Methods of treatment with psilocybin and psilocin derivatives

Abstract

The present disclosure provides methods of therapy using psilocybin or psilocin pegylated derivatives for the treatment of prediabetes, type-II diabetes, obesity, metabolic dysfunction-associated steatotic liver disease (MASLD and MetALD), metabolic dysfunction-associated steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), liver steatosis, dyslipidemia, nonalcoholic steatohepatitis (NASH), or sarcopenia.

Description

METHODS OF TREATMENT WITH PSILOCYBIN AND PSILOCIN DERIVATIVESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 589,384, filed October 11th, 2023, the disclosure of which is incorporated by reference in its entirety.BACKGROUND

[0002] Psilocybin produces alterations in consciousness and emotion, including various psychedelic effects. Psychedelic substances are presently under investigation for the treatment of several diseases and symptoms, including depression, post-traumatic stress disorder, obsessive, and addiction. From the clinical studies to date, the psychedelic experience is an integral part of the intended treatments so far investigated.

[0003] Considerable efforts have been made to understand the mechanism and the comorbidities of metabolic disorders so as to better design treatment modalities. Sarcopenia is often present in patients with metabolic disorders. Sarcopenia is a medical term describing the loss of skeletal muscle mass often occurring in metabolic disorders, aging, cancer or because of other diseases and their treatments, including treatments for obesity and metabolic disorders, that can impact overall health and quality of life. Sarcopenia may be triggered or worsened by metabolic disorder, including obesity, prediabetes, type-2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease (MASLD), being in this case defined as dysmetabolic sarcopenia and may be related to insulin resistance / glucose intolerance. Accordingly, there is a need to develop new compositions and methods for treating metabolic disorders and sarcopenia.SUMMARY OF THE DISCLOSURE

[0004] The present disclosure provides methods of treating a metabolic disorder and / or sarcopenia in a patient in need thereof.

[0005] In embodiments, the present disclosure provides a method of treating prediabetes, Type-11 diabetes mellitus, obesity, metabolic dysfunction associated steatotic liver disease including metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatotic liver disease (MetALD), metabolic dysfunction steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), liver steatosis, nonalcoholic steatohepatitis (NASH), dyslipidemia, or sarcopenia in a patient in need thereof, the method comprising:orally administering a therapeutically effective, non-psychedelic amount of psilocybin to the patient; wherein about 0.01 mg to about 20 mg of psilocybin is administered; and wherein the psilocybin is administered in an extended-release dosage form.

[0006] In embodiments, the present disclosure provides a method of treating prediabetes, T2DM, obesity, metabolic dysfunction associated steatotic liver disease including MASLD and MetALD, metabolic dysfunction steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), liver steatosis, nonalcoholic steatohepatitis (NASH), dyslipidemia, or sarcopenia in a patient in need thereof, the method comprising: orally administering a therapeutically effective amount of a psilocin 4-O-PEGylated derivative wherein about 0.01 mg to about 40 mg of a psilocin derivative is administered; and wherein the derivative is administered in an extended-release dosage form.

[0007] In embodiments, the administration of the psilocin derivative does not produce psychoactive effects.

[0008] Other embodiments will be readily apparent to the skilled person based on the present disclosure.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 is a set of graphs that shows the Body weight increase and area under the curve of body weight increase in the 3 study groups. *p<0.05, ***p<0.001; ****p<0.0001.

[0010] FIG. 2 is a set of graphs that shows the blood glucose levels after an oral glucose tolerance test (upper panel), fasting blood glucose and area under the blood glucose vs time curve in the 3 study groups. **p<0.01, ***p<0.001, ****p<0.0001.

[0011] FIG. 3 is a set of graphs and images that shows the liver histology of the 3 study groups (left panel). Psilocybin treatment reduced liver steatosis, and the concentration of triglycerides in liver and plasma. *p<0.05, **p<0.01.

[0012] FIG. 4 is a graph that shows the leptin plasma levels of the 3 study group. *p<0.05, ****p<0.0001

[0013] FIG. 5 is a set of graphs that shows the gene ontology analysis of the biological processes “Response to leptin in muscles” and “Cellular response to Leptin stimulus in myocytes”. *p<0.05, vs controls,#p<0.05 vs MASLD mice.

[0014] FIG. 6 is a set of graphs that shows the gene ontology analysis of the biological processes “Glucose import’" and “Regulation of glucose transmembrane transport in muscles’". *p<0.05, **p<0.01 vs controls, ^<0.01 vs MASLD mice.

[0015] FIG. 7 is a graph and image that shows the protein expression of IRS 1 in the liver of the 3 study group. **p<0.01 vs control.

[0016] FIG. 8 is a graph that shows the area under the curve of body weight increase in the 3 study groups. *p<0.05; ****p<0.0001.

[0017] FIG. 9 is a graph that shows the blood glucose levels after an oral glucose tolerance test. * p<0.05 vs controls.

[0018] FIG. 10 is a set of images that shows the liver histology of the 3 study groups. PEG8- psilocin treatment reduced liver steatosis.

[0019] FIG. 11A is a set of photomicrographs (top brightfield, bottom Hoechst 33342) of WI- 38 cells with the indicated treatments. Scalebar = 200 pm.

[0020] FIG. 11B is a graph that shows the quantification of SA-P-Gal positive cells, n = 4 from 2 biological replicates and 2 technical replicates in UT, Doxo, Psib 0.1 and Psib 1 groups and n = 2 technical replicates in Psin 0.1 and Psin 1. One-Way ANOVA with Dunnett’s multiple comparison’s test, ** = p<0.01, **** = p<0.0001.

[0021] FIG. 12A is a representative immunoblot of phosphorylated p38 in WI-38 fibroblasts treated with the indicated compounds, n = 3 for UT, Doxo, Psib 0.1 and Psib 1. n = 1 for Psin 0.1 and Psin 1.

[0022] FIG. 12B is a representative immunoblot of Histone H3 in WI-38 fibroblasts treated with the indicated compounds, n = 2 for UT, Doxo, Psib 0.1 and Psib 1. n = 1 for Psin 0.1 and Psin 1.

[0023] FIG. 13 is a set of graphs that shows the pharmacokinetic profile and main PK parameters of PEG4, PEG6, PEG8 and PEGlO-psilocin.

[0024] FIG. 14 is a graph that shows the number of head twitch responses after the administration of 3 mg / kg psilocybin or psilocin equiv. of the Pegylated derivatives.

[0025] FIG. 15 is a set of graphs that shows agonist activity of psilocin and PEG4, PEG6, PEG8 and PEGlO-psilocin, at human 5-HT2A (green), 5-HT2B (red) and 5-HT2C (blue)receptors evaluated by the FLIPR (Fluorometric Imaging Plate Reader) Penta assay. All the pegylated compounds maintain a pharmacodynamic profile very similar to the one of psilocin.

