WO2025006703A2

WO2025006703A2 - Combination therapies using psilocybin

Info

Publication number: WO2025006703A2
Application number: PCT/US2024/035751
Authority: WO
Inventors: Paolo L. Manfredi; Charles E. Inturrisi; Sara DE MARTIN; Andrea Mattarei; Marco Pappagallo; Franco Folli; Gianfranco Pasut; Stefano COMAI
Original assignee: Universita degli Studi di Padova
Current assignee: Universita degli Studi di Padova
Priority date: 2023-06-27
Filing date: 2024-06-27
Publication date: 2025-01-02
Anticipated expiration: 2025-12-27
Also published as: WO2025006703A3

Abstract

Methods of therapy using compounds of formula (I) in combination with or as adjunctive to a GLP-1 receptor agonist, metformin, a PPARγ-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, acarbose or pramlintide or one or more amino acids, one or more vitamins, or one or more hormones are described.

Description

COMBINATION THERAPIES USING PSILOCYBIN

BACKGROUND

[0001] 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, PTSD, OCD, and addiction. In clinical studies to date, the psychedelic experience and central nervous system (CNS) psychoactive effects are integral parts of the intended treatment. However, the effect of these substances on other biological processes, including lipid and sugar metabolism, the dysregulation of which leads to metabolic disorders, is poorly understood.

[0002] Sarcopenia is often present in patients with metabolic disorders. Sarcopenia is a medical term describing the loss of skeletal muscle mass, in particular with metabolic disorders, aging, cancer or as a consequence of other diseases and their treatments, including treatments for obesity and metabolic disorders, that can impact overall health and quality of life.

[0003] Accordingly, there is a need to develop new compositions, formulations, and methods for treating metabolic disorders and sarcopenia and/or to treat metabolic disorders without causing/worsening 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, comprising administering psilocybin or other molecules with a similar pharmacodynamic profile (e.g., as reported in Example 1, agonism to 5-HT2A and 5-HT2C and antagonism to 5-HT2B), for example as an adjunctive therapy to another therapeutic or even in combination with another therapeutic.

[0005] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising: administering a non-psychedelic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a GLP- 1 receptor agonist to the patient,

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, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

R3 is hydrogen, deuterium, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-R are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

[0006] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of the compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a biguanide to the patient.

[0007] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a PPARy-agonist to the patient.

[0008] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and a sulfonylurea-based compound to the patient. [0009] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and a DPP-IV inhibitor to the patient.

[0010] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and pramlintide to the patient.

[0011] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and one or more amino acids, one or more vitamins, or one or more hormones to the patient.

[0012] In embodiments, the present disclosure provides a method of treating a metabolic disorder in a patient in need thereof, the method comprising co-administering to the patient a pharmaceutical composition comprising:

(a) a non-psychedelic amount of psilocybin and

(b) a GLP-1 receptor agonist.

[0016] In embodiments, the present disclosure provides a method of treating a metabolic disorder in a patient in need thereof, the method comprising co-administering to the patient a pharmaceutical composition comprising:

(a) a non-psychedelic amount of psilocybin and

(b) a GLP-1 receptor agonist and

(c) either metformin, a PPARy- agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or pramlintide or one or more amino acids, or one or more vitamins, or one or more hormones.

[0017] In embodiments, the metabolic disorder is prediabetes, type-II diabetes mellitus, 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), or dyslipidemia.

[0018] In embodiments, the disorder is sarcopenia associated with a metabolic disorder. In embodiments, the disorder is sarcopenia associated with aging and other disorders and their treatment. In embodiments, the disorder is sarcopenia.

[0019] In embodiments the GLP-1 receptor agonist is semaglutide.

[0020] Other embodiments will be readily apparent to the skilled person based on the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1. Psilocin activity (agonist mode) on 5-HT2A (**), 5-HT2B (***), and 5- HT2C (*) receptors.

[0022] Figure 2. Psilocin activity (antagonist mode) on 5-HT2B receptors.

[0023] Figure. 3. Effect of psilocin and semaglutide, and psilocin and metformin coadministration to hepatic cells. *p<0.05, **p<0.01, ***p<0.001 vs control cells, ^$p<0.05, ^wp<0.01 vs PA:OA treated cells. [0024] Figure 4. Fluorescence data of cells co-administered psilocin and semaglutide.

[0025] Figure 5. Body weight increase (A) and area under the curve of body weing increase (B) in the 5 study groups. *p<0.05, ***p<0.001; p<0.0001 vs controls, ^###p<0.001, ^####p<0.0001 vs MASLD mice, ®®p<0.001 vs psilocybin-treated mice.

[0026] Figure 6. Liver histology of the 5 study groups. All the treatments reduced liver steatosis. The histology of mice treated with the combination of semaglutide and psilocybin is virtually identical to that of the healthy control group.

[0027] Figure 7. Blood glucose levels after an intraperitoneal glucose tolerance test (A), fasting blood glucose (B) and area under the blood glucose vs time curve (C) in the 5 study groups. *p<0.05 vs controls.

[0028] Figure 8. Grid test score of the 5 study groups after 6, 8, 10, and 12 weeks after treatment. *p<0.05, ***p<0.001; p<0.0001 vs controls, ^##p<0.0 l vs MASLD mice.

[0029] Figure 9. Leptin plasma levels of the 5 study group. *p<0.05, vs controls, ^#p<0.05 vs MASLD mice.

[0030] Figure 10. mRNA expression of PLIN4 in the 5 study group. *p<0.05.

[0031] Figure 11. 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.

[0032] Figure 12. 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, ^##p<0.01 vs MASLD mice.

[0033] Figure 13. Protein expression of IRS1 in the liver of the 3 study group. **p<0.01 vs control.

[0034] Figure 14. Quantification of cFos protein positive cells by means of immunohistochemical detection in the dorsomedial hypothalamus (DMH), ventromedial hypothalamus (VMH) and arcuate nucleus (Arc). *p<0.05, **p<0.01 vs vehicle-treated mice.

