 mL THF. To this was added 235 mg of isoferulic acid dissolved in 6 mLTHF. The solution was allowed to stand forone hour. Some white solid began to precipitate. The mixture was cooled to -10°C for 15 min and then filtered to yield 390 mg (87%) of a white powder; mp. 196-198°C. A second crop, 31 mg, was obtained after additional cooling of the filtrate. Total yield: 421 mg (92%).

[0087] b) Psilocin, 400 mg (1.96 mmol) was dissolved in 10 mL of THF with slight warming. To this was added 425 mg (2.2 mmol) of isoferulic acid. The solution was kept at -10°C overnight and then filtered. The yield of a white powder was 621 mg. The filtrate was evaporated to dryness and triturated with 15 mL of acetone. The greyish precipitate was filtered to give 118 mg of solid. Total yield 739 mg (95%)

[0088] EXAMPLE 3: 3,4 Dihydroxycinnamic acid (caffeic) salt of psilocin

[0089] Psilocin, 195 mg (greyish in color), was dissolved in 5 mL of THF and mixed with 170 mg of caffeic acid dissolved in 3 mL of THF. The mixture was cooled. When scratched in the presence of DCM a slight brownish solid formed. Yield: 230 mg (63%). A second crop of white powder, 122 mg was obtained upon further cooling of the filtrate to provide a total yield of 352 mg (96%). Mp. 121-122°C

[0090] 3H NMR (400MHz, methanol-d4) 6: 2.79 (s, 6H), 3,21 (t, J=7.4 Hz,2H), 3,57 (t, J=7.Hz, 2H) 3.83 (s, 6H), 6.26 (d, J16 Hz, 1H), 6.34 (d, J= 7.2Hz, 1H) 6.71 (d, J = 8.4 Hz, 1H), 6.93-6-95 ( m, 3H), 6.96 (s,lH), 7.29 (d, J =16 Hz, 1H

[0091] 13C 6: 174.4, 151.1, 146.8, 145.2141.0, 139.3, 127.7, 122.4, 121.5, 120.6, 120.5, 116.3, 115.0, 109.0, 103.1, 102.9, 67.5, 59.7, 42.3, 25.1, 22.3.

[0092] EXAMPLE 4: p-Coumaric acid salt of psilocin.C21H24N2O4. Mw — 368

[0093] This compound was prepared in a similar manner as the caffeic acid salt using acetone as solvent.

[0094] 3H NMR (400MHz, methanol-d4) 8: 2.79 (s, 6H), 3.22 (t, J=7.4 Hz, 2H), 3.36 (t, J=7.Hz, 2H) 3.83 (s, 6H), 6.34 (dd, J= 8.8, 0.8 Hz, 1H), 6.80, m, 2H), 6.96 (s,lH), 7.31(s,2H).

[0095] 13C NMR (methanol d4): 8: 173.3, 151.1, 147.0, 139.3, 138.0, 126.1 122.3, 121.5, 116.3, 109.50, 121.5, 116.3, 109. 106.7, 103.1, 102.9, 67.5, 59.7, 55.2, 42.3, 25.1, 22.3.

[0096] EXAMPLE 5: 3,5-Dimethoxy-4-hydroxybenzoic acid (syringic acid) salt of psilocinC21H26N2O: MW = 402

[0097] a) Psilocin, 175 mg, was dissolved in 5 mL of THF and mixed with 175 mg of 3,5-dimethoxy-4-hydroxybenzoic acid dissolved in 3 mL of THF. The mixture was cooled to -10°C overnight and the hard crystals formed were filtered to yield 260 mg (80%) of a slight pinkish powder. The mp of the solid is 183-185°C. A second crop, 72 mg was obtained upon further cooling and partial evaporation of the filtrate. Total yield: 332 mg (95%)

[0098] b) Psilocin, 410 mg (2.0 mmol) was dissolved in 10 mL of THF. To this was added 440 mg (2.2 mmol) of syringic acid. The mixture was kept overnight at -10°C and the precipitate was filtered to give 661 mg (75%) of a white solid. A second crop, 62 mg was obtained by evaporating the solvent, triturating with 10 mL of acetone followed by filtration. Total yield. 89%.