[0026] FIG. 16 is a powder x-ray diffractogram of anhydrous psilocybin.DETAILED DESCRIPTION

[0027] Psilocybin is a phosphate ester prodrug; its active compound psilocin is rapidly released in the gut by dephosphorylation. It is well known that psilocin is a receptor agonist, exerting its psychedelic effects by activating the serotonin (5-HT) receptor isoform 2A (5-HT2AR) in the CNS. Furthermore, it was demonstrated that, besides being a partial agonist at the 5- HT2AR, psilocin is partial agonist at 5-HT2CR, and a partial antagonist at 5-HT2BR.

[0028] All these 5-HT2R are also expressed outside the CNS, for example in the gut, the adipose tissue, in the pancreas, and in the liver (Oh CM, Park S, Kim H. Serotonin as a New Therapeutic Target for Diabetes Mellitus and Obesity. Diabetes Metab J. 2016;40(2):89-98.), where they are involved in the regulation of biological processes, including metabolic processes. However, the potential pharmacological effects of psilocybin on metabolic disorders are poorly understood and investigated. In this context, the selective target of the peripheral 5- HTRs by serotonergic compounds unable to cross the blood brain barrier (BBB), might allow the therapy of metabolic diseases, avoiding undesired central psychedelic effects.

[0029] Globally, the most prevalent metabolic disorders are obesity, Type 2 diabetes mellitus (T2DM), and metabolic dysfunction associated steatotic liver diseases (MASLD), which can progress to its complication metabolic dysfunction associated steatohepatitis (MASH), characterized by fibrosis and inflammation, and an increased risk of developing liver cirrhosis and or liver cancer. Furthermore, a novel category of liver steatosis was recently introduced, termed MetALD, which delineates a spectrum of conditions and is defined as a daily intake of20 to 50 g of alcohol (or weekly 140-350 g) for females and 30 to 60 g daily for males (or weekly 210-420 g). Within the MetALD spectrum, some individuals might predominantly exhibit MASLD characteristics, whereas others might be more inclined toward alcoholic liver disease (ALD).

[0030] In recent years, an increasing amount of data suggests that MASLD can be associated with aging (He QJ, Li YF, Zhao LT, Lin CT, Yu CY, Wang D. Recent advances in age-related metabolic dysfunction-associated steatotic liver disease. World J Gastroenterol. 2024 Feb21 ;30(7):652-662. doi: 10.3748 / wjg.v30.i7.652. PMID: 38515956; PMCID: PMC10950625). In this context, age-related MASLD will become a major global health problem. Accordingly,the burden of senescent hepatocytes correlates with the severity of MASLD (Jun JH, Du K, Dutta RK, Maeso-Diaz R, Oh SH, Wang L, Gao G, Ferreira A, Hill J, Pullen SS, Diehl AM. The senescence-associated secretome of Hedgehog-deficient hepatocytes drives MASLD progression. J Clin Invest. 2024 Aug 27;134(19):el80310. doi: 10.1172 / JCI180310. PMID: 39190624; PMCID: PMC11444248).

[0031] Notably, it is well known that the resistance to leptin, a hormone secreted by adipose tissue in proportion to fat mass, is a common feature of metabolic diseases. Leptin is one important adipocytokine involved in energy expenditure, lipid and glucose metabolism and inflammation. Alterations in the levels of adipocytokines, including leptin, are associated with an increased risk of obesity, insulin resistance, prediabetes, T2DM and cardiovascular diseases. Recent research has focused on leptin and its role in the energy balance and food intake and regulation. Accordingly, there is a general consensus that leptin may serve as a pharmacological target for the therapy of obesity and other metabolic diseases. Furthermore, plasma concentration of leptin was found to be related to the risk of developing sarcopenia in obese patients, and it has been demonstrated that leptin plays a fundamental role in regulating muscle mass and strength, indicating that drugs with an effect on leptin levels / leptin action may be useful for controlling metabolic abnormalities and also related sarcopenia.Definitions

[0032] Throughout this disclosure, various patents, patent applications and publications (including non-patent publications) are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.

[0033] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0034] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or isinconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.

[0035] The term “therapeutically effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient or subject in need thereof.

[0036] In embodiments, an effective amount of psilocybin or psilocin derivative is that amount that is required to reduce at least one symptom of a metabolic disorder or sarcopenia as otherwise described herein in a patient. In embodiments, the therapeutically effective amount can vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The specific dose will vary depending on, for example, the dosing regimen to be followed, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0037] The term “treating” as used herein with regard to a patient, refers to improving at least one symptom of the patient’s disorder (for example, a metabolic disorder or sarcopenia). Treating can be improving, or at least partially ameliorating a disorder.

[0038] The phrase “pharmaceutically acceptable” as used herein refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0039] The term “salts” as used herein embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. Salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citricacid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine dicyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0040] The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0041] “Cyano” refers to the -CN radical.

[0042] “Hydroxy” or “hydroxyl” refers to the -OH radical.

[0043] “Alkyl” as used herein, refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20 alkyl”). In embodiments, an alkyl group has 1 to 12 carbon atoms (“Ci-12 alkyl”). In embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In embodiments, an alkyl group has 1 to 8 carbon atoms (“Ci-s alkyl”). In embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”, which is also referred to herein as “lower alkyl”). In embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In embodiments, an alkyl group has 1 carbon atom (“Ci alkyl”). Examples of C 1-6 alkyl groups include methyl (Ci), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), .v c-butyl (C4),isobutyl (C4), n-pentyl (C5), 3-pentanyl (Cs), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (Cs), tertiary amyl (C5), and n-hexyl (Ce). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (Cs) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In embodiments, the alkyl group is unsubstituted C1-10 alkyl (e.g., -CH3). In embodiments, the alkyl group is substituted C1-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), z-Pr (-CH(CHs)2), n-Pr (- CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or z-Bu ( CH2CH(CH3)2).

[0044] “Alkenyl” as used herein, refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20 alkenyl”). In embodiments, alkenyl does not contain any triple bonds. In embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2- 10 alkenyl”). In embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”). In embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2- butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cs), octatrienyl (Cs , and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In embodiments, the alkenyl group is unsubstituted C2-10 alkenyl. In embodiments, the alkenyl group is substituted C2-10 alkenyl.

[0045] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C&-14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“Ce aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“Cio aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; e.g., anthracyl).

[0046] Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particular aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In embodiments, the aryl group is unsubstituted Cs-14 aryl. In embodiments, the aryl group is substituted Ce-14 aryl.

