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WO2025006703A2 - Polythérapies à l'aide de psilocybine - Google Patents

Polythérapies à l'aide de psilocybine Download PDF

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Publication number
WO2025006703A2
WO2025006703A2 PCT/US2024/035751 US2024035751W WO2025006703A2 WO 2025006703 A2 WO2025006703 A2 WO 2025006703A2 US 2024035751 W US2024035751 W US 2024035751W WO 2025006703 A2 WO2025006703 A2 WO 2025006703A2
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alkyl
heterocyclyl
deuterium
aryl
amino
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WO2025006703A3 (fr
Inventor
Paolo L. Manfredi
Charles E. Inturrisi
Sara DE MARTIN
Andrea Mattarei
Marco Pappagallo
Franco Folli
Gianfranco Pasut
Stefano COMAI
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Universita degli Studi di Padova
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Universita degli Studi di Padova
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Priority to TW113129027A priority Critical patent/TW202510853A/zh
Priority to ARP240102048A priority patent/AR133444A1/es
Publication of WO2025006703A2 publication Critical patent/WO2025006703A2/fr
Publication of WO2025006703A3 publication Critical patent/WO2025006703A3/fr
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    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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Definitions

  • 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.
  • CNS central nervous system
  • the psychedelic experience and central nervous system (CNS) psychoactive effects are integral parts of the intended treatment.
  • CNS central nervous system
  • 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.
  • 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.
  • a similar pharmacodynamic profile e.g., as reported in Example 1, agonism to 5-HT2A and 5-HT2C and antagonism to 5-HT2B
  • 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, alkyla
  • 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
  • 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,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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:
  • 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.
  • MASLD and MetALD metabolic dysfunction associated steatotic liver disease
  • MASH metabolic dysfunction steatohepatitis
  • NAFLD non-alcoholic fatty liver disease
  • liver steatosis liver steatosis
  • NASH nonalcoholic steatohepatitis
  • dyslipidemia dyslipidemia
  • 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.
  • the GLP-1 receptor agonist is semaglutide.
  • FIG. 1 Psilocin activity (agonist mode) on 5-HT2A (**), 5-HT2B (***), and 5- HT2C (*) receptors.
  • 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, w p ⁇ 0.01 vs PA:OA treated cells. [0024] Figure 4. Fluorescence data of cells co-administered psilocin and semaglutide.
  • FIG. 1 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.
  • FIG. 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.
  • FIG. 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.
  • 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.
  • Figure 9 Leptin plasma levels of the 5 study group. *p ⁇ 0.05, vs controls, # p ⁇ 0.05 vs MASLD mice.
  • FIG. 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.
  • FIG. 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.
  • FIG. 13 Protein expression of IRS1 in the liver of the 3 study group. **p ⁇ 0.01 vs control.
  • FIG. 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.
  • the term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value).
  • “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.
  • “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.
  • the term “about” when preceding a series of numerical values or a range of values refers, respectively to all values in the series, or the endpoints of the range.
  • an 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.
  • phrases “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.
  • 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.
  • lysine and arginine dicyclohexylamine and the like examples include lithium, sodium, potassium, magnesium, calcium salts and the like.
  • metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butyl ammonium, tetramethylammonium salts and the like.
  • organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
  • 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.
  • 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.
  • treating 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.
  • disorder for example, a metabolic disorder or sarcopenia.
  • 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 isoform 1 in the CNS.
  • 5-HT2AR serotonin
  • 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.
  • 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 intolerance 5 .
  • Sarcopenia is associated with increased risk of falls, fractures, disability, hospitalization and mortality, especially in older patients.
  • sarcopenia can increase the medical, social and economic burden of metabolic and other diseases 6 ' 7 .
  • Sarcopenia is a frequent complication of chronic liver diseases, with an estimated prevalence of ranging from 25 to 70% in these patients 8 . Higher rates have been identified among male patients 9 .
  • 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.
  • muscle proteins 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 breakdown 10 , and finally to sarcopenia. The primary impairment may be in synthesis or degradation or both.
  • leptin a hormone secreted by adipose tissue in proportion to fat mass
  • plasma concentration of leptin was found to be related to the risk of developing sarcopenia in obese patients 11 .
  • leptin may serve as a pharmacological target for the therapy of obesity and other metabolic diseases.
  • leptin plays a fundamental role in regulating muscle mass and strength 12 , indicating that drugs with an effect on leptin levels/leptin action may be useful for controlling metabolic abnormalities and also related sarcopenia.
  • 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.
  • Metabolic diseases including Type II diabetes mellitus, obesity, and MASLD, are often associated with muscle dysfunction and the so called dysmetabolic sarcopenia.
  • 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.
  • 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.
  • 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.
  • a GLP-1 receptor agonist metformin
  • a PPARy-agonist a sulfonylurea-based compound
  • DPP-IV inhibitor a DPP-IV inhibitor
  • 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:
  • 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;
  • 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, alkyla
  • 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
  • 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,
  • 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.
  • the compound of formula (I) is a pegylated psilocin, or a psilocin carbamate.
  • 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.
  • the psilocin carbamate is:
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of formula (I) is administered in a modified- release dosage form.
  • 0.5 mg the compound of formula (I) is administered in a modified- release dosage form.