DETAILED DESCRIPTION

[0035] 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.

[0036] 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.

[0037] 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 is inconsistent 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. 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.

[0038] The terms “effective amount" and "therapeutically effective amount" are used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to a subject, is capable of performing the intended result.

[0039] 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.

[0040] 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, citric acid, 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, butyl ammonium, 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.

[0041] In embodiments, an effective amount of psilocybin and/or GLP-1 receptor agonist, metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or pramlintide or amino acids, vitamins, or one or more hormones is that amount that is required to improve at least one symptom/biochemical marker of a metabolic disorder or sarcopenia as otherwise described herein in a patient or to restore normal blood levels of the substance or therapeutic blood levels of the drug. 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.

[0042] 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.

Administration of psilocybin or of molecules with similar structure and pharmacodynamic profile [0043] Psilocybin is a prodrug; the active compound, psilocin, is rapidly released in the gut by dephosphorylation. Psilocin is a serotonin (5-HT) receptor agonist, exerting its psychedelic effects by activating the 5-HT2AR isoform¹ in the CNS. However, the activity of psilocin on the 5-HT2AR isoform and other 5-HT2R isoforms within or outside of the CNS and the involvement of specific 5-HT2R isoform in psilocin- mediated metabolic effects have not been evaluated. Furthermore, preclinical and clinical evidence point at 5-HT2B agonism as a risk factor for the development of valvular heart disease, similarly to the cardiac effects caused by pergolide and cabergoline²^. Considerable efforts have been made to understand the mechanism of metabolic disorders in order to expand the current limited treatment modalities. Globally, the most prevalent metabolic disorders are obesity, Type 2 diabetes mellitus, and metabolic dysfunction associated steatotic liver diseases (MASLD). Sarcopenia is often present in patients with metabolic disorders. Sarcopenia is a medical term describing the loss of skeletal muscle mass, in particular with metabolic disorders, aging, cancer or as a consequence 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, Type 2 diabetes, MASLD, being in this case defined as dysmetabolic sarcopenia and may be related to insulin resistance/glucose intolerance⁵. Sarcopenia is associated with increased risk of falls, fractures, disability, hospitalization and mortality, especially in older patients. In this context, sarcopenia can increase the medical, social and economic burden of metabolic and other diseases⁶'⁷. Sarcopenia is a frequent complication of chronic liver diseases, with an estimated prevalence of ranging from 25 to 70% in these patients⁸. Higher rates have been identified among male patients⁹. The mechanisms of muscle loss in chronic liver diseases have been only partially understood and are partly related to an unbalanced regulation of muscle protein turnover. The synthesis of muscle proteins is regulated by several molecular signaling pathways. An unbalance between synthesis and degradation of muscle proteins and their bioproducts in muscle tissue leads to muscle breakdown¹⁰, and finally to sarcopenia. The primary impairment may be in synthesis or degradation or both.

[0044] Notably, plasma concentration of leptin, a hormone secreted by adipose tissue in proportion to fat mass, was found to be related to the risk of developing sarcopenia in obese patients¹¹. Accordingly, there is a general consensus that leptin may serve as a pharmacological target for the therapy of obesity and other metabolic diseases. Furthermore, it has been demonstrated that leptin plays a fundamental role in regulating muscle mass and strength¹², indicating that drugs with an effect on leptin levels/leptin action may be useful for controlling metabolic abnormalities and also related sarcopenia.

[0045] To date, the treatment of sarcopenia is usually not pursued by the administration of drugs but with different approaches, such as for instance resistance exercise and nutritional supplements. However, there are several compounds currently in clinical development with the aim of reversing age-related loss of muscle mass and function, including androgens/androgen receptor modulators, metformin, estrogens, and angiotensin converting enzyme inhibitors^{13 14}.

[0046] Furthermore, therapeutic drugs used for the treatment of metabolic diseases including dyslipidemia such as statins and GLP-1 agonists can cause muscle-related side effects and sarcopenia.

[0047] Metabolic diseases, including Type II diabetes mellitus, obesity, and MASLD, are often associated with muscle dysfunction and the so called dysmetabolic sarcopenia. Furthermore, also therapeutic drugs used for the treatment of metabolic diseases can be the cause of muscle- related side effects and sarcopenia. The treatment of sarcopenia is usually not pharmacological, including resistance exercise and nutritional supplements. On this basis, there is a need to develop new compositions, formulations, and methods for treating metabolic disorders and sarcopenia and/or to treat metabolic disorders without causing/worsening sarcopenia.

[0048] Combination or adjunctive treatments using psilocybin for the treatment of metabolic disorders and/or sarcopenia are disclosed herein. Also, herein are disclosed molecules with the similar molecular scaffold and pharmacodynamic profile of psilocin.

[0049] As described herein, a non-psychedelic amount of compounds of formula (I) may be administered in combination or as an adjunctive therapy to a GLP-1 receptor agonist, metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or pramlintide, or alpha-glucosidase inhibitor or one or more amino acids, one or more vitamins, or one or more hormones. Formula (I) is described below:

wherein:

Ri and R2 are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, C -Cs alkenyl, C2-C8 alkynyl, C Cs cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3- Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

[0050] In embodiments, the compound of formula (I) is psilocybin. In embodiments, the compound of formula (I) is psilocin. The compound of formula (I) may be any suitable pharmaceutical salt thereof. Further compounds of formula (I) are described, for example, in International Patent Application nos. PCT/US2020/021400 and PCT/US2022/028559, both of which are incorporated herein in their entirety. In embodiments, the compound of formula (I) is a pegylated psilocin, or a psilocin carbamate. In embodiments, the pegylated psilocin is obtained by O-alkylation of psilocin with methoxy poly(ethylene glycol) chains containing 4 to 10 units of ethylene glycol, with general formula:

wherein: n is 4-10.

