Cooley Docket no. RMTH-001/00US
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`COMBINATION THERAPIES USING PSILOCYBIN
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`BACKGROUND
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`[0001] Psilocybin is known for its ability to produce 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. From the clinical studies to date, the psychedelic experience is an integral
`part of the intended treatment. However, the effect of these substances on other biological
`processes is poorly understood.
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`[0002] Considerable efforts have been made to understand the mechanism
`of metabolic disorders so as to better design treatment modalities. Sarcopeniaisa medical term
`describing the loss of skeletal muscle mass, in particular with aging or as a consequence of
`other diseases, for example liver diseases, that can impact overall health and quality of life.
`Sarcopenia may be triggered or worsened by metabolic disorder.
`
`[0003] Accordingly, there is a need to develop new compositions, formulations, and methods
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`for treating metabolic disorders and sarcopenia.
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`SUMMARY OF THE DISCLOSURE
`[0004] The present disclosure provides methods of treating a metabolic disorder or sarcopenia
`in a patient in need thereof, comprising administering psilocybin, for example as an adjunctive
`therapy to another therapeutic.
`[0005] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a GLP-1 receptor agonist.
`[0006] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a biguanide.
`[0007] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a PPARy-agonist.
`[0008] In embodiments, the present disclosure provides a method of treating a metabolic
`
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
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`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a sulfonylurea-based compound.
`[0009] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a DPP-IV inhibitor.
`[0010] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to pramlintide.
`[0011] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to one or more amino acids, one or more
`vitamins, or one or more hormones.
`[0012] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder in a patient in need thereof, the method comprising co-administering to the patient:
`
`(a) a non-psychedelic amount of psilocybin and
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`(b) a GLP-1 receptor agonist, metformin, a PPARy-agonist, a sulfonylurea-based
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`compound, a DPP-IV inhibitor, or pramlintide.
`[0013] In embodiments, the metabolic disorder is prediabetes, type-II diabetes, obesity,
`metabolic dysfunction associated steatotic liver disease (MASLD and MetALD), metabolic
`dysfunction steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), liver
`steatosis, nonalcoholic steatohepatitis (NASH), or dyslipidemia. In embodiments, the disorder
`is sarcopenia.
`[0014] Other embodiments will be readily apparent to the skilled person based on the present
`disclosure.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
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`[0015] FIG. 1 is a graph showing the results of psilocin and semaglutide co-administration
`according to an embodiment of the present disclosure.
`[0016] FIG. 2 shows fluorescence data of cells co-administered psilocin and semaglutide
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`according to an embodiment of the present disclosure.
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`DETAILED DESCRIPTION
`[0017] Combination treatments using psilocybin for the treatment of metabolic disorders
`
`and/or sarcopenia are disclosed herein. In particular,
`
`Definitions
`
`[0018] Throughout this disclosure, various patents, patent applications and publications
`(including non-patent publications) are referenced. The disclosures of these patents, patent
`applications and publications in their entireties are incorporated into this disclosure by
`reference for all purposes in order to more fully describe the state of the art as known to those
`skilled therein as of the date of this disclosure. This disclosure will govern in the instance that
`there is any inconsistency between the patents, patent applications and publications cited and
`this disclosure.
`
`[0019] For convenience, certain terms employed in the specification, examples and claims are
`collected here. Unless defined otherwise, all technical and scientific terms used in this
`disclosure have the same meanings as commonly understood by one of ordinary skill in the art
`to which this disclosure belongs.
`
`[0020] The term “about” when immediately preceding a numerical value means a range (e.g.,
`plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000”
`can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is
`inconsistent with such an interpretation. For example, in a list of numerical values such as
`“about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the
`interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5.
`Similarly, the term “about” when preceding a series of numerical values or a range of values
`(e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the
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`endpoints of the range.
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`[0021] The term “therapeutically effective” applied to dose or amount refers to that quantity
`of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical
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`benefit after administration to a patient or subject in need thereof.
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`[0022] In embodiments, an effective amount of psilocybin and/or GLP-1 receptor agonist,
`metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or
`pramlintide is that amount that is required to reduce at least one symptom/biochemical marker
`of a metabolic disorder or sarcopenia as otherwise described herein in a patient. In
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`embodiments, the therapeutically effective amount can vary depending upon the intended
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`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.