[0047] “Heteroaryl” refers to a radical of a 5- to 14-membered monocyclic or polycyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having ring carbon atoms and 1-8 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 14-membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

[0048] “Heteroaryl” also includes ring systems wherein the heteroaryl group, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the heteroaryl or the one or more aryl groups, and in such instances, the number of ring members designates the total number of ring members in the fused (aryl / heteroaryl) ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heteroaryl or the one or more aryl groups. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0049] In embodiments, a heteroaryl is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 10-membered heteroaryl”). In embodiments, a heteroaryl is a 5- to 9-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 9-membered heteroaryl”). In embodiments, a heteroaryl is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heteroaryl”). In embodiments, a heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heteroaryl”). In embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In embodiments, the 5- to 6-membered heteroaryl has 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In embodiments, the heteroaryl group is unsubstituted 5- to 14-membered heteroaryl. In embodiments, the heteroaryl group is substituted 5- to 14-membered heteroaryl.

[0050] Exemplary 5 -membered heteroaryl containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl containing one heteroatom include, without limitation, pyridinyl. Exemplary 6- membered heteroaryl containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl include, without limitation, indolyl,isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0051] “Heterocyclyl” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 12-membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Exemplary 3- membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5 membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6- membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a G, aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0052] In embodiments, a heterocyclyl group is a 5- to 12-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 12-membered heterocyclyl”). In embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5- to 10-membered heterocyclyl”). In embodiments, a heterocyclyl group is a 5- to 8-membered non- aromatic ring system having ring carbon atoms and 1 -4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 8-membered heterocyclyl”). In embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5- to 6-membered heterocyclyl”). In embodiments, the 5- to 6-membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In embodiments, the 5- to 6-membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In embodiments, the 5- to 6-membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0053] As the foregoing examples illustrate, In embodiments, a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (“polycyclic heterocyclyl”) that contains a fused, bridged or spiro ring system, and can be saturated or can be partially unsaturated. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl group, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, and in such instances, the number of ring members designates the total number of ring members in the entire ring system. When substitution is indicated in such instances, unless otherwise specified, substitution can occur on either the heterocyclyl or the one or more carbocyclyl groups. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In embodiments, the heterocyclyl group is unsubstituted 3- to 12-membered heterocyclyl. In embodiments, the heterocyclyl group is substituted 3- to 12-membered heterocyclyl.

[0054] “Alkoxy” as used herein, refers to the group -OR, wherein R is alkyl as defined herein. Ci-6 alkoxy refers to the group -OR, wherein each R is Ci-6 alkyl, as defined herein. Exemplary Ci -6 alkyl is set forth above.

[0055] “Oxo” refers to =0. When a group other than aryl and heteroaryl or an atom is substituted with an oxo, it is meant to indicate that two geminal radicals on that group or atom form a double bond with an oxygen radical. When a heteroaryl is substituted with an oxo, it is meant to indicate that a resonance structure / tautomer involving a heteroatom provides a carbon atom that is able to form two geminal radicals, which form a double bond with an oxygen radical.

[0056] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In embodiments, the halo group is either fluoro or chloro.Psilocybin or psilocin derivative administration

[0057] As described herein, a non-psychedelic amount of psilocybin, or a psilocin derivative, is administered to a patient in need thereof. The psilocybin may be any suitable pharmaceutical salt thereof. Certain psilocin derivatives are described, for example, in International Patent Application nos. PCT / US2020 / 021400 and PCT / US2022 / 028559. In embodiments, the psilocin derivative is 4-O-Pegylated psilocin, such as PEG8-psilocin, or psilocin 4-O- carbamate ester.

[0058] In embodiments, the psilocybin is crystalline psilocybin. In embodiments, the crystalline psilocybin is hydrous or anhydrous. In embodiments, the psilocybin may be a mixture of one or more crystalline forms. In embodiments, the psilocybin is anhydrous psilocybin with a crystalline purity of at least 80%, or at least 90% , or at least 95%, or at least 99%. In embodiments, the anhydrous psilocybin is characterized by peaks in a powder X-ray diffractogram at 11.5, 12.0, 14.5, 17.5, and 19.7° 20 ± 0.1° 20. In embodiments, the anhydrous psilocybin is characterized by peaks in a powder X-ray diffractogram with one or more peaks at 10.1° ±0.2° 20, 11.5° ±0.2° 20, 12.1° ±0.2° 20, 14.6° ±0.2° 20, 19.6° ±0.2° 20, 20.5° ±0.2° 20, and 25.8° ±0.2° 20, as measured on a Cu X-ray source. In embodiments, the anhydrous psilocybin has an X-ray diffraction pattern according to Fig. 16 In embodiments, the psilocybin comprises no more than 20% hydrous psilocybin, or no more than 10%, or no more than 5%, or no more than 1%, or substantially no hydrous psilocybin. In embodiments, the hydrous psilocybin is the trihydrate. Psilocybin crystalline purity is measured as molar units of the psilocybin molecule.

[0059] The present disclosure also provides methods of treatment utilizing extended-release compositions of psilocin 4-O-carbamate ester, to further prolong the effect of psilocin by its in vivo slower release from the carbamate ester prodrug compared to the phosphate ester prodrug present in psilocybin. In embodiments, the present invention also provides compositions of a psilocin 4-O-PEGylated derivative, such as PEGn-psilocin. “PEGn” represents a methoxy terminated oligomer composed of n ethylene glycol monomers and linked to the 4-hydroxy position of psilocin through an ether bond, for example PEG8-psilocin represents a methoxy terminated oligomer composed of 8 ethylene glycol monomers and linked to the 4-hydroxy position of psilocin through an ether bond. It has been found that pegylated psilocin is unable to cross the blood brain barrier in amount comparable to unmodified psilocin, and thus unable or less able to induce psychedelic effects after oral administration.

[0060] In embodiments, the psilocin derivative is according to Formula I:pharmaceutically acceptable salt thereof, wherein:T is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, wherein T is optionally substituted at one or more positions by one or more of deuterium, halo, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate.

[0061] n is in the range of 1 to 100.

[0062] In embodiments, T is hydrogen or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted by one or two of halogen, CF3, hydroxy, nitro, or cyano.

[0063] In embodiments, T is hydrogen, CH3, or CH2CH3. In embodiments, T is CH3.

[0064] In embodiments, n is in the range of 1 to 20. In embodiments, n is in the range of 1 to 12. In embodiments, n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0065] In embodiments, the psilocin derivative is according to Formula (II):pharmaceutically acceptable salt thereof, wherein:Ri and R2 are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, optionally substituted at one or more positions by deuterium, halo, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or a methoxy polyethylene glycol chain of formula (CH3-(OCH2CH2)n-) wherein n is comprised between 1 and 100.

[0066] In embodiments, Ri is Ci-Cs alkyl optionally substituted with halo, alkyl ester, hydroxy, alkoxy, amino, alkylamino, nitro, cyano, thiol, thioalkyl, or methoxy polyethylene glycol chain of formula (CH3-(OCH2CH2)n-) wherein n is comprised between 1 and 20.

[0067] In embodiments, Ri is Ci-Cs alkyl optionally substituted with halo, alkyl ester, hydroxy, alkoxy, amino, alkylamino, or methoxy polyethylene glycol chain of formula (CH3- (OCH2CH2)n-) wherein n is comprised between 1 and 20.

