Psychedelic "brain boost" combinations for enhancing cellular energy production

Abstract

Disclosed are therapeutic "brain boost" combinations of agents and pharmaceutical kits and compositions thereof, such as combinations of serotonergic (5-HT 2A receptor agonist) psychedelics, with mitochondrial energy enhancers, such as metabolic cofactors and metabolic coenzymes, in some embodiments together with antioxidants and glucose regulators. In some embodiments, the combinations are used in methods of enhancing energy, such as increasing cellular energy production or metabolism, and for optimizing glucose levels and protecting cells from oxidative damage. In some embodiments, the combinations have applications as longevity treatments, for end-of-life care, for the treatment and prevention of mental health conditions, and for the betterment of mental functioning and overall health and wellbeing, such as by heightening consciousness and enhancing cognitive function.

Description

[0001] PSYCHEDELIC “BRAIN BOOST” COMBINATIONS FOR ENHANCING CELLULAR ENERGY PRODUCTION

[0002] CROSS-REFERENCE

[0003]

[0001] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional Application No. 63 / 526,949, filed July 14, 2023, and incorporated by reference for all purposes as if fully set forth herein.

[0004] FIELD OF THE INVENTION

[0005]

[0002] The disclosure relates to combinations of agents and compositions thereof, such as combinations of serotonin 2A receptor agonist psychedelics and mitochondrial energy enhancers, optionally together with antioxidants and glucose regulators, for use in methods of enhancing cellular energy metabolism, optimizing glucose levels, and protecting cells from oxidative damage and degradation, and with application as medical treatments, for the improvement of mental functioning, and for overall health and wellbeing.

[0006] BACKGROUND OF THE INVENTION

[0007]

[0003] Since 1966, the inventor of the present disclosure has been inspired by the hypothesis that serotonergic psychedelics such as LSD and psilocybin can increase the energy level of the brain. According to this hypothesis, serotonergic psychedelics increase blood supply to the capillaries of the brain, and thus to the neurons, providing them with more glucose and oxygen, crucial components required to produce cellular energy. This occurs through the effects that stimulating the serotonin 2A (5-HT2A) receptor has on the tone of the microvascular walls throughout the brain and body, and more particularly by vasoconstriction of the veins.

[0004] Inside the cell, energy is stored and transported in the form of the ATP molecule, which is primarily produced inside the cell's mitochondria. While the increase in blood supply is still being investigated, including by research pursued by the inventor, recent research has discovered that stimulation of the 5-HT2Areceptor triggers a cascade of events that ultimately lead to the biogenesis of new mitochondria, allowing the cell to produce more ATP, an effect that would be further maximized through an increase of blood supply.

[0008]

[0005] It is believed that ATP production by the mitochondria, and the biogenesis of new mitochondria triggered by stimulation of the 5-HT2Areceptor, are both reliant on a number of molecules, including one that has gained interest within the healthy longevity field in recent years: NAD+. Not only do ATP levels decrease by about half between the ages of 40 and 60, but levels of NAD+ also decline over the lifespan, and mitochondrial dysfunction has been linked to multiple health problems, particularly in older populations.

[0009]

[0006] To overcome these issues and promote healthy longevity, the inventor has discovered novel and breakthrough combinations of compounds that, having multiple mechanisms of action, and working together in synergy, will increase the cell's capacity to produce ATP, enhancing vitality, health, mood, and cognitive functioning. Further benefits and advantages of these “Brain Boost” combinations are detailed herein. INCORPORATION BY REFERENCE

[0010]

[0007] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated by reference individually, and as if each is fully set forth herein. However, no such citation should be construed as an admission that a cited reference is from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an admission that a document or underlying information, in any jurisdiction, is prior art or part of the common general knowledge in the art.

[0011] BRIEF SUMMARY OF THE INVENTION

[0012]

[0008] The following presents a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. It is not an extensive overview of the invention, and is not intended to identify key or critical elements of the invention, or to delineate its full scope. Its sole purpose is to present some embodiments of the invention in a simplified form as a prelude to the more detailed description below.

[0013]

[0009] In some aspects are provided therapeutic “brain boost” combinations, or kit of parts comprising such combinations, where such combinations and kits of parts are for enhancing energy production, the combinations and kits of parts comprising: (a) a serotonergic psychedelic; (b) a mitochondrial energy enhancer; and (c) an antioxidant or glucose regulator. In some embodiments, the serotonergic psychedelic is lysergic acid diethylamide (LSD); the mitochondrial energy enhancer is nicotinamide adenine dinucleotide as NAD+; and the antioxidant or glucose regulator is ascorbic acid (vitamin C). In some embodiments, the serotonergic psychedelic is a tryptamine, a phenethylamine, or a lysergamide. In some embodiments, the serotonergic psychedelic is any of LSD, 1 P-LSD, AL-LAD, psilocybin, psilocin, psilacetin, mescaline, DMT, DOI, 5-MeO-DMT, and ibogaine. In some embodiments, the serotonergic psychedelic is LSD.

[0014]

[0010] In some embodiments, the mitochondrial energy enhancer is a metabolic cofactor or a metabolic coenzyme. In some embodiments, the mitochondrial energy enhancer is a nicotinamide adenine dinucleotide (NAD) compound. In some embodiments, the NAD compound is any of NAD+, NADH, O-NAD+, a-NADH, P-NAD+, P-NADH, and a combination thereof. In some embodiments, the NAD compound is NAD+.

[0015]

[0011] In some embodiments, the mitochondrial energy enhancer is a NAD+ precursor. In some embodiments, the NAD+ precursor is any of nicotinic acid (NA), nicotinic acid mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NAAD), nicotinic acid riboside (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), inositol hexanicotinate (IHN), and tryptophan (Trp).

[0016]

[0012] In some embodiments, the mitochondrial energy enhancer is any of flavin adenine dinucleotide (FAD), coenzyme Q10 (CoQ10), acetyl-L-carnitine (ALC), alpha-lipoic acid (ALA), a B-complex vitamin, and a mineral. In some embodiments, the B-complex vitamin is vitamin B1, B2, B3, B5, B6, B7, B9, B12, or a combination thereof. In some embodiments, the mineral is iodine, sulfur, or magnesium.

[0017]

[0013] In some embodiments, the antioxidant or glucose regulator is vitamin C or CoQ10.

[0018]

[0014] In some embodiments, the combination or kit of parts further comprises a NAD+ degradation inhibitor. In some embodiments, the NAD+ degradation inhibitor is any of a CD38 inhibitor, a PARP inhibitor, a SIRT inhibitor, and a SARM1 inhibitor. In some embodiments, the combination or kit of parts further comprises any of a SIRT activator, an agent that increases SIRT activity, an agent that preserves SIRT activity, an agent that enhances SIRT synthesis or protein expression, an agent that enhances the half-life of a SIRT protein, an agent that promotes NADH oxidation, an activator of AMP-activated kinase, an agent that increases expression of nicotinamide phosphoribosyltransferase (PRT), an agent that acts as a substrate for NAD+ synthesis, an agent that lessens the reduction of NAD+ mediated by glycolysis, a methyl-donor supplement, and a NAMPT activating agent. In some embodiments, the methyl-donor supplement is trimethylglycine. In some embodiments, the NAMPT activating agent is berberine, resveratrol, or P7C3.

[0019]

[0015] In some embodiments, the combination or kit of parts further comprises an additional active agent. Additional active agents for use in embodiments are disclosed herein, or known in view of the disclosure.

[0020]

[0016] In some embodiments, each of the serotonergic psychedelic, the mitochondrial energy enhancer, and the antioxidant or glucose regulator are separately formulated as a pharmaceutical composition, each further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the serotonergic psychedelic is LSD, the mitochondrial energy enhancer is NAD+, and the antioxidant or glucose regulator is vitamin C. In embodiments, LSD is in an amount of between about 1 pg and 50 pg, between about 5 pg and 20 pg, less than about 50 pg, less than about 20 pg, less than about 10 pg, or about 10 pg.

[0021]

[0017] In some additional aspects are provided pharmaceutical compositions for enhancing energy production, comprising each of the serotonergic psychedelic, the mitochondrial energy enhancer, and the antioxidant or glucose regulator of a disclosed embodiment, and further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pharmaceutical composition is suitable for enteral or parenteral administration. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is in unit dosage form. In some embodiments, the pharmaceutical composition comprises LSD, NAD+, and vitamin C.

[0022]

[0018] In some other aspects are provided methods for enhancing energy production in a subject, comprising administering to the subject the combination or kit of parts or the pharmaceutical composition of any of the disclosed embodiments. In some embodiments, enhancing energy production in the subject treats a medical condition. In some embodiments, the medical condition is any of a nervous system condition or disorder; a mental, behavioral, or neurodevelopmental disorder; a mental health disorder; a neurodegenerative disorder; a mitochondrial disorder; and a condition related to energy production. Exemplary medical conditions are disclosed, and others will be appreciated in view of the teachings herein.

[0023]

[0019] In some embodiments, enhancing energy production in the subject improves mental health and functioning, or improves overall health and wellness. In embodiments, a method comprises administering to the subject the combination or kit of parts of a disclosed embodiment. In embodiments, the serotonergic psychedelic, the mitochondrial energy enhancer, and the antioxidant or glucose regulator are administered in separate dosage forms. In embodiments, the serotonergic psychedelic, the mitochondrial energy enhancer, and the antioxidant or glucose regulator are administered separately, sequentially, or simultaneously. In embodiments, a method comprises administering a pharmaceutical composition of a disclosed embodiment.

[0020] In some further aspects, a therapeutic “brain boost” combination or kit of parts for enhancing energy production, a pharmaceutical composition comprising a combination or kit of parts, or a method of their administration, comprises a serotonergic psychedelic and a mitochondrial energy enhancer.

[0024]

[0021] In embodiments, a method comprises administering LSD, NAD+, and vitamin C; or LSD and NAD+.

[0025]

[0022] I n some yet further aspects are provided the use of a disclosed combination or kit of parts, or the use of a disclosed pharmaceutical composition, for enhancing energy production. In some embodiments, the use of a combination, kit of parts, or pharmaceutical composition to enhance energy production treats a medical condition, improves mental health and functioning, or improves overall health and wellness. In some aspects are also provided the use of a disclosed combination, kit of parts, or pharmaceutical composition, for the manufacture of a medicament for the therapeutic and / or prophylactic treatment of a medical condition

[0026]

[0023] The foregoing has outlined broadly some pertinent features of certain exemplary embodiments of the present disclosure so that the detailed description of the invention that follows may be better understood and so that the present contribution to the art can be more fully appreciated. Additional features of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the disclosed aspects and embodiments may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present disclosure. It should be also realized that such equivalent embodiments do not depart from the spirit and scope of the invention as set forth in the appended claims. Hence, this summary has been made with the understanding that it is to be considered as a brief and general synopsis of only some of the aspects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled.

[0027] BRIEF DESCRIPTION OF THE FIGURES

[0028]

[0024] FIG. 1 shows certain exemplary proposed synergistic effects of 5-HT2Areceptor activation and increased NAD concentration on cellular processes.

[0029]

[0025] FIG. 2 shows the ATP concentration of astrocytes after 1 , 2, and 3 days of medium change.

[0030]

[0026] FIG. 3 shows the astrocyte ATP concentration after 48 hour treatment with LSD, -NAD and DOI.

[0031]

[0027] FIG. 4 shows the astrocyte ATP concentration after 48 hour treatment with LSD, P-NAD and DOI. 0.1 nM LSD induced a 1.35-fold increase in ATP production, 0.1 pM 0-NAD induced a 1.27-fold increase in ATP production, and DOI induced a 1.16-fold increase in ATP production at 0.0001 pM.

[0032]

[0028] FIG. 5 shows the astrocyte cell count after 48 hour treatment with LSD, -NAD, and DOI.

[0033]

[0029] FIG. 6 shows the astrocyte ATP concentration after 48-hour treatment with LSD, -NAD, DOI, and LSD + p-NAD. Results are from at least 3 independent replicates, from 3 independent experiments.

[0034]

[0030] FIG. 7 shows the astrocyte cell count after 48-hour treatment with LSD, P-NAD, DOI, and LSD + P-NAD. Cells were incubated with Hoechst 33342 (#H1399, Thermo Fisher Scientific) for 30 minutes. Images were acquired using the Cytation Biotek Imaging System and the cell counting was performed using Cytation Analysis software. Results are from at least 3 replicates, from 2 independent experiments.

[0031] FIG. 8 shows the astrocyte ROS after 48-hour treatment with LSD, p-NAD, DOI (control), and LSD + P-NAD. LSD, -NAD, and LSD + P-NAD results are from at least 3 independent replicates, from 3 independent experiments. DOI results are from 2 independent experiments.

[0035]

[0032] FIG. 9 shows the neurosphere ATP concentration after 48-hour treatment with LSD, p-NAD, and DOI. Three technical replicates per condition.

[0036]

[0033] FIG. 10 shows the neurosphere area after 48-hour treatment with LSD, P-NAD, and DOI. One replicate per condition.

[0037]

[0034] FIG. 11 shows the neurosphere ATP after 48-hour treatment with LSD, p-NAD, DOI, and LSD + P-NAD. Results are from 3 independent replicates, from 3 independent experiments.

[0038]

[0035] FIG. 12 shows the neurosphere area after 48-hour treatment with LSD, p-NAD, DOI, and LSD + P-NAD. LSD, P-NAD, and LSD + P-NAD results are from at least 2 independent replicates, from 3 independent experiments. DOI results are from 2 independent experiments.

[0039]

[0036] FIG. 13 shows the neurosphere ROS after 48-hour treatment with LSD, p-NAD, DOI , and LSD + p-NAD. LSD, p-NAD, and LSD + p-NAD results are from 3 independent replicates from 3 independent experiments. DOI results are from 3 independent replicates, from 1 independent experiment.

[0040]

[0037] FIG. 14 shows the basal ATP concentration at 1, 2, 4, and 6 days after medium change.

[0041]

[0038] FIG. 15 shows the neuronal ATP after 48-hour treatment with LSD, p-NAD, DOI, and LSD + p-NAD. Results are from 3 independent replicates, from 3 independent experiments.

[0042]

[0039] FIG. 16 shows the neuronal ROS after 48-hour treatment with LSD, p-NAD, DOI, and LSD + p-NAD. LSD, p-NAD, and DOI results are from 3 replicates, from 2 independent experiments. LSD + p-NAD results are from 4 independent experiments.

[0043]

[0040] FIG. 17 shows a neurosphere summary of ATP and ROS results treated with 10 nM LSD, 10 pM p-NAD, and 10 nM LSD + 10 pM p-NAD. The combination of p-NAD + LSD potentiated ATP production and decreased ROS levels. The dashed line indicates the control condition. Significance: p > 0.05 = No; p < 0.05 = *; p < 0.005 = **.

[0044]

[0041] FIG. 18 shows a summary of ATP results from neurospheres treated with LSD, p-NAD, and combinations of LSD + P-NAD. The combination of P-NAD + LSD potentiated ATP production. The dashed line indicates the control condition. Significance: p > 0.05 = No; p < 0.05 = *; p < 0.005 = **; p < 0.0005 = ***; p < 0.0001 = ****.

[0045]

[0042] FIG. 19 shows a summary of ROS results from neurospheres treated with LSD, p-NAD, and combinations of LSD + p-NAD. The combination of LSD + p-NAD decreased ROS levels in higher concentrations. The dashed line indicates the control condition. Significance: p > 0.05 = No; p < 0.05 = *; p < 0.005 = **.

[0046]

[0043] FIG. 20 shows fold change of ATP in neurospheres after 48h-treatment with LSD concentration curve (A), p-NAD concentration curve (B), LSD + p-NAD concentration curve (C), 0.01 nM LSD + 0.01 pM p-NAD (D), 0.1 nM LSD + 0.1 pM p-NAD (E), 1nM LSD + 1 pM p-NAD (F), and 10nM LSD + 10pM p-NAD (G). The combination of 0-NAD and LSD potentiated ATP production. The dashed line indicates the control condition to facilitate comparison between the conditions. Results from at least 3 independent replicates, from 3 independent experiments. Significance: p < 0.05 = *; p < 0.005 = **; p < 0.0005 = ***; p < 0.0001 = ****

[0047]

[0044] FIG. 21 shows fold change of H2O2in neurospheres after 48h-treatment with LSD concentration curve (A), p-NAD concentration curve (B), LSD + -NAD concentration curve (C), 0.01 nM LSD + 0.01 pM p-NAD (D), 0.1 nM LSD + 0.1 pM P-NAD (E), 1 nM LSD + 1 pM P-NAD (F). The combination of 10nM LSD + 10pM p-NAD decreased ROS levels (G). The dashed line indicates the control condition to facilitate comparison between the conditions. Results from at least 3 independent replicates, from 3 independent experiments. Significance: p < 0.05 = *; p < 0.005 = **; p < 0.0005 = ***; p < 0.0001 = ****.

[0048]

[0045] FIG. 22 shows fold change of ATP in neurospheres after 48h-treatment with LSD (A), p-NAD (B), LSD + P-NAD (C). Results from at least 3 independent replicates, from 3 independent experiments. The dashed line indicates the control condition to facilitate comparison between the conditions. Data are shown as mean ± SEM. Significance: p > 0.05 = Ns; p < 0.05 = *; p < 0.005 = **; p < 0.0005 = ***.

[0049]

[0046] FIG. 23 shows fold change of ROS in neurospheres after 48h-treatment with LSD (A), p-NAD (B), LSD + P-NAD (C). Results from at least 3 independent replicates from 3 independent experiments. The dashed line indicates the control condition to facilitate comparison between the conditions. Data are shown as mean ± SEM. Significance: p > 0.05 = Ns; p < 0.05 = *; p < 0.005 = **; p < 0.0001 = ****.

[0050] DETAILED DESCRIPTION OF THE INVENTION

[0051]

[0047] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates several exemplary embodiments in further detail to enable one of skill to practice such embodiments, and to make and use the full scope of the invention claimed. The described examples are only for illustrative purposes and not intended to limit the scope of the invention or its applications. It will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention can be made by those in the art without departing from the spirit of the invention, or the scope of the invention as described in the claims.

[0052]

[0048] In aspects of the disclosure are combinations of a serotonergic psychedelic with a mitochondrial energy enhancer and optionally an antioxidant or a glucose regulator. In some embodiments (equivalently, as shorthand, “in embodiments”), are combinations of a serotonergic psychedelic with a mitochondrial energy enhancer and an antioxidant or a glucose regulator. In embodiments are combinations of a serotonergic psychedelic with a mitochondrial energy enhancer, an antioxidant, and a glucose regulator. In embodiments are combinations of a serotonergic psychedelic with a metabolic coenzyme and an antioxidant or a glucose regulator. In embodiments are combinations of a serotonergic psychedelic with a metabolic coenzyme, an antioxidant, and a glucose regulator. In embodiments are combinations of a serotonergic psychedelic with a metabolic cofactor and an antioxidant or a glucose regulator. In embodiments are combinations of a serotonergic psychedelic with a metabolic cofactor, an antioxidant, and a glucose regulator.

[0053]

[0049] Among other aspects of the disclosure are pharmaceutical compositions comprising the disclosed compound(s), such as comprising one or more of the compounds, or comprising a disclosed therapeutic combination, together with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0054]

[0050] Herein, a therapeutic combination and a pharmaceutical composition may be referred to individually, and only as shorthand, unless context clearly indicates otherwise, as a “combination” and as a “composition.”

[0055]

[0051] Among yet other aspects of the disclosure are methods for using the disclosed combinations, such as for increasing cellular energy metabolism, protecting cells from oxidative damage, and regulating glucose levels, among other disclosed beneficial and advantageous effects. In embodiments, a combination is useful in increasing metabolic energy (e.g. , by increasing the amounts of ATP in the brain and body, such as by increasing mitochondrial energy production) and protecting cells from oxidative damage. In embodiments, increasing energy available to the brain and body while optimizing glucose levels will result in increases in healthy function, such as a heightened level of consciousness and an increased level of concentration.

[0056]

[0052] Among further aspects of the disclosure are methods of treatment, by administration of the disclosed therapeutic combinations and pharmaceutical compositions. In embodiments, the combinations and compositions are useful for the treatment and prevention of conditions, diseases, and disorders such as chronic depression and other depressive disorders, addiction and substance use disorders, and neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease. In further embodiments, the combinations and compositions are useful for end-of-life care and palliative care, as well as for longevity.

[0057]

[0053] Th disclosure includes all embodiments and equivalents thereof, not only those expressly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described aspects, embodiments, applications, and details of the disclosure can be made by those in the art without departing from the spirit of the invention, or the scope of the invention as set forth in the claims.

[0058]

[0054] Headings are only for organizational purposes, and should not be construed as limiting the invention.

[0059] A. General Definitions and Terms

[0060]

[0055] The singular forms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Thus, “a compound” includes reference to not only one but also to two or more compounds, and “an excipient” includes reference to not only one but also to two or more excipients. While the term “one or more” also may be used, its absence (or its replacement by the singular “a” or “an”) does not signify the singular only, but simply provides emphasis to the possibility of multiples in some particular embodiments.

[0061]

[0056] “Or” means, and is interchangeable with, the term “and / or” unless context clearly indicates otherwise.

[0062]

[0057] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., they do not limit lists to recited elements), and are interchangeable with the phrase “including but not limited to.”