[0051] In embodiments, the psilocin carbamate is:

Wherein:

Ri and R2 are, independently for each occurrence, hydrogen, Ci-Cs alkyl, C2-C8 alkenyl, C2- Cs alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; m is 1-10.

[0052] In embodiments, the non-psychedelic amount of the compound of formula (1) is about 0.1 mg to about 7 mg. In embodiments, the non-psychedelic amount of the compound of formula (I) 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. In embodiments, the non-psychedelic amount of the compound of formula (I) is about 0.5 mg, about 1 mg, about 2 mg, or about 3 mg, for example, about 0.5 mg.

[0053] In embodiments, the non-psychedelic amount of the compound of formula (I) 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, about 0.01 mg/kg to about 0.1 mg/kg, or about 0.05 mg/kg.

[0054] In embodiments, the compound of formula (I) is administered in a modified- release dosage form. [0055] In embodiments, 0.5 mg the compound of formula (I) is administered in a modified- release dosage form.

[0056] The compound of formula (I) may be administered at various time points. In embodiments, the compound of formula (I) is administered once a day, twice a day, or three times a day. In other embodiments, the psilocybin 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

[0057] In embodiments, the non-psychedelic amount of psilocin is about 0.1 mg to about 7 mg. In embodiments, the non-psychedelic amount of psilocin 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. In embodiments, the non-psychedelic amount of psilocin is about 0.5 mg, about 1 mg, about 2 mg, or about 3 mg, for example, about 0.5 mg.

[0058] In embodiments, the non-psychedelic amount of psilocin 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, about 0.01 mg/kg to about 0.1 mg/kg, or about 0.05 mg/kg.

[0059] In embodiments, the psilocin is administered in a modified-release dosage form. [0060] In embodiments, 0.5 mg psilocin is administered in a modified-release dosage form.

[0061] The psilocin may be administered at various time points. In embodiments, the psilocin is administered once a day, twice a day, or three times a day. In other embodiments, the psilocin 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

[0062] In embodiments, the non-psychedelic amount of psilocybin is 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 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. In embodiments, the non-psychedelic amount of psilocybin is about 0.5 mg, about 1 mg, about 2 mg, or about 3 mg, for example, about 0.5 mg. [0063] 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, about 0.01 mg/kg to about 0.1 mg/kg, or about 0.05 mg/kg.

[0064] In embodiments, the psilocybin is administered in a modified-release dosage form. [0065] In embodiments, 0.5 mg psilocybin is administered in a modified-release dosage form. [0066] The psilocybin may be administered at various time points. In embodiments, the psilocybin is administered once a day, twice a day, or three times a day. In other embodiments, the psilocybin 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.

Combination Therapies

[0067] In embodiments, the present disclosure provides a method of treating a metabolic disorder and/or sarcopenia in a patient in need thereof, the method comprising administering a non-psychedelic amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a GLP-1 receptor agonist to the patient,

wherein:

Ri and R2 are, independently for each occurrence, hydrogen, deuterium, C -Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5. [0068] In embodiments, the compound of formula (I) is administered as an adjunctive therapy to the GLP-1 receptor agonist. In embodiments, the compound of formula (I) is administered in combination with the GLP- 1 receptor agonist.

[0069] In embodiments, psilocybin is administered as an adjunctive therapy to the GLP-1 receptor agonist. In embodiments, the psilocybin s administered in combination with the GLP- 1 receptor agonist.

[0070] In embodiments, psilocin is administered as an adjunctive therapy to the GLP-1 receptor agonist. In embodiments, the psilocin is administered in combination with the GLP-1 receptor agonist.

[0071] In embodiments, the GLP-1 agonist comprises dulaglutide, exenatide, semaglutide, liraglutide, or lixisenatide.

[0072] In embodiments, the GLP-1 agonist is semaglutide. Semaglutide may be administered as known in the art. In embodiments, about 0.25 mg, about 0.5 mg, about 1 mg, about 2.4 mg, or about 3 mg of semaglutide is administered parenterally weekly to the patient. In embodiments, about 3 to about 21 mg of oral semaglutide is administered daily to the patient. In embodiments, about 3 mg, about 7 mg, or about 14 mg of oral semaglutide is administered daily to the patient.

[0073] In embodiments, the GLP-1 receptor agonist is dulaglutide. Dulaglutide may be administered as known in the art. In embodiments, about 0.75 mg, about 1.5 mg, or about 3 mg of dulaglutide is administered weekly to the patient.

[0074] In embodiments, the GLP-1 receptor agonist is exenatide. Exenatide may be administered as known in the art. In embodiments, about 5 mcg or about 10 mcg of exenatide is administered twice daily to the patient. In embodiments, the GLP1 receptor agonist is slow- release exenatide. Slow release exenatide may be administered as known in the art. In embodiments, about 1 or 2 mg of slow release exenatide is administered weekly to the patient. [0075] In embodiments, the GLP-1 receptor agonist is liraglutide. Liraglutide may be administered as known in the art. In embodiments about 0.6, about 1.2 mg or about 1.8 mg of liraglutide is administered daily to the patient.

[0076] In embodiments, the GLP-1 receptor agonist is lixisenatide. Lixisenatide may be administered as known in the art. In embodiments about 10 mcg or about 20 mcg lixisenatide is administered daily to the patient, [0077] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of the compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a biguanide to the patient,

wherein:

RI and R2 are, independently for each occurrence, hydrogen, deuterium, C -Cs alkyl, O-Cs alkenyl, C2-C8 alkynyl, Ci-Cs cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C -Cs alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

[0078] In embodiments, the compound of formula (1) is administered as an adjunctive therapy to the biguanide. In embodiments, the compound of formula (I) is administered in combination with the biguanide.