`
`[0023] The term “treating” as used herein with regard to a patient, refers to improving at least
`one symptom/biochemical marker of the patient’s disorder (for example, a metabolic disorder
`or sarcopenia). Treating can be improving, or at least partially ameliorating a disorder.
`Psilocybin Administration
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`[0024] As described herein, a non-psychedelic amount of psilocybin may be administered as
`an adjunctive therapy to a GLP-1 receptor agonist, metformin, a PPARy-agonist, a
`sulfonylurea-based compound, a DPP-IV inhibitor, or pramlintide. The psilocybin may be any
`suitable pharmaceutical salt thereof. Psilocybin derivatives are described, for example, in
`International Patent Application nos. PCT/US2020/021400 and PCT/US2022/028559, both of
`which are incorporated herein in their entirety. In embodiments, the psilocybin is pegylated
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`psilocybin, or psilocin carbamate.
`
`[0025] In embodiments, the non-psychedelic amount of psilocybin is about 0.1 mg to about 7
`mg. In embodiments, the non-psychedelic amount of psilocybin is about 0.1 mg to about 6 mg,
`or about 0.1 mg to about 5 mg, or about 0.1 mg to about 4 mg, or about 0.1 mg to about 3 mg,
`or about 0.1 mg to about 2 mg, or about 0.1 mg to 1 mg, or about 0.2 mg to about 6 mg, or
`about 0.2 mg to about 5 mg, or about 0.2 mg to about 4 mg, or about 0.2 mg to about 3 mg, or
`about 0.2 mg to about 2 mg, or about 0.2 mg to 1 mg, or about0.3 mg to about 6 mg, or about
`0.3 mg to about 5 mg, or about 0.3 mg to about 4 mg, or about 0.3 mg to about 3 mg, or about
`0.3 mg to about 2 mg, or about 0.3 mg to 1 mg, or about 0.4 mg to about 6 mg, or about 0.4
`mg to about 5 mg, or about 0.4 mg to about 4 mg, or about 0.4 mg to about 3 mg, or about 0.4
`mg to about 2 mg, or about 0.4 mg to 1 mg. In embodiments, the non-psychedelic amount of
`psilocybin is about 0.5 mg, about 1 mg, about 2 mg, or about 3 mg, for example, about 0.5 mg.
`[0026] 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.
`
`[0027] In embodiments, the psilocybin is administered in an extended-release dosage form.
`[0028] The psilocybin may be administered at various time points. In embodiments, the
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`psilocybin is administered once a day, twice a day, or three times a day. In other embodiments,
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`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.
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`Combination Therapies
`
`[0029] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
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`psilocybin is administered as an adjunctive therapy to a GLP-1 receptor agonist.
`
`[0030] In embodiments, the GLP-1 agonist comprises dulaglutide, exenatide, semaglutide,
`liraglutide, or lixisenatide.
`
`[0031] In embodiments, the GLP-1 agonist agonist is semaglutide. Semaglutide may be
`administered as known in the art. In embodiments, about 0.25 mg, about 0.5 mg, about 1 mg,
`about 2.4 mg, or about 3 mg of semaglutide is administered parenterally weekly to the patient.
`In embodiments, about 3 to about 21 mg of oral semaglutide is administered daily to the patient.
`In embodiments, about 3 mg, about 7 mg, or about 14 mg of oral semaglutide is administered
`daily to the patient.
`
`[0032] In embodiments, the GLP-1 receptor agonist is dulaglutide. Dulaglutide may be
`administered as known in the art. In embodiments, about 0.75 mg, about 1.5 mg, or about 3
`mg of dulaglutide is administered weekly to the patient.
`
`[0033] In embodiments, the GLP-1 receptor agonist is exenatide. Exenatide may be
`administered as known in the art. In embodiments, about 5 mcg or about 10 mcg of exenatide
`is administered twice daily to the patient. In embodiments, the GLP1 receptor agonist is slow-
`release exenatide. Slow release exenatide may be administered as known in the art. In
`embodiments, about 1 or 2 mg of slow release exenatide is administered weekly to the patient.
`[0034] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a biguanide.
`
`[0035] In embodiments, the biguanide is metformin. Metformin may be administered as
`known in the art. In embodiments, about 850 mg to about 2550 mg of metformin hydrochloride
`is administered to the patient per day. In embodiments, about 500 mg of metformin
`hydrochloride is administered twice a day, or about 850 mg of metformin hydrochloride is
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`administered once a day. In embodiments, about 500 mg, about 1000 mg, about 1500 mg, or
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`about 2000 mg of metformin hydrochloride is administered to the patient a day in an extended-
`release tablet.