[0063]

[0058] Numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values set forth in the examples are reported as precisely as practicable. Numerical values presented in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0059] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, should be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers should be understood as not being modified by the term “about.” In embodiments, the numerical parameters are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. In other embodiments, “about” refers to plus or minus ten percent (±10%) of the recited unit of measure. Where “about” is used to modify one number in a series or range, it should be understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range. Thus, the term “about 1, 2, or 3” is understood to mean “about 1 , about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.” The term “substantially,” where it is used to modify a feature or limitation, must be read in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, such as by using a standard recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the relevant art.

[0064]

[0060] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs (as shorthand, “one of skill”).

[0065]

[0061] Generally, the nomenclature used and procedures performed herein are those known to one of skill in fields relating to one or more aspects of the disclosure, such as biology, pharmacology, neuroscience, organic chemistry, synthetic chemistry, formulation chemistry, pharmaceutics, and / or the like, and are those that will be well known and commonly employed in such fields, unless otherwise described herein. Standard techniques and procedures will be those generally performed according to conventional methods in the art.

[0066]

[0062] Further definitions to assist a reader in understanding the embodiments are below and throughout; however, it will be appreciated that such definitions are not intended to limit the scope of the invention, which is properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill in the relevant art) in view of the language used in the claims. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0067] B. Therapeutic Combinations

[0068]

[0063] In some aspects are provided therapeutic combinations comprising a serotonergic psychedelic.

[0069]

[0064] In embodiments, a therapeutic combination comprises a serotonergic psychedelic together with a mitochondrial energy enhancer and optionally an antioxidant or a glucose regulator.

[0070]

[0065] Herein, “together with” in reference to compounds and / or compositions means the compounds or compositions are intended for use together (such as in a disclosed combination or composition), including for administration together, but irrespective of whether administration is simultaneous, separate, or sequential.

[0071]

[0066] For example, in embodiments where a combination comprises a serotonergic psychedelic “together with” a mitochondrial energy enhancer, the serotonergic psychedelic can in some embodiments be administered simultaneously with the mitochondrial energy enhancer (in the same composition, or in separate compositions), and in other embodiments the serotonergic psychedelic can be administered before or after the mitochondrial energy enhancer. In embodiments where a combination comprises a serotonergic psychedelic “together with” a mitochondrial energy enhancer and optionally an antioxidant or glucose regulator, the serotonergic psychedelic can in some embodiments be administered simultaneously with the antioxidant and / or glucose regulator (in the same composition, or in separate compositions), and in other embodiments the psychedelic can be administered before or after the antioxidant and / or glucose regulator.

[0072]

[0067] In embodiments, a combination comprises a serotonergic psychedelic together with any of a metabolic coenzyme, a metabolic cofactor, an antioxidant, and a glucose regulator. A combination comprising a serotonergic psychedelic and any of a metabolic coenzyme, a metabolic cofactor, and a glucose regulator may include, as examples, two or more metabolic coenzymes, two or more metabolic cofactors, or two or more glucose regulators. In embodiments, a combination comprises one metabolic coenzyme, one metabolic cofactor, and / or one glucose regulator, and all numerical combinations thereof (e.g., zero or one metabolic coenzyme and one or more metabolic cofactors; one or more metabolic coenzymes and zero or one metabolic cofactors; zero or one metabolic coenzyme and one or more glucose regulators; one or more metabolic coenzymes and zero or one glucose regulator; zero or one metabolic cofactor and one or more glucose regulators; one or more metabolic cofactors and zero or one glucose regulator; and the like).

[0073]

[0068] Exemplary serotonergic psychedelics, mitochondrial energy enhancers, metabolic cofactors and coenzymes, antioxidants, glucose regulators, and other disclosed agents are as further described below.

[0074] 1. Serotonergic Psychedelics

[0075]

[0069] In some aspects are disclosed combinations of a serotonergic psychedelic and one or more other agents, with such other agents discussed in further detail below and elsewhere herein.

[0076]

[0070] A “serotonergic psychedelic” herein refers to a psychedelic that has activity at (e.g., agonizes), or has affinity for, the serotonin 2A (5-HT2A) receptor, which is generally understood to be responsible for the “psychedelic” effects of such substances. That is, upon binding with the 5-HT2Areceptor, serotonergic psychedelics, such as the disclosed compounds, and other phenethylamines, tryptamines, and lysergamides, can cause a subject to experience subjective psychedelic effects, when administered at a sufficient dose. In embodiments, the serotonergic psychedelic is not administered at a dose that causes psychedelic effects.

[0077]

[0071] In embodiments, the serotonergic psychedelic has selective activity at (e.g., selectively agonizes), or has selective affinity for, the serotonin 2A receptor, over another receptor, such as the serotonin 2B receptor.

[0078]

[0072] Serotonin receptor (e.g., 2A or 2B receptor) binding affinity and activity will be as appreciated or as ascertainable in the art (see, e.g., Ray T. S. PloS one. 2010;5(2):e9019; Bryan Roth, The National Institutes of Mental Health Psychoactive Drug Screening Program, Assay Protocol Book, Version III (2018)).

[0079]

[0073] In embodiments, stimulation of the 5-HT2Areceptor (such as by administering a serotonergic psychedelic) increases mitochondrial biogenesis and function, and the production of antioxidant enzymes.

[0080]

[0074] Serotonergic psychedelics include, as non-limiting examples, LSD, 1 -propanoyl-lysergic acid diethylamide (1 P-LSD), 6-allyl-6-nor-LSD (AL-LAD), psilocybin, 4-acetoxy-DMT (psilacetin), mescaline, N, N-dimethyltryptamine (DMT), 2,5-dimethoxy-4-iodoamphetamine (DOI), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), and ibogaine. In embodiments, a serotonergic psychedelic is any of LSD, 1 P-LSD, AL-LAD, psilocybin, psilocin, psilacetin, mescaline, DMT, DOI, 5-MeO-DMT, and ibogaine, and combinations thereof.

[0081]

[0075] In embodiments, a combination comprises LSD. In embodiments, a combination comprises 1 P-LSD. In embodiments, a combination comprises AL-LAD. In embodiments, a combination comprises psilocybin. In embodiments, a combination comprises psilacetin. In embodiments, a combination comprises mescaline. In embodiments, a combination comprises DMT. In embodiments, a combination comprises DOI. In embodiments, a combination comprises ibogaine. A composition may comprise any such combination.

[0082]

[0076] In embodiments, a serotonergic psychedelic is a phenethylamine, a tryptamine, or a lysergamide.

[0083]

[0077] In embodiments, a serotonergic psychedelic is a psychedelic phenethylamine disclosed in Shulgin & Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1994), or a psychedelic tryptamine disclosed in Shulgin & Shulgin, TiHKAL: The Continuation, Transform Press (1997), both incorporated by reference in their entirety, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, active metabolite, derivative, analog, prodrug, stereoisomer, or tautomer thereof, or a combination thereof.

[0084]

[0078] In embodiments, a psychedelic phenethylamine has the structure below, wherein RN1, RN2, Ra, Rp, and each of R2-R6are as taught herein and generally understood in the art:

[0085]

[0079] In embodiments, RN1, RN2, Ra, Rp, and each of R26are independently hydrogen (H), deuterium (D), halogen (F, Cl, Br, or I), or any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. In embodiments, R3and R4are joined together to form an optionally substituted heterocyclyl, such as a dioxole, furan, tetrahydrofuran, thiophene, pyrrole, pyridine, pyrrolidine, ethylene oxide, ethylenimine, trimethylene oxide, pyran, piperidine, imidazole, thiazole, dioxane, morpholine, or pyrimidine. In embodiments, R3and R4are joined together to form an optionally substituted aryl, such as a phenyl. In embodiments, the phenethylamine comprises a quaternary ammonium cation wherein each of RN1, RN2, and an additional RN3are independently an alkyl group or an aryl group, and with all other substituents as above. In embodiments, the phenethylamine is a quaternary salt, where an additional RN3is connected to the nitrogen to which RN1and RN2are bound; and RN3is any of alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted.

[0086]

[0080] In embodiments, a psychedelic tryptamine has the structure below, wherein RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7are as defined herein and generally understood in the art:

[0087]

[0081] In embodiments, RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7are each independently H, deuterium, halogen, OH, phosphoryloxy, or any of alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. Any two of RN1, RN2, Ra, Rp, R2, R4, R5, R6, and R7and the intervening atoms also can be taken together to form any of cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. In embodiments, the tryptamine is a quaternary salt, where an additional RN3is connected to the nitrogen to which RN1and RN2are bound; and RN3is any of alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted.

[0088]

[0082] In embodiments, a psychedelic tryptamine is a complex tryptamine. In embodiments, a complex tryptamine is an ergoline or a lysergamide. In embodiments, a lysergamide has the structure below, wherein RN1, RN2, R1, R2, R4, RB, R7, R8, R9, R12, R13, and R14are as defined herein and generally understood in the art:

[0089]

[0083] In embodiments, RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are each independently H, deuterium, halogen, or any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. Additionally, any two of RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14and the intervening atoms can be taken together to form a cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted. In embodiments, the lysergamide is a quaternary salt, in which an additional R6Ais connected to the nitrogen to which R6is bound; wherein R6Ais alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, all of which may be optionally substituted.

[0090]

[0084] In embodiments, a psychedelic lysergamide is selected from the group consisting of lysergic acid diethylamide (LSD), 6-ethyl-6-nor-lysergic acid diethylamide (ETH-LAD), 6-propynyl-6-nor-lysergic acid diethylamide (PARGY-LAD), 6-allyl-6-nor-lysergic acid diethylamide (AL-LAD), 6-propyl-6-nor-lysergic acid diethylamide (PRO-LAD), 6-isopropyl-6-nor-lysergic acid diethylamide (IP-LAD), 6-cylopropyl-6-nor-lysergic acid diethylamide (CIP-LAD), 6-butyl-6-nor-lysergic acid diethylamide (BU-LAD), 6-(2-fluoroethyl)-6-nor- lysergic acid diethylamide (FLUOROETH-LAD), 1 -acetyl-lysergic acid diethylamide (ALD, ALD-52, N-acetyl-LSD), 1 -propionyl-lysergic acid diethylamide (1 P-LSD), 1 -butyryl-lysergic acid diethylamide (1 B-LSD), 1 -valeryl-lysergic acid diethylamide (1V-LSD), 1 -(cyclopropyl-methanoyl)-lysergic acid diethylamide (1cP-LSD), 1 -(1 ,2-dimethylcyclobutane-1-carbonyl)-lysergic acid diethylamide (1 D-LSD), 1-propionyl-6-allyl-6-nor-lysergic acid diethylamide (1 P-AL-LAD), 1-(cyclopropylmethanoyl)-6-allyl-6-nor- lysergic acid diethylamide (1cP-AL-LAD), 1 -propionyl-6-ethyl-6-nor-lysergic acid diethylamide (1P-ETH-LAD), lysergic acid 2,4-dimethylazetidide (LA-SS-Az, LSZ), lysergic acid piperidide (LSD-Pip), 1-(trimethylsilyl)-lysergic acid diethylamide; 1-(trimethylsilyl-propionyl)-lysergic acid diethylamide (1S-LSD); and lysergic acid methylisopropyl amide (MIPLA), including pharmaceutical salts and solid forms thereof.

[0091]

[0085] In embodiments, the serotonergic psychedelic is lysergic acid 2-butyl amide, lysergic acid 2-pentyl amide, lysergic acid 3-pentyl amide, lysergic acid 2-hexyl amide, N,N-diallyl lysergamide, lysergic acid methylisopropyl amide, lysergic acid diethylamide (LSD), 6-ethyl-6-nor-lysergic acid diethylamide, 6-propynyl-6-nor-lysergic acid diethylamide, 6-allyl-6-nor-lysergic acid diethylamide, 6-propyl-6-nor-lysergic acid diethylamide, 6-cyclopropyl-6-nor 15 lysergic acid diethylamide, 6-butyl-6-nor-lysergic acid diethylamide, 1-acetyl lysergic acid diethylamide, 1-propyonyl lysergic acid diethylamide, 1-propyonyl-6- ethyl-6-nor-lysergic acid diethylamide, N-morpholinyl lysergamide, N-pyrrolidyl lysergamide, or N-piperidyl lysergamide, lysergic acid 2,4-dimethylazetidine, including pharmaceutical salts and solid forms thereof.

[0092]

[0086] In embodiments, a complex tryptamine is a natural plant indole alkaloid. In embodiments, the natural plant indole alkaloid is a beta-carboline. In embodiments, the natural plant indole alkaloid is an iboga alkaloid. In embodiments, the iboga alkaloid is ibogaine. In embodiments, the beta-carboline is any of harmine, harmane, norharmine, harmaline, perlolyrine, or harmol, such as synthetic or from B. caapi or P. harmala.

[0093]

[0087] In some embodiments where a composition for oral administration comprises a psychedelic tryptamine that has limited bioavailability via oral administration such as DMT, the composition will further comprise a beta-carboline or another monoamine oxidase-A inhibitor (MAOI). In embodiments, the MAOI is a reversible inhibitor of monoamine oxidase-A (RIMA). Where an embodiment comprises a beta-carboline, MAOI, or RIMA, it preferably is provided in such dosage to provide for sufficient bioavailability upon oral administration of the psychedelic tryptamine in the composition.

[0094]

[0088] Additional examples of serotonergic psychedelics will be appreciated by reference to the general knowledge in the art (see, e.g., Araujo, A. M., et al. 2015;89(8):1151-1173; Luethi, D., Liechti, M.E., Arch Toxicol. 2020;94:1085-1133; Nichols D.E., Psychedelics. 2016;68(2):264— 355; Glennon R., Pharmacol Biochem Behav. 1999;64:251-256), including for example, any of the more than 300 “new psychoactive substances” (NPS) that have been synthesized in recent years, where such are serotonergic psychedelics.

[0095]

[0089] In embodiments, a serotonergic psychedelic is a synthetic or semi-synthetic compound, and is produced via complete or partial chemical synthesis. In embodiments, a serotonergic psychedelic is naturally occurring and is obtained, e.g., by extraction, purification, and / or isolation, or in whole plant or fungal form.

[0096]

[0090] In embodiments, a serotonergic psychedelic is obtained from a plant or fungal (e.g., Psilocybe spp.) source. For example, DMT may be extracted from, among other sources, Phalaris, Delosperma, Acacia, Desmodium, Mimosa, Virola, and Psychotria spp. In embodiments, fungi, plants, plant matter, and mixtures and concoctions thereof, as well as extracts and isolates thereof, and combinations thereof, are used in a combination, and embodiments include extracts of fresh or dried psilocybin-containing mushrooms, microdoses of DMT-containing ayahuasca brew, microdoses of ibogaine extract, and the like

[0097]

[0091] Also included are pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, active metabolites, derivatives, analogs, prodrugs, stereoisomers, tautomers, and combinations thereof.

[0098]

[0092] In embodiments, a combination comprises a serotonergic psychedelic together with a mitochondrial energy enhancer, and optionally an antioxidant or a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic and a mitochondrial energy enhancer. In embodiments, a combination comprises a serotonergic psychedelic, a mitochondrial energy enhancer, and an antioxidant or a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic and any one or more of a metabolic coenzyme, a metabolic cofactor, and an antioxidant or a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic and any two or more, any three or more, or greater than any three of a metabolic coenzyme, a metabolic cofactor, and an antioxidant or a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic and any of the additional agents herein.

[0099] 2. Mitochondrial Energy Enhancers

[0100]

[0093] In embodiments, a combination comprises a serotonergic psychedelic together with a mitochondrial energy enhancer. In embodiments, the mitochondrial energy enhancer is a metabolic cofactor or a metabolic coenzyme. As used herein, the term “mitochondrial energy enhancer” refers to a cofactor, coenzyme, or any other compound that can increase mitochondrial production of adenosine triphosphate (ATP).

[0101]

[0094] Mitochondria have many functions in the cell and throughout the body, including cell signaling, inflammation, metabolism, hormone production, and energetics. Mitochondria play a role in neural plasticity (Steib et al. J Neurosci. 2014;34:6624-33), and in stress response (Daniels et al. Annu Rev Clin Psychol. 2020;16:165-186)). Mitochondria are the cells’ primary site of energy production, and provide most of the energy needed for cellular functions by metabolizing fuel molecules into ATP through oxidative phosphorylation. Mitochondria carry out oxidative phosphorylation through the ETC that generates adenosine triphosphate (ATP), the universal energy currency. The genes of mitochondrial DNA encode for protein complexes that serve as the main machinery for supplying cellular energy: the electron transport chain (ETC) (Daniels, Olsen & Tyrka, 2020). Maintaining mitochondrial energy-transducing capacity is important for a healthy brain and body (Yin et al. Antioxid Redox Signal. 2014;20(2):353-371). The brain, a highly energy-dependent organ, is densely populated by mitochondria (Juster et al. Dev Psychopathol. 2016;28:1117-46). Mitochondrial energy metabolism can be measured by methods known in the art, e.g., measuring ATP production and oxygen consumption (Lewis et al. Methods Mol Biol. 2022;2497:141-172).

[0102]

[0095] Mitochondrial health has been increasingly recognized for its importance in the aging process. Aging is associated with problems in mitochondrial structure and function, including alterations in mitochondrial DNA (mtDNA) copy number, impaired replication, increased reactive oxygen species (ROS) production, mtDNA mutations, and organelle damage (Lagouge & Larsson, J Internal Med. 2013;273:529-43). Under chronic stress exposure, negative changes in mitochondrial health, including mitochondrial energy usage and metabolism, may accumulate, increasing a subject’s risk of developing age and stress-related conditions (Daniels, Olsen & Tyrka, 2020). Mental health conditions and cellular aging are intertwined, as mental illness can increase the risk of premature death and earlier-onset of age-related chronic medical conditions (id.).

[0103]

[0096] A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme’s role as a catalyst; that is, it increases the rate of a chemical reaction. Metabolic cofactors are “helper molecules” that assists in biochemical transformations as part of cellular metabolism, generally in a group-transfer reaction wherein chemical functional groups are transferred between different reactants. Metabolic cofactors may be classified into two types, inorganic ions and complex organic molecules, the latter of which also may be referred to as metabolic coenzymes. Broadly, and without being bound by theory, metabolic coenzymes are generally derived from vitamins and other organic essential nutrients.

[0104]

[0097] In embodiments, a combination comprises a metabolic cofactor. In embodiments, a combination comprises a metabolic coenzyme. In embodiments, the metabolic coenzyme is nicotinamide adenine dinucleotide (NAD). The term "nicotinamide adenine dinucleotide” or “NAD” includes both the oxidized and reduced forms of NAD, indicated by "NAD+" and ''NADH,'' respectively, in any possible stereochemical configuration. Hence, unless context clearly indicates otherwise, any reference to “nicotinamide adenine dinucleotide” or “NAD” herein includes both alpha-NAD or a-NAD (including a-NAD+ and a-NADH) and beta-NAD or -NAD (including 0-NAD+ and 0-NADH). Also included in “NAD” are mixtures of multiple forms of NAD, including compositions comprising multiple forms of NAD, such as mixtures of NAD+ and NADH, in any stereochemical configuration. In embodiments, a combination comprising NAD may in embodiments comprise NAD+ only, NADH only, or both NAD+ and NADH, in any stereochemical configuration. In embodiments, a combination comprising NAD may comprise any one or more of a-NAD+, a-NADH, 0-NAD+, 0-NADH, and any other isomer (e.g., stereoisomer) of NAD, whether in an oxidized or reduced form, or a mixture of oxidation states. In embodiments, a combination comprising NAD may comprise any one or more of the a and 0 forms of NAD, a and 0 forms of NAD+, and / or a and 0 forms of NADH, in any proportions.

[0105]

[0098] In embodiments, administering a metabolic cofactor or a metabolic coenzyme as part of a combination enhances mitochondrial energy in the brain and body. In embodiments herein, “in the brain and body” means in the brain and / or in the body. Thus, in some embodiments, in the brain and body means in the brain and in the body. In other embodiments, in the brain and body means in the brain or in the body. In embodiments, in the brain and body means in the brain and not in the body. In embodiments, in the brain and body means in the body and not in the brain. “Not in the body” and “not in the brain” may refer to, for example, an enhancement of mitochondrial energy not being demonstrated in the body or in the brain. In other embodiments, “not in the body” and “not in the brain” may refer to, for example, an enhancement of mitochondrial energy not being present in the body or in the brain.

[0106]

[0099] In embodiments, increasing the concentration of a metabolic cofactor or a metabolic coenzyme, for example where such concentration is increased directly by administering the cofactor or coenzyme, or where such concentration is increased indirectly by administering a compound that produces such increase, enhances mitochondrial energy in the brain and body while administering a serotonergic psychedelic.

[0107]

[0100] In embodiments, administering a combination increases energy production and promotes the biogenesis of new mitochondria, as well as improves mitochondrial functioning, while assuring that enough NAD+ is available to power the newly synthesized mitochondria. In embodiments, administering a disclosed combination increases glucose concentrations in the brain and body, thus increasing amounts of Acetyl CoA available for the Krebs cycle; and increases the amount of oxygen available for the electron transport chain. a. Nicotinamide Adenine Dinucleotide (NAD)

[0108]

[0101] Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism that exists in various forms, including as oxidized and reduced forms (NAD+ and NADH, respectively), and as stereoisomers. NAD plays an important role in maintaining cellular homeostasis, and participates in over 500 enzymatic reactions (Wang et al. Front Cell Dev Biol. 2021 ; 9 :668491 ). NAD+ manages major biological metabolism in the cytosol, nucleus, and mitochondria and contributes to overall cellular health (id.). Mammalian cells synthesize NAD+ from dietary precursors through the de novo pathway, the Preiss-Handler pathway, and the salvage pathway (Navas & Camera, Signal Transduc Targeted Ther. 2021 ;6(1):2). NAD+ is central to cellular energy metabolism broadly, because it is a coenzyme for redox reactions (Covarrubias et al. 2020;22(2):119-141 ).