[0079] In embodiments, the biguanide is metformin. Metformin may be administered as known in the art. In embodiments, about 850 mg to about 2550 mg of metformin hydrochloride is administered to the patient per day. In embodiments, about 500 mg of metformin hydrochloride is administered twice a day, or about 850 mg of metformin hydrochloride is administered once a day. In embodiments, about 500 mg, about 1000 mg, about 1500 mg, or about 2000 mg of metformin hydrochloride is administered to the patient a day in an extended- release tablet.

[0080] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a PPARy-agonisl to the patient,

wherein:

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rx are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

[0081] In embodiments, the compound of formula (I) is administered as an adjunctive therapy to the PPARy-agonist. Tn embodiments, the compound of formula (I) is administered in combination with the PPARy-agonist.

[0082] In embodiments, the PPARy-agonist is pioglitazone. Pioglitazone may be administered as known in the art. In embodiments, about 15 mg, about 30 mg, or about 45 mg of pioglitazone hydrochloride is administered per day (e.g., about 15 mg of pioglitazone hydrochloride is administered per day).

[0083] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and a sulfonylurea-based compound to the patient,

wherein:

Ri and R are, independently for each occurrence, hydrogen, deuterium, C -Cx alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5. [0084] In embodiments, the compound of formula (I) is administered as an adjunctive therapy to the sulfonylurea-based compound. In embodiments, the compound of formula (I) is administered in combination with the sulfonylurea-based compound.

[0085] In embodiments, the sulfonylurea-based compound comprises glimepiride, gliclazide, or glibenclamide.

[0086] In embodiments, the sulfonylurea-based compound is glimepiride. Glimepiride may be administered as known in the art. In embodiments, about 1 mg or about 2 mg of glimepiride is administered per day to the patient.

[0087] In embodiments, the sulfonylurea-based compound is gliclazide. Gliclazide may be administered as known in the art. In embodiments, about 40 mg to about 120 mg of glimepiride is administered per day to the patient.

[0088] In embodiments, the sulfonylurea-based compound is glibenclamide. Glibenclamide may be administered as known in the art. In embodiments, about 2.5 mg to about 10 mg of glibenclamide is administered per day to the patient.

[0089] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and a DPP-IV inhibitor to the patient,

wherein:

Ri and R 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, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; Rs is hydrogen, deuterium, halogen, Ci-Cs alkyl, Cz-Cs alkenyl, Cz-Cs alkynyl, Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

R4 is hydrogen, deuterium, Ci-Cs alkyl, Cz-Cs alkenyl, Cz-Cs alkynyl, Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, Cz-Cs alkenyl, Cz-Cs alkynyl, Cs-Cs cycloalkyl, Cs-Cs cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

[0090] In embodiments, the compound of formula (I) is administered as an adjunctive therapy to the DPP-IV inhibitor. In embodiments, the compound of formula (I) is administered in combination with the DPP-IV inhibitor.

[0091] In embodiments, the DPP-IV inhibitor comprises vildagliptin, linagliptin, sitagliptin, alogliptin, or evogliptin. [0092] In embodiments, the DPP-IV inhibitor is vildagliptin. Vildagliptin may be administered as known in the art. In embodiments, about 50 mg to about 100 mg of vildagliptin is administered per day to the patient.

[0093] In embodiments, the DPP-IV inhibitor is linagliptin. Linagliptin may be administered as known in the art. In embodiments, about 5 mg of linagliptin is administered per day to the patient.

[0094] In embodiments, the DPP-IV inhibitor is sitagliptin. Sitagliptin may be administered as known in the art. In embodiments, about 50 mg to about 100 mg of sitagliptin is administered per day to the patient.

[0095] In embodiments, the DPP-IV inhibitor is alogliptin. Alogliptin may be administered as known in the art. In embodiments, about 12.5 mg to about 25 mg of alogliptin is administered per day to the patient.

[0096] In embodiments, the DPP-IV inhibitor is evogliptin. Evogliptin may be administered as known in the art. In embodiments, about 5 mg of evogliptin is administered per day to the patient.

[0097] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and a alpha-glucosidase inhibitor (e.g., acarbose) to the patient,

wherein:

Ri and R2 are, independently for each occurrence, hydrogen, deuterium, C -Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cs-Cs cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

Rr is hydrogen, deuterium, halogen, Ci-Cs alkyl, Cb-Cs alkenyl, Ch-Cs alkynyl, Cr-Cs cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, Cs-Cs cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

[0098] In embodiments, the alpha-glucosidase inhibitor is acarbose. Acarbose may be administered as known in the art. In embodiments, about 25mg PO every 8 hours, at meals. In embodiments, the administration of acarbose can be increased to 50 or 100 mg PO every 8 hours, at 4 to 8 weeks intervals.

[0099] In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and pramlintide to the patient,

wherein:

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkyl sulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

[0100] In embodiments, the compound of formula (I) is administered as an adjunctive therapy to pramlintide. In embodiments, the compound of formula (I) is administered in combination with pramlintide.

[0101] In embodiments, about 60 pg to about 360 pg of pramlintide is administered to the patient per day.

In embodiments, the present disclosure provides a method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and one or more amino acids, one or more vitamins, or one or more hormones to the patient,

wherein:

[0102] In embodiments, the compound of formula (I) is administered as an adjunctive therapy to the one or more amino acids, one or more vitamins, or one or more hormones. In embodiments, the compound of formula (I) is administered in combination with the one or more amino acids, one or more vitamins, or one or more hormones.

[0103] In embodiments, the one or more amino acid comprises leucine. In embodiments, the one or more amino acid comprises creatine.

[0104] In embodiments, the one or more vitamins comprises vitamin D and/or vitamin B. For example, the vitamin B may comprise vitamin Bl, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, or vitamin B12. In particular embodiments, the one or more vitamin comprises vitamin D and/or vitamin B 12.

[0105] In embodiments, the one or more hormones comprises testosterone or estrogen.