[0099] 3H NMR (400MHz, methanol-d4): 82.79 (s, 6H), 3.22 (t, J=7.4 Hz, 2H), 3.36 (t, J=7.Hz, 2H) 3.83 (s, 6H), 6.34 (dd, J= 8.8, 0.8 Hz, 1H), 6.80, m, 2H), 6.96 (s,lH), 7.31(s,2H).[000100]13C NMR (methanol d4). 8: 173.3, 151.1, 147.0, 139.3, 138.0, 126.1 122.3, 121.5, 116.3, 109.50, 121.5, 116.3, 109. 106.7, 103.1, 102.9, 67.5, 59.7, 55.2, 42.3, 25.1, 22.3.[000101] EXAMPLE 6: 4-Hydroxy-3-methoxybenzoic acid (vanillic) salt of psilocinC2OH24N205: MW = 372[000102] a) Psilocin (102 mg, 0.50 mmol) was dissolved in 5 ml of acetone. To this was added 84 mg (0.50 mmol) of 4-hydroxy-3-methoxybenzoic acid followed by 20 mL of hexane. The milky white solution was rotovaped to dryness producing 164 mg of an off-white powder.[000103] b) Psilocin (204 mg, 1.0 mmol) was dissolved in 5 mL of THF with slight heating. To this was added 164 mg of 4-hydroxy-3-methoxybenzoic acid dissolved in 3 mL of THF. The mixture was stored at -10 C. No solid formed. A gum was obtained when the solvent was allowed to evaporate.[000104] c) Psilocin (102 mg) was dissolved in 5 mL of acetone and added to a solution of 76 mg of 3-hydroxy-4-methoxybenzoic acid in 10 mL of acetone. The solvents were evaporated, and attempts were made to obtain crystals from a mixture of methanol and 1,2-dichloroethane. This yielded a blackish oil no longer very soluble in 10 mL of acetone. To this mixture was added 30 mL of hexane and a milky white mixture was obtained. The milky white mixture was decanted from the insoluble black oil and evaporated. The yield of the salt, as an almost white fluffy powder, was 76 mg.[000105] EXAMPLE 7: 3-Hydroxy-4-methoxybenzoic acid (isovanillic) salt of psilocinC20H24N2O5: MW = 372[000106] A solution of 200 mg of isovanillic acid, dissolved in 5 mL of ethyl acetate was added to 180 mg of psilocin was dissolved in 15 mL of ethyl acetate. An immediate white precipitate formed. The mixture was cooled to -10°C for 15 min and then filtered. The yield of white solid was 290 mg (85%).[000107]3H NMR (400 MHz, in acetone-d6). 8: 2.37 (s, 6H), 2.50 (t, 2H), 2.92 (t, 2H), 3.96(s, 3H), 6.32 (d, 1H), 6.33 (d, 1H), 6.77-6.87( m, 2H), 6.93 -6.98 (m, 2H), 7.05(dd, 1H), 7.16 (d, 1H, 7.58(d, 1H). The spectrum indicated the presence of about 10% of an impurity, possibly psilocin.[000108] EXAMPLE 8: 3,5-Di-tbutyl-4-hydroxybenzoic acid salt of psilocinC27H38N2O4. MW = 454[000109] To a solution of psilocin 204 mg (1.0 mmol) in 10 mL of slightly warmed dichloromethane (DCM) was added 275 mg (1.10 mmol) of the above acid dissolved in 10 mL of DCM. The mixture was cooled to -10°C for 1 h, and then filtered. The yield of a fine white powder, mp 198-199°C was 378 mg (83 %)[000110]TH NMR in acetone-d6. 8: 1.49 (s, 18H) 2.36 (s,3H), 2.72*m, 2H), 2.98 (m, 2H), 6.37 (dd, 1H) 6.81-6.91(m,2H), 6.97 (s,lH),7.95 (s,2H)[000111]13C NMR. 8: 30.04, 39.40, 49.72, 66.81, 107.76, 110.18, 118.76, 122.69, 126.37, 127.16, 127.59, 132.07, 141.77, 144.58, 157.21, 163.21.), 172.81. Note. One aliphatic C is missing; it is hidden under the solvent peaks.[000112] EXAMPLE 9: Gallic acid salt of psilocinC19H22N2O6. MW = 374[000113] Psilocin, 140 mg (0.51 mmol), was dissolved in 10 ml of ethyl acetate. A solution of 180 mg of gallic acid in 15 ml of ethyl acetate was added. This caused immediate precipitation of a flocculent white precipitate. The mixture was cooled to -10°C and then filtered yielding 177 (93%) mg of a fluffy almost white powder. The1H NMR spectrum of thesolid indicated a 5:1 mixture of the desired salt and gallic acid. Further purification was not attempted.