[0109]

[0102] NAD+ directly and indirectly influences key metabolic pathways, chromatin remodeling, DNA repair, and immune cell function (Covarrubias et al. 2020). NAD+ may be required for proper ATP production (Stein & Imai, Trends Endocrinol Metab. 2012;23(9):420-428). NAD+ may activate the expression of longevity genes activated through 5-HT2Areceptors. NAD+ may activate sirtuin enzymes, and sirtuin enzymes may play a role in aging and longevity control in humans (Imai & Guarente, Trends Cell Biol. 2014;24(8):464-471 ).

[0110]

[0103] NAD+ travels to the mitochondria where it is reduced to NADH (Xie et al, Signal Transduc Targeted Ther. 2020;5(1):22). NADH is oxidized back to NAD+ (id.). NADH also releases an electron to the electron transport chain, leading to synthesis of ATP, and increasing available energy to the cells (Stein & Imai, 2012).

[0111]

[0104] Levels of NAD+ decline with age, with NAD+ depletion being linked to the characteristic misfolding of proteins seen in Alzheimer’s disease, Parkinson’s disease, and other diseases (see Zhou et al. Brain. 2015;138(4):992-1008). Lower levels of NAD+ also decrease the mitochondria’s ability to produce ATP, leading to disorders that stem from mitochondrial dysfunction, such as cardiovascular and neurodegenerative disorders (Gardner & Boles, Progress Neuro-Psychopharmacol Biol Psych. 2011 ;35(3):730-743). Without being bound by theory, because NAD+ is a precursor to produce ATP, increasing mitochondrial biogenesis through 5-HT2areceptor stimulation together with NAD+ replenishment, such as in disclosed methods, and by administering a combination, may reduce mitochondrial dysfunction and / or enhance mitochondrial function.

[0112]

[0105] “Mitochondrial dysfunction” refers to any condition or impairment affecting the functioning of mitochondria. Such dysfunction may manifest in many ways known to one of skill, including as reduced ATP production, altered mitochondrial membrane potential, impaired mitochondrial dynamics, or disrupted cellular signaling pathways involving mitochondria. Such dysfunction can arise from factors such as genetic mutations, environmental factors, disease states, or aging processes, leading to various cellular and physiological consequences, including metabolic disorders, neurodegenerative diseases, cardiovascular complications, and overall cellular dysfunction. Diagnosis and symptoms of such dysfunction are known in the art, and can include seizures, strokes, developmental delays, heart and kidney issues, speech problems, sight problems, chronic fatigue, digestion problems, and motor control problems (Parikh et al. Genetics Med. 2015;17:689-701). Such dysfunction is implicated in mitochondrial disease, and is a contributing factor in many conditions and disorders including neurodegenerative disorders (e.g., ALS, PD, AD), cardiomyopathies, metabolic syndrome, cancer, and obesity (Lezi & Swerdlow, Adv Exp Med Biol. 2012;942:269-86).

[0113]

[0106] In embodiments, a combination comprises a serotonergic psychedelic and a metabolic coenzyme, where the metabolic coenzyme is NAD, as NADH, NAD+, or a combination thereof. In embodiments, a combination comprises a serotonergic psychedelic and NAD. In embodiments, a combination comprises a serotonergic psychedelic and NAD+. In embodiments, a combination comprises a serotonergic psychedelic and NADH. In embodiments, a combination comprises a serotonergic psychedelic and NAD+ and NADH.

[0114]

[0107] In embodiments, administering NAD (e.g., as NAD, NAD+, NADH, or a combination thereof) in a combination increases the concentration of NAD in the brain and body. In embodiments, administering NAD (e.g., as NAD, NAD+, NADH, or a combination thereof) in a combination increases the concentration of NAD+ in the brain and body. In embodiments, administering NAD (e.g., as NAD, NAD+, NADH, or a combination thereof) in a combination increases the concentration of NADH in the brain and body.

[0115]

[0108] In embodiments, mitochondrial ATP production can be enhanced by (1) increasing the concentration of NAD+ in the brain and body by administering NAD, and (2) administering a serotonergic psychedelic.

[0116]

[0109] In embodiments, the concentration of NAD+ in the brain and body is increased by administering NAD, NAD+, and / or NADH. In embodiments, NAD+ is administered parenterally, such as by injecting NAD+ intramuscularly (IM), or by infusing NAD+ intravenously (IV). In embodiments, NAD+ is administered orally, such as by liposomal NAD+, taken orally. In embodiments, NAD is administered parenterally, such as by injecting NAD IM, or by infusing NAD IV. In embodiments, NAD is administered orally, such as by liposomal NAD, taken orally. In embodiments, NADH is administered parenterally, such as by injecting NADH IM, or by infusing NADH IV. In embodiments, NADH is administered orally, such as by liposomal NADH, taken orally.

[0117]

[0110] In embodiments, the concentration of NAD+ in the brain and body is increased by administering an NAD+ precursor. In embodiments, the concentration of NAD+ in the brain and body is increased by inhibiting NAD+ degradation (e.g., by administering an agent that inhibits NAD+ degradation). “NAD+ degradation” refers to a decreased in the amount of NAD+ in the brain and body, such as when NAD+ is consumed by sirtuins and converted to NAM, poly(ADP-ribose) polymers (PARPs), and / or cyclic ADP ribose hydrolase (CD38). A “NAD+ degradation inhibitor” refers to a molecule that, when administered, reduces or eliminates NAD+ degradation, such as a CD38 inhibitor, a PARP inhibitor, a SIRT inhibitor, and a SARM1 inhibitor. b. NAD+ Precursors and Other Means of Increasing NAD

[0118]

[0111] In embodiments, a combination comprises a serotonergic psychedelic together with a precursor of a metabolic coenzyme, where the precursor of a metabolic coenzyme is a NAD+ precursor. A NAD+ precursor is a compound that is converted to NAD+ / n vivo. In embodiments, administering a combination comprising a serotonergic psychedelic and a NAD+ precursor increases the concentration of NAD in the brain and body.

[0119]

[0112] In embodiments, the NAD+ precursor is any of tryptophan (Trp), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), nicotinamide (NAM), nicotinic acid (niacin, NA), and inositol hexanicotinate (IHN). In embodiments, the NAD+ precursor is Trp. In embodiments, the NAD+ precursor is NR. In embodiments, the NAD+ precursor is NMN. In embodiments, the NAD+ precursor is NAM. In embodiments, the NAD+ precursor is NA. In embodiments, the NAD+ precursor is IHN.

[0120]

[0113] In embodiments, a combination comprises a serotonergic psychedelic together with one NAD+ precursor, with two NAD+ precursors, with three NAD+ precursors, with four NAD+ precursors, with five NAD+ precursors, or with more than five NAD+ precursors, and may further comprise other agent(s) herein.

[0121]

[0114] The precursors NR, NAM, and NMN can increase NAD+ concentration when administered on their own, i.e., without further supplementation of NAD+ itself (Canto et al., Cell Metab. 2015;22:31-53). NR and NMN are bioavailable and effective agents to increase NAD+ concentration (Wang et al, 2021). NaR, NaMN, and NAAD are also potential agents to boost NAD+ concentration (id.). NR and NMN can be converted to NAM in the liver before being transformed again into NAD+ which indicates that NAM may be a direct dietary NAD+ precursor (Liu et al,. Call Metab. 2018;27:1067-1080). Other NAD-boosting agents, useful in embodiments of the disclosure, will be known in the art (e.g., Rajman et al., Cell Metab. 2018;27(3):529-547).

[0122]

[0115] In embodiments, administering a combination comprising a serotonergic psychedelic and a NAD+ precursor or another NAD-boosting agent will increase the concentration of NAD+ in the brain and body.

[0123]

[0116] Various processes in the body may decrease the concentration of NAD+. For example, when NAD+ is consumed by sirtuins (SIRTs), PARPs, or CD38, NAD+ may be converted to NAM (Hwang & Song, Biomol. 2020; 10(5):687). If the amount of NAM increases beyond a certain level, NAM may be methylated, producing methylated NAM (Me-NAM) id.). This may signal the cell to remove Me-NAM through the urine (id.). Excessive methylation of NAM may lead to methyl-donor depletion, causing or increasing the risk of detrimental health effects (Pissios, Trends Endocrinol Metab. 2017;28(5):340-353).

[0124]

[0117] In some embodiments where a combination comprises any of NAD+, NADH, NAM, Trp, NA, NR, NMN, and IHN, the combination further comprises a methyl-donor supplement. In some embodiments wherein a combination comprises any of NAD+, NADH, NAM, Trp, NA, NR, NMN, and IHN, the risk of methyl-donor depletion is decreased by administering a methyl-donor supplement with the combination, such as a betaine, e.g., N, N, N-trimethylglycine (TMG), or by activating the nicotinamide phosphoribosyltransferase (NAMPT) enzyme, which recycles NAM back into NAD+ (Obeid, Nutrients. 2013; 5(9):3481 -3495).

[0125]

[0118] In embodiments, the methyl-donor supplement is any of vitamin B2, vitamin B6, vitamin B9, vitamin B12, methionine, and choline. Methods for detecting methyl-donor depletion are known to one of skill, and include liquid chromatography-mass spectrometry (LC-MS), a methylation sensitive restriction enzyme (MSRE), a digestion-based analytical technique, bisulfite treatment, sodium bisulfite conversion and sequencing, differential enzymatic cleavage of DNA, and affinity capture of methylated DNA.

[0126]

[0119] In some embodiments where the NAD+ precursor administered is NAM, the risk of methyl-donor depletion can be reduced or eliminated by administering a methyl-donor supplement. In some embodiments wherein the NAD+ precursor administered is NAM, the risk of methyl-donor depletion is reduced or eliminated by administering a methyl-donor supplement. In embodiments, a combination comprises a methyl-donor supplement. In embodiments, the methyl-donor supplement is trimethylglycine.

[0127]

[0120] In embodiments, a combination comprises NAM and NAMPT. In some embodiments wherein the NAD+ precursor administered is NAM, NAMPT is activated by administering a NAMPT activating agent. In embodiments, NAMPT is activated by administering berberine and / or resveratrol. In embodiments, NAMPT is activated by administering 3,6-dibromo-a-[(phenylamino)methyl]-9H-carbazol-9-ethanol (P7C3). In embodiments, a combination comprises a NAMPT activating agent, such as berberine, resveratrol, or P7C3.

[0128]

[0121] In embodiments, administering a combination increases the concentration of NAD+ in the brain and body. In embodiments, increasing the concentration of NAD+ in the brain and body increases energy levels in the brain and body (e.g., mitochondrial energy) when administering, e.g, microdosing, a serotonergic psychedelic. In embodiments, increasing the concentration of NAD+ increases mitochondrial energy levels in the brain and body (e.g., mitochondrial energy) after administering a serotonergic psychedelic.

[0129]

[0122] In embodiments, NAD+ concentration in the brain and body is increased by activation of NAD+ biosynthesis enzymes (e.g., P7C3). In embodiments, administering a combination results in an increase, e.g., a temporary increase, in cellularly available NAD+. In embodiments, a combination comprises a NAD+ biosynthesis enzyme activator, e.g., P7C3. In embodiments, administering a combination increases cellularly available NAD+ by inhibiting one or more of a SIRT, PARP, CD38 / CD157, and SARM1. In embodiments, administering a combination results in an increase in cellularly available NAD+ by such inhibition through a process of competition for the degradation of NAD+ (cf. Lautrup et al, Cell Metab. 2019; 30 : 630-655) .

[0130]

[0123] In embodiments, a combination comprises a serotonergic psychedelic together with an NAD+ degradation inhibitor, where the NAD+ degradation inhibitor is any of a CD38 inhibitor, a PARP inhibitor, a SIRT inhibitor, and a SARM1 inhibitor. In embodiments, the concentration of NAD+ in the brain and body is increased by inhibiting NAD+ degradation (i.e., by administering an agent that reduces or eliminates NAD+ degradation, such as a CD38 inhibitor, PARP inhibitor, SIRT inhibitor, or SARM1 inhibitor).

[0131]

[0124] In embodiments, a combination comprises a SIRT inhibitor. In embodiments, administering a SIRT inhibitor inhibits NAD+ degradation and increases cellularly available NAD+. In embodiments, the SIRT inhibitor is nicotinamide (and structurally similar analogs, e.g., 1,4-dihydropyridine), N-thiocarbamoyl lysine, / V-TFA lysine, sirtinol, salermide, cambinol, splitomicin, indole derivatives, suramin, tenovin, or aristoforin.

[0132]

[0125] In embodiments, a combination comprises a CD38 inhibitor. In embodiments, administering a CD38 inhibitor inhibits NAD+ degradation and increases cellularly available NAD+. In embodiments, the CD38 inhibitor is daratumumab (Darzalex), isatuximab, apigenin, quercetin, luteolin, luteolinidin, kuromanin, 78c, or another CD38 inhibitor known in the art.

[0126] In embodiments, a combination comprises a PARP inhibitor. In embodiments, administering a PARP inhibitor inhibits NAD+ degradation and increases cellularly available NAD+. In embodiments, the PARP inhibitor is olaparib (Lynparza), rucaparib (Rubraca), talazoparib, niraparib (Zejula), veliparib, iniparib, PJ34, DPQ, 3-aminobenzamide, BGB-290, CEP-9722, or E7016.

[0133]

[0127] In embodiments, a combination comprises a SARM1 inhibitor. In embodiments, administering a SARM1 inhibitor inhibits NAD+ degradation and increases cellularly available NAD+. In embodiments, the SARM1 inhibitor is berberine (e.g., berberine chloride), XAV939, or zinc (e.g., zinc chloride).

[0134]

[0128] In embodiments, a combination comprises a SIRT activator. In embodiments, administering a SIRT activator increases cellularly available NAD+ by activating the SIRT pathway. A SIRT activator can be an activator of any of the seven sirtuin isoforms (i.e., SIRT1- SIRT7), and may be any of a SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, or SIRT7 activator. In embodiments, the SIRT activator is butein, cyanidin, fisetin, ginsenoside Rc, honokiol, isoliquiritigenin, piceatannol, quercetin, resveratrol, SRT501, SRT1720, SRT2104, ADTL-SA1215, UBCS039, LPA, MDL-811, or another sirtuin-activating compound (STAC) known in the art.

[0135]

[0129] In embodiments, a combination comprises an agent that increases SIRT activity. In embodiments, the agent that increases SIRT activity is glucosamine or an agent that promotes hydrogen sulfide synthesis.

[0136]

[0130] In embodiments, a combination comprises an agent that preserves SIRT activity. In embodiments, the agent that preserves SIRT activity is an antioxidant, such as an antioxidant disclosed herein.

[0137]

[0131] In embodiments, a combination comprises an agent that enhances SIRT synthesis or protein expression. In embodiments, the agent that enhances SIRT synthesis or protein expression is ferulic acid, tetrahydrocurcumin, urolithin A, melatonin, astaxanthin, carnosic acid, or neochlorogenic acid.

[0138]

[0132] In embodiments, a combination comprises an agent that enhances the half-life of a SIRT protein. In embodiments, the agent that enhances the half-life of a SIRT protein is N1 -methylnicotinamide.

[0139]

[0133] In embodiments, a combination comprises an agent that promotes NADH oxidation. In embodiments, the agent that promotes NADH oxidation is thymoquinone, pyrroloquinoline quinone, or another quinone.

[0140]

[0134] In embodiments, a combination comprises an activator of AMP-activated kinase or an agent that increases expression of nicotinamide phosphoribosyltransferase (PRT). In embodiments, the activator of AMP-activated kinase or agent that increases expression of nicotinamide PRT is berberine.

[0141]

[0135] In embodiments, a combination comprises an agent that acts as a substrate for NAD+ synthesis. In embodiments, the agent that acts as a NAD+ synthesis substrate is nicotinamide riboside or mononucleotide.

[0142]

[0136] In embodiments, a combination comprises an agent that lessens the reduction of NAD+ mediated by glycolysis. In embodiments, lessening the reduction of NAD+ mediated by glycolysis increases NAD+ in the brain. In embodiments, the agent that lessens such reduction of NAD+ is medium-chain triglycerides (MCTs).

[0143]

[0137] Assessing cellularly available NAD+ and NAD+ concentrations in the brain and body can be performed according to methods known in the art, including, for example, measuring NAD+ blood plasma concentration before and after administering a combination (e.g., measuring a change in a subject’s NAD+ levels). NAD+ levels can also be measured by LC-MS or enzymatic assays (Braidy, Villalva & Grant, Life (Basel). 2021 ;11 (6):512). Liquid chromatography allows the separation of individual metabolites, and may allow for the chromatographic separation and quantification of metabolites, including NAD+ and NADH) (id.). c. Other Mitochondrial Energy Enhancers

[0144]

[0138] In embodiments, a combination comprises a serotonergic psychedelic together with a mitochondrial energy enhancer. In embodiments, the mitochondrial energy enhancer is coenzyme Q10 (CoQ10). In embodiments, the mitochondrial energy enhancer is flavin adenine dinucleotide (FAD). In embodiments, the mitochondrial energy enhancer is magnesium. In embodiments, the mitochondrial energy enhancer is any of alpha lipoic acid (ALA), pyrroloquinoline (PQQ), apigenin, leucine, genistein, quercetin, anthocyanins (cyanidin, delphinidin, malvidin), hydroxytyrosol, curcumin, tangeretin, rutin, cyanidin-3-glucoside (Cy3g), nobiletin, sudachitin, and ALC. In embodiments, the mitochondrial energy enhancer is a B-complex vitamin. In embodiments, the mitochondrial energy enhancer is a mineral.

[0145]

[0139] Assessing mitochondrial energy enhancement can be performed according to methods known in the art, including, for example, by measuring an increase in ATP production. In embodiments, mitochondrial energy enhancement is measured by an increase in cellular oxygen consumption.

[0146]

[0140] In embodiments, the mitochondrial energy enhancer is CoQ10. CoQ10 is part of the mitochondrial oxidative phosphorylation system, and is critical for energy metabolism. CoQ10 can be used as a supplement to help treat many illnesses (Saini, J Pharm Bioallied Sci. 2011;3:466-467). CoQ10 is a lipid antioxidant, and can prevent the generation of free radicals and modifications of proteins, lipids, and DNA.

[0147]

[0141] It will be appreciated that disclosed compounds need not be limited to a single defined class only, as for example CoQ10 may be considered both a mitochondrial energy enhancer and an antioxidant.

[0148]

[0142] In embodiments, the mitochondrial energy enhancer is FAD. FAD is part of the electron transport chain that makes ATP (Mansoorabadi et al. J Org Chem. 2017;6329-6342). FAD may ensure the functionality of enzymes involved in mitochondrial electron transport and in oxidative metabolism of carbohydrates, amino acids, and fatty acids (id.). FAD is synthesized from riboflavin, and decreased riboflavin ingestion or metabolism can lead to reduced ATP production (Hirano & Namihira, Open Bio. 2017;7(12):1932-1942).

[0149]

[0143] In embodiments, the mitochondrial energy enhancer is magnesium. Magnesium plays a role in the production and utilization of ATP. Each molecule of ATP binds to a magnesium ion, and most cellular ATP exists as ATP-Mg complexes (Tardy et al. Nutrients. 2020;12(1):228). In the mitochondria, ATP-Mg complexes may help export mitochondrial ATP into the cytosol, delivering energy within the cell (id.).

[0150]

[0144] In embodiments, the mitochondrial energy enhancer is any of ALA, PQQ, ALC, apigenin, leucine, anthocyanins (e.g., cyanidin, delphinidin, malvidin), hydroxytyrosol, curcumin, tangeretin, rutin, Cy3g, nobiletin, sudachitin, genistein, or a polyphenol as in Chodari et al. Oxid Med Cell Longev. 2021 :4946711.

[0151]

[0145] In embodiments, the mitochondrial energy enhancer is a B-complex vitamin, such as any of vitamins B1 , B2, B3, B5, B6, B7, B9, and B12. B-complex vitamins have important roles in energy production, including glucose metabolism. B-complex vitamins are shown to improve glycemic control and renal function by decreasing homocysteine (Kennedy, Nutrients. 2016;8(2), 68). Again, and not only here but for any disclosed compounds, it will be readily appreciated that compounds need not be limited to a single defined class only, but may be of multiple classes, such as a mitochondrial energy enhancer and a glucose regulator.

[0152]

[0146] In embodiments, the mitochondrial energy enhancer is thiamin (vitamin B1). In embodiments, the mitochondrial energy enhancer is riboflavin (vitamin B2). In embodiments, the mitochondrial energy enhancer is niacin (vitamin B3). In embodiments, the mitochondrial energy enhancer is pantothenic acid (vitamin B5). In embodiments, the mitochondrial energy enhancer is pyridoxine (vitamin B6). In embodiments, the mitochondrial energy enhancer is biotin (vitamin B7). In embodiments, the mitochondrial energy enhancer is folate (vitamin B9). In embodiments, the mitochondrial energy enhancer is cobalamin (vitamin B12).

[0153]

[0147] In embodiments, the mitochondrial energy enhancer is a mineral. Minerals can play important roles in energy production (Huskisson et al. Int’l Med Res. 2007;35(3):277-289). Minerals useful in combinations include iodine, sulfur, and magnesium. In embodiments, the mineral is iodine. In embodiments, the mineral is sulfur. In embodiments, the mineral is magnesium (e.g., as magnesium oxide, citrate, or chloride).