[0106] In embodiments as described herein, the compound of formula (I) may be administered as an adjunctive therapy to another therapeutic or may be co-administered. Accordingly, in embodiments, the present disclosure provides a method of treating a metabolic disorder in a patient in need thereof, the method comprising co-administering to the patient:

(a) a non-psychedelic amount of the compound of formula (I); and

(b) a GLP-1 receptor agonist, metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or pramlintide or one or more amino acids, one or more vitamins, or one or more hormones.

[0107] Co-administration of psilocybin and another therapeutic or supplement as described herein may have a synergistic effect, providing enhanced efficacy for metabolic disorders or sarcopenia than either used alone. Accordingly, in embodiments, the combination may produce a dose-sparing effect, where the dosage of either psilocybin or the other therapeutic as described herein, or both, may be reduced. Accordingly, in embodiments, the GLP-1 receptor agonist, metformin, a PPARy- agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, acarbose, or pramlintide is administered at a dose less than the dosage administered when used as a monotherapy, or at the lowest approved dose. As used herein, the lowest approve dose is the lowest dosage approved for patient administration by a government agency, such as the FDA.

[0108] 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), or dyslipidemia. In embodiments, the disorder is sarcopenia.

[0109] In embodiments, sarcopenia may be associated with a metabolic disorder, or the sarcopenia may be associated with aging or medical treatments or diseases. For example, aging may be accelerated by cancer, noxious agents, including medical treatments, including treatments for metabolic disorders, including cancer treatments and other diseases and their treatments.

EXAMPLES

[0110] The present invention is further illustrated by reference to the following Examples, which are illustrative and are not to be construed as restricting the scope of the invention in any way.

Example 1: Psilocin pharmacodynamics

[0111] A study was designed to characterize the activity (either agonist or antagonist) of psilocin, the active form of psilocybin, at human 5-HT2A, 5-HT2B and 5-HT2C receptors expressed in CHO-K1 (Chinese Hamster Ovary) cells, using an intracellular calcium mobilization assay, i.e., the FLIPR (Fluorometric Imaging Plate Reader) Penta assay, performed in 384- well format.

[0112] The recombinant 5-HT2A, 5-HT2B and 5-HT2C CHO cell lines, pharmacologically validated with reference compounds, were cultured in a humidified incubator with 5% CO2 in F12K medium supplemented with 10% dialyzed, heat-inactivated fetal bovine serum, and 450 pg/ml of Geneticin (G418). The cells were grown in T175 flasks and passaged when 80 - 90% of confluence was reached. [0113] To assess the agonist activity, psilocin was tested for its ability to induce a calcium response at 5-HT2A, 2B or 2C receptors using Cal-520 as no washing calcium dye. The response was measured in real time upon receptor stimulation. The ability to inhibit the calcium response induced by a submaximal concentration (EC80) of the endogenous ligand serotonin (5-HT) was also evaluated by following a dual-addition FLIPR protocol (antagonism modality).

[0114] Psilocin was profiled in 11 -point titration curves in duplicate in two independent test occasions including 5-HT as reference compound in each test, following a standardized protocol. Briefly, after seeding and medium removal, 5-HT2A and 5-HT2B-CHO cells were loaded for 30 min and 5-HT2C-CHO cells for Ih at 37°C with 30 pL/well of a loading solution IX (assay buffer containing 5 pM Cal-520 AM), 2.5 mM probenecid and 0.01 % Pluronic F- 127).

[0115] The loaded cell plates were transferred to the FLIPR instrument and calcium response was monitored during the two on-line addition protocol.

[0116] 1st FLIPR addition: 10 pL/well of psilocin (4X concentration) or 10 pL/well of EC100 of 5-HT (positive control) or buffer containing DMSO 2% (4X) (basal) were added to the loaded cells and calcium mobilization responses were measured (Agonist Mode).

[0117] 2nd FLIPR addition: after 10 minutes, 10 pL/well of EC80 of 5-HT (5X concentration) were added in the compound treated wells to evaluate the potential inhibitory effect (Antagonist Mode).

[0118] These assays provided in vitro agonist and antagonist potency values of psilocin, defined as pEC50 (-log EC50) and pIC50 (-logIC50), respectively at the 5-HT2A, 5-HT2B and 5-HT2C receptors stably expressed in CHO cells.

[0119] Psilocin displayed a peculiar pharmacodynamic profile on 5-HT2 receptors, behaving as partial agonist at 5-HT2A and 5-HT2C receptors with pEC50 of 7.95 and 7.38, respectively (Fig. 1), and as an antagonist at 5-HT2B with potency of 7.62 (Fig. 2).

Example 2. In Vitro combination treatment of GLP-1 receptor agonist and psilocin [0120] Psilocybin is endogenously metabolized to psilocin. The effects of psilocin in combination with the GLP-1 receptor agonist semaglutide were investigated. Lipid accumulation in the hepatic cell line HepG2 were induced by incubating the cells with a 0.1 mM 1: 1 mixture of palmitic acid (PA) and oleic acid (OA) according to literature methods ¹⁵. Subsequently, the cells were treated with combinations of semaglutide, psilocin, and metformin, and the percent lipid positive area measured. Semaglutide in combination with psilocin was found to decrease the accumulation of lipids in an in vitro model of steatotic liver disease, suggesting a synergistic effect. In contrast, the combination of psilocin with the antidiabetic drug metformin was found to be less effective in reducing the accumulation of lipids in the in vitro model of steatotic liver disease. Results of these experiments are shown in Fig. 3 and Fig. 4, and Table 1 below.

[0121] Table 1

Example 3: In Vivo combination treatment of a GLP-1 receptor agonist and psilocin in a mouse model of metabolic-associated steatotic liver disease (MASLD)

[0122] The effect of the combination of psilocybin (0.05 mg/kg daily, by oral gavage) and the GLP-1 agonist semaglutide (40 pg, twice weekly, subcutaneous route) and of the two single drugs in mice with MASLD obtained by the administration of a diet rich in fat (60% kcal from fat) boosted with 30% fructose in drinking water (n=10 animals per group) was tested. All treated mice showed a significant reduction of body weight gain, more evident in the group treated with the combination of psilocybin and semaglutide (Fig. 5) and of liver steatosis (Fig. 6) with respect to untreated mice with MASLD.