  • the compound of formula (I) may be administered at various time points.
  • the compound of formula (I) is administered once a day, twice a day, or three times a day.
  • 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
  • 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.
  • 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.
  • 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.
  • the psilocin is administered in a modified-release dosage form.
  • 0.5 mg psilocin is administered in a modified-release dosage form.
  • 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
  • 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 about 3 mg, or about 0.4 mg to about 2 mg, or about 0.4 mg to 1 mg, or about 0.4 mg to about 6 mg, or about 0.4 mg to about 5 mg, or about
  • 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.
  • the psilocybin is administered in a modified-release dosage form.
  • 0.5 mg psilocybin is administered in a modified-release dosage form.
  • 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.
  • 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;
  • 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, alkyla
  • 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
  • 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,
  • 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.
  • 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.
  • the GLP-1 agonist comprises dulaglutide, exenatide, semaglutide, liraglutide, or lixisenatide.
  • the GLP-1 agonist is semaglutide.
  • Semaglutide may be administered as known in the art.
  • 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.
  • about 3 to about 21 mg of oral semaglutide is administered daily to the patient.
  • about 3 mg, about 7 mg, or about 14 mg of oral semaglutide is administered daily to the patient.
  • 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.
  • 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.
  • 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]
  • 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;
  • 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, alkyla
  • 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
  • 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
  • the compound of formula (1) is administered as an adjunctive therapy to the biguanide.
  • the compound of formula (I) is administered in combination with the biguanide.
  • the biguanide is metformin.
  • Metformin may be administered as known in the art.
  • about 850 mg to about 2550 mg of metformin hydrochloride is administered to the patient per day.
  • about 500 mg of metformin hydrochloride is administered twice a day, or about 850 mg of metformin hydrochloride is administered once a day.
  • 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.
  • 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:
  • 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, alkyla
  • 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
  • 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,
  • the compound of formula (I) is administered as an adjunctive therapy to the PPARy-agonist.
  • the compound of formula (I) is administered in combination with the PPARy-agonist.
  • the PPARy-agonist is pioglitazone.
  • Pioglitazone may be administered as known in the art.
  • 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).
  • 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;
  • 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, alkyla
  • 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
  • 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,
  • 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.
  • the sulfonylurea-based compound comprises glimepiride, gliclazide, or glibenclamide.
  • 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.
  • 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.
  • 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.
  • 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 al
  • 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, alkylcarbamo
  • 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 este
  • 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.
  • the DPP-IV inhibitor comprises vildagliptin, linagliptin, sitagliptin, alogliptin, or evogliptin.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, alkyla
  • 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
  • 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,
  • 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.
  • 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:
  • 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, alkyla
  • 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
  • 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
  • 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.
  • about 60 pg to about 360 pg of pramlintide is administered to the patient per day.
  • 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,
  • 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, alkyla
  • 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
  • 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,
  • 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.
  • the one or more amino acid comprises leucine. In embodiments, the one or more amino acid comprises creatine.
  • the one or more vitamins comprises vitamin D and/or vitamin B.
  • the vitamin B may comprise vitamin Bl, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, or vitamin B12.
  • the one or more vitamin comprises vitamin D and/or vitamin B 12.
  • the one or more hormones comprises testosterone or estrogen.
  • 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 GLP-1 receptor agonist 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.
  • 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.
  • 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.
  • the lowest approve dose is the lowest dosage approved for patient administration by a government agency, such as the FDA.
  • 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.
  • the disorder is sarcopenia.
  • sarcopenia may be associated with a metabolic disorder, or the sarcopenia may be associated with aging or medical treatments or diseases.
  • 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.
  • FLIPR Fluorometric Imaging Plate Reader
  • EC80 submaximal concentration
  • 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).
  • 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.
  • PA palmitic acid
  • OA oleic acid
  • 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)
  • mice showed a significant reduction of fasting glucose (Fig. 7B)
  • 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.
  • 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).
  • 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).
  • Fig. 1 1 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.
  • 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.

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Abstract

L'invention concerne des méthodes de thérapie utilisant des composés de formule (I) en combinaison ou en association avec un agoniste du récepteur GLP-1, la metformine, un agoniste de PPARγ, un composé à base de sulfonylurée, un inhibiteur de DPP-IV, l'acarbose ou le pramlintide ou un ou plusieurs acides aminés, une ou plusieurs vitamines, ou une ou plusieurs hormones.
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