[0068] In embodiments, Ri is Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted by one or two of halogen, CF3, hydroxy, nitro, or cyano.

[0069] In embodiments, Ri is C2-C4 alkyl, optionally substituted with 1, 2, or 3 fluoro groups.

[0070] In embodiments, Ri is C2-C6 alkyl, optionally substituted with a carboxy, methyl ester, or ethyl ester group.

[0072] In embodiments, the psilocin derivative (e.g., according to Formula (I) or Formula (II)) is the hydrochloride salt thereof.

[0073] In embodiments, the non-psychedelic amount of psilocybin is about 0.1 mg to about 10 mg, or about 0.1 mg to about 7 mg. In embodiments, the non-psychedelic amount of psilocybin is about 0.1 mg to about 6 mg, or about 0. 1 mg to about 5 mg, or about 0.1 mg to about 4 mg, or about 0.1 mg to about 3 mg, or about 0.1 mg to about 2 mg, or about 0.1 mg to 1 mg, or about 0.2 mg to about 6 mg, or about 0.2 mg to about 5 mg, or about 0.2 mg to about 4 mg, or about 0.2 mg to about 3 mg, or about 0.2 mg to about 2 mg, or about 0.2 mg to 1 mg, or about0.3 mg to about 6 mg, or about 0.3 mg to about 5 mg, or about 0.3 mg to about 4 mg, or about 0.3 mg to about 3 mg, or about 0.3 mg to about 2 mg, or about 0.3 mg to 1 mg, or about 0.4 mg to about 6 mg, or about 0.4 mg to about 5 mg, or about 0.4 mg to about 4 mg, or about 0.4 mg to about 3 mg, or about 0.4 mg to about 2 mg, or about 0.4 mg to 1 mg of psilocybin. In embodiments, the non-psychedelic amount of psilocybin is about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, or about 5 mg, for example, about 0.5 mg of psilocybin.

[0074] In embodiments, the non-psychedelic amount of psilocybin is about 0.001 mg / kg to about 0.1 mg / kg, e.g., about 0.005 mg / kg to about 0.1 mg / kg.

[0075] In embodiments, the amount of psilocin derivative (e.g., a derivative according to Formula (I) or Formula (II)) is about 0.1 mg to about 1000 mg, or about 0.1 mg to about 500 mg, or about 0.1 mg to about 100 mg, or about 0.1 mg to about 50 mg, or about 0.1 mg to about 20 mg, or about 0.1 mg to about 14 mg. In embodiments, the amount of psilocin derivative (e.g., a derivative according to Formula (I) or Formula (II)) is about 0.1 mg to about 6 mg, or about 0.1 mg to about 5 mg, or about 0.1 mg to about 4 mg, or about 0.1 mg to about 3 mg, or about 0.1 mg to about 2 mg, or about 0.1 mg to 1 mg, or about 0.2 mg to about 6 mg, or about 0.2 mg to about 5 mg, or about 0.2 mg to about 4 mg, or about 0.2 mg to about 3 mg, or about 0.2 mg to about 2 mg, or about 0.2 mg to 1 mg, or about 0.3 mg to about 6 mg, or about 0.3 mg to about 5 mg, or about 0.3 mg to about 4 mg, or about 0.3 mg to about 3 mg, or about 0.3 mg to about 2 mg, or about 0.3 mg to 1 mg, or about 0.4 mg to about 6 mg, or about 0.4 mg to about 5 mg, or about 0.4 mg to about 4 mg, or about 0.4 mg to about 3 mg, or about 0.4 mg to about 2 mg, or about 0.4 mg to 1 mg (including all values and ranges therebetween) of derivative. In embodiments, the amount of psilocin derivative (e.g., a derivative according to Formula (I) or Formula (II)) is about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 10 mg, for example, about 0.5 mg of psilocin derivative. In embodiments, the amount of psilocin derivative (e.g., a derivative according to Formula (I) or Formula (II))is about 20 mg to about 1000 mg, or about 100 mg to about 1000 mg, or about 200 mg to about 1000 mg, or about 500 mg to about 1000 mg (including all values and ranges therebetween).

[0076] In embodiments, the amount of psilocin derivative is about 0.001 mg / kg to about 1 mg / kg, or about 0.001 mg / kg to about 0.1 mg / kg or about 0.005 mg / kg to about 0.1 mg / kg.

[0077] In embodiments, the psilocybin or psilocybin derivative (e.g., according to Formula II) is administered in an extended-release dosage form.

[0078] In embodiments, the psilocin derivative (e.g., according to Formula I) is administered in an extended-release or in an immediate-release dosage form.

[0079] The psilocybin or psilocin derivative may be administered at various time points. In embodiments, the psilocybin or psilocin derivative is administered once a day, twice a day, or three times a day. In other embodiments, the psilocybin or psilocin derivative is administered once every other week, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week.

[0080] In embodiments, the 2 mg of psilocybin or psilocin derivative is administered once per day. In other embodiments, 4 mg of psilocybin is administered as 2 mg twice per day. In other embodiments, 1 mg of psilocybin is administered once per day. In other embodiments, 2 mg of psilocybin is administered as 1 mg twice per day. In other embodiments, the 0.5 mg of psilocybin is administered once per day. In other embodiments, 1 mg of psilocybin is administered as 0.5 mg twice per day.

[0081] In embodiments, the psilocybin is administered to the patient while fasted. For example, the psilocybin is administered before breakfast and / or before dinner. In embodiments, the psilocybin is administered to the patient with meals.

[0082] In embodiments, the extended-release dosage form comprises 0.5 mg psilocybin in a tablet.Pharmacokinetics

[0083] It has been presently found that extended-release psilocybin formulations provide for improved pharmacokinetic parameters.

[0084] In embodiments, the administration of an extended-release psilocybin or psilocin derivative dosage form provides a drug Cma of no more than about 10 ng / mL. In embodiments, the administration of an extended-release psilocybin or psilocin derivative dosage form provides a drug Cmax of no more than about 8 ng / mL, or about 6 ng / mL, or about 5 ng / mL, or about 4 ng / mL, or about 3 ng / mL, or about 2 ng / mL, or about 1 ng / mL, or about 0.5 ng / mL In embodiments, the administration of an extended-release psilocybin or psilocin derivativedosage form provides a drug Cmax of at least about 0. 1 ng / mL, for example, at least about 0.2 ng / mL, or about 0.5 ng / mL, or about 1 ng / mL.

[0085] Extended-release compositions of psilocybin allow a therapeutic, non-psychedelic, blood level of psilocin for a prolonged time thus allowing less frequent administration of psilocybin or a more durable effect. Accordingly, in embodiments, the administration of an extended-release psilocybin dosage form provides a psilocin Tmax of at least about 1 h (e.g., at least about 1.4 h, 1.5 h, 1.6 h, 1.7 h, 1.8 h, 1.9 h, 2.0 h, 2.1 h, 2.2 h, 2.3 h, 2.4 h, 2.5 h, 3 h, or 4 h). In embodiments, the administration of an extended-release psilocybin dosage form provides a psilocin Tmax of no more than 24 h (e.g., no more than about 12 h, or about 10 h, or about 8 h, or about 4 h, or about 2 h).