[0123] Although all the treated mice showed a significant reduction of fasting glucose (Fig. 7B), only mice treated with the combination of the two drugs show a signficant reduction of the area under the blood glucose- vs-time in the intraperitoneal glucose tolerance test (Fig. 7A and 7C), indicating a dramatic amelioration of insulin resistance. [0124] The muscle strength of these mice was evaluated by the grid test. The results of this experiment indicated that only the groups treated with psilocybin or the combination of psilocybin and semaglutide had a significant delay in the decay of their motor performance, which was quickly achieved by the untreated MASLD mice and by those treated only with semaglutide (Fig. 8, see Table 2).

Table 2:

[0125] Notably, plasma levels of leptin were increased in MASLD untreated mice (indicating the presence of leptin-resistance) and reduced by the treatments (Fig. 9).

[0126] Accordingly, the mRNA levels of PLIN4, which plays a detrimental role in skeletal muscle^{16 17}, is significantly reduced in the quadriceps of psilocybin-treated mice with respect to untreated MASLD mice (Fig. 10).

[0127] 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. 11). 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.

[0128] 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. 12).

[0129] 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. 13).

Example 4: In Vivo effect of psilocybin on the activation of the hypothalamus, a brain region that regulates feeding and energy expenditure. [0130] It was investigated whether psilocybin (0.05 mg/kg daily, by intraperitoneal injection for 30 days) could affect the activity of the hypothalamus by determining c-Fos activation, which is an indicator of neuronal activity. This helps in understanding which neurons in the hypothalamus are active in response to specific stimuli, such as food intake or satiety signals. Treatment with psilocybin significantly reduced the neuronal activation in the right and left dorsomedial hypothalamus but did not affect the neuronal activation in the right and left ventromedial hypothalamus (Fig. 14). A tendency for a reduction of neuronal activation by psilocybin in the arcuate nucleus of the hypothalamus was observed (Fig. 1 1 ). The dorsomedial hypothalamus plays a crucial role in regulating metabolism and feeding behavior, impacting on hunger and satiety signals. Indeed, activation of the dorsomedial hypothalamus can influence energy expenditure, food intake, and body weight by modulating the autonomic nervous system and interacting with other hypothalamic nuclei.

[0131] In conclusion, considering the data reported in Examples 1, 2, and 3, patients with 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), or dyslipidemia can be treated with psilocybin or structurally related molecules with the same activity on 5- HT2A, 5-HT2B and 5-HT2C receptors as adjunctive treatment or in combination with a GLP- 1 receptor agonist (e.g., semaglutide), for the therapy of their metabolic disorder and related dysmetabolic sarcopenia. Alternatively, patients can be administered psilocybin in combination with metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, acarbose, or pramlintide or one or more amino acids, one or more vitamins, or one or more hormones.

INCORPORATION BY REFERENCE

[0132] 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.

[0133] Bibliography 1. Madsen MK, Fisher PM, Burmester D, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacol. 2019;44(7): 1328-1334. doi:10.1038/s41386-019-0324-9

2. Gbrnemann T, Hiibner H, Gmeiner P, et al. Characterization of the Molecular Fragment That Is Responsible for Agonism of Pergolide at Serotonin 5 -Hydroxy tryptamine 2B and 5- Hydroxytryptamine 2A Receptors. J Pharmacol Exp Ther. 2008;324(3): 1136-1145. doi:10.1124/jpet.l07.133165

3. Hutcheson JD, Setola V, Roth BL, Merryman WD. Serotonin receptors and heart valve disease — It was meant 2B. Pharmacology & Therapeutics. 2011;132(2):146-157. doi: 10.1016/j.pharmthera.2011.03.008

4. McIntyre RS. Serotonin 5-HT 2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents. Expert Opinion on Drug Safety. 2023;22(10):881-883. doi: 10.1080/14740338.2023.2248883

5. Armandi A, Rosso C, Caviglia GP, Ribaldone DG, Bugianesi E. The Impact of Dysmetabolic Sarcopenia Among Insulin Sensitive Tissues: A Narrative Review. Front Endocrinol. 2021;12:716533. doi: 10.3389/fendo.2021.716533

6. McKee A, Morley JE. Hormones and sarcopenia. Current Opinion in Endocrine and Metabolic Research. 2019;9:34-39. doi: 10.1016/j.coemr.2019.06.006

7. Lello S, Capozzi A, Scambia G. Osteoporosis and sarcopenia. Maturitas. 2019;124: 122. doi:10.1016/j.maturitas.2019.04.038

8. Allen SL, Quinlan JI, Dhaliwal A, et al. Sarcopenia in chronic liver disease: mechanisms and countermeasures. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2021 ;320(3):G241-G257. doi: 10.1152/ajpgi.00373.2020

9. Kim G, Kang SH, Kim MY, Baik SK. Prognostic value of sarcopenia in patients with liver cirrhosis: A systematic review and meta- analysis. Lin HC, ed. PLoS ONE.