[0154]

[0148] In embodiments, the mitochondrial energy enhancer is a sulfoxide or a sulfone. In embodiments, the mitochondrial energy enhancer is dimethyl sulfoxide or methylsulfonylmethane. d. Antioxidants and Glucose Regulators

[0155]

[0149] In embodiments, a combination comprises a serotonergic psychedelic together with an antioxidant and / or a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic together with an antioxidant. In embodiments, a combination comprises a serotonergic psychedelic together with a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic together with an antioxidant and a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic together with an antioxidant that is also a glucose regulator. In embodiments, a combination comprises a serotonergic psychedelic together with an antioxidant that is also a mitochondrial energy enhancer.

[0156]

[0150] LSD and other serotonergic psychedelics may increase the volume of blood in the capillaries, accompanied by a decrease in cerebrospinal fluid (CSF) volume, and in turn, increase the amount of glucose that reaches the neurons. In embodiments, glucose consumption is increased after administering a serotonergic psychedelic. In embodiments, and without being bound by theory, when glucose levels drop beyond a certain threshold, the adrenal glands release adrenaline which signals to the liver to release glucose into the bloodstream (Verberne et al. Br J Pharmacol. 2016;173(9):1425-1437). Vitamin C is a cofactor of adrenaline, but is not stored in human bodies (Bornstein et al. FASEB J. 2003;17(13):1928-30). In embodiments, ascorbic acid from a combination is taken up by the mitochondria, and may preserve the mitochondrial membrane potential (Vineetha et al., Mitochondrial Physiology Vegetal Mol. 2021 :613-24).

[0157]

[0151] In embodiments, a combination comprises ascorbic acid (vitamin C). In embodiments, a combination comprising vitamin C maintains optimal blood glucose levels. In embodiments, a combination comprising vitamin C sustains heightened concentration and consciousness. In embodiments, maintaining optimal glucose levels supports increased energy production in the brain and body. In embodiments, a combination comprising vitamin C decreases oxidative stress and ROS.

[0152] In embodiments, a combination comprises timed-release vitamin C. “Timed-release vitamin C” (alternatively, “time release”) refers to a formulation of vitamin C that is released over a period of time (e.g., about 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, and greater than 8 hours) within the body rather than released within the body all at once. An alternative equivalent to timed-release vitamin C in some embodiments is extended-release, prolonged-release, or sustained-release vitamin C. Examples include ENDUR-C® Vitamin C 500 mg, Nutrilite™ Vitamin C Extended Release, Webber Naturals® Vitamin C Timed Release, and 21st Century Vitamin® C-500 Prolonged Release 90S. Water soluble vitamins, such as vitamin C, are generally not stored in the body (as in the fat), but are eliminated. In embodiments, timed-release vitamin C or an equivalent advantageously helps maintain appropriate blood glucose levels.

[0158]

[0153] In embodiments, a combination comprises the oxidized form of ascorbic acid, dehydroascorbic acid (DHA). DHA may enter mitochondria via facilitative glucose transporter 1 (Glutl) and accumulate mitochondrially as ascorbic acid (mtAA) (Sagan, FASEB J. 2005; 19(12): 1657-1667). mtAA may quench mitochondrial ROS and inhibit oxidative mitochondrial DNA damage (Dhar-Mascareno et al. Free Radio Biol Med. 2005;38(10): 1311-1322). In embodiments, a combination comprises DHA, which acts as an antioxidant and protects the mitochondria from oxidative damage (id.). A combination may comprise DHA and vitamin C.

[0159]

[0154] In embodiments, a combination comprises a glucose regulator. In embodiments, the glucose regulator is a B-complex vitamin, such as any of vitamins B1, B2, B3, B5, B6, B7, B9, and B12. In embodiments, the glucose regulator is any of thiamin (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folate (B9), and cobalamin (B12), including combinations thereof.

[0160]

[0155] In embodiments, a combination comprises eriocitrin, a metabolite associated with blood glucose support and improved antioxidant response (Meng et al. Front Microbiol. 2022;13: 1111200), which acts as a glucose regulator and an antioxidant, and may be in a combination as a glucose regulator or an antioxidant.

[0161]

[0156] In embodiments, a combination comprises an antioxidant. In embodiments, the antioxidant is CoQ10. In embodiments, the antioxidant is idebenone. Idebenone is an antioxidant that is structurally similar to CoQ10, and functions as an electron carrier (Maher et al. JAMA. 2019;321 (5):512-523). In embodiments, the antioxidant is N-acetyl cysteine (NAC). NAC is a pharmacological antioxidant and cytoprotectant (Ezerina et al. Cell Chem Biol. 2018;25(4):447-459). In embodiments, the antioxidant is curcumin, which has cytoprotective effects on multiple cell types, is an effective scavenger of free radicals, and may upregulate cytoprotective cell response by modulating the expression of genes encoding antioxidant properties, such as SOD, CAT, and HO-1 (Gibellini et al. Evid Based Complement Alternat Med. 2015;527209). In embodiments, the antioxidant is dimethylglycine (DMG), which can neutralize free radicals to alleviate oxidative damage (Gibellini et al. 2015). In embodiments, the antioxidant is glycyrrhizic acid (GA), which has antioxidant, anti-inflammatory, and anti-excitotoxic properties (Gibellini et al. 2015). In embodiments, the antioxidant is a phenolic acid, such as hydroxycinnamic acid (Chen et al. Scientific Reporter. 2020; 10:2611). In embodiments, the antioxidant is an anthocyanin, such as cyanidin, malvidin, and delphinidin (Garcia & Blesso, Free Radical Biol Med. 2021 ;172:152-166). In embodiments, the antioxidant is a catechin, such as epicatechin, which can scavenge free radicals (McDonald et al. Muscle Nerve. 2020;63(2):239-249). In embodiments, the antioxidant is isorhamnetin (ISOR), which is a quercetin-derived compound and can protect cells against inflammation, oxidative damage and apoptosis (Yang et al. Toxicol Appl Pharmacol. 2014;274(2):293-301). In embodiments, the antioxidant is nobiletin, which can reduce mitochondrial ROS production (Cajas et al. Int J Mol Sci. 2020;21 (15):5340).

[0162]

[0157] In embodiments, administering a combination comprising an antioxidant or glucose regulator together with a mitochondrial energy enhancer, such as a metabolic cofactor or metabolic coenzyme, synergistically causes additional or enhanced benefits when administered with a serotonergic psychedelic.

[0163]

[0158] As one example, in embodiments, administering a combination comprising vitamin C, such as timed-release vitamin C, together with NAD or a NAD+ precursor, synergistically causes additional or enhanced therapeutic benefits when also administered together with a serotonergic psychedelic, e.g., LSD.

[0164] C. Forms of the Compounds or Agents Used in the Therapeutic Combinations

[0165]

[0159] Compounds (also, “agents”) in disclosed combinations may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. All such possible isomers, as well as mixtures thereof, including racemic and optically pure forms, are included in the disclosure. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art to prepare optically active forms and determine activity. Methods include standard tests described herein and others known in the art.

[0166]

[0160] Included are also compounds as a pure or substantially pure individual enantiomer, or as an enantiomerically enriched mixture having an optical purity of between 0-25%, between 25-50%, between 50-75%, between 75-90%, between 90-95%, at least 95%, or at least 99% enantiomeric excess. Where a compound is present as a non-racemic mixture, the mixture may have any ratio of stereoisomers.

[0167]

[0161] When a compound contains olefinic double bonds or other centers of geometric asymmetry, the compound includes both E and Z geometric isomers. Likewise, tautomeric forms are included.

[0168]

[0162] Included are compounds with at least one isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons.

[0169]

[0163] Examples of isotopes that can be incorporated into disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine such as2H,3H,11C,13C,14C,15N,17O,18O, and36CI respectively. Isotopes of hydrogen including deuterium (2H) and tritium (3H) may be substituted anywhere on a disclosed compound that achieves a desired result. Isotopes of carbon, e.g.,13C and14C also may be used.

[0170]

[0164] Isotopic substitutions, e.g., deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain embodiments, the isotope is at least 60%, 70%, 80%, 90%, 95%, or 99% or more enriched in an isotope at any location of interest. In non-limiting embodiments, deuterium is 90%, 95%, 99%, or 99.9% enriched at a desired location.

[0165] Included are also compounds as a pharmaceutically acceptable salt. A “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, and which may be synthesized by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base forms a compound with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile) are preferred. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, zinc, and the like (see Berge et al. J Pharm Sci. 1977;66:1-19)

[0171]

[0166] Included are also prodrugs of the disclosed compounds. A “prodrug” includes any precursor of a compound that undergoes a conversion after administration to become the compound. A prodrug can be converted in vivo to the compound by the action of a metabolic process, an enzymatic process, or a degradative process that removes the prodrug moiety, such as a glycoside or acetyl group, to form the compound. Exemplary prodrugs can be created by the addition of a hydroxyl group (Tsujikawa et al. Xenobiotica, 2011 ;41 (7):578-584; Yamamoto et al. Xenobiotica, 1984;14(11):867-875), an acyloxy alkyl carbonyl derivative, an amino acid (such as lysine), or a peptide (Vig et al. Adv. Drug Delivery Rev., 2013;65(10): 1370-1385), and in some embodiments, a prodrug moiety is added to an amine, such as a lysergamide (e.g., LSD), and is removed within the body by a chemical reaction or enzyme. Other prodrugs, including at other sites, are also within the scope of the disclosure (see Simpllcio et al. Molecules. 2008; 13(3):519-547; Shah et al. (Eds.) Recent Advancement in Prodrugs. CRC Press (2020)). Other prodrugs include those that are transformed in various organs or locations in the body (e.g., liver, kidney, G.I., lung, tissue) to release the compound. For example, liver prodrugs include the compound conjugated with a polymer or chemical moiety that is not released until acted upon by liver cytochrome enzymes; CYP metabolism includes dealkylation, dehydrogenation, reduction, hydrolysis, oxidation, and the breakdown of aromatic rings. Kidney prodrugs include a compound conjugated to L-gamma-glutamyl or N-acetyl-L-gamma glutamic moieties so that it are metabolized by gamma-glutamyl transpeptidase before it is bioactive; alternatively, it may be conjugated to an alkylglucoside moiety to create a glycosylation-based prodrug. Digestive or G.l. prodrugs include those where a compound is, e.g., formulated into microspheres or nanospheres that do not degrade until the spheres are subjected to an acidic pH; formulated with an amide that will resist biochemical degradation until colonic pH is achieved; or conjugated with a linear polysaccharide such as pectin that delays activation until the combination reaches the bacteria in the colon. Besides these exemplary prodrug forms, many others will be known to one of skill, in view of the disclosure.

[0172]

[0167] Other examples of prodrugs include those with biologically labile or cleavable (protecting) groups on a functional moiety of the compound. Other examples of prodrugs include those that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or dephosphorylated to produce the compound. Examples of prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U.S. Pat. Nos. 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference. Disclosed prodrugs are metabolized to produce an active agent as described herein, and above referred to as the “compound.” Conventional procedures for selection and preparation of prodrugs are also described in “Design of Prodrugs” Ed. H. Bundgaard, Elsevier, 1985.

[0173]

[0168] Compounds may exist in different forms, and when prepared in solid compositions may exist in stable and metastable crystalline forms, isotropic and amorphous forms, milled forms, and nano-particulate forms, all of which are within the scope of the disclosure. Compounds also include crystalline forms, such as polymorphs. Polymorphs may have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility, and various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. The screening and characterization of the pharmaceutically acceptable salts, polymorphs, hydrates, solvates, co-crystals, amorphous forms, and the like, may be accomplished using a variety of techniques including thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address thermo chemical degradation or thermo physical processes including polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, determine weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include: Differential scanning calorimetry (DSC), Modulated Differential Scanning Calorimetry (MDCS), Thermogravimetric analysis (TGA), and Thermogravimetric and Infrared analysis (TG / IR). X-ray diffraction methods include single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include Raman, FTIR, UVIS, and NMR (liquid and solid state). The various microscopy techniques include polarized light microscopy, Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis (EDX), Environmental Scanning Electron Microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0174]

[0169] Among derivatives of a compound are included its “physiologically functional derivatives,” which refer to physiologically tolerated chemical derivatives of the compound having the same physiological function thereof, for example, by being convertible in the body thereto, and which on administration to a mammal such as a human is able to form (directly or indirectly) the compound or an active metabolite thereof (acting therefore, like a prodrug), or by otherwise having the same or substantially the same physiological, therapeutic, or other function, despite one or more structural differences. Examples of physiologically functional derivatives include esters, amides, carbamates, ureas, and heterocycles. In embodiments, a derivative is a disclosed compound modified to increase or decrease their blood-brain barrier permeability.

[0175]

[0170] In embodiments, a compound is produced by chemical synthesis. In embodiments, a compound is produced by biosynthesis, such as in bacteria, yeast, or another bioengineered host cell. In embodiments, a compound is extracted from a natural source, and additionally may be purified or isolated therefrom. For example, DMT may be extracted from sources such as Phalaris, Delosperma, Acacia, Desmodium, Mimosa, Virola, and Psychotria spp. A “natural” compound may refer to a compound isolated, extracted, or otherwise obtained from a natural source, such as a plant, animal, or mineral. Methods of extracting compounds from plants and fungi, and creating plant and fungi extracts, and methods of obtaining purified products comprising compounds free from undesired plant or fungal matter, chemicals, and other impurities, are known in the art.

[0176] D. Additional Active Agents

[0177]

[0171] A disclosed combination may further comprise one or more additional active agents, which may, for example, contribute to, enhance, or provide an additional therapeutic effect, or contribute to or provide a synergistic effect or additional synergistic effect. A “therapeutic effect” includes, but is not limited to, an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, consciousness expanding, consciousness heightening, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, entheogenic, entactogenic or empathogenic, psychedelic, sedative, and stimulant effects. A goal of increasing an existing therapeutic effect, providing an additional therapeutic effect, increasing a desired property such as stability or shelf-life, decreasing an unwanted effect or property, altering a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulating a desired system or pathway (e.g, a neurotransmitter system), or otherwise inducing synergy, in some embodiments is achieved by the inclusion of an additional active agent.

[0178]

[0172] In embodiments, an additional active agent is administered in a separate dosage form or as a single dosage form comprising a disclosed compound or combination formulated with the additional active agent.

[0173] In embodiments, an additional active agent is from any of the classes of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic agents, antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, hypnotics, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, entactogens, psychedelics, plasticity-inducing agents, psychoplastogens, neuroplastogens, monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase-A (RIMAs), tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins, including salts thereof.

[0179]

[0174] In embodiments, the additional active agent acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, increase plasticity (e.g., neural plasticity, neuroplasticity, “meta” plasticity), or alter pharmacokinetics (PK) or pharmacodynamics (PD). In embodiments, the additional therapeutic effect is any of an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0180] E. Exemplary Therapeutic Combinations and Compositions

[0181]

[0175] In some aspects are disclosed therapeutic combinations (“combinations”) and pharmaceutical compositions (“compositions”). Combinations and compositions comprise disclosed compounds, which also may be referred to herein as “active agents” or simply “agents.” In general, a “combination” comprises two or more agents, for example in some embodiments, a serotonergic psychedelic, a mitochondrial energy enhancer, and optionally an antioxidant or glucose regulator, and in other embodiments, a serotonergic psychedelic, a metabolic cofactor or metabolic coenzyme, and optionally an antioxidant or a glucose regulator. In general, a “composition” comprises one or more agents and at least one carrier, diluent, or excipient. Herein, any reference to a “combination” will include, unless context clearly indicates otherwise, reference to a composition comprising the combination and one or more compositions comprising the agents. Any reference to a “composition,” such as to administration thereof, will include reference to the combination.

[0182]

[0176] In embodiments, a combination comprises a serotonergic psychedelic, a mitochondrial energy enhancer, and optionally an antioxidant or glucose regulator, administered together but not formulated as part of a single pharmaceutical composition. In embodiments, a combination comprises a serotonergic psychedelic, a metabolic cofactor or metabolic coenzyme, and optionally an antioxidant or a glucose regulator, administered together but not formulated as part of a single pharmaceutical composition. In embodiments, a combination comprises a serotonergic psychedelic, a mitochondrial energy enhancer, and optionally an antioxidant or glucose regulator, where the combination is formulated as a single pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, a combination comprises a serotonergic psychedelic, a metabolic cofactor or coenzyme, and optionally an antioxidant or a glucose regulator, where the combination is formulated as a single pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, a combination comprises a serotonergic psychedelic, a mitochondrial energy enhancer, an NAD+ degradation inhibitor, and optionally an antioxidant or glucose regulator, where the combination is formulated as a single pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, diluent, or excipient. A single composition may be, e.g., a fixed-dose combination (FDC) or combination drug.

[0183]

[0177] In embodiments, a therapeutic combination comprises a serotonergic psychedelic, a metabolic cofactor or coenzyme, an NAD+ degradation inhibitor, and optionally an antioxidant or a glucose regulator, where the combination is formulated as a single pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, a therapeutic combination comprises LSD and NAD+. In embodiments, a combination comprises LSD, NAD+, and vitamin C.

[0184]

[0178] In embodiments, a therapeutic combination comprises a serotonergic psychedelic, NAD (e.g., any of NAD+, p-NAD, and NADH), an NAD+ precursor, an NAD+ degradation inhibitor, and vitamin C (e.g., timed-release vitamin C), where the combination is formulated as a single pharmaceutical composition, further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

[0185]

[0179] In embodiments, the serotonergic psychedelic is any of LSD, 1 P-LSD, AL-LAD, psilocybin, psilocin, psilacetin, mescaline, DMT, DOI, 5-MeO-DMT, and ibogaine, as well as combinations thereof.

[0186]

[0180] In embodiments, the mitochondrial energy enhancer is any of ALC, ALA, a B-complex vitamin (e.g., B1 , B2, B3, B5. B7, and B12), CoQ10, flavin adenine dinucleotide (FAD), iodine, magnesium, nicotinamide (NAM), nicotinic acid (NA), nicotinic acid adenine dinucleotide (NAAD), nicotinamide adenine dinucleotide (NAD+), NaMN (nicotinic acid mononucleotide), nicotinic acid riboside (NaR), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), sulfur, or Trp, as well as combinations thereof.

[0187]

[0181] In embodiments, the metabolic cofactor or metabolic coenzyme is any of NAD+, NADH, NAM, NA, NAAD, NaMN, NaR, NMN, NR, and Trp. In embodiments, the metabolic cofactor or metabolic coenzyme is any of NAD+, NADH, NA, NaR, NMN, and Trp.

[0188]

[0182] In embodiments, the antioxidant or glucose regulator is vitamin C (e.g., ascorbic acid).

[0189]

[0183] In embodiments, the NAD+ degradation inhibitor is a PARP inhibitor, SARM1 inhibitor or SIRT inhibitor.

[0190]

[0184] In embodiments, a combination further comprises trimethylglycine, berberine, or resveratrol.

[0191]

[0185] In embodiments, a combination further comprises trimethylglycine, berberine, or resveratrol, including in some embodiments where the combination also comprises NAM.

[0192]

[0186] Exemplary Therapeutic Combinations and Pharmaceutical Compositions

[0193]

[0187] In embodiments, a combination, which may be formulated as one or more pharmaceutical compositions comprising the agent(s) of the combination, and is useful in methods of treatment comprising administering the combination, or administering the pharmaceutical composition(s) comprising it, is any of:

[0194]

[0188] (1 ) a serotonergic psychedelic; and (2) a mitochondrial energy enhancer.

[0195]

[0189] (1 ) a serotonergic psychedelic; and (2) a metabolic cofactor.

[0190] (1 ) a serotonergic psychedelic; and (2) a metabolic coenzyme.

[0196]

[0191] (1 ) a serotonergic psychedelic; (2) a mitochondrial energy enhancer; and (3) a glucose regulator.

[0197]

[0192] (1 ) a serotonergic psychedelic; (2) a metabolic cofactor; and (3) a glucose regulator.

[0198]

[0193] (1 ) a serotonergic psychedelic; (2) a metabolic coenzyme; and (3) a glucose regulator.

[0199]

[0194] (1) a serotonergic psychedelic; (2) a mitochondrial energy enhancer; and (3) an antioxidant.

[0200]

[0195] (1 ) a serotonergic psychedelic; (2) a metabolic cofactor; and (3) an antioxidant.

[0201]

[0196] (1) a serotonergic psychedelic; (2) a metabolic coenzyme; and (3) an antioxidant.

[0202]

[0197] (1) a serotonergic psych; (2) a mito. energy enhancer; (3) a glucose regulator; and (4) an antioxidant.

[0203]

[0198] (1) a serotonergic psych; (2) a metabolic cofactor; (3) a glucose regulator; and (4) an antioxidant.

[0204]

[0199] (1) a serotonergic psych; (2) a metabolic coenzyme; (3) a glucose regulator; and (4) an antioxidant.

[0205]

[0200] (1) LSD; and (2) NAD, as a and forms of NAD, NAD+, and / or NADH (as shorthand, simply “NAD”).

[0206]

[0201] (1 ) LSD; and (2) a NAD+ precursor.

[0207]

[0202] (1 ) LSD; and (2) NA, NMN, Trp, or NR.

[0208]

[0203] (1) LSD; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0209]

[0204] (1 ) LSD; and (2) an agent that inhibits NAD+ degradation.