[0086] Extended-release dosage forms provide a reduced Cmax and / or an increased Tmax compared to an immediate-release dosage form. In embodiments, the administration of an extended-release psilocybin or psilocin derivative dosage form provides a drug Cmax at least 10% less, at least 15% less, or at least 20% less, than the Cmax from an equivalent psilocybin dosage in an immediate-release dosage form. In embodiments, the administration of an extended-release psilocybin or psilocin derivative dosage form provides a drug Cmax at least 25% less, at least 35% less, at least 50% less, than the Cmax from an equivalent drug dosage in an immediate-release dosage form. In embodiments, administration of an extended-release psilocybin or psilocin derivative dosage form provides a psilocin Cmax about 10% less, about 15% less, about 20% less, about 25% less, about 35% less, or about 50% less than the Cmax from an equivalent drug dosage in an immediate-release dosage form.

[0087] In embodiments, the administration of an extended-release psilocybin or psilocin derivative dosage form provides a psilocin Tmax at least 10% greater, at least 15% greater, or at least 20% greater than the Tmafrom an equivalent psilocybin dosage in an immediate-release dosage form. In embodiments, the administration of an extended-release psilocybin or psilocin derivative dosage form provides a psilocin Tmax at least 100% greater, at least 50% greater, or at least 35% greater than the Tmax from an equivalent psilocybin or psilocin derivative dosage in an immediate-release dosage form. In embodiments, the administration of an extended- release psilocybin or psilocin derivative dosage form provides a psilocin Tmax about 10% greater, about 15% greater, about 20% greater, about 35% greater, about 50% greater, or about 100% greater than the Tmaxfrom an equivalent drug dosage in an immediate-release dosage form. In embodiments, the administration of the composition provides a T1 / 2 of about 1 to about 2 h.

[0088] In embodiments, the administration of the composition provides an AUC0-24 in the range of about 1 to about 2 pg-h / L, or about 2 to about 3 pg-h / L, or about 3 to about 4 pg-h / L, or about 4 to about 6 pg-h / L, or about 5 to about 8 pg-h / L, or about 8 to about 12 pg-h / L. In embodiments, the administration of the composition provides an AUC0-24 in the range of about 1 pg-h / L, about 2 pg-h / L, about 3 pg-h / L, about 4 pg-h / L, about 5 pg-h / L, about 6 pg-h / L, about 7 pg-h / L, about 8 pg-h / L, about 9 pg-h / L, about 10 pg-h / L, about 11 pg-h / L, or about 12 pg-h / L (including all ranges therebetween).

[0089] In embodiments, the administration of the composition provides a Cmaxof about 0.2 to about 0.5 pg / L, or about 0.5 to about 1.0 pg / L, or about 0.8 to about 1.2 pg / L, or about 1.2 to about 1.6 pg / L. In embodiments, the administration of the composition provides a Cmax of about 0.2 pg / L, about 0.3 pg / L, about 0.4 pg / L, about 0.5 pg / L, about 0.6 pg / L, about 0.7 pg / L, about 0.8 pg / L, about 0.9 pg / L, about 1.0 pg / L, about 1.1 pg / L, about 1.2 pg / L, about 1.3 pg / L, about 1.4 pg / L, about 1.5 pg / L or about 1.6 pg / L (including all ranges therebetween).

[0090] In embodiments, the administration of the composition provides a Tmax of about 2 to about 6 h, or about 3 to about 6 h, or about 3 to about 5 h, or about 4 to about 5 h. In embodiments, the administration of the composition provides a Tmaxof about 2 h, about 3 h, about 4 h, about 5 h or to about 6 h (including all ranges therebetween).

[0091] In embodiments, the administration of the composition provides a Tmax of more than two times (e.g., 2-3 times) that of the Tmaxof an equivalent immediate release formulation.

[0092] Conventional psilocybin pharmacokinetics are disclosed, for example, in Holze, et al., “Pharmacokinetics and pharmacodynamics of Oral Psilocybin Administration in Healthy Participants.” Clin. Pharm. & Therap. 113:4-822 (2023).Clinical endpoints

[0093] In embodiments, the methods of the present disclosure provide a reduction in total body fat mass compared to prior to the treatment as determined by dual energy X-ray absorptiometry. In embodiments, the methods of the present disclosure provide a reduction in total body fat mass of at least about 1%, or at least about 2%, or at least about 5%, or at least about 10%. In embodiments, the methods of the present disclosure provide a relative or absolute increase in lean mass compared to prior to the treatment as determined by dual energy X-ray absorptiometry.

[0094] In embodiments, the methods of the present disclosure provide a reduction in MRL derived hepatic fat fraction compared to prior to the treatment. In embodiments, the reduction in MRI-derived hepatic fact fraction as compared to prior to the treatment is at least about 5%(e.g., in the range of about 5% to about 20%, or about 5% to about 15%, or about 8% to about 20%, or about 8% to about 15%).

[0095] In embodiments, the methods of the present disclosure provide a reduction in liver stiffness compared to prior to the treatment as measured by Fibroscan. In embodiments, the reduction in liver stiffness is at least about 3 kPa (e.g., at least about 3 kPa, or in the range of about 3 kPa to about 12 kPa, or in the range of about 5 kPa to about 12 kPa, or in the range of about 3 kPa to about 10 kPa, or in the range of about 5 kPa to about 10 kPa).

[0096] In embodiments, the methods of the present disclosure provide at least one of, or at least two of, or at least two of, or at least three of, or at least four of: a reduction in body weight, by an amount in the range of about 2 kg to about 8 kg (e.g., about 4 kg to about 6 kg); a reduction in fasting plasma glucose, by an amount in the range of about 10 mg / dl to about 60 mg / dl (e.g., in the range of about 15 mg / dl to about 45 mg / dl); a reduction in serum HbAlc, by an amount in the range of 0.5 to 1.0%, and / or about 3.5 mmol to about 7.0 mmol); a reduction in serum triglycerides; by an amount in the range of about 10 mg / dl to about 80 mg / dl (e.g., about 15 mg / dl to about 60 mg / dl); or an increase in serum HDL cholesterol, by an amount in the range of about 2 mg / dl to about 15 mg / dl (e.g., about 5 mg / dl to about 10 mg / dl).

[0097] In embodiments, the increase or reduction is initially observed 60 ± 7, 90 ± 7, or 120 ± 7 or 160 ± 7 days or 180 ± 7 or 360 ± 7 after beginning administration.

