Combination therapies using psilocybin

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

The abstract describes the use of compounds of formula (I) in combination with GLP-1 receptor agonists, metformin, PPARγ-agonists, sulfonylureas, DPP-IV inhibitors, acarbose or pramlintide, or one or more amino acids, one or more vitamins, or one or more hormones, or the use of compounds of formula (I) as adjunctive therapy.

Claims

CLAIMSWhat 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: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, Cs-Cs cycloalkenyl, aryl, or heterocyclyl, and may be optionally substituted at m positions bydeuterium, 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;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.

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: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-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 acompound 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;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-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 acompound according to formula (I), or a pharmaceutically acceptance salt thereof, and a DPP- IV inhibitor 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;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-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.

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;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.

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: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-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.

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: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-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.

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;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-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.

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 ata 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.

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