[0210]

[0205] (1) LSD; and (2) a CD38 inhibitor.

[0211]

[0206] (1 ) LSD; and (2) a PARP inhibitor.

[0212]

[0207] (1) LSD; and (2) a SIRT inhibitor.

[0213]

[0208] (1) LSD; and (2) a SARM1 inhibitor.

[0214]

[0209] (1) LSD; (2) an agent that inhibits NAD+ degradation; and (3) NAD.

[0215]

[0210] (1) LSD; (2) a PARP inhibitor; and (3) NAD.

[0216]

[0211] (1) LSD; (2) a SIRT inhibitor; and (3) NAD.

[0217]

[0212] (1) LSD; (2) a CD38 inhibitor; and (3) NAD.

[0218]

[0213] (1) LSD; (2) a SARM1 inhibitor; and (3) NAD.

[0219]

[0214] (1) LSD; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0220]

[0215] (1) LSD; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0221]

[0216] (1) LSD; (2) NAD; and (3) an antioxidant.

[0222]

[0217] (1) LSD; (2) NAD; and (3) a glucose regulator.

[0223]

[0218] (1) LSD; (2) NAD; and (3) coenzyme Q10 (CoQ10).

[0224]

[0219] (1) LSD; (2) NAD; and (3) ascorbic acid (e.g., as also for all others below, timed-release vitamin C).

[0225]

[0220] (1) LSD; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0226]

[0221] (1) LSD; (2) a NAD+ precursor; and (3) a glucose regulator.

[0227]

[0222] (1) LSD; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0228]

[0223] (1) LSD; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0229]

[0224] (1) LSD; (2) a NAD+ precursor; (3) an antioxidant (e.g., timed-release vitamin C).

[0230]

[0225] (1 ) LSD; (2) NA, NMN, Trp, or NR; and (3) CoQ10.

[0226] (1) LSD; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10.

[0231]

[0227] (1) 1 P-LSD; and (2) NAD.

[0232]

[0228] (1 ) 1 P-LSD; and (2) a NAD+ precursor.

[0233]

[0229] (1 ) 1 P-LSD; and (2) NA, NMN, Trp, or NR.

[0234]

[0230] (1) 1 P-LSD; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0235]

[0231] (1) 1 P-LSD; and (2) an agent that inhibits NAD+ degradation.

[0236]

[0232] (1 ) 1 P-LSD; and (2) a CD38 inhibitor.

[0237]

[0233] (1) 1 P-LSD; and (2) a PARP inhibitor.

[0238]

[0234] (1) 1 P-LSD; and (2) a SIRT inhibitor.

[0239]

[0235] (1) 1 P-LSD; and (2) a SARM1 inhibitor.

[0240]

[0236] (1 ) 1 P-LSD; (2) a PARP inhibitor; and (3) NAD.

[0241]

[0237] (1) 1 P-LSD; (2) a SIRT inhibitor; and (3) NAD.

[0242]

[0238] (1 ) 1 P-LSD; (2) a CD38 inhibitor; and (3) NAD.

[0243]

[0239] (1) 1 P-LSD; (2) a SARM1 inhibitor; and (3) NAD.

[0244]

[0240] (1 ) 1 P-LSD; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0245]

[0241] (1) 1 P-LSD; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0246]

[0242] (1) 1 P-LSD; (2) NAD; and (3) an antioxidant.

[0247]

[0243] (1 ) 1 P-LSD; (2) NAD; and (3) a glucose regulator.

[0248]

[0244] (1) 1 P-LSD; (2) NAD; and (3) CoQ10.

[0249]

[0245] (1) 1 P-LSD; (2) NAD; and (3) ascorbic acid.

[0250]

[0246] (1) 1 P-LSD; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0251]

[0247] (1 ) 1 P-LSD; (2) a NAD+ precursor; and (3) a glucose regulator.

[0252]

[0248] (1) 1 P-LSD; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0253]

[0249] (1) 1 P-LSD; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0254]

[0250] (1) 1 P-LSD; (2) a NAD+ precursor; and (3) an antioxidant.

[0255]

[0251] (1) 1 P-LSD; (2) NA, NMN, Trp, or NR; and (3) CoQ10

[0256]

[0252] (1) 1 P-LSD; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10

[0257]

[0253] (1) AL-LAD; and (2) NAD.

[0258]

[0254] (1 ) AL-LAD; and (2) a NAD+ precursor.

[0259]

[0255] (1 ) AL-LAD; and (2) NA, NMN, Trp, or NR.

[0260]

[0256] (1) AL-LAD; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0261]

[0257] (1 ) AL-LAD; and (2) an agent that inhibits NAD+ degradation.

[0262]

[0258] (1) AL-LAD; and (2) a CD38 inhibitor.

[0263]

[0259] (1) AL-LAD; and (2) a PARP inhibitor.

[0264]

[0260] (1) AL-LAD; and (2) a SIRT inhibitor.

[0265]

[0261] (1) AL-LAD; and (2) a SARM1 inhibitor.

[0262] (1 ) AL-LAD; (2) a PARP inhibitor; and (3) NAD.

[0266]

[0263] (1) AL-LAD; (2) a SIRT inhibitor; and (3) NAD.

[0267]

[0264] (1 ) AL-LAD; (2) a CD38 inhibitor; and (3) NAD.

[0268]

[0265] (1) AL-LAD; (2) a SARM1 inhibitor; and (3) NAD.

[0269]

[0266] (1) AL-LAD; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0270]

[0267] (1) AL-LAD; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0271]

[0268] (1) AL-LAD; (2) NAD; and (3) an antioxidant.

[0272]

[0269] (1) AL-LAD; (2) NAD; and (3) a glucose regulator.

[0273]

[0270] (1 ) AL-LAD; (2) NAD; and (3) CoQ10.

[0274]

[0271] (1) AL-LAD; (2) NAD; and (3) ascorbic acid.

[0275]

[0272] (1) AL-LAD; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0276]

[0273] (1 ) AL-LAD; (2) a NAD+ precursor; and (3) a glucose regulator.

[0277]

[0274] (1) AL-LAD; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0278]

[0275] (1) AL-LAD; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0279]

[0276] (1 ) AL-LAD; (2) a NAD+ precursor; and (3) an antioxidant.

[0280]

[0277] (1 ) AL-LAD; (2) NA, NMN, Trp, or NR; and (3) CoQ10.

[0281]

[0278] (1) AL-LAD; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10.

[0282]

[0279] (1) psilocybin; and (2) NAD.

[0283]

[0280] (1 ) psilocybin; and (2) a NAD+ precursor.

[0284]

[0281] (1) psilocybin; and (2) NA, NMN, Trp, or NR.

[0285]

[0282] (1) psilocybin; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0286]

[0283] (1 ) psilocybin; and (2) an agent that inhibits NAD+ degradation.

[0287]

[0284] (1) psilocybin; and (2) a CD38 inhibitor.

[0288]

[0285] (1) psilocybin; and (2) a PARP inhibitor.

[0289]

[0286] (1) psilocybin; and (2) a SIRT inhibitor.

[0290]

[0287] (1) psilocybin; and (2) a SARM1 inhibitor.

[0291]

[0288] (1) psilocybin; (2) a PARP inhibitor; and (3) NAD.

[0292]

[0289] (1) psilocybin; (2) a SIRT inhibitor; and (3) NAD.

[0293]

[0290] (1) psilocybin; (2) a CD38 inhibitor; and (3) NAD.

[0294]

[0291] (1) psilocybin; (2) a SARM1 inhibitor; and (3) NAD.

[0295]

[0292] (1) psilocybin; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0296]

[0293] (1) psilocybin; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0297]

[0294] (1) psilocybin; (2) NAD; and (3) an antioxidant.

[0298]

[0295] (1) psilocybin; (2) NAD; and (3) a glucose regulator.

[0299]

[0296] (1) psilocybin; (2) NAD; and (3) CoQ10.

[0300]

[0297] (1) psilocybin; (2) NAD; and (3) ascorbic acid.

[0298] (1) psilocybin; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0301]

[0299] (1) psilocybin; (2) a NAD+ precursor; and (3) a glucose regulator.

[0302]

[0300] (1) psilocybin; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0303]

[0301] (1) psilocybin; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0304]

[0302] (1) psilocybin; (2) a NAD+ precursor; and (3) an antioxidant.

[0305]

[0303] (1) psilocybin; (2) NA, NMN, Trp, or NR; and (3) CoQ10

[0306]

[0304] (1) psilocybin; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10

[0307]

[0305] (1) psilacetin; and (2) NAD.

[0308]

[0306] (1 ) psilacetin; and (2) a NAD+ precursor.

[0309]

[0307] (1) psilacetin; and (2) NA, NMN, Trp, or NR.

[0310]

[0308] (1) psilacetin; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0311]

[0309] (1 ) psilacetin; and (2) an agent that inhibits NAD+ degradation.

[0312]

[0310] (1) psilacetin; and (2) a CD38 inhibitor.

[0313]

[0311] (1) psilacetin; and (2) a PARP inhibitor.

[0314]

[0312] (1) psilacetin; and (2) a SIRT inhibitor.

[0315]

[0313] (1) psilacetin; and (2) a SARM1 inhibitor.

[0316]

[0314] (1) psilacetin; (2) a PARP inhibitor; and (3) NAD.

[0317]

[0315] (1) psilacetin; (2) a SIRT inhibitor; and (3) NAD.

[0318]

[0316] (1) psilacetin; (2) a CD38 inhibitor; and (3) NAD.

[0319]

[0317] (1) psilacetin; (2) a SARM1 inhibitor; and (3) NAD.

[0320]

[0318] (1) psilacetin; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0321]

[0319] (1) psilacetin; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0322]

[0320] (1) psilacetin; (2) NAD; and (3) an antioxidant.

[0323]

[0321] (1) psilacetin; (2) NAD; and (3) a glucose regulator.

[0324]

[0322] (1) psilacetin; (2) NAD; and (3) CoQ10.

[0325]

[0323] (1) psilacetin; (2) NAD; and (3) ascorbic acid.

[0326]

[0324] (1) psilacetin; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0327]

[0325] (1 ) psilacetin; (2) a NAD+ precursor; and (3) a glucose regulator.

[0328]

[0326] (1) psilacetin; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0329]

[0327] (1) psilacetin; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0330]

[0328] (1 ) psilacetin; (2) a NAD+ precursor; and (3) an antioxidant.

[0331]

[0329] (1) psilacetin; (2) NA, NMN, Trp, or NR; and (3) CoQ10

[0332]

[0330] (1) psilacetin; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10

[0333]

[0331] (1) mescaline; and (2) NAD.

[0334]

[0332] (1) mescaline; and (2) a NAD+ precursor.

[0335]

[0333] (1) mescaline; and (2) NA, NMN, Trp, or NR.

[0334] (1) mescaline; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0336]

[0335] (1) mescaline; and (2) an agent that inhibits NAD+ degradation.

[0337]

[0336] (1) mescaline; and (2) a CD38 inhibitor.

[0338]

[0337] (1) mescaline; and (2) a PARP inhibitor.

[0339]

[0338] (1) mescaline; and (2) a SIRT inhibitor.

[0340]

[0339] (1) mescaline; and (2) a SARM1 inhibitor.

[0341]

[0340] (1) mescaline; (2) a PARP inhibitor; and (3) NAD.

[0342]

[0341] (1) mescaline; (2) a SIRT inhibitor; and (3) NAD.

[0343]

[0342] (1) mescaline; (2) a CD38 inhibitor; and (3) NAD.

[0344]

[0343] (1) mescaline; (2) a SARM1 inhibitor; and (3) NAD.

[0345]

[0344] (1) mescaline; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0346]

[0345] (1) mescaline; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0347]

[0346] (1) mescaline; (2) NAD; and (3) an antioxidant.

[0348]

[0347] (1) mescaline; (2) NAD; and (3) a glucose regulator.

[0349]

[0348] (1) mescaline; (2) NAD; and (3) CoQ10.

[0350]

[0349] (1) mescaline; (2) NAD; and (3) ascorbic acid.

[0351]

[0350] (1) mescaline; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0352]

[0351] (1) mescaline; (2) a NAD+ precursor; and (3) a glucose regulator.

[0353]

[0352] (1) mescaline; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0354]

[0353] (1) mescaline; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0355]

[0354] (1) mescaline; (2) a NAD+ precursor; and (3) an antioxidant.

[0356]

[0355] (1) mescaline; (2) NA, NMN, Trp, or NR; and (3) CoQ10.

[0357]

[0356] (1) mescaline; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10.

[0358]

[0357] (1) DMT; and (2) NAD.

[0359]

[0358] (1 ) DMT; and (2) a NAD+ precursor.

[0360]

[0359] (1 ) DMT; and (2) NA, NMN, Trp, or NR.

[0361]

[0360] (1) DMT; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0362]

[0361] (1 ) DMT; and (2) an agent that inhibits NAD+ degradation.

[0363]

[0362] (1) DMT; and (2) a CD38 inhibitor.

[0364]

[0363] (1) DMT; and (2) a PARP inhibitor.

[0365]

[0364] (1) DMT; and (2) a SIRT inhibitor.

[0366]

[0365] (1) DMT; and (2) a SARM1 inhibitor.

[0367]

[0366] (1 ) DMT; (2) a PARP inhibitor; and (3) NAD.

[0368]

[0367] (1) DMT; (2) a SIRT inhibitor; and (3) NAD.

[0369]

[0368] (1) DMT; (2) a CD38 inhibitor; and (3) NAD.

[0370]

[0369] (1) DMT; (2) a SARM1 inhibitor; and (3) NAD.

[0370] (1) DMT; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0371]

[0371] (1) DMT; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0372]

[0372] (1) DMT; (2) NAD; and (3) an antioxidant.

[0373]

[0373] (1) DMT; (2) NAD; and (3) a glucose regulator.

[0374]

[0374] (1 ) DMT; (2) NAD; and (3) CoQ10.

[0375]

[0375] (1) DMT; (2) NAD; and (3) ascorbic acid.

[0376]

[0376] (1) DMT; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0377]

[0377] (1 ) DMT; (2) a NAD+ precursor; and (3) a glucose regulator.

[0378]

[0378] (1) DMT; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0379]

[0379] (1) DMT; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0380]

[0380] (1) DMT; (2) a NAD+ precursor; and (3) an antioxidant.

[0381]

[0381] (1 ) DMT; (2) NA, NMN, Trp, or NR; and (3) CoQ10

[0382]

[0382] (1) DMT; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10

[0383]

[0383] (1) DOI; and (2) NAD.

[0384]

[0384] (1) DOI; and (2) a NAD + precursor.

[0385]

[0385] (1) DOI; and (2) NA, NMN, Trp, or NR.

[0386]

[0386] (1) DOI; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0387]

[0387] (1) DOI; and (2) an agent that inhibits NAD+ degradation.

[0388]

[0388] (1) DOI; and (2) a CD38 inhibitor.

[0389]

[0389] (1) DOI; and (2) a PARP inhibitor.

[0390]

[0390] (1) DOI; and (2) a SIRT inhibitor.

[0391]

[0391] (1) DOI; and (2) a SARM1 inhibitor.

[0392]

[0392] (1) DOI; (2) a PARP inhibitor; and (3) NAD.

[0393]

[0393] (1) DOI; (2) a SIRT inhibitor; and (3) NAD.

[0394]

[0394] (1) DOI; (2) a CD38 inhibitor; and (3) NAD.

[0395]

[0395] (1) DOI; (2) a SARM1 inhibitor; and (3) NAD.

[0396]

[0396] (1) DOI; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0397]

[0397] (1) DOI; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0398]

[0398] (1) DOI; (2) NAD; and (3) an antioxidant.

[0399]

[0399] (1) DOI; (2) NAD; and (3) a glucose regulator.

[0400]

[0400] (1) DOI; (2) NAD; and (3) CoQ10.

[0401]

[0401] (1) DOI; (2) NAD; and (3) ascorbic acid.

[0402]

[0402] (1) DOI; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0403]

[0403] (1) DOI; (2) a NAD+ precursor; and (3) a glucose regulator.

[0404]

[0404] (1) DOI; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0405]

[0405] (1) DOI; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0406] (1) DOI; (2) a NAD+ precursor; and (3) an antioxidant.

[0406]

[0407] (1) DOI; (2) NA, NMN, Trp, or NR; and (3) CoQ10

[0407]

[0408] (1) DOI; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10

[0408]

[0409] (1) ibogaine; and (2) NAD.

[0409]

[0410] (1) ibogaine; and (2) a NAD+ precursor.

[0410]

[0411] (1) ibogaine; and (2) NA, NMN, Trp, or NR.

[0411]

[0412] (1) ibogaine; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0412]

[0413] (1) ibogaine; and (2) an agent that inhibits NAD+ degradation.

[0413]

[0414] (1) ibogaine; and (2) a CD38 inhibitor.

[0414]

[0415] (1) ibogaine; and (2) a PARP inhibitor.

[0415]

[0416] (1) ibogaine; and (2) a SIRT inhibitor.

[0416]

[0417] (1) ibogaine; and (2) a SARM1 inhibitor.

[0417]

[0418] (1) ibogaine; (2) a PARP inhibitor; and (3) NAD.

[0418]

[0419] (1) ibogaine; (2) a SIRT inhibitor; and (3) NAD.

[0419]

[0420] (1) ibogaine; (2) a CD38 inhibitor; and (3) NAD.

[0420]

[0421] (1) ibogaine; (2) a SARM1 inhibitor; and (3) NAD.

[0421]

[0422] (1) ibogaine; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0422]

[0423] (1) ibogaine; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0423]

[0424] (1) ibogaine; (2) NAD; and (3) an antioxidant.

[0424]

[0425] (1) ibogaine; (2) NAD; and (3) a glucose regulator.

[0425]

[0426] (1) ibogaine; (2) NAD; and (3) CoQ10.

[0426]

[0427] (1) ibogaine; (2) NAD; and (3) ascorbic acid.

[0427]

[0428] (1) ibogaine (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0428]

[0429] (1) ibogaine; (2) a NAD+ precursor; and (3) a glucose regulator.

[0429]

[0430] (1) ibogaine; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0430]

[0431] (1) ibogaine; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0431]

[0432] (1) ibogaine; (2) a NAD+ precursor; and (3) an antioxidant.

[0432]

[0433] (1) ibogaine; (2) NA, NMN, Trp, or NR; and (3) CoQ10

[0433]

[0434] (1) ibogaine; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10

[0434]

[0435] (1 ) 5-MeO-DMT; and (2) NAD.

[0435]

[0436] (1 ) 5-MeO-DMT; and (2) a NAD+ precursor.

[0436]

[0437] (1 ) 5-MeO-DMT; and (2) NA, NMN, Trp, or NR.

[0437]

[0438] (1) 5-Me0-DMT; (2) NAM; and (3) trimethylglycine, berberine, or resveratrol.

[0438]

[0439] (1 ) 5-MeO-DMT; and (2) an agent that inhibits NAD+ degradation.

[0439]

[0440] (1) 5-MeO-DMT; and (2) a CD38 inhibitor.

[0440]

[0441] (1) 5-MeO-DMT; and (2) a PARP inhibitor.

[0442] (1) 5-MeO-DMT; and (2) a SIRT inhibitor.

[0441]

[0443] (1) 5-MeO-DMT; and (2) a SARM1 inhibitor.

[0442]

[0444] (1) 5-MeO-DMT; (2) a PARP inhibitor; and (3) NAD.

[0443]

[0445] (1) 5-MeO-DMT; (2) a SIRT inhibitor; and (3) NAD.

[0444]

[0446] (1 ) 5-MeO-DMT; (2) a CD38 inhibitor; and (3) NAD.

[0445]

[0447] (1) 5-MeO-DMT; (2) a SARM1 inhibitor; and (3) NAD.

[0446]

[0448] (1) 5-MeO-DMT; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) an antioxidant.

[0447]

[0449] (1) 5-MeO-DMT; (2) an agent that inhibits NAD+ degradation; (3) NAD; and (4) a glucose regulator.

[0448]

[0450] (1) 5-MeO-DMT; (2) NAD; and (3) an antioxidant.

[0449]

[0451] (1) 5-MeO-DMT; (2) NAD; and (3) a glucose regulator.

[0450]

[0452] (1 ) 5-MeO-DMT; (2) NAD; and (3) CoQ10.

[0451]

[0453] (1) 5-MeO-DMT; (2) NAD; and (3) ascorbic acid.

[0452]

[0454] (1) 5-MeO-DMT; (2) NAD; (3) an antioxidant; and (4) a glucose regulator.

[0453]

[0455] (1) 5-MeO-DMT; (2) a NAD+ precursor; and (3) a glucose regulator.

[0454]

[0456] (1) 5-MeO-DMT; (2) NA, NMN, Trp, or NR; and (3) ascorbic acid.

[0455]

[0457] (1) 5-MeO-DMT; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) ascorbic acid.

[0456]

[0458] (1) 5-MeO-DMT; (2) a NAD+ precursor; and (3) an antioxidant.

[0457]

[0459] (1 ) 5-MeO-DMT; (2) NA, NMN, Trp, or NR; and (3) CoQ10

[0458]

[0460] (1) 5-MeO-DMT; (2) NAM; (3) trimethylglycine, berberine, or resveratrol; and (4) CoQ10

[0459]

[0461] As will be readily appreciated by one of skill in view of the disclosure, any of the above agents can be substituted with one or more other agents of the same class to create additional embodiments.