[0098] The presently disclosed methods involve the administration of non-psychedelic amounts of psilocybin, and / or psilocin derivatives that are not psychoactive or poorly psychoactive (e.g., are not significantly psychoactive at the claimed dosage). Accordingly, in embodiments, the method further comprises:(a) monitoring the patient for psychoactive symptoms, and(b) if psychoactive symptoms are observed, reducing the amount of psilocybin or psilocin derivative administered to the patient.

[0099] In embodiments, the metabolic disorder is prediabetes, type-II diabetes, obesity, metabolic dysfunction-associated steatotic liver disease (MASLD and MetALD), metabolic dysfunction steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), liver steatosis, nonalcoholic steatohepatitis (NASH), dyslipidemia, or sarcopenia.

[0100] In embodiments, sarcopenia is associated with a metabolic disorder, or the sarcopenia is associated with aging.EXAMPLES

[0101] The present invention is further illustrated by reference to the following Examples. The Examples are illustrative and are not to be construed as restricting the scope of the invention in any way.Example 1. Metabolic in vivo effects of Psilocybin

[0102] Low dose (0.05 mg / kg) of psilocybin were daily administered for 12 weeks to C57BL6 mice fed with for 17 weeks with a high-fructose, high-fat diet (HFHFD). Psilocybin treatment reduced body weight increase in this animal model (Fig. 1), improved glucose tolerance, as shown by the results of the oral glucose tolerance test and the fasting glucose levels (Fig. 2), and reduced liver fat and plasma triglycerides (Fig. 3).

[0103] Notably, plasma levels of leptin were increased in MASLD untreated mice (indicating the presence of leptin-resistance) and reduced by Psilocybin. (Fig. 4).

[0104] To understand the effect of psilocybin in muscles affected by dysmetabolic conditions, the presence of alterations in the global hepatic transcriptome was evaluated by RNA sequencing. The gene sets involved in the response to leptin were upregulated by psilocybin treatment (Fig. 5). Since in the muscle leptin resistance leads to a reduction of protein synthesis5, that can cause muscle atrophy and sarcopenia, this effect, peculiar of psilocybin, can explain the amelioration of muscle performance during the first weeks of treatment.

[0105] Furthermore, it was noticed that psilocybin-treated MASLD mice showed a significant increase of glucose uptake by skeletal muscle, further demonstrating the restoration of insulin sensitivity (Fig. 6). Also, the hepatic insulin signaling was ameliorated by psilocybin, since the protein expression of insulin receptor IRS-1 , a key regulator of insulin action, was restored to controls levels by psilocybin treatment in MASLD mice (Fig. 7).Example 2. Metabolic in vivo effects of PEG8-psilocin

[0106] Low dose of PEG8-psilocin (0.11 mg / kg, equiv. to 0.05 mg / kg psilocybin) were daily administered for 12 weeks to C57BL6 mice fed with for 17 weeks with a high-fructose, high- fat diet (HFHFD). PER8-psilocin treatment reduced body weight increase in this animal model (Fig. 8), improved glucose tolerance, as shown by the results of the oral glucose tolerance test and the fasting glucose levels (Fig. 9), and reduced liver steatosis (Fig. 10).Example 3. Psilocybin and psilocin ameliorate cell senescence

[0107] Psilocybin is naturally found within Psilocybe genera fungi and is converted to its metabolically active form psilocin in vivo. A growing body of evidence shows that it regulates inflammation and neuroprotection, both of which are dysregulated in aging. Therefore, the effects of low concentrations of psilocybin (Psib) and psilocin (Psin) in the doxorubicin (Doxo) induced model of cellular senescence were assessed in WI-38 human lung fibroblasts. Pretreatment with both Psib and Psin significantly prevented Doxo-induced SA-P-Gal positivity, indicating senescence prevention. Results of these studies can be found in Fig. 11.

[0108] To understand the biochemical events underlying the anti-senescence effects of Psib and Psin in vitro, western immunoblot was performed on cells following 48 hours of pretreatment with Psib or Psin prior to 48 hours exposure to 100 nM of Doxo. Psib and Psin ameliorated p38 phosphorylation, an oxidative stress-responsive kinase. Furthermore, Psib and Psin prevented histone H3 cleavage induced by doxorubicin, a post-translational modification that occurs in senescence. Results of the western blot are shown in Fig. 12.Example 4. Pharmacokinetic profile and CNS activity of 4-O-Pegylated psilocin derivatives (PEG4, PEG6, PEGS, and PEGlO-psilocin)

[0109] A pharmacokinetic study of the compounds PEG4, PEG6, PEG8, and PEGlO-psilocin was performed to evaluate the main PK parameters of the derivatives after oral administration. The compounds were administered to c57BL6 mice by oral gavage at a dose of 50 mg / kg, and blood was collected at 9 time points between 0 and 48 h.

[0110] The derivatives with shorter PEG chains (4 and 6 units) showed a remarkable higher Cmax and AUC than PEG8 and PEGlO-psilocin, being characterized by a higher bioavailability (Fig. 3).

[0111] Compounds were administered to c57BL6 mice by oral gavage at a dose of 50 mg / kg, and blood was collected at 9 time points between 0 and 48 h.The derivatives with shorter PEG chains (4 and 6 units) showed a remarkable higher Cmax and AUC than PEG8 and PEGlO-psilocin, being characterized by a higher bioavailability (Fig. 13).

[0112] Moreover, all the compounds are very poorly permeable to the BBB, since they were not able to trigger the head-twitch response in mice when administered at the psychedelic 3 mg / kg dose, at variance with psilocybin (Fig. 14), even in presence of preserved 5-HT2A activity (Fig. 15).

[0113] Example 5. Human Psilocybin Trials

[0114] In order to assess the safety, tolerability, and efficacy of psilocybin treatment in human patients, a randomized, double-blind, placebo-controlled study is designed and carried out. Volunteers are recruited with the following inclusion criteria:BMI 24.99-50 kg / m2inclusive;Body weight between 55 and 300 kg (inclusive) at screening;Stable body weight (±5 kg) by history (subject report) and stable physical activity within 3 months prior to screening by history (subject report);Steatotic Liver disease: Metabolic Dysfunction Associated Steatotic Liver Disease: MASLD, previously known as NAFLD, and MetALD (patients with metabolic dysfunction and also consuming limited amounts of alcohol (from 20 to 60 g per day) (Rinella et al. 2023);Magnetic Resonance Imaging Proton Density Fat Fraction (MRI PDFF) >8% Liver Fat Content (LFC);ALT between 21 and 75 U / L inclusive;AST between 21 and 75 U / L inclusive;FibroScan evidencing a liver stiffness < 14 kilo Pascal (KPa);Type 2 diabetes with diagnosed by any of the following criteria: fasting glucose > 126 mg / dl; any random glucose value > 200 mg / d; glucose > 200 mg / dl at 120 minutes after OGTT 75; HbAlc > 6.5%;HbAlc between 6 and 10% (between 42 and 86 mmol / mol); andAbsence of circulating autoantibodies against GAD.On one of the following with stable treatment for approximately 3 months prior to randomization: a) metformin monotherapy b) DPP4 inhibitor agent monotherapy c) combination therapy of metformin and a DPP4 inhibitor agent d) or no anti-diabetes pharmacotherapyDyslipidemia defined as fasting serum levels: triglycerides > 150 mg / dlHDL cholesterol < 40 mg / dl (male) or < 50 mg / dl (female)LDL cholesterol > 100 mg / dlThese three alterations can be present alone or in combination.Any treatment with statins or PSK9 inhibitors must be stable for approximately 3 months prior to randomizationHistory (subject report) of stable physical activity within 3 months prior to screening by history (subject report).GFR > 45 mL / min / 1.73m2.