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`[0036] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a PPARy-agonist.
`
`[0037] In embodiments, the PPARy-agonist is pioglitazone. Pioglitazone may be administered
`as known in the art. In embodiments, about 15 mg, about 30 mg, or about 45 mg of pioglitazone
`hydrochloride is administered per day (e.g., about 15 mg of pioglitazone hydrochloride is
`administered per day).
`
`[0038] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a sulfonylurea-based compound.
`
`[0039] In embodiments, the sulfonylurea-based compound comprises glimepiride, gliclazide,
`or glibenclamide.
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`[0040] In embodiments, the sulfonylurea-based compound is glimepiride. Glimepiride may
`be administered as known in the art. In embodiments, about 1 mg or about 2 mg of glimepiride
`is administered per day to the patient.
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`[0041] In embodiments, the sulfonylurea-based compound is gliclazide. Gliclazide may be
`administered as known in the art. In embodiments, about 40 mg to about 120 mg of glimepiride
`is administered per day to the patient.
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`[0042] In embodiments, the sulfonylurea-based compound is glibenclamide. Glibenclamide
`may be administered as known in the art. In embodiments, about 2.5 mg to about 10 mg of
`glibenclamide is administered per day to the patient.
`
`[0043] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to a DPP-IV inhibitor.
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`[0044] In embodiments, the DPP-IV inhibitor comprises vildagliptin, linagliptin, sitagliptin,
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`alogliptin, or evogliptin.
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`[0045] In embodiments, the DPP-IV inhibitor is vildagliptin. Vildagliptin may be
`administered as known in the art. In embodiments, about 50 mg to about 100 mg of vildagliptin
`is administered per day to the patient.
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`[0046] In embodiments, the DPP-IV inhibitor is linagliptin. Linagliptin may be administered
`as known in the art. In embodiments, about 5 mg of linagliptin is administered per day to the
`patient.
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`[0047] In embodiments, the DPP-IV inhibitor is sitagliptin. Sitagliptin may be administered
`as known in the art. In embodiments, about 50 mg to about 100 mg of sitagliptin is
`administered per day to the patient.
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`[0048] In embodiments, the DPP-IV inhibitor is alogliptin. Alogliptin may be administered as
`known in the art. In embodiments, about 12.5 mg to about 25 mg of alogliptin is administered
`per day to the patient.
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`[0049] In embodiments, the DPP-IV inhibitor is evogliptin. Evogliptin may be administered
`as known in the art. In embodiments, about 5 mg of evogliptin is administered per day to the
`patient.
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`[0050] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to pramlintide. In embodiments, about 60
`ug to about 360 pg of pramlintide is administered to the patient per day.
`
`[0051] In embodiments, the present disclosure provides a method of treating a metabolic
`disorder or sarcopenia in a patient in need thereof, the method comprising administering a
`therapeutically effective, non-psychedelic amount of psilocybin to the patient, wherein the
`psilocybin is administered as an adjunctive therapy to one or more amino acid, one or more
`vitamin, or one or more hormones.
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`[0052] In embodiments, the one or more amino acid comprises leucine. In embodiments, the
`one or more amino acid comprises creatine.
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`[0053] In embodiments, the one or more vitamin comprises vitamin D and/or vitamin B. For
`example, the vitamin B may comprise vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin
`B6, vitamin B7, vitamin B9, or vitamin B12. In particular embodiments, the one or more
`vitamin comprises vitamin D and/or vitamin B12.
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`[0054] In embodiments, the one or more hormone comprises testosterone or estrogen.
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`[0055] As described herein, psilocybin may be administered as an adjunctive therapy to
`another therapeutic, or may be co-administered. Accordingly, in embodiments, the present
`disclosure provides a method of treating a metabolic disorder in a patient in need thereof, the
`method comprising co-administering to the patient:
`(a) a non-psychedelic amount of psilocybin; and
`(b) a GLP-1 receptor agonist, metformin, a PPARy-agonist, a sulfonylurea-based
`compound, a DPP-IV inhibitor, or pramlintide.