[0460] F. Synergy, Synergism, and Synergistic Effects

[0461]

[0462] I n embodiments, disclosed combinations or compositions are synergistic or have synergistic effects.

[0462]

[0463] In embodiments, a synergy, synergism, or synergistic effect (together as shorthand, “synergy”), is the result of two or more agents in a disclosed combination or composition, and results from, for example, the effect of such agents on a subject, when administered thereto. As non limiting examples: In embodiments, a synergy is the result of the serotonergic psychedelic and the mitochondrial energy enhancer. In embodiments, a synergy is the result of the serotonergic psychedelic and the metabolic cofactor. In embodiments, a synergy is the result of the serotonergic psychedelic and the metabolic coenzyme. In embodiments, a synergy is the result of the serotonergic psychedelic and the glucose regulator. In embodiments, a synergy is the result of the serotonergic psychedelic and the antioxidant. In embodiments, a synergy is the result of the mitochondrial energy enhancer and the glucose regulator. In embodiments, a synergy is the result of the metabolic cofactor and the glucose regulator. In embodiments, a synergy is the result of the metabolic coenzyme and the glucose regulator. In embodiments, a synergy is the result of the mitochondrial energy enhancer and the antioxidant. In embodiments, a synergy is the result of the metabolic cofactor and the antioxidant. In embodiments, a synergy is the result of the metabolic coenzyme and the antioxidant. In embodiments, a synergy is the result of any one or more of the serotonergic psychedelic, the mitochondrial energy enhancer, the glucose regulator, and the antioxidant, along with another agent such as disclosed herein. In embodiments, a synergy is the result of any three of the serotonergic psychedelic, the mitochondrial energy enhancer, the glucose regulator, and the antioxidant (three-way synergy). In embodiments, a synergy is the result of any four of the serotonergic psychedelic, the mitochondrial energy enhancer, the glucose regulator, and the antioxidant (four-way synergy), or any more than four-way synergy.

[0463]

[0464] In embodiments, combinations and compositions including a metabolic coenzyme or a metabolic cofactor, such as NAD+ or its precursors, provide synergistic effects when administered together with a serotonergic psychedelic, such as in improving cellular energy metabolism and oxidative damage protection. In embodiments, combinations including a glucose regulator, such as ascorbic acid, provide synergistic effects when administered together with a serotonergic psychedelic, such as in optimizing glucose levels.

[0464]

[0465] A synergy includes any increase in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect that is greater than the additive contributions of the (two or more) agents acting alone, and / or is greater than the contributions of the isolated agents on their own. A synergy, for example, may permit the effective use of a lower dose. This includes lower doses of a first agent or a second agent (“apparent one-way synergy”), or lower doses of both agents (“two-way synergy”), than would normally be required when either agent is used alone. Such lower doses may result in lower toxicity without reduced efficacy. A synergy may result in improved efficacy. Numerous methods are known in the art to determine if there is synergy as to a particular effect, e.g., whether two or more agents provide an effect greater than the sum of the effects of the individual agents alone, producing “1+1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang et al. 2019), the equation of Loewe additivity (Loewe & Muischnek, Arch Exp Pathol Pharmacol. 1926;114:313-326), the Sigmoid-Emax equation (Holford & Scheiner, Clin. Pharmacokinet. 1981;6:429-453), and the median-effect equation (Chou & Talalay, Adv. Enzyme Regul. 1984;22:27-55). Graphs associated with equations such as above include the concentration-effect curve and combination index curve, and both may be applied to experimental data to generate a graph to aid in assessing the effects of a combination.

[0465] G. Pharmaceutical Compositions and Formulations

[0466]

[0466] In some aspects, provided herein are compositions, such as pharmaceutical compositions, comprising disclosed compounds (e.g., any of the serotonergic psychedelics, mitochondrial energy enhancers, antioxidants, glucose regulators, or other agents described herein). “Pharmaceutical compositions” are compositions comprising disclosed compound(s) (i.e., agent(s)) together in an amount (for example, in a unit dosage form) with a (preferably, pharmaceutically acceptable), carrier, diluent, or excipient.

[0467]

[0467] “Pharmaceutically acceptable” used in connection with a carrier, diluent, excipient, or other ingredient means the ingredient is generally safe and, within the scope of sound medical judgment, suitable for use in contact with cells of humans and animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio. Some embodiments will not have a single carrier, diluent, or excipient alone, but will include multiple carriers, diluents, and / or excipients. Compositions can be prepared by standard pharmaceutical formulation techniques as disclosed in, e.g., Remington: The Science & Practice of Pharmacy (2020) 23th ed., Academic Press., Cambridge, Mass.; The Merck Index (1996) 12th ed., Merck Pub. Group, Whitehouse, N.J.; Pharm. Principles of Solid Dosage Forms (1993), Technomic Pub. Co., Inc., Lancaster, Pa.; and Ansel & Stoklosa, Pharm. Calculations (2001) 11th ed., Lippincott Williams & Wilkins, Baltimore, Md.; Poznansky et al. Drug Delivery Systems (1980), R.L. Juliano, ed., Oxford, N.Y., pp. 253-315). In embodiments, pharmaceutical compositions comprising disclosed compounds are formulated as mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, or intranasal compositions. Such compositions (also herein, “formulations”) are prepared in a manner well known in the pharmaceutical arts (e.g., Remington 2020 and references cited above, all incorporated herein). a. Dosage Forms, Exemplary Formulations, and Methods for their Preparation

[0468]

[0468] The disclosed combinations, and the individual compounds (i.e., agents) which they comprise, can be formulated into any suitable dosage form, including aqueous oral dispersions, aqueous oral suspensions, solid dosage forms including oral solid dosage forms, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, self-emulsifying dispersions, solid solutions, liposomal dispersions, lyophilized formulations, tablets, capsules, pills, powders, delayed-release formulations, immediate-release formulations, modified release formulations, extended-release formulations, pulsatile release formulations, multi particulate formulations, and mixed immediate release and controlled release formulations.

[0469]

[0469] In embodiments, a combination is formulated in a unit dosage form, each dosage form containing, for example, a therapeutically effective amount of the active agent(s), such as in the dosage amounts disclosed herein. “Unit dosage form” refers to a physically discrete unit suited as unitary dosages for a subject, each unit comprising a quantity of active agent to produce a therapeutic effect, further comprising a suitable pharmaceutical carrier, diluent, or excipient. Unit dosage forms may be used for ease of administration and uniformity of dosage. Unit dosage forms may contain a single or individual dose or unit, a sub-dose, or an appropriate fraction thereof (e.g., one half a “full” dose), of the agent(s) administered. Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules and vials, and may include a composition in a freeze-dried or lyophilized state; a sterile liquid carrier, for example, can be added prior to administration or delivery in vivo. Unit dosage forms include ampules and vials with liquid compositions disposed therein. Unit dosage forms also include formulations for transdermal administration, such as a transdermal patch.

[0470]

[0470] In some aspects are provided compositions, and methods for preparing such compositions, such as a pharmaceutical composition (or herein, “formulation”) comprising a combination. In embodiments, a composition (or formulation) comprises one or more (preferably, pharmaceutically acceptable) excipients. Non-limiting exemplary excipients include fillers, diluents, lubricants, surfactants, glidants, binders, dispersing agents, suspending agents, disintegrants, solubilizing agents, viscosity-increasing agents, film-forming agents, granulation aids, flavoring agents, coating agents, sweeteners, and combinations thereof.

[0471]

[0471] In embodiments, a combination is formulated as an oral dosage form. Oral dosage forms may comprise one or more excipients. Oral dosage forms include oral liquid dosage forms (such as tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like) and oral solid dosage forms.

[0472]

[0472] In embodiments, a combination is formulated as an oral solid dosage form. Oral solid dosage forms include lozenges, troches, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combinations thereof. Oral solid dosage forms may be formulated as immediate release, controlled release, sustained release, extended release, or modified release formulations. In embodiments, an oral solid dosage form is in the form of a tablet (e.g., a suspension tablet, fast-melt tablet, bite-disintegration tablet, rapid-disintegration tablet, or effervescent tablet), a caplet, a pill, a powder (e.g., a sterile packaged powder, dispensable powder, or effervescent powder), or a soft or hard capsule.

[0473]

[0473] Oral solid dosage forms can comprise additives such as one or more compatible carriers, complexing agents, ionic dispersion modulators, disintegrating agents, surfactants, lubricants, colorants, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, preservatives, antioxidants, and antimicrobial agents. Preservatives include EDTA, EGTA, benzalkonium chloride, benzoic acid, and benzoates. Antioxidants include provitamins, vitamins A, C, and E, and ALA.

[0474]

[0474] Solid dosage forms may be prepared by conventional pharmaceutical techniques, e.g., dry mixing, direct compression, milling, dry or non-aqueous granulation, wet granulation, fusion, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, and extruding, and combinations thereof (see, e.g., Lachman et al. 1986).

[0475]

[0475] In embodiments, a combination is formulated to achieve a specific release profile. In embodiments, oral solid dosage forms are prepared as immediate release formulations, or as modified release formulations, such as controlled release, extended release, sustained release, or delayed release. In embodiments of a modified release formulation, the plasma half-life versus that of an immediate release formulation is greater by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 50%, 75%, or at least 100%, and values in between.

[0476]

[0476] In embodiments, a formulation is designed to be a product with a specific time course, such as less than about 30 minutes, about 30 minutes, about 45 minutes, about 60 minutes, about 90 minutes, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, and greater than 8 hours, including lengths of time in between. In embodiments, the active agents in a disclosed pharmaceutical composition are formulated such that they have a similar duration of action.

[0477]

[0477] In embodiments, a combination is formulated as a pharmaceutically acceptable oral liquid dosage form. Non-limiting examples of oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, and solutions, and the like. In embodiments, oral liquid dosage forms are formulated with any pharmaceutically acceptable excipient known to those of skill for the preparation of such forms, and with solvents, diluents, carriers, excipients, and the like, chosen as appropriate to the solubility and other properties of the disclosed active agents and other ingredients. Non-limiting examples of solvents include, e.g., water, glycerin, simple syrup, alcohol, medium chain triglycerides (MCT), and combinations thereof.

[0478]

[0478] Oral liquid dosage forms may be in monophasic forms (e.g., syrups, linctuses, spirits / essences, elixirs, and fluid extracts) or biphasic forms (e.g., oral suspensions, oral emulsions, and mixtures), and also may be in the form of emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water. Liquid dosage forms for oral administration may be prepared as liquid suspensions or solutions using a sterile liquid, including an oil, water, an alcohol, combinations of pharmaceutically suitable surfactants, suspending agents, and emulsifying agents. In embodiments, liquid formulations are prepared as single-dose or multi-dose beverages. In embodiments, suspensions include oils, such as peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil, as well as carrier oils such as MCT and long-chain triglyceride (LCT) oils. In embodiments, a suspension contains esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. In embodiments, a suspension includes alcohols, such as ethanol, isopropyl alcohol, hexadecyl alcohol; glycerol, and propylene glycol. A suspension also may comprise ethers, e.g., polyethylene glycol; petroleum hydrocarbons, e.g., mineral oil and petrolatum; and water. A suspension may be an aqueous or non-aqueous liquid, and an oil-in-water or water-in-oil emulsion.

[0479]

[0479] Oral liquid dosage forms include aqueous suspensions such as aqueous oral dispersions, emulsions, solutions, and syrups (e.g., Singh et al. 2002; Warbrick J, Boylan JC. Encyc Pharm Tech. 2nd ed. CRC Press; 2002:754-757), and may comprise one or more additives, e.g., disintegrating agents, dispersing agents, wetting agents, preservatives, viscosity enhancing agents, sweetening agents, and / or flavoring agents. Liquid formulations also may comprise inert diluents, e.g., water, solvents, solubilizing agents, emulsifiers, flavorants, and sweeteners. Liquid dosage forms also may comprise co-solvents and adjuvants.

[0480]

[0480] In embodiments, a combination is formulated as an effervescent powder, for example as effervescent salts added to water for oral administration. Effervescent salts may be packaged as single-dose or multi-dose drink mixes, alone or in combination with other ingredients, such as vitamins or electrolytes.

[0481]

[0481] In embodiments, a combination is formulated into a topical dosage form. Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. Topical dosage forms may comprise a penetrant or carrier. Penetrants include, for transmucosal administration, detergents, bile salts, fusidic acid derivatives, and combinations. Carriers include Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations.

[0482]

[0482] In embodiments, a combination is formulated for transdermal application. In general, transdermal delivery involves contacting the formulations with a subject’s skin under conditions effective for the active agent(s) to penetrate the skin and cause an effect. Transdermal formulations include ointments, creams, suspensions, lotions, pastes, gels, sprays, foams, oils, and combinations thereof. An exemplary transdermal delivery form is a transdermal “patch,” which may be used to provide continuous or discontinuous infusion of active agent(s) in controlled amounts. Patches may be constructed for continuous, gradual, pulsatile, or on demand delivery of the agents. In embodiments, a patch is a medicated adhesive patch, a single-layer or multi-layer drug-in-adhesive patch, a “matrix” (or “monolithic”) patch, or a “reservoir” patch. In embodiments, a patch is part of a delivery system, such as used with an electronic device coupled to a subjects mobile device, and / or coupled with a mobile app (e.g., to control a delivery rate from a reservoir, and / or to provide information about delivery to the app or user). Various such technologies will be known and may be used.

[0483] In embodiments, a combination is formulated for subcutaneous, IV, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, or intracerebroventricular injection. In embodiments, formulations for injection are prepared by dissolving, suspending, or emulsifying the compounds in an aqueous or nonaqueous solvent, including oils, such as vegetable oil, synthetic aliphatic acid glycerides, and esters of higher aliphatic acids or propylene glycol. Formulations for injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, liposomes, and sterile powders for reconstitution into sterile solutions or dispersions, and also may comprise additives such as solubilizers, stabilizers, and suspending, preserving, wetting, emulsifying, dispensing, and isotonic agents.

[0483]

[0484] In embodiments, a combination is formulated as a nanoformulation, such as a nanoemulsion, nanocapsule, nanoparticle conjugate, or nano-encapsulated oral or nasal spray (see, e.g., Jaiswal 2015). “Nanoparticles” of the active agent(s) include those in the range of about 1 to 100 nm, about 100 to 200 nm, about 200 to 400 nm, about 400 to 600 nm, about 600 to 800 nm, and about 800 to 1000 nm. In other embodiments are “microparticles” in the range of about 1000 to 2000 nm (1-2 micrometer (“pm”) scale). Particles of certain sizes may be particularly advantageous for certain routes of administration (e.g., for oral liquid emulsion versus for transdermal or topical application). In embodiments, lipid-based nanoparticles (LBNPs) such as liposomes, solid lipid nanoparticles (SLN), or nanostructured lipid carriers (NLC) are used.

[0484]

[0485] In embodiments, a composition or formulation comprises one or more additional agents or is otherwise modified according to ordinary skill to facilitate absorption through a specific route of administration (e.g., gastrointestinal, transdermal, etc.), to extend the effect of an active agent, and / or attain higher or more stable serum levels or enhance the therapeutic effect of one or more active agents in the composition.

[0485]

[0486] By way of non-limiting and merely suggestive example, the following formulations may be prepared:

[0486]

[0487] Exemplary formulation of tablets: Exemplary tablets are prepared using ingredients in the quantities (per tablet) as follows: (1) LSD, 10 g; (2) NMN, 300 mg; (3) Riboflavin, 1.1 mg; (4) Extended-release vitamin C (optional), 80 mg; (5) Cellulose, microcrystalline, 170 mg; (6) Colloidal silicon dioxide, 10 mg; and (7) Stearic acid, 7.5 mg. The ingredients are blended and compressed to form tablets.

[0487]

[0488] Exemplary alternate formulation of tablets: Exemplary scorable tablets are prepared using ingredients in the quantities (per tablet) as follows: (1) LSD, 12.5 pg; (2) Liposomal NAD+, 225 mg; (3) Niacin, 20 mg; (4) Vitamin C (optional), 1 ,000 mg; (5) Starch, 45.0 mg (6) Microcrystalline cellulose, 35.0 mg; (7) PVP (as 10% solution in water), 4.0 mg; (8) Sodium carboxymethyl starch, 4.5 mg; (9) Magnesium stearate, 0.5 mg; and (10) Talc, 1.0 mg. The active agents (i.e., those disclosed herein as providing a desired effect), starch and cellulose are passed through a 20 mesh U.S. sieve and mixed thoroughly. The polyvinylpyrrolidone (PVP) solution is mixed with the resultant powders, and then passed through a 16 mesh sieve. Granules so produced are dried at 50-60 °C and passed through a 16 mesh sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a 30 mesh sieve, are added to the granules, mixed, and compressed on a machine to yield tablets, which are scored to show half doses.

[0488]

[0489] Exemplary formulation of capsules: Exemplary capsules are prepared using ingredients in the quantities (per capsule) as follows: (1) LSD, 10 pg; (2) Liposomal NAD+, 500 mg; (3) Starch, 119.0 mg; and (4) Magnesium stearate, 1.0 mg. The active agents, cellulose, starch, and magnesium stearate are blended, passed through a 20 mesh U.S. sieve, and filled into hard or soft gelatin capsules.

[0489]

[0490] Exemplary formulation of capsules with additional active serotonergic agent: Exemplary capsules are prepared using ingredients in the quantities (per capsule) as follows: (1) LSD, 10 pig; (2) NR, 300 mg; (3) Serotonergic agent, 250 mg; (4) Starch, 100 mg; and (5) Magnesium stearate, 1 mg. The active agents, cellulose, starch, and magnesium stearate are blended, passed through a 20 mesh U.S. sieve, and filled into hard or soft gelatin capsules. The serotonergic agent may be an antidepressant or anxiolytic, such as an agent known to one of skill or described herein. Dosage amounts of the serotonergic agent will be as generally known or knowable in the art for the selected agent. A “serotonergic agent” is a compound that binds to, blocks, or otherwise influences (e.g., via an allosteric reaction) activity at serotonin receptors, including any of the receptor subtypes. In embodiments, a serotonergic agent is not a serotonergic psychedelic. In embodiments, a serotonergic agent binds to a serotonin receptor. In embodiments, a serotonergic agent indirectly affects a serotonin receptor, e.g., via interactions affecting the reactivity of other molecules at the serotonin receptor. In embodiments, a serotonergic agent is a serotonin receptor agonist. In embodiments, a serotonergic agent is a serotonin receptor antagonist. In embodiments, a serotonergic agent is an effector molecule. In embodiments, a serotonergic agent acts (directly or indirectly) at more than one type of receptor, including receptors other than serotonergic or other monoaminergic receptors. In embodiments, a serotonergic agent blocks the serotonin transporter (SERT), elevates the synaptic concentration of serotonin, and / or increases neurotransmission. In embodiments, a serotonergic agent acts as a reuptake modulator, inhibits serotonin reuptake, and / or increases extracellular serotonin concentrations. In embodiments, a serotonergic agent inhibits the activity of one or both monoamine oxidase enzymes. In embodiments, a serotonergic agent is an antidepressant, anxiolytic, SSRI, serotonin-norepinephrine reuptake inhibitor (SNRI), tricyclic antidepressant (TCA), monoamine oxidase inhibitor (MAOI), or atypical antidepressant. In embodiments, a serotonergic agent is selected from: (1) serotonin transport inhibitors; (2) serotonin receptor modulators; (3) serotonin reuptake inhibitors; (4) serotonin and norepinephrine reuptake inhibitors; (5) serotonin dopamine antagonists; (6) monoamine reuptake inhibitors; (7) pyridazinone aldose reductase inhibitors; (8) stimulants of serotonin receptors; (9) stimulants of serotonin synthesis; (10) serotonin receptor agonists; (11) serotonin receptor antagonists; and (12) serotonin metabolites.

[0490]

[0491] Exemplary formulation of suspension: Exemplary suspensions are prepared using ingredients in the quantities (per unit dose) as follows: (1) LSD, 10 g (2) NAM, 100 mg; (3) Vitamin C (optional), 1,000 mg; (4) Xanthan gum, 4.0 mg; (5) Sodium carboxymethyl cellulose (11 %), 50.0 mg; (6) Microcrystalline cellulose (89%), 50.0 mg; (7) Sucrose, 1.75 g; (8) Sodium benzoate, 10.0 mg; (9) Flavor or color (optional), q.v.; and (10) Purified water, to 5.0 ml. The active agents, sucrose and xanthan gum are blended, passed through a 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate and optional flavor and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.

[0491]

[0492] Exemplary formulation of intravenous (IV) solution: Exemplary IV formulations are prepared using ingredients in the quantities (per solution, comprising, e.g., 10 doses) as follows: (1) LSD, 100 pg; (2) NAD+, 1,000 mg; and (3) Isotonic saline, 10 mL. Active agents are dissolved in isotonic saline or another suitable solvent, and additional active or inactive ingredients such as preservatives may be added. The amount of therapeutic compound can be adjusted accordingly to reach the desired mg / mL or provide the desired doses.

[0492]

[0493] Exemplary formulation of injectable solution: Exemplary injectable formulations are prepared using ingredients in the quantities (per dose) as follows: (1) LSD, 20 pg; (2) NAD+, 200 mg; (3) Vitamin C (optional), 125 mg; and (4) Isotonic saline, 5 mL. Active agents are dissolved in isotonic saline or another suitable solvent, and additional active or inactive ingredients such as preservatives may be added.