[0115] Thirty-six participants are randomly assigned to receive a 2 mg psilocybin dose once per day. An additionally thirty-six participants receive 2 mg psilocybin twice per day, and a final thirty-six participants receive a placebo. Dosages are performed with a 0.5 mg modified release psilocybin oral tablet, with participants taking four tablets once or twice daily as indicated before breakfast or before dinner.

[0116] The full analysis set population will be used for all analyses of efficacy endpoints and consists of all randomly assigned patients who receive any trial treatment and have a baseline weight measurement and a day 120 + 7 assessment.

[0117] The sample size estimation was determined by the postulated Cohens effect size (group comparison) of 0.8 as well as the previously determined requirements of the significance level of 5.0% (double-sided) and power of 80%. Taking into account the estimated dropout rate of 20% and the block randomization, a total sample size of 36 individuals per study group (total 108 subjects) was recommended in order to achieve 30 completed subjects per arm.

[0118] The change from baseline to day 180 + 7 in total body FM measured by dual energy x- ray absorptiometry (DXA) will be compared among treatment groups. Differences in least square means with standard errors, 90% confidence intervals for the difference in least square means, and corresponding p values will be presented. In addition, Cohen’s d effect size and its 90% confidence interval will be estimated to measure the magnitude of REL-P11 effect compared with placebo. For efficacy evaluation total body FM measured by dual energy x-ray absorptiometry (DXA) fat mass at baseline and at day 180 + 7 are required. Patients who discontinued the trial prematurely will not be replaced. All analyses were based on available data, and no imputation for missing data will be made.

[0119] Estimation of REL-P11 main metabolite (psilocin) PK profile (maximum observed plasma concentration [Cmax], trough concentration [Ctrough], Area Under the concentration-vs- time Curve (AUC), and apparent terminal elimination half-life at steady state [ti / 2] based on PK sampling. For the first 45 subjects, PK sampling and psilocin plasma concentration will be performed just prior to the first dose and at 0.25, 0.5, 1, 2, 4, 6, 8, 12 hours (just prior the second dose). For subjects 46-90, PK sampling and psilocin plasma concentration will be performed just prior to the first dose and at Tmax + 15 minutes on the first day of treatment. For all subjects, psilocin plasma concentration will also be assessed once only on days 14, 30, 60, 90, 120, 150 and 180 + 7 and 194 + 2.

[0120] The primary efficacy endpoint is a change from baseline to day 120 ± 7 in total body fat mass (FM) measured by dual energy x-ray absorptiometry (DXA). Secondary efficacy endpoints include changes from baseline to day 120 + 7 in: body composition, including DXA- measured bone mineral-free lean mass; magnetic resonance imaging (MRI)-derived hepatic fat fraction; magnetic resonance imaging (MRI)-derived subcutaneous and abdominal visceral adipose tissue; metabolic status 1: Efficacy endpoints related to glucose metabolism and insulin sensitivity: HbAlc level, homeostatic model assessment [H0MA2], quantitative insulin sensitivity check [QUICK!], and Matsuda Index; metabolic status 2: Laboratory efficacy endpoints related to weight loss; body weight and BMI; waist circumference and waist-to-hip ratio; blood pressure; physical performance, including hand grip strength by dynamometry; liver stiffness as measured by Fibroscan.

[0121] Laboratory efficacy endpoints include improvement in parameters associated with metabolic diseases, and also liver laboratory parameters. Tn particular a change from baseline is assessed with respect to: serum lipid levels; high- sensitivity C-reactive protein [hsCRP] level; interleukin 6 level; leptin level; adiponectin level; ALT; AST; yGT; Platelet count; FIB4 index; hs-CRP; APO-B; Ceramides; Dihydroceramides; Sphingosine; Free fatty acids (total); and Glycosylated ceramides.INCORPORATION BY REFERENCE

[0122] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

CLAIMSWhat is claimed is:

1. A method of treating prediabetes, type-II diabetes, obesity, metabolic dysfunction associated steatotic liver disease (MASLD and MetALD), metabolic dysfunction steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), liver steatosis, nonalcoholic steatohepatitis (NASH), dyslipidemia, or sarcopenia in a patient in need thereof, the method comprising: orally administering a therapeutically effective, non-psychedelic amount of psilocybin or psilocin derivative to the patient; wherein about 0.001 mg to about 40 mg of psilocybin or psilocin derivative is administered; and wherein the psilocybin is administered in an extended-release dosage form.

2. The method of claim 1 , wherein the method comprising administering psilocybin, wherein the psilocybin is anhydrous psilocybin with a crystalline purity of at least 80%.

3. The method of claim 1, wherein the method comprises administering a psilocin derivative, wherein the psilocin derivative is according to Formula I:pharmaceutically acceptable salt thereof, whereinT is hydrogen, deuterium, Ci-Cs alkyl, Cz-Cs alkenyl, Cz-Cs alkynyl, Cz-Cs cycloalkyl, Cz-Cs cycloalkenyl, aryl, or heterocyclyl, wherein T is optionally substituted at one or more positions by one or more of deuterium, halo, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate. n is in the range of 1 to 100.

4. The method of claim 3, wherein T is hydrogen or Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted by one or two of halogen, methyl, CF3, hydroxy, nitro, or cyano.

5. The method of claim 3, wherein T is hydrogen, CH3, or CH2CH3.

6. The method of any of claims 3-5, wherein n is in the range of 1 to 20.

7. The method of any of claims 3-5, wherein n is in the range of 1 to 12.

8. The method of any of claims 3-5, wherein n is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

9. The method of claim 1, wherein the method comprises administering a psilocin derivative, wherein the psilocin derivative is according to Formula II:pharmaceutically acceptable salt thereof, wherein:Ri and R2 are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, optionally substituted at one or more positions by deuterium, halo, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, or a methoxy polyethylene glycol chain of formula (CH3-(OCH2CH2)n-) wherein n is comprised between 1 and 100.

10. The method of claim 9, wherein Ri is Ci-Cs alkyl optionally substituted with halo, alkyl ester, hydroxy, alkoxy, amino, alkylamino, nitro, cyano, thiol, thioalkyl, or methoxypolyethylene glycol chain of formula (CH3-(OCH2CH2)n-) wherein n is comprised between 1 and 20.