2017; 12(10):e0186990. doi:I0.1371/joumal.pone.0I86990

10. Morrison WL, Bouchier IAD, Gibson JNA, Rennie MJ. Skeletal muscle and wholebody protein turnover in cirrhosis. Clinical Science. 1990;78(6):613-619. doi: 10.1042/cs0780613

11. Yang ZY, Chen WL. Examining the Association Between Serum Leptin and Sarcopenic Obesity. JIR. 2021;Volume 14:3481-3487. doi:10.2147/JIR.S320445

12. Collins KH, Gui C, Ely EV, et al. Leptin mediates the regulation of muscle mass and strength by adipose tissue. The Journal of Physiology. 2022;600(16):3795-3817. doi: 10.1113/JP283034

13. Fitts RH, Peters JR, Dillon EL, Durham WJ, Sheffield-Moore M, Urban RJ. Weekly Versus Monthly Testosterone Administration on Fast and Slow Skeletal Muscle Fibers in Older Adult Males. The Journal of Clinical Endocrinology & Metabolism. 2015;100(2):E223-E231. doi: 10.1210/jc.2014-2759

14. Rooks D, Roubenoff R. DEVELOPMENT OF PHARMACOTHERAPIES FOR THE TREATMENT OF SARCOPENIA. J Frailty Aging. Published online 2019: 1-11. doi:!0.14283/jfa.2019.11

15. Eynaudi A, Diaz-Castro F, Borquez JC, Bravo-Sagua R, Parra V, Troncoso R. Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in the Hepatic Cell Line HepG2. Front Nutr. 2021;8:775382. doi: 10.3389/fnut.2021.775382

16. Pourteymour S, Lee S, Langlei te TM, et al. Perilipin 4 in human skeletal muscle: localization and effect of physical activity. Physiol Rep. 2015;3(8):el2481. doi:10.14814/phy2.12481

17. Zhu L, Hu F, Li C, Zhang C, Hang R, Xu R. Perilipin 4 Protein: an Impending Target for Amyotrophic Lateral Sclerosis. Mol Neurobiol. 2021;58(4):1723-1737. doi : 10. 1007/s 12035-020-02217-5

Claims

CLAIMS What is claimed is:

1. A method for treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising: administering a non-psychedelic amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a GLP- 1 receptor agonist to the patient,

wherein:

R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, Cs-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino;

Rs-Rg are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may he optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

2. The method of claim 1, wherein the compound of formula (I) is administered as an adjunctive therapy to the GLP- 1 receptor agonist.

3. The method of claim 1, wherein the compound of formula (I) is administered in combination with the GLP-1 receptor agonist.

4. The method of any of claims 1-3, wherein the GLP-1 receptor agonist comprises dulaglutide, exenatide, semaglutide, liraglutide, or lixisenatide.

5. The method of claim 4, wherein the GLP- 1 receptor agonist is semaglutide.

6. The method of claim 5, wherein about 0.125 mg, 0.25 mg, about 0.5 mg, about 1 mg, about 2.4 mg, or about 3 mg of semaglutide is administered parenterally to the patient.

7. The method of claim 5, wherein 1-21 mg of oral semaglutide is administered to the patient.

8. The method of any of claim 4, wherein the GLP-1 receptor agonist is dulaglutide.

9. The method of claim 8, wherein about 0.75 mg, about 1.5 mg, about 3 mg, or about 4.5 mg of dulaglutide is administered parentally to the patient.

10. The method of claim 4, wherein the GLP-1 receptor agonist is exenatide.

11. The method of claim 10, wherein about 5 mcg or about 10 mcg of exenatide is administered to the patient, or wherein 1-2 mg of slow release exenatide is administered to the patient.

12. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of the compound according to formula (1), or a pharmaceutically acceptable salt thereof, and a biguanide to the patient,

wherein:

Ri and Ry are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, Cy-Cs alkenyl, Cy-Cs alkynyl, Ci-Cs cycloalkyl, Cy-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

Rs is hydrogen, deuterium, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Cr-Cs cycloalkyl, Cr-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino;

13. The method of claim 12, wherein the compound of formula (I) is administered as an adjunctive therapy to the biguanide.

14. The method of claim 12, wherein the compound of formula (I) is administered in combination with the biguanide.

15. The method of cl ai ms 12-14, wherei n the bi guanide i s metformin .

16. The method of any of claim 15, wherein about 850 mg to about 2550 mg of metformin hydrochloride is administered to the patient per day.

17. The method of claim 15, wherein about 500 mg of metformin hydrochloride is administered twice a day.

18. The method of claim 15, wherein about 850 mg of metformin hydrochloride is administered once a day.

19. The method of claim 15, wherein about 500 mg, about 1000 mg, about 1500 mg, or about 2000 mg of metformin hydrochloride is administered to the patient a day in an extended- release tablet.

20. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and a PPARy- agonist to the patient,

wherein:

R3 is hydrogen, deuterium, halogen, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R3 is selected from the group consisting of alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate; R4 is hydrogen, deuterium, Ci-C» alkyl, C2-C8 alkenyl, Cz-Cs alkynyl, Cs-Cs cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino;

Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R5-R8 are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

21. The method of claim 20, wherein the compound of formula (I) is administered as an adjunctive therapy to the PPARy-agonist.

22. The method of claim 20, wherein the compound of formula (I) is administered in combination with the PPARy-agonist.

23. The method of any of claims 20-22, wherein the P ARy-agonist is pioglitazone.

24. The method of any of claim 23, wherein about 15 mg, about 30 mg, or about 45 mg of pioglitazone hydrochloride is administered per day.

25. The method of any of claim 23, wherein about 15 mg of pioglitazone hydrochloride is administered per day.

26. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and a sulfonylurea-based compound to the patient,

wherein:

Ri and R2 are, independently for each occurrence, hydrogen, deuterium, C -Cs alkyl, C2-C8 alkenyl, Cb-Cx alkynyl, Ci-Cs cycloalkyl, Cx-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

R4 is hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or R4 is selected from the group consisting of alkyl ester, formyl, hydroxy, arylamido, alkylamido, alkylcarbamoyl, arylcarbamoyl, amino, alkylsulfonyl, alkylamino; Rs-Rs are, independently for each occurrence, hydrogen, deuterium, halogen, or Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and any of which may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate; or Rs-Rs are selected, independently for each occurrence, from the group consisting of, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryloxy, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, nitrate, phosphate, alkylphosphate, sulfate, alkylsulfate, carbamaic acid, alkylcarbamate, sulfonamide, alkylsulfonamide, or sulfonylurea; n is 1-5; and m is 1-5.