[000114]1H NMR in acetone-d6, (focusing on the signals for the salt). 8: 2.37(s,6H), 2.75 (m, 2H), 2.94(m,2H), 6.32(d, 1H), 6.77-6.86(m, 2H), 6.88 (bs, 1H), 7.13(s, 2H).[000115] EXAMPLE 10: 3-Methoxy-4-hydyoxyphenylacetic acid salt of psilocin.CH3O-CH3[000116] Psilocin, 182 mg, was dissolved in 10 mL of slightly warmed ethyl acetate. A solution of 170 mg of 3-methoxy-4-hydroxyphenylacetic acid dissolved in 5 mL of ethyl acetate was added. A white precipitate formed during the addition of the acid-containing solution. The mixture was cooled for 30 min at -10°C and then filtered. The yield of a white powder with mp. 192-194°C was 267 mg (77%).[000117]XH NMR (400 MHz)in acetone d6. 8: 2.33 (s,6H), 2.68 (m,2H), 2.94 (m,2H) 3.52(s,2H), 3.84(ms,3H) 6.36 d, 2H), 6, 75-6.96 (m, 6H).[000118]13C NMR, 8: 173.5, 150.6, 146.3, 145.3, 141.4, 137.1, 136.1, 130, 128.1,120.9, 115.4, 109.7, 101.1. 95.8, 66.8. 53.4. 38.1, 23.3, 21.6.[000119] EXAMPLE 11: 3-(-3,5-di-tbutyl-4-hydroxyphenyl)-propanoic acid salt of psilocinOH CH3H C29H42N2O4. MW= 482 CH3NH[000120] 3-(3,5-Di-tbutyl-4-hydroxyphenyl)-propanoic acid, 150 mg, dissolved in 5 mL of ethyl acetate was added to 102 mg of psilocin dissolved in 5 ml of ethyl acetate. Thesolution was cooled to -10°C. A white precipitate began to appear within an hour. The mixture was left at -10°C overnight and then filtered. The yield of a white powder, mp. 122-123°C, was 212 mg (88%).[000121]3H NMR (400 MHz) in acetone d6. 8: 1.39(s. 18H), 2.36 (s,3H), 2.51(dd, 2H), 2.74 (d,2H), 2.80 (t,2H02.96 (t,2H), 6.33 (d,lH) 6.75-6.85 (m,2H), 6.93(d,lH), 7.02 (s,2H).[000122]13C NMR, 8:179.9, 152, 150.3, 138.6, 135.8, 131.9, 124.9, 124.2, 119.5, 115.7, 114.4, 105.5, 102.9, 66.5, 64, 44.8, 37.9, 34.3, 31.7, 30.4.[000123] EXAMPLE 12: 2,5-Dihydroxybenzoic acid (gentisic acid).3H CigH22N2OO5" Mw— 356CH3(-)O2C[000124] Addition of 0.65 mmol of gentisic acid dissolved in 10 mL of ethyl acetate to a solution of psilocin, 0.5 mmol, in ethyl acetate did not result in formation of a solid salt. The solvent was allowed to evaporated to 5 mL resulting in the separation of an oil that did not solidify upon cooling to -10°C.[000125] EXAMPLE 13: 3,4-Dihydroxyphenylacetic acid.CH3OH C20H24N2O5. MW= 372[000126] 3,4-Dihydroxyphenylacetic acid, 200 mg, dissolved in 10 mL of warmed, about 40°C, ethyl acetate was added to a solution of 102 mg of psilocin dissolved in 10 mL of ethyl acetate. Several attempts at inducing crystallization of the salt were made, including evaporation of most of the solvent and cooling to -10°C. A small amount, 53 mg of solid was obtained.[000127] Examples 12 and 13 illustrate that certain counterions within Formula I may present challenges for isolation as crystalline solids under the standard conditionsemployed. However, one of ordinary skill in the art would recognize that such salts may be isolated using alternative crystallization conditions (e.g., different solvents, seeding, slower evaporation) or may be used in amorphous form or as solutions without the need for isolation as a crystalline solid. The difficulty in crystallization does not affect the utility of these salts as pharmaceutical compositions, as they retain the improved oxidative stability conferred by the antioxidant counterion regardless of physical form.