[0493]

[0494] Exemplary formulation of topical: Exemplary topical formulations are prepared using ingredients in the quantities (per dose) as follows: (1) Psilacetin, 5.0 mg; (2) NAM, 10.0 mg; (3) Emulsifying Wax, 30.0 mg;

[0494] (4) Liquid Paraffin, 20.0 mg; and (5) White Soft Paraffin, to 100 mg. The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active agents are added and stirring is continued until dispersed. The mixture is cooled until solid.

[0495]

[0495] Exemplary formulation of cut matrix sublingual or buccal tablets: Exemplary sublingual or buccal tablets are made as a single matrix and then cut to size, with ingredients in the quantities (per tablet) as follows: (1) LSD, 8 pg; (2) NR, 150 mg; (3) Glycerol, 210.5 mg; (4) Water, 143.0 mg; (5) Sodium Citrate, 4.5 mg; (6) Polyvinyl Alcohol, 26.5 mg; (7) PVP, 15.5 mg. The glycerol, water, sodium citrate, polyvinyl alcohol, and PVP are admixed together by continuous stirring and maintaining the temperature at about 90 °C. When the polymers have gone into solution, the solution is cooled to about 50-55 °C and the active agents are slowly admixed. The homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm, then cut to form individual tablets.

[0496]

[0496] Exemplary formulation of individually formed sublingual or buccal lozenges: Exemplary sublingual or buccal lozenges are made from individual forms or molds, with ingredients in the quantities (per lozenge) as follows: (1) LSD, 5 pg; (2) NMN, 200 mg; (3) Silica gel powder, 350.0 mg; (4) Citric acid powder, 400.0 mg;

[0497] (5) Acacia powder, 600.0 mg; (6) Flavor (optional), 100.0 mg; and (7) Polyethylene glycol, 1 ,000 mg. The inactive ingredients are admixed by continuous stirring and maintaining the temperature at about 90 °C. When the PEG has melted and the other ingredients have gone into solution, the solution is cooled to about 50-55 °C and the active agents are slowly admixed. The homogenous mixture is poured into separate molds and allowed to cool. Reference also may be made to U.S. Patent No. 10,034,832 and the Examples therein.

[0498]

[0497] Exemplary formulation of intranasal delivery form: Exemplary nasal spray formulations for intranasal delivery are prepared as follows, with ingredients in the quantities (per dose) as follows: (1) Psilocin, 4 mg; (2) NR, 300 mg; (3) DMSO, 50 pL; (4) MCT, 5 mL; and (5) Saline (1 % cremaphor), to 10 mL. The solution at 10mg / mL of disclosed compounds in 49.5% MCT, 49.5% saline, .5% DMSO, and .5% cremophor is prepared for use in a nasal spray device. In other embodiments, a nasal formulation is prepared as a dry powder for inhalation, e.g., by combining the active agents with lactose and mixing for use with a dry powder inhaling appliance, or prepared as disclosed in U.S. Pub. No. US2015 / 367091 A1 and references cited therein.

[0499]

[0498] It will be appreciated that the above formulation examples are illustrative only. The examples are not limited to the specific disclosed active and inactive agents, but may comprise other agents. The agents in the above examples will be appreciated to be substituted by any of the disclosed serotonergic psychedelics, disclosed mitochondrial energy enhancers, metabolic cofactors, metabolic coenzymes, antioxidants, glucose regulators, and the like. In alternative embodiments, any of the compounds are provided in a different dosage amount. In alternative embodiments, one or more compounds are substituted with any other disclosed compounds of the same or like classes, with such dose amounts adjusted as would be known by reference to the teachings herein and ordinary skill. Particular doses and compounds thus are known as only illustrative, and the active and inactive agents as well as their amounts in any example may be substituted or modified.

[0500]

[0499] Hence, in alternative embodiments, LSD in any of the formulation examples above is replaced with a different serotonergic psychedelic, including another exemplary disclosed serotonergic psychedelic, such as 1P-LSD, AL-LAD, psilocybin, psilocin, psilacetin, mescaline, DMT, DOI, 5-MeO-DMT, and ibogaine, as well as such other psychedelics as disclosed herein and known to those of skill, or provided at another dose.

[0501]

[0500] For any agent, substitution of the agent by its ion, free base, salt form, polymorph, hydrate or solvate form, co-crystal, or an isomer, single enantiomer, enantiomerically enriched mixture, or non-racemic mixture, will provide an alternative embodiment within the scope hereof (with modifications to a composition and / or dose amount made according to the teachings herein and ordinary skill, if necessary or desired).

[0502]

[0501] Unless clearly expressed otherwise (e.g., by use of “consisting of’ or “consisting essentially of”) compositions are open-ended, and therefore may include additional active or inactive agents and ingredients.

[0503]

[0502] The disclosed compositions can be prepared to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects.

[0504]

[0503] In embodiments, agents comply with current Good Manufacturing Practice (“GMP” or “cGMP”).

[0505]

[0504] The type of formulation employed for administering disclosed compound(s) generally may be dictated by the properties of the compound(s) themselves, the type of pharmacokinetic (PK) profile desired from the compounds and their route of administration, and the state of the subject. It will be appreciated that any embodiments, and any classes of embodiments, can be combined to form additional embodiments. a. Routes of Administration

[0506]

[0505] In some aspects, provided are therapeutic combinations comprising disclosed compounds, as well as pharmaceutical compositions thereof, suitable for administration by a variety of routes. Examples of routes of administration include enteral administration, such as oral, sublingual, rectal, and buccal administration; and parenteral administration, such as bolus injection, continuous infusion, intravenous (IV), intra-arterial, intraperitoneal, intraosseous, intramuscular (IM), intrathecal, intracerebroventricular, vaginal, ocular, nasal, cutaneous, topical, otic, ocular, transdermal, and subcutaneous administration.

[0507]

[0506] A composition, including comprising any one or more agents in a combination, can be administered to a subject by one or more routes of administration, including oral, mucosal (e.g., buccal, sublingual), rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes. In embodiments, administration is sublingually, buccally, topically, rectally, vaginally, ocularly, oticly, nasally, cutaneously, topically, and transdermal ly; or by intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, and subcutaneous injection.

[0508]

[0507] In embodiments, one or more agents in a combination are administered by multiple routes. In an example, the serotonergic psychedelic is administered as an oral solid or oral liquid dosage form; sublingually or buccally; as an injection, including intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, and intracerebroventricular; rectally, vaginally, ocularly, nasally, cutaneously, topically, oticly, transdermally, or subcutaneously. In this example, the mitochondrial energy enhancer and / or the antioxidant or glucose regulator is administered as any other of such dosage forms or by any other of such routes of administration. In embodiments, the serotonergic psychedelic and the mitochondrial energy enhancer and / or the antioxidant or glucose regulator are administered by different routes of administration.

[0509]

[0508] In one exemplary embodiment, a combination comprises LSD for administration as an oral dosage form, such as an oral liquid dosage form, and NAD+for administration by injection or infusion.

[0510]

[0509] In embodiments, administration may comprise separate, sequential, or simultaneous administrations.

[0511]

[0510] In embodiments, agents are administered by the same (which may be any) route of administration.

[0512]

[0511] The choice of route of administration may differ between subjects according to, e.g., subject or health care provider preferences, comorbidities, side effect profiles, PK and PD considerations, and other factors. b. Methods of Administration

[0513]

[0512] In some aspects, provided are methods of administering a combination or composition. As used herein, the terms “subject,” “user,” “patient,” and “individual” are used interchangeably and refer to any mammal, preferably a human. Such terms include a subject for whom a disclosed combination, composition, or method may be useful. In general, all of the disclosed compounds, compositions, and methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood.

[0514]

[0513] The disclosure provides methods for using therapeutically effective amounts of the disclosed combinations in a mammal, and preferably a human. Such methods include those for treating a mental health disorder and for improving mental health and functioning, including in a healthy individual.

[0515]

[0514] Administration of a combination in an “effective amount,” a “therapeutically effective amount,” or a “therapeutically effective dose,” refers to a combination comprising agents in dose amounts sufficient to provide a desired therapeutic effect, for example, relieving to some extent one or more of the symptoms of a condition being treated. The effect can be a reduction and / or alleviation of the signs, symptoms or causes of a disease or disorder, or any other desired alteration of a biological system. A “therapeutically effective amount” includes, in embodiments, a prophylactically effective amount, e.g., a dose used for prevention.

[0515] A therapeutically effective dose may, in embodiments, refer to a dose of an agent that provides measurable effects in the treatment or prevention of a condition, to reduce or manage symptoms of a condition, for the benefit of general welfare and longevity, or for treatment in palliative care or end-of-life care.

[0516]

[0516] An “effective amount” of an agent or composition therefore is an amount effective to achieve, for example, a desired pharmacologic effect or meaningful therapeutic improvement. “An effective amount” or “a therapeutically effective amount” can vary from subject to subject, such as due to variation in metabolism of a disclosed compound, of age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, the judgment of a prescribing physician, and the like.

[0517]

[0517] An effective amount may in embodiments vary depending upon the subject and the disease condition being treated or health benefit sought, the weight and age of the subject, the severity of the disease condition or degree of health benefit sought, the manner of administration, and the like, all of which can be determined in view of the disclosure. Pharmacogenomic information about a particular subject (e.g., the effect of genotype on the pharmacokinetic, pharmacodynamic, or efficacy profile) also may affect the dosage chosen.

[0518]

[0518] As used herein, “therapeutic effect” or “therapeutic efficacy” means the responses(s) in a mammal, and preferably a human, after treatment that is judged to be desirable and beneficial. Hence, depending on the disorder to be treated, or improvement in physiological or psychological functioning sought, and depending on the particular agent(s) in the disclosed combination or composition under consideration, those responses shall differ, but would be readily understood by those of skill. For example, in some embodiments, “therapeutic effect” may refer to increasing mitochondrial energy, increasing antioxidant production, and optimizing glucose levels, as disclosed herein. Measures of therapeutic effect include subject-reported data. c. Doses, Dosages, and Dosing Regimens

[0519]

[0519] It will be readily appreciated that doses, dosages, and dosing regimens all may vary depending upon whether the treatment is therapeutic or prophylactic, the onset, progression, severity, frequency, duration, probability of or susceptibility of the symptom to which treatment is directed, clinical endpoint desired, previous, simultaneous or subsequent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse systemic, regional or local side effects, the presence of other disorders or diseases in the subject, and other factors appreciated by one of skill (e.g., medical or familial history).

[0520]

[0520] An agent may be administered in an amount effective to achieve a plasma level commensurate with concentrations found effective in vivo, for a period of time effective to produce one or more desired effects.

[0521]

[0521] In embodiments, a composition comprises a serotonergic psychedelic in an amount so that a “single dose” is (herein, whether or not such “single dose” is present in a unit dosage form), about 1 mg or less (including a dose of about 0.5 mg or less, about 0.25 mg or less, about 0.1 mg or less, about 0.05 mg or less, about 0.005 mg or less, about 0.001 mg or less, and about 0.0005 mg or less), or at least about 1 mg or more, including 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, and 200 mg, as well as amounts within these ranges. In embodiments, a single dose is greater than 200 mg, including 225 mg, 250 mg, and greater than 250 mg.

[0522]

[0522] In embodiments, such as embodiments of an ergoline or lysergamide, such as embodiments where the serotonergic psychedelic is LSD, 1P-LSD, or AL-LAD, a disclosed combination comprises a serotonergic psychedelic in an amount so that a single dose is about 1 pg or less (including a dose of about 0.5 pg or less, about 0.25 pg or less, about 0.1 pg or less, about 0.05 pg or less, about 0.005 pg or less, about 0.001 pg or less, and about 0.0005 pg or less), or at least about 1 pg or more, including 1 pg, 2 pg, 3 pg, 4 pg, 5 pg, 6 pg,

[0523] 7 pg, 8 pg, 9 pg, 10 pg, 11 pg, 12 pg, 13 pg, 14 pg, 15 pg, 16 pg, 17 pg, 18 pg, 19 pg, 20 pg, 21 pg, 22 pg, 23 pg, 24 pg, 25 pg, 26 pg, 27 pg, 28 pg, 29 pg, 30 pg, 31 pg, 32 pg, 33 pg, 34 pg, 35 pg, 36 pg, 37 pg, 38 pg,

[0524] 39 pg, 40 pg, 41 pg, 42 pg, 43 pg, 44 pg, 45 pg, 46 pg, 47 pg, 48 pg, 49 pg, 50 pg, 51 pg, 52 pg, 53 pg, 54 pg, 55 pg, 56 pg, 57 pg, 58 pg, 59 pg, 60 pg, 61 pg, 62 pg, 63 pg, 64 pg, 65 pg, 66 pg, 67 pg, 68 pg, 69 pg,

[0525] 70 pg, 71 pg, 72 pg, 73 pg, 74 pg, 75 pg, 76 pg, 77 pg, 78 pg, 79 pg, 80 pg, 81 pg, 82 pg, 83 pg, 84 pg, 85 pg, 86 pg, 87 pg, 88 pg, 89 pg, 90 pg, 91 pg, 92 pg, 93 pg, 94 pg, 95 pg, 96 pg, 97 pg, 98 pg, 99 pg, 100 pg, 101 pg, 102 pg, 103 pg, 104 pg, 105 pg, 106 pg, 107 pg, 108 pg, 109 pg, 110 pg, 111 pg, 112 pg, 113 pg, 114 pg, 115 pg, 116 pg, 117 pg, 118 pg, 119 pg, 120 pg, 121 pg, 122 pg, 123 pg, 124 pg, 125 pg, 126 pg, 127 pg, 128 pg, 129 pg, 130 pg, 131 pg, 132 pg, 133 pg, 134 pg, 135 pg, 136 pg, 137 pg, 138 pg, 139 pg, 140 pg,

[0526] 141 pg, 142 pg, 143 pg, 144 pg, 145 pg, 146 pg, 147 pg, 148 pg, 149 pg, 150 pg, 151 pg, 152 pg, 153 pg,

[0527] 154 pg, 155 pg, 156 pg, 157 pg, 158 pg, 159 pg, 160 pg, 161 pg, 162 pg, 163 pg, 164 pg, 165 pg, 166 pg,

[0528] 167 pg, 168 pg, 169 pg, 170 pg, 171 pg, 172 pg, 173 pg, 174 pg, 175 pg, 176 pg, 177 pg, 178 pg, 179 pg,

[0529] 180 pg, 181 pg, 182 pg, 183 pg, 184 pg, 185 pg, 186 pg, 187 pg, 188 pg, 189 pg, 190 pg, 191 pg, 192 pg,

[0530] 193 pg, 194 pg, 195 pg, 196 pg, 197 pg, 198 pg, 199 pg, and 200 pg, as well as amounts within these ranges. In embodiments, a single dose is greater than (“>”) 200 pg, including 225 pg, 250 pg, and >250 pg.

[0531]

[0523] In embodiments, a composition comprises a serotonergic psychedelic in an amount so that a single dose is, when administered to an subject, about 1 mg / kg or less (including a dose of about 0.5 mg / kg or less, about 0.25 mg / kg or less, about 0.1 mg / kg or less, about 0.05 mg / kg or less, about 0.005 mg / kg or less, about 0.001 mg / kg or less, and about 0.0005 mg / kg or less), or at least about 1 mg / kg or more, including 1 .0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, 3.0 mg / kg, 3.1 mg / kg, 3.2 mg / kg, 3.3 mg / kg, 3.4 mg / kg, 3.5 mg / kg, 3.6 mg / kg, 3.7 mg / kg, 3.8 mg / kg, 3.9 mg / kg, 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5.0 mg / kg, as well as amounts within these ranges. In embodiments, a single dose is greater than 5.0 mg / kg, including 7.5 mg / kg, 10.0 mg / kg, and greater than 10 mg / kg.

[0532]

[0524] In embodiments, a composition comprises a serotonergic psychedelic in an amount so that a single dose is, when administered to an subject, about 1 pg / kg or less (including a dose of about 0.5 pg / kg or less, about 0.25 pg / kg or less, about 0.1 pg / kg or less, about 0.05 pg / kg or less, about 0.005 pg / kg or less, about 0.001 pg / kg or less, and about 0.0005 pg / kg or less), or at least about 1 pg / kg or more, including 1.0 pg / kg, 1.1 pg / kg, 1.2 pg / kg, 1.3 pg / kg, 1.4 pg / kg, 1.5 pg / kg, 1.6 pg / kg, 1.7 pg / kg, 1.8 pg / kg, 1.9 pg / kg, 2.0 pg / kg, 2.1 pg / kg, 2.2 pg / kg, 2.3 pg / kg, 2.4 pg / kg, 2.5 pg / kg, 2.6 pg / kg, 2.7 pg / kg, 2.8 pg / kg, 2.9 pg / kg, 3.0 pg / kg, 3.1 pg / kg, 3.2 pg / kg, 3.3 pg / kg, 3.4 pg / kg, 3.5 pg / kg, 3.6 pg / kg, 3.7 pg / kg, 3.8 pg / kg, 3.9 pg / kg, 4.0 pg / kg, 4.1 pg / kg, 4.2 pg / kg, 4.3 pg / kg, 4.4 pg / kg, 4.5 pg / kg, 4.6 pg / kg, 4.7 pg / kg, 4.8 pg / kg, 4.9 pg / kg, 5.0 pg / kg, as well as amounts within these ranges. In embodiments, a single dose is greater than 5.0 pg / kg, including 7.5 pg / kg, 10.0 pg / kg, and greater than 10 pg / kg.

[0533]

[0525] In embodiments, a composition comprises a mitochondrial energy enhancer, metabolic cofactor, metabolic coenzyme, antioxidant, glucose regulator, NAD+ degradation inhibitor, or additional active agent, including such other active agents as disclosed herein, in an amount so that a single dose is about 1 mg or less (including a dose of about 0.5 mg or less, about 0.25 mg or less, about 0.1 mg or less, about 0.05 mg or less, about 0.005 mg or less, about 0.001 mg or less, and about 0.0005 mg or less), or at least about 1 mg or more, including 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151 mg, 152 mg, 153 mg, 154 mg, 155 mg, 156 mg, 157 mg, 158 mg, 159 mg, 160 mg, 161 mg, 162 mg, 163 mg, 164 mg, 165 mg, 166 mg, 167 mg, 168 mg, 169 mg, 170 mg, 171 mg, 172 mg, 173 mg, 174 mg, 175 mg, 176 mg, 177 mg, 178 mg, 179 mg, 180 mg, 181 mg, 182 mg, 183 mg, 184 mg, 185 mg, 186 mg, 187 mg, 188 mg, 189 mg, 190 mg, 191 mg, 192 mg, 193 mg, 194 mg, 195 mg, 196 mg, 197 mg, 198 mg, 199 mg, and 200 mg, as well as amounts within these ranges. In embodiments, a single dose is greater than 200 mg, including 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, 1,100, 1,200 mg, 1,300 mg, 1,400 mg, 1,500 mg, 1,600 mg, 1,700 mg, 1,800 mg, 1,900 mg, 2,000 mg, 2,100 mg, 2,200 mg, 2,300 mg, 2,400 mg, 2,500 mg 2,600 mg, 2,700 mg, 2,800 mg, 2,900 mg, 3,000 mg, and greater than 3,000 mg, as well as amounts within these ranges.

[0534]

[0526] In embodiments, a composition comprises a mitochondrial energy enhancer, metabolic cofactor, metabolic coenzyme, antioxidant, glucose regulator, NAD+ degradation inhibitor, or additional active agent, including such other active agents as disclosed herein, in an amount so that a single dose is, when administered to an subject, between about 1 and 3,000 mg, including about 1 mg or less (including a dose of about 0.5 mg or less, about 0.25 mg or less, about 0.1 mg or less, about 0.05 mg or less, about 0.005 mg or less, about 0.001 mg or less, and about 0.0005 mg or less), 1 mg, 1 and 100 mg, 1 and 200 mg, 1 and 300 mg, 1 and 400 mg, 1 and 500 mg, 1 and 600 mg, 1 and 700 mg, 1 and 800 mg, 1 and 900 mg, 1 and 1,000 mg, 1 and 1,500 mg, 1 and 2,000 mg, 1 and 2,500 mg, and greater than 2,500 mg. In embodiments, a composition comprises any such agent in an amount so that a single dose is, when administered to an subject, between about 1 and 100 mg, 100 and 200 mg, 200 and 300 mg, 300 and 400 mg, 400 and 500 mg, 500 and 600 mg, 600 and 700 mg, 700 and 800 mg, 800 and 900 mg, 900 and 1,000 mg, 1,000 and 1,100 mg, 1,100 and 1,200 mg, 1,200 and 1,300 mg, 1,300 and 1,400 mg, 1,400 and 1,500 mg, 1,500 and 1,600 mg, 1,600 and 1,700 mg, 1,700 and 1,800 mg, 1,800 and 1,900 mg, 1,900 and 2,000 mg, 2,000 and 2,100 mg, 2,100 and 2,200 mg, 2,200 and 2,300 mg, 2,300 and 2,400 mg, 2,400 and 2,500 mg, 2,500 and 2,600 mg, 2,600 and 2,700 mg, 2,700 and 2,800 mg, 2,800 and 2,900 mg, 2,900 and 3,000, and greater than 3,000 mg. In embodiments, a composition comprises greater than about 3,000 mg of any such agent. In embodiments, a composition comprises less than about 1 mg of any such agent.