27. The method of claim 26, wherein the compound of formula (I) is administered as an adjunctive therapy to the sulfonylurea-based compound.

28. The method of claim 26, wherein the compound of formula (I) is administered in combination with the sulfonylurea-based compound.

29. The method of claims 26-28, wherein the sulfonylurea-based compound comprises glimepiride, gliclazide, or glibenclamide.

30. The method of claim 29, wherein the sulfonylurea-based compound is glimepiride.

31. The method of claim 30, wherein about 1 mg or about 2 mg of glimepiride is administered per day to the patient.

32. The method of claim 29, wherein the sulfonylurea-based compound is gliclazide.

33. The method of claim 32, wherein about 40 mg to about 120 mg of gliclazide is administered per day to the patient.

34. The method of claim 29, wherein the sulfonylurea-based compound is glibenclamide.

35. The method of claim 34, wherein about 2.5 mg to about 10 mg of glibenclamide is administered per day to the patient.

36. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and a DPP- IV inhibitor to the patient,

wherein:

37. The method of claim 36, wherein the compound of formula (I) is administered as an adjunctive therapy to the DPP-IV inhibitor.

38. The method of claim 36, wherein the compound of formula (I) is administered in combination with the DPP-IV inhibitor.

39. The method of claims 36-38, wherein the DPP-IV inhibitor comprises vildagliptin, linagliptin, sitagliptin, alogliptin, or evogliptin.

40. The method of claim 39, wherein the DPP-IV inhibitor is vildagliptin.

41. The method of claim 40, wherein about 50 mg to about 100 mg of vildagliptin is administered per day to the patient.

42. The method of claim 39, wherein the DPP-IV inhibitor is linagliptin.

43. The method of claim 42, wherein about 5 mg of linagliptin is administered per day to the patient.

44. The method of claim 39, wherein the DPP-IV inhibitor is sitagliptin.

45. The method of claim 44, wherein about 50 mg to about 100 mg of sitagliptin is administered per day to the patient.

46. The method of claim 39, wherein the DPP-IV inhibitor is alogliptin.

47. The method of claim 46, wherein about 12.5 mg to about 25 mg of alogliptin is administered per day to the patient.

48. The method of claim 39, wherein the DPP-IV inhibitor is evogliptin.

49. The method of claim 48, wherein about 5 mg of evogliptin is administered per day to the patient.

50. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and acarbose to the patient,

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, and may be optionally substituted at tn positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

51. The method of claim 50, wherein the compound of formula (I) is administered as an adjunctive therapy to acarbose.

52. The method of claim 50, wherein the compound of formula (I) is administered in combination with acarbose.

53. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptable salt thereof, and pramlintide to the patient,

wherein:

54. The method of claim 53, wherein the compound of formula (I) is administered as an adjunctive therapy to pramlintide.

55. The method of claim 53, wherein the compound of formula (I) is administered in combination with pramlintide.

56. The method of claims 53-55, wherein about 60 pg to about 360 pg of pramlintide is administered to the patient per day.

57. A method of treating a metabolic disorder or sarcopenia in a patient in need thereof, the method comprising administering a therapeutically effective, non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and one or more amino acids, one or more vitamins, or one or more hormones to the patient,

wherein:

58. The method of claim 57, wherein the compound of formula (I) is administered as an adjunctive therapy to the one or more amino acids, one or more vitamins, or one or more hormones.

59. The method of claim 57, wherein the compound of formula (I) is administered in combination with the one or more amino acids, one or more vitamins, or one or more hormones.

60. The method of claims 57-59, wherein the one or more amino acids comprises leucine.

61. The method of claims 57-59, wherein the one or more vitamins comprises vitamin D, vitamin Bl, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, or vitamin Bl 2.

62. The method of claims 57-59, wherein the one or more hormones comprises testosterone or estrogen.

63. A method of treating a metabolic disorder in a patient in need thereof, the method comprising co-administering to the patient:

(a) a non-psychedelic amount of a compound according to formula (I), or a pharmaceutically acceptance salt thereof, and

(b) a GLP-1 receptor agonist, metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, acarbose, pramlintide, one or more amino acids, one or more vitamins, or one or more hormones,

wherein:

Ri and R2 are, independently for each occurrence, hydrogen, deuterium, Ci-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, Gi-Cs cycloalkyl, C3-C8 cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions by deuterium, halogen, alkyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, arylcarbamoyl, nitro, cyano, or nitrate;

64. The method of claim 63, wherein the GLP-1 receptor agonist, metformin, a PPARy- agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or pramlintide is administered at a dose less than the dosage administered when used as a monotherapy, or at the lowest approved dose.

65. The method of any of claims 1-64, wherein 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), or dyslipidemia.

66. The method of claims 1-65, wherein the compound according to formula (I) is psilocybin.

67. The method of claims 1-65, wherein the compound according to formula (I) is psilocin.

68. The method of claims 1-67, wherein the non-psychedelic amount of the compound according to formula (I) is about 0.1 mg to about 7 mg.

69. The method of claims 1-67, wherein the non-psychedelic amount of the compound according to formula (I) is about 0.1 mg to about 5 mg.

70. The method of claims 1-67, wherein the non-psychedelic amount of the compound according to formula (I) is about 0.5 mg.

71. The method of claims 1-67, wherein the non-psychedelic amount of the compound according to formula (I) is about 0.001 mg/kg to about 0.1 mg/kg.

72. The method of claims 1-71, wherein the compound according to formula (I) is provided in an oral formulation, parenteral formulation, or transdermal formulation.

73. The method of any of claims 1-72, wherein the compound according to formula (I) is administered in an extended-release or modified release dosage formulation.

74. The method of any of claims 1-73, wherein the compound according to formula (I) is administered once a day, twice a day, or three times a day.

75. The method of any of claims 1-74, wherein the compound according to formula (I) 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.