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`[0056] Co-administration of psilocybin and another therapeutic or Supplement as described
`herein may have a synergistic effect, providing enhanced efficacy for metabolic disorders or
`sarcopenia than either used alone. Accordingly, in embodiments, the combination may produce
`a dose-sparing effect, where the dosage of either psilocybin or the other therapeutic as
`described herein, or both, may be reduced. Accordingly, in embodiments, the GLP-1 receptor
`agonist, metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or
`pramlintide is administered at a dose less than the dosage administered when used as a
`monotherapy, or at the lowest approved dose. As used herein, the lowest approve dose is the
`lowest dosage approved for patient administration by a government agency, such as the FDA.
`[0057] In embodiments, the metabolic disorder is prediabetes, type-I1I diabetes, obesity,
`metabolic dysfunction associated steatotic liver disease (MASLD and MetALD), metabolic
`dysfunction steatohepatitis (MASH), non-alcoholic fatty liver disease (NAFLD), liver
`steatosis, nonalcoholic steatohepatitis (NASH), or dyslipidemia. In embodiments, the disorder
`is sarcopenia.
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`[0058] In embodiments, sarcopenia may be associated with a metabolic disorder, or the
`sarcopenia may be associated with aging or medical treatments or diseases. For example, aging
`may be accelerated by cancer, noxious agents, including medical treatments, cancer treatments
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`and other diseases.
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`EXAMPLES
`[0059] The present invention is further illustrated by reference to the following Examples. The
`Examples are illustrative and are not to be construed as restricting the scope of the invention
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`in any way.
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`Example 1. In Vitro combination treatment of GLP-1 receptor agonist and psilocin
`[0060] Psilocybin is endogenously metabolized to psilocin. The effects of psilocin in
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`combination with the GLP-1 receptor agonist semaglutide were investigated. Lipid
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`accumulation in the hepatic cell line HepG2 were induced with a 0.1 mM administration of a
`1:1 mixture of palmitic acid and oleic acid according to literature methods (Eynaudi, et al.,
`“Differential Effects of Oleic and Palmitic Acids on Lipid Droplet-Mitochondria Interaction in
`the Hepatic Cell Line HepG2.” Front. Nutr. 12;8:775382 (2021)). Subsequently, the cells were
`treated with combinations of semaglutide, psilocin, and metformin, and the percent lipid
`positive area measured. Semaglutide in combination with psilocin was found to dramatically
`decrease the accumulation of lipids in an in vitro model of steatotic liver disease, suggesting a
`synergistic effect. In contrast, the combination of psilocin with the antidiabetic drug metformin
`was found to be ineffective in reducing the accumulation of lipids in the in vitro model of
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`steatotic liver disease. Results of these experiments are shown in FIG. 1 and FIG. 2.
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`Treatment Concentration Percent Reduction
`Control 0%
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`Semaglutide 2 uM 51%
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`Semaglutide 5 uM 21%
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`Metformin 2 uM 40%
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`Metformin 5 uM 11%
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`Semaglutide + Psilocin 2 uM + 10 uM 80%
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`Semaglutide + Psilocin SuM+ 10 uM 93%
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`Metformin + Psilocin 2 uM + 10 uM 46%
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`Metformin + Psilocin SuM+ 10 uM 39%
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`[0061] The administration of psilocbin and/or psilocybin is repeated with dulaglutide,
`exenatide, semaglutide, liraglutide, and lixisenatide.
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`Example 2: Treatment of patients with metabolic disorder or sarcopenia
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`[0062] Patients with prediabetes, type-II diabetes, obesity, metabolic dysfunction associated
`steatotic liver disease (MASLD and MetALD), metabolic dysfunction steatohepatitis (MASH),
`non-alcoholic fatty liver disease (NAFLD), liver steatosis, nonalcoholic steatohepatitis
`(NASH), or dyslipidemia are treated with psilocybin in combination with a GLP-1 receptor
`agonist (e.g., semaglutide). Alternatively, patients are administered psilocybin in combination
`with metformin, a PPARy-agonist, a sulfonylurea-based compound, a DPP-IV inhibitor, or
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`pramlintide.
`INCORPORATION BY REFERENCE
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`[0063] All references, articles, publications, patents, patent publications, and patent
`applications cited herein are incorporated by reference in their entireties for all purposes.
`However, mention of any reference, article, publication, patent, patent publication, and patent
`application cited herein is not, and should not be taken as, an acknowledgment or any form of
`suggestion that they constitute valid prior art or form part of the common general knowledge
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`in any country in the world.
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