11. The method of claim 9, wherein Ri is Ci-Cs alkyl optionally substituted with halo, alkyl ester, hydroxy, alkoxy, amino, alkylamino, or methoxy polyethylene glycol chain of formula (CH3-(OCH2CH2)n-) wherein n is comprised between 1 and 20.

12. The method of claim 9, wherein Ri is Ci-Ce alkyl, wherein the Ci-Ce alkyl is optionally substituted by one or two of halogen, CF3, hydroxy, nitro, or cyano.

13. The method of claim 9, wherein Ri is C2-C4 alkyl, optionally substituted with 1, 2, or 3 fluoro groups.

14. The method of claim 9, wherein Ri is C2-C6 alkyl, optionally substituted with a carboxy, methyl ester, or ethyl ester group.

16. The method of any of claims 9-15, wherein R2 is hydrogen or CH3.

17. The method of any of claims 3-16, wherein the psilocin derivative is the hydrochloride salt thereof.

18. The method of claims 1-17, wherein the amount of psilocybin or psilocin derivative is about 0.05 mg to about 10 mg.

19. The method of claims 1-17, wherein the amount of psilocybin or psilocin derivative is about 0.1 mg to about 5 mg.

20. The method any of claims 1-19, wherein about 0.5 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg or about 6 mg of psilocybin or psilocin derivative is administered.

21. The method of any of claims 1-19 wherein about 0.001 mg / kg to about 0. 1 mg / kg of psilocybin or psilocin derivative is administered.

22. The method of any of claims 1-22, wherein the psilocybin or psilocin derivative is administered once a day or twice a day.

23. The method of any of claims 1-22, wherein the psilocybin or psilocin derivative is administered once every other week, once a week, twice a week, three times a week, four times a week, five times a week, or six times a week.

24. The method of any of claims 1-23, wherein 0.5 mg of psilocybin or psilocin derivative (according to claims 3 and 4) is administered once per day.

25. The method of any of claims 1-23, wherein 1 mg of psilocybin or psilocin derivative (according to claims 3 and 4) is administered once per day.

26. The method of any of claims 1-23, wherein 2 mg of psilocybin or psilocin derivative (according to claims 3 and 4) is administered once per day.

27. The method of any of claims 1-23, wherein 1 mg of psilocybin or psilocin derivative (according to claims 3 and 4) is administered as 0.5 mg twice per day.

28. The method of any of claims 1-23, wherein 2 mg of psilocybin or psilocin derivative (according to claims 3 and 4) is administered as 1 mg twice per day.

29. The method of any of claims 1-23, wherein 4 mg of psilocybin or psilocin derivative (according to claims 3 and 4) is administered as 2 mg twice per day.

30. The method of any of claims 1 -29, wherein the psilocybin or psilocin derivative (according to claims 3 and 4) is administered to the patient while fasted.

31. The method of claims 1-30, wherein the extended-release dosage form comprises 0.5 mg of psilocybin or psilocin derivative (according to claims 3 and 4).

32. The method of any of claims 1-31, wherein administration provides a dosage with a psilocin or psilocin derivative (according to claims 3 and 4) Cmax of no more than about 10 ng / mL (e.g., no more than about 8 ng / mL, 6 ng / mL, 5 ng / mL, 4 ng / mL, 3 ng / mL, or 2 ng / mL)33. The method of claim 32, wherein administration provides a dosage with a psilocin or psilocin derivative (according to claims 3) Cmaxof at least about 0. 1 ng / mL.

34. The method of any of claims 1-33, wherein administration provides a dosage with a psilocin or psilocin derivative (according to claims 3 and 4) Tmaxof at least about 1.5 h (e.g., at least about 1.7 h, 1.8 h, 1.9 h, 2 h, 2.1 h, 2.2 h, 2.3 h, 2.4 h, or 2.5).

35. The method of claim 34, wherein administration provides a dosage with a psilocin or psilocin derivative Tmaxof no more than about 24 h (e.g., no more than about 12 h, or about 8 h).

36. The method of any of claims 1-35, wherein administration provides a psilocin or psilocin derivative (according to claims 3) Cmaxat least 10% less than the Cmaxfrom an equivalent psilocybin or psilocin derivative (according to claims 3 and 4) dosage that is not administered in an extended-release dosage form.

37. The method of any of claims 1-36, wherein administration provides a psilocin or psilocin derivative Tmaxat least 10% greater than the Tmaxfrom an equivalent psilocybin or psilocin derivative (according to claims 3 and 4) dosage that is not administered in an extended-release dosage form.

38. The method of any of claims 1-36, wherein the administration provides a reduction in total body fat mass compared to prior to the treatment as determined by dual energy X-ray absorptiometry.

39. The method of any of claims 1-36, wherein the administration provides a reduction in MRI-derived hepatic fat fraction compared to prior to the treatment.

40. The method of claim 39, wherein the reduction in MRI-derived hepatic fat fraction as compared to prior to the treatment is at least about 5% (e.g., in the range of about 5% to about 20%, or about 5% to about 15%, or about 8% to about 20%, or about 8% to about 15%).

41. The method of any of claims 1-40, wherein the administration provides a reduction in liver stiffness compared to prior to the treatment as measured by Fibroscan.

42. The method of claim 41, wherein the reduction in liver stiffness is at least about 3 kPa (e.g., at least about 3 kPa, or in the range of about 3 kPa to about 12 kPa, or in the range of about 5 kPa to about 12 kPa, or in the range of about 3 kPa to about 10 kPa, or in the range of about 5 kPa to about 10 kPa).

43. The method of any of claims 1-42, wherein the administration provides at least one of: a reduction in body weight, by an amount in the range of about 2 kg to about 8 kg (e.g., about 4 kg to about 6 kg); a reduction in fasting plasma glucose, by an amount in the range of about 10 mg / dl to about 60 mg / dl (e.g., in the range of about 15 mg / dl to about 45 mg / dl); a reduction in serum HbAlc, by an amount in the range of 0.5 to 1.0%, and / or about 3.5 mmol to about 7.0 mmol); a reduction in serum triglycerides; by an amount in the range of about 10 mg / dl to about 80 mg / dl (e.g., about 15 mg / dl to about 60 mg / dl); or an increase in serum HDL cholesterol, by an amount in the range of about 2 mg / dl to about 15 mg / dl (e.g., about 5 mg / dl to about 10 mg / dl).

44. The method of any of claims 41-43, wherein the increase or reduction is observed 120 ± 7 days or 150 + 7 days 180 + 7 days after beginning administration.

45. The method of any of claims 41-43, wherein the increase or reduction is observed within 360 + 7 days after beginning administration.

46. The method of any of claims 1-45, further comprising:(a) monitoring the patient for psychoactive symptoms, and(b) if psychoactive symptoms are observed, reducing the amount of psilocybin or psilocin derivative administered to the patient.

33. The method of any of claims 1-46 where psilocybin or a psilocin derivative is combined with a GLP- 1 agonist.

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