[000128] EXAMPLE 14: (Comparative) Benzoic acid salt of psilocin.C.19H22N2O3. MW = 326[000129] Psilocin (129 mg, 0.63 mmol) was dissolved in 10 ml of DCM. To this was added 75 mg, 0.61 mmol) of benzoic acid dissolved in 8 mL of DCM. The salt began to precipitate within less than one minute. The mixture was allowed to stand for 1 h and then filtered yielding 182 mg (92%) of almost white powder having a mp. of 227-230 °C.[000130] EXAMPLE 15: Stability studies[000131] A solution of psilocin isoferulate salt in acetone was exposed to typical laboratory light and kept open to the environment for a period of a week, at room temperature. The solution remained colorless over this period. In contrast, a similar solution of the benzoic acid salt of psilocin, maintained under the same conditions, changed to a purplish color after one day and became almost black within one week. The color change is indicative of oxidation. Accordingly, the lack of color change observed in the acetone solution of the isoferulic acid salt of psilocin demonstrated the greater oxidative stability of the isoferulate salt compared to the benzoate salt.[000132] Crystalline isoferulate salt was stored in a clear glass vial at room temperature in a drawer for two years. The1H NMR of the sample after storage, taken at 400 MHZ, was identical to that taken when the sample was first prepared.[000133] Crystalline caffeic acid salt was stored at room temperature in a clear glass vial for six months. The1H NMR of the sample after storage, taken at 400 MHZ, was identical to that taken when the sample was first prepared six months earlier[000134] Crystalline 3,5-ditbutyl-4-hydroxybenzoic acid salt was stored at room temperature in a clear glass vial. The1H NMR of the sample after storage, taken at 400 MHZ, was identical to that taken when the sample was first prepared four months earlier.[000135] Crystalline 3-(3,5-ditbutyl-4-hydroxyphenyl) propanoic acid salt was stored at room temperature in a clear glass vial. TheXH NMR of the sample after storage, taken at 400 MHZ, was identical to that taken when the sample was first prepared four months earlier.[000136] TheXH NMR studies demonstrated longterm stability of the psilocin salts of the present disclosure.[000137] The stability studies presented above, while conducted on representative salts, demonstrate the oxidative stability benefits provided by counterions of Formula I across the structural diversity of the claims. Specifically, the data supports stability for: cinnamic acid derivatives (isoferulate, caffeate), benzoic acid derivatives (3,5-di-tbutyl-4-hydroxybenzoic acid), and phenylpropanoic acid derivatives (3-(3,5-di-tbutyl-4-hydroxyphenyl)propanoic acid). One of ordinary skill in the art would expect that other counterions within Formula I, having similar structural features, optionally with O-H BDE values within the disclosed ranges, would exhibit comparable stability. The comparative example (Example 14, benzoic acid salt) and comparative stability study demonstrate that the presence of at least one phenolic hydroxyl group, as required by Formula I, provides improved oxidative stability.[000138] All publications, patents and patent applications mentioned in this Specification are indicative of the level of skill of those skilled in the art to which this invention pertains and are herein incorporated by reference to the same extent as if each individual publication, patent, or patent applications was specifically and individually indicated to be incorporated by reference.[000139] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims

Claims

1. We Claim:

1. A compound that is a salt of psilocin wherein the salt comprises psilocin and a carboxylate-containing counterion of Formula IOowherein:each of R1, R2, and R3is independently H, OH, methyl, t-butyl, or OCH3, wherein at least one of R1, R2, and R3is OH,each of R4and R5is H or methyl, andA is absent, CH=CH, CH2-CH2, or CH2.

2. The compound according to claim 1, wherein the carboxylate-containing counterion of Formula I comprises at least one hydroxyl having an O-H bond dissociation energy (BDE) of less than 90 Kcal / mol or in the range of from about 75 kcal / mol to about 90 kcal / mol.

3. The compound according to claim 1 or 2, wherein the carboxylate-containing counterion has the structure of Formula laR'4. The compound according to claim 3, wherein the carboxylate-containing counterion is:

5. The compound according to claim 4, wherein the carboxylate containing counterion is syringate.The compound according to claim 1 or 2, wherein the carboxylate-containing counterion has the structure of Formula lbO O'R R5R R3R2lb7. The compound according to claim 6, wherein the carboxylate-containing counterion is:

8. The compound according to claim 7, wherein the carboxylate-containing counterion is isoferulate or caffeate.

9. The compound according to claim 1 or 2, wherein the carboxylate-containing counterion has the structure of Formula IcCK J?10. The compound according to claim 9, wherein the carboxylate-containing counterion is:OH11. The compound according to claim 1 or 2, wherein the carboxylate-containing counterion has the structure of Formula Id12. The compound according to claim 11, wherein the carboxylate-containing counterion is:

13. The compound according to any one of claims 1 to 12, wherein the compound provides a dual therapeutic effect based on therapeutic properties of psilocin and therapeutic properties of the counterion.

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 and one or more pharmaceutically acceptable excipients.

15. The pharmaceutical composition of claim 14, further comprising at least one pharmaceutically acceptable additive or excipient, optionally selected from the group consisting of antioxidants, preservatives, buffering agents, fillers, binders,sweetening agents, colouring agents, chelating agents, disintegrants, coating agents, anti-adherents, lubricants, glidants, surface acting agents, humectants, viscosity imparting agents, diluents and cosolvents.

16. The pharmaceutical composition of claim 14 or 15, wherein the composition comprises at least one antioxidant agent that is ascorbate, pyruvate, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), calcium stearate, citrate, potassium metabisulfite, propyl gallate, sodium metabisulfite, sodium thiosulfate, vitamin E (a-tocopherol), resveratrol, sodium edetate, or a combination of two or more thereof.

17. The pharmaceutical composition of any one of claims 14 to 16 for use in treatment of a disease or condition in a subject in need thereof, wherein the disease or condition is a neurological injury, a neurodegenerative disease, an inflammatory condition, chronic pain, or a psychological condition.

18. A method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject the salt of psilocin according to any one of claims 1 to 13 or the pharmaceutical composition of any one of claims 14 to 16, wherein the disease or condition is a neurological injury, a neurodegenerative disease, an inflammatory condition, chronic pain, or a psychological condition.

19. The composition for use according to claim 17 or the method of claim 18, wherein the disease or condition is an inflammatory condition, such as lung inflammation, neuroinflammation, rheumatoid arthritis, atherosclerosis, psoriasis, type II diabetes, inflammatory bowel disease, Crohn's disease, multiple sclerosis, septicemia, chronic obstructive pulmonary disease (COPD), or Alzheimer's disease.

20. The composition for use according to claim 17 or the method of claim 18, wherein the disease or condition is a neurological injury, such as a stroke, a traumatic brain injury, or a spinal cord injury.

21. The composition for use according to claim 17 or the method of claim 18, wherein the disease or condition is chronic pain, such as chronic pain from post-operative pain, tension headaches, chronic lower back pain, fibromyalgia, nephropathy, multiple sclerosis, shingles, complex regional pain syndrome, cephalic pain, sciatica, or episodic or chronic trigeminal autonomic cephalalgia (e.g., episodic and chronic cluster headache (CH), episodic and chronic paroxysmal hemicrania (PH), or shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)).

22. The composition for use according to claim 17 or the method of claim 18, wherein the condition is a psychological condition, such as post -traumatic stress, attention deficit hyperactivity disorder, anxiety, addiction, depression, compulsion, IBS (irritable bowel syndrome), fibromyalgia, CRPS (complex regional pain syndrome), phantom limb, an eating disorder or compulsive behavior.

23. The composition for use according to claim 17 or the method of claim 18, wherein the disease or condition is a neurodegenerative disease, such as Alzheimer's disease, Huntington's disease, or Parkinson's disease.

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