[0535]

[0527] In embodiments, a composition comprises NAD+ in an amount so that a single dose is, when administered to a subject, between about 50 and 400 mg, 75 and 350 mg, and 100 and 300 mg. In embodiments, a composition comprises NAD+ in an amount so that a single dose is, when administered to an subject, about 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, and greater than 300 mg. In embodiments, a composition comprises greater than about 300 mg of NAD+. In embodiments, a composition comprises NAD+ in an amount so that a single dose is between about 50 and 1,500 mg, between about 75 and 1,200 mg, and between about 100 and 1,000 mg, or about 1,500 mg, about 1,000 mg, or about 500 mg. In embodiments, a composition comprises less than about 50 mg of NAD+.

[0536]

[0528] In embodiments, a composition comprises NADH in an amount so that a single dose is, when administered to a subject, between about 1 and 25 mg, 2 and 22 mg, 4 and 21 mg, and 5 and 20 mg. In embodiments, a composition comprises NADH in an amount so that a single dose is, when administered to an subject, about 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, and greater than 20 mg. In embodiments, a composition comprises greater than about 20 mg of NADH. In embodiments, a composition comprises less than about 1 mg of NADH.

[0537]

[0529] In embodiments, a composition comprises a methyl-donor supplement in an amount so that a single dose is, when administered to a subject, between about 0.0001 mg and 1,000 mg. In embodiments, a composition comprises a methyl-donor supplement in an amount so that a single dose is, when administered to a subject, between about 3,000 and 6,000 mg. In embodiments, wherein the methyl-donor supplement is trimethylglycine (i.e., betaine), a disclosed combination comprises trimethylglycine in an amount between about 1,000 and 7,000 mg, between about 2,000 and 6,500 mg, and between about 3,000 and 6,000 mg. In embodiments, a composition comprises trimethylglycine in an amount of about 3,000 mg.

[0538]

[0530] In embodiments, a composition comprises NAM, NAAD, NaMN, NaR, NMN, or NR in an amount so that a single dose is, when administered to an subject, between about 200 and 2,500 mg, between about 225 and 2,250 mg, or between about 250 and 2,000 mg. Where the single dose of NAM, NAAD, NaMN, NaR, NMN, or NR is between about 200 and 2,500 mg, between about 225 and 2,250 mg, or between about 250 and 2,000 mg, the single dose, when administered to an subject, in embodiments is an amount between about 200 and 300 mg, 300 and 400 mg, 400 and 500 mg, 500 and 600 mg, 600 and 700 mg, 700 and 800 mg, 800 and 900 mg, 900 and 1,000 mg, 1,000 and 1,100 mg, 1,100 and 1,200 mg, 1,200 and 1,300 mg,

[0539] 1,300 and 1,400 mg, 1,400 and 1,500 mg, 1,500 and 1,600 mg, 1,600 and 1,700 mg, 1,700 and 1,800 mg,

[0540] 1,800 and 1,900 mg, 1,900 and 2,000 mg, 2,000 and 2,100 mg, 2,100 and 2,200 mg, 2,300 and 2,400 mg, and 2,400 and 2,500 mg, inclusive. In other embodiments, for any such agents, a single dose will be an amount less than 200 mg, and greater than 2,500 mg.

[0541]

[0531] In embodiments, a composition comprises NA in an amount so that a single dose is, when administered to an subject, between about 0.1 and 30 mg, about 1 and 20 mg, or about 2 and 16 mg.

[0542]

[0532] In embodiments, a composition comprises Trp in an amount so that a single dose is, when administered to an subject, between about 200 and 500 mg, 225 and 475 mg, and 250 and 425 mg. In embodiments, a composition comprises Trp in an amount so that a single dose is, when administered to an subject, about 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 425 mg, and greater than 425 mg.

[0543]

[0533] In embodiments, a composition comprises ALC in an amount between about 500 and 3,000 mg. In embodiments, a composition comprises ALA in an amount between about 100 and 2,000 mg. In embodiments, a composition comprises FAD in an amount between about 10 and 150 mg. In embodiments, a composition comprises any of vitamin B1, vitamin B2, and vitamin B6 in an amount between about 0.1 and 5 mg. In embodiments, a composition comprises vitamin B3 in an amount between about 1 and 50 mg. In embodiments, a composition comprises vitamin B5 in an amount between about 0.1 and 10 mg. In embodiments, a composition comprises vitamin B7 in an amount between about 0.001 and 5 mg. In embodiments, a composition comprises vitamin B9 in an amount between about 100 and 500 mg. In embodiments, a composition comprises vitamin B12 in an amount between about 0.001 and 3 mg. In embodiments, a composition comprises iodine in an amount between about 0.001 and 4 mg. In embodiments, a composition comprises magnesium in an amount between about 50 and 2,000 mg.

[0544]

[0534] In embodiments, a composition comprises an antioxidant or glucose regulator in an amount so that a single dose is, when administered to an subject, between about 1 and 1,000 mg, 10 and 900 mg, 20 and 800 mg, and 30 and 600 mg. In embodiments, a composition comprises an antioxidant or glucose regulator in an amount so that a single dose is, when administered to an subject, between about 1 and 10 mg, 10 and 20 mg, 20 and 30 mg, 30 and 40 mg, 40 and 50 mg, 50 and 60 mg, 60 and 70 mg, 70 and 80 mg, 80 and 90 mg, 90 and 100 mg, 100 and 200 mg, 200 and 300 mg, 300 and 400 mg, 400 and 500 mg, 500 and 600 mg, and greater than 600 mg. In other embodiments, for any such agents, a single dose will be an amount less than 1 mg, or greater than 600 mg.

[0545]

[0535] In embodiments, a composition comprises vitamin C (e.g., extended release vitamin C) in an amount so that a single dose is, when administered to an subject, between about 5 and 2,000 mg, 100 and 1,750 mg, 200 and 1,500 mg, 250 and 1 ,250 mg, and 300 and 1,000 mg. In embodiments, a composition comprises vitamin C in an amount of about 1 ,000 mg. In embodiments, a composition comprises vitamin C in an amount between about 1 and 100 mg, 100 and 200 mg, 200 and 300 mg, 300 and 400 mg, 400 and 500 mg, 500 and 600 mg, 600 and 700 mg, 700 and 800 mg, 800 and 900 mg, 900 and 1,000 mg, and greater than 1,000 mg. In embodiments, a composition comprises vitamin C in an amount of about 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1,000 mg, and greater than 1,000 mg. In embodiments, a single dose will be an amount less than 100 mg, and greater than 1 ,000 mg. In embodiments, exemplary daily dose amounts or daily dose ranges for vitamin C are from about 45 mg to about 1 ,000 mg.

[0546]

[0536] In embodiments, a composition comprises CoQ10 in an amount so that a single dose is, when administered to a subject, between about 1 and 1,000 mg, 10 and 900 mg, 20 and 800 mg, and 30 and 600 mg. In embodiments, a composition comprises CoQ10 in an amount so that a single dose is, when administered to an subject, between about 20 and 30 mg, 30 and 40 mg, 40 and 50 mg, 50 and 60 mg, 60 and 70 mg, 70 and 80 mg, 80 and 90 mg, 90 and 100 mg, 100 and 200 mg, 200 and 300 mg, 300 and 400 mg, 400 and 500 mg, 500 and 600 mg, and greater than 600 mg. In embodiments, exemplary daily dose amounts or daily dose ranges for CoQ10 are from about 30 mg to about 600 mg.

[0547]

[0537] In embodiments, two or more agents in a combination or composition are provided in a defined ratio, such as by moles, %w / w, %w / v, or %v / v. In embodiments, a combination or composition comprises a serotonergic psychedelic and a mitochondrial energy enhancer in a defined ratio, such as a defined molar ratio. In embodiments, a combination or composition comprises LSD and NAD+ in a defined ratio, such as a defined molar ratio. In embodiments, a combination or composition comprises any other agents, including three or more agents, in a defined ratio. Where agents are in a defined ratio, for example where LSD and NAD+ are in a defined molar ratio, and including defined ratios such as molar ratios of any other two agents, the combination or composition may comprise the agents in a ratio, such as a molar ratio, of about 1 :1 , 1:1.001, 1 :1.01, 1 :1.1, 1 :1.2, 1 :1.25, 1 :1.5, 1 :1.75, 1 :2, 1 :2.5, 1 :5, 1 :7.5, 1 :10, 1 :20, 1 :30, 1 :40, 1 :50, 1 :60, 1:70, 1 :80, 1 :90, 1 :100, 1 :200, 1 :300, 1 :400, 1:500, 1 :600, 1 :700, 1 :800, 1 :900, 1 :1 ,000, 1 :1 ,500, 1:2,000, 1:2,500, 1 :5,000, 1 :10,000 including amounts in between these numbers and amounts greater than 1 :10,000.

[0548]

[0538] In embodiments, a combination or composition comprises LSD and NAD+ in a defined molar ratio of about 1:1, 1 :1.001, 1 :1.01 , 1 :1.1 , 1 :1.2, 1 :1.25, 1 :1.5, 1 :1.75, 1 :2, 1 :2.5, 1 :5, 1 :7.5, 1 :10, 1 :20, 1 :30, 1 :40, 1:50, 1 :60, 1 :70, 1 :80, 1 :90, 1 :100, 1 :200, 1 :300, 1 :400, 1 :500, 1 :600, 1 :700, 1 :800, 1 :900, 1 :1 ,000, 1 :1,500, 1:2,000, 1 :2,500, 1 :5,000, 1:10,000, and greater than 1:10,000, as a ratio of LSD:NAD+ or of NAD+:LSD.

[0549]

[0539] In embodiments, two or more agents in a defined ratio provides certain beneficial and / or synergistic effects, such as any of the effects disclosed herein, for example defined ratios of LSD and NAD+ are particularly advantageous in producing certain effects, including synergistic effects, such as reducing ROS.

[0550]

[0540] In embodiments, a subject will be administered or will self-administer a therapeutically effective dose of a combination disclosed herein on a regular (or sometimes referred to as a “chronic”) basis, where the subject is administered a therapeutically effective dose of the combination daily, several times per day (at least one, at least two, at least three, at least four, and greater than four times per day), or over a period of days, weeks, months, or indefinitely, such as daily, or on a disclosed dosing regimen of on and off days.

[0551]

[0541] In embodiments, a subject will be administered or will self-administer a therapeutically effective dose of a combination disclosed herein on a set, repeating schedule, where the subject is administered a therapeutically effective dose of the combination every other day, every three days, every four days, every five days, every six days, every seven days, or more than every seven days.

[0552]

[0542] In embodiments, a subject is administered or self-administers (together herein as shorthand, unless context indicates otherwise, “administers” and other conjugations) a therapeutically effective dose of a disclosed combination as part of a dosing schedule, where the subject is administered a combination daily, once every other day, once every two days, or for a plurality of consecutive days followed by at least one day “off” (wherein no administration occurs). In embodiments, a subject is administered a therapeutically effective dose of a combination on a varying schedule comprised of a plurality of days “on” (where administration occurs), and a plurality of days “off,” such as one day on two days off, two days on three days off, three days on four days off, and such schedules known in the art (e.g., the Stamets or Fadiman microdosing protocols). In embodiments, a schedule is determined by the subject, and is made by reference to information online, provided upon pickup or purchase, or provided with a combination, such as a package insert as part of a kit.

[0553]

[0543] In embodiments, a subject is administered a combination on a schedule determined by a clinician (e.g., physician, specially trained douala, nurse practitioner, nurse, physician’s assistant, etc.), by the subject themselves, or by a combination thereof. In embodiments, a subject begins administering a combination on a given schedule, but that schedule is subsequently modified by a clinician and / or the subject as needed.

[0554]

[0544] In embodiments, the dose of the serotonergic psychedelic administered to, or taken by, a subject in need thereof, is a “macrodose.” A “macrodose” may be equivalently referred to in embodiments as a “psychedelic dose” or a “full psychedelic dose.” In embodiments, the macrodose is sufficient to cause a subject to experience one or more subjective effects, including psychoactive and / or psychedelic effects.

[0555]

[0545] In embodiments, a dose of the serotonergic psychedelic administered to, or taken by a subject (e.g., by self-administration) is a “sub-psychedelic” or “sub-threshold” “microdose” (i.e. , a dose below the threshold for subjective psychedelic effects). In embodiments, the microdose is in an amount insufficient to cause the subject to experience one or more subjective effects, including psychoactive and / or psychedelic effects.

[0556]

[0546] In embodiments, a microdose is a dose that is between about 0.001 to about 0.25 of a macrodose of a serotonergic psychedelic, such as 0.003, 0.005, 0.007, 0.009, 0.01, 0.03, 0.05, 0.07, 0.09, 0.1, 0.2, and 0.25 of a macrodose of the serotonergic psychedelic (where the list is inclusive, and each amount may be modified by the term “about”). In embodiments, a microdose is between about 0.001 to 0.25 of a macrodose, such as 0.003, 0.005, 0.007, 0.009, 0.01, 0.03, 0.05, 0.07, 0.09, 0.1, 0.2, and 0.25 of a macrodose.

[0557]

[0547] In embodiments, a microdose is between about 0.001 mg and 50 mg, including 0.001 mg, 0.005 mg,

[0558] 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 1 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg and values in between.

[0559]

[0548] In embodiments, a microdose is between about 0.001 pg and about 50 pg, including 0.001 pg, 0.005 pg, 0.01 pg, 0.05 pg, 0.1 pg, 0.5 pg, 1 pg, 2 pg, 3 pg, 4 pg, 5 pg, 6 pg, 7 pg, 8 pg, 9 pg, 10 pg, 11 pg, 12 pg, 13 pg, 14 pg, 15 pg, 16 pg, 17 pg, 18 pg, 19 pg, 20 pg, 21 pg, 22 pg, 23 pg, 24 pg, 25 pg, 26 pg, 27 pg, 28 pg, 29 pg, 30 pg, 31 pg, 32 pg, 33 pg, 34 pg, 35 pg, 36 pg, 37 pg, 38 pg, 39 pg, 40 pg, 41 pg, 42 pg, 43 pg, 44 pg, 45 pg, 46 pg, 47 pg, 48 pg, 49 pg, 50 pg and values in between.

[0560]

[0549] In embodiments, where the serotonergic psychedelic administered to, or taken by a subject is LSD, 1P-LSD, or AL-LAD the dose is between about 0.001 pg and about 50 pg, including 0.001 pg, 0.005 pg, 0.01 pg, 0.05 pg, 0.1 pg, 0.5 pg, 1 pg, 2 pg, 3 pg, 4 pg, 5 pg, 6 pg, 7 pg, 8 pg, 9 pg, 10 pg, 11 pg, 12 pg, 13 pg, 14 pg, 15 pg, 16 pg, 17 pg, 18 pg, 19 pg, 20 pg, 21 pg, 22 pg, 23 pg, 24 pg, 25 pg, 26 pg, 27 pg, 28 pg, 29 pg, 30 pg, 31 pg, 32 pg, 33 pg, 34 pg, 35 pg, 36 pg, 37 pg, 38 pg, 39 pg, 40 pg, 41 pg, 42 pg, 43 pg, 44 pg, 45 pg, 46 pg, 47 pg, 48 pg, 49 pg, 50 pg and values in between.

[0561]

[0550] In embodiments, where the serotonergic psychedelic administered to, or taken by a subject is a psilocybin extract or ibogaine extract the dose is between about 1 and 300 mg of the total extract, including 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, and values in between.

[0562]

[0551] In embodiments, where the serotonergic psychedelic administered to, or taken by a subject is psilacetin or synthetic psilocybin, the dose is between about 0.01 and 25 mg, including 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, and values in between.

[0563]

[0552] In embodiments, where the serotonergic psychedelic administered is DMT, the dose is between about 0.001 and 15 mg, including 0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, and values in between.

[0564]

[0553] In embodiments, where the serotonergic psychedelic administered to, or taken by a subject is mescaline, the dose is between about 5 mg and about 75 mg, including 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg,

[0565] 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, and values in between.

[0566]

[0554] In embodiments, where the serotonergic psychedelic administered is DOI, the dose is between about 0.001 mg and 1.5 mg, including 0.001 mg, 0.005 mg, 0.01 mg, 0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, and values in between.

[0567]

[0555] In some embodiments, the serotonergic psychedelic is present as a macrodose or as a microdose. In some embodiments, a combination comprises a macrodose of a serotonergic psychedelic. In other embodiments, a combination comprises a microdose of a serotonergic psychedelic.

[0568]

[0556] In embodiments, the dose administered is determined by a physician or other clinician, in light of, for example, the method of delivery, the age of the subject, the weight of the subject, whether the subject has any comorbidities, other medications the subject is taking (routinely or presently), and any subject-specific aspects that could affect the way in which the agents in a combination interact with the subject, such as variations in metabolism, variations in subject response, etc., and accordingly the dose ranges herein are not intended to limit the scope of the disclosure. In embodiments, dose levels below the lower limit of a disclosed range are administered. In other embodiments, doses above the upper limit of a disclosed range are administered, and for example do not produce any adverse events. In some embodiments, larger doses of one or more agents are divided into smaller doses for administration, and may be taken separately.

[0569]

[0557] In embodiments, the dose of a serotonergic psychedelic is determined by a healthcare professional, in accordance with a personalized microdosing protocol. In embodiments, the dose of a serotonergic psychedelic is determined by a specially trained doula, in accordance with such a personalized protocol.

[0570]

[0558] Determination of dosing may include not only the determination of single dose amounts, but also the determination of the number and timing of doses, e.g., administering a dose amount once per day, twice per day, or more than twice per day, and the time(s) of day or time(s) during treatment for administration.

[0571]

[0559] Individual dosages, including starting and maintenance dosages if different, may differ between subjects, for an individual subject over time, and for different combinations, but will be known in view hereof.

[0572]

[0560] In embodiments, such as where a formulation is prepared in single unit dosage form, such as a capsule, tablet, or lozenge, suggested dosage amounts are known by reference to the format of the formulation. In embodiments, such as where a formulation is prepared in multiple dosage form, for instance liquid suspensions and topical preparations, suggested dosage amounts are known by reference to the means of administration or by reference to the packaging and labeling, package insert(s), marketing materials, training materials, or other information and knowledge available to those of skill or the public.

[0573]

[0561] In embodiments, rather than being formulated together as a single pharmaceutical composition, the agents in a combination are individually formulated as separate pharmaceutical compositions, e.g., as separate dosage forms, which are administered to a subject separately, sequentially, or simultaneously.

[0574]

[0562] In embodiments, “sequential” administration refers to administering a composition soon after administering another composition, for example within about five minutes, 10 minutes, or 15 minutes; “simultaneous” administration refers to administering each composition at substantially the same time; and “separate” administration refers to administration with substantial time elapsing in between. Where administrations are “simultaneous,” and at substantially the same time, the administrations nevertheless may be separated by a reasonable amount of time, for example as is necessary for or as would reasonably separate multiple administrations, but where the administrations are still understood to be in, for example, the same session. In embodiments where two or more compositions are administered separately, or where a composition is administered “before” or “after” another, the period of time separating such administrations may be about 30 minutes, about 45 minutes, or about 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, and more than 48 hours.

[0575]

[0563] The frequency of dosing may depend on the condition and symptoms being treated, or the cognitive enhancements or improvements to general wellness desired by administering the serotonergic psychedelic. In one example, a combination is administered twice per day or three times per day. In another example, one compound in a combination is administered three times per day, or four times per day, while another compound in the combination is administered at a different frequency, such as once per day, or twice per day.

[0576]

[0564] In embodiments, the dosing schedule continues in the same pattern or a modified one for a specific duration of time, including 1-7 days, and greater than 7 days, including 14, 21, 28, 29, 30, 31, 35, 42, 49, 60, 75, 90, or 120 days; and the manner in which the administration is completed (e.g., separately, sequentially, or simultaneously) is adjusted as needed, such that the entire dosing schedule only includes sequential, simultaneous, or separate dosing; or includes a combination of two of sequential, simultaneous, or separate dosing; or includes all of sequential, simultaneous, or separate dosing. In embodiments, the frequency of dosing and duration of elapsed time between administrations depends on the combination, including in examples any one or more of the serotonergic psychedelic, metabolic coenzyme, metabolic cofactor, glucose regulator, antioxidant, additional active agent(s), or other agent(s) present, and the condition sought to be treated, or cognitive enhancement or general wellness desired, but will be readily understood by one of skill.

[0577]

[0565] In embodiments, a combination is administered according to a regimen comprising multiple administrations, such as where a subject is administered a combination daily, several times per day (at least one, at least two, at least three, at least four, and greater than four times per day); on a set, repeating schedule, where the subject is administered a therapeutically effective dose of the combination every other day, every three days, every four days, every five days, every six days, every seven days, or more than every seven days; or, In embodiments, a varying schedule comprised of a plurality of days “on”, and a plurality of days “off’, such as 1 day on 2 days off, 2 days on 3 days off, 3 days on 4 days off, 5 days off, 6 days off, 7 days off, or other such schedules known (e. g. , the Paul Stamets or James Fadiman microdosing protocols).

[0578]

[0566] In embodiments, a combination is administered according to a regimen comprising multiple administrations, such as where administration of a combination is every 4 days (i.e., 1 day “on” and 3 days “off’) over a defined time period (e.g, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, and greater than 11 months). In embodiments, a combination is administered according to a regimen comprising multiple administrations, such as where a subject is administered a combination every five days (i.e., one day “on” and four days “off’) over a defined time period (e.g, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, and greater than 11 months). Administration to a subject can be every x days, where x is an integer.

[0579]

[0567] In embodiments, the dose or dosing regime is selected to produce a desired effect in a subject, such as creating or maintaining any of a positive mood, energy, cognition (e.g., cognitive transformation), heightened consciousness, empathy, and a sense of enjoyment during the “off’ days.

[0580]

[0568] In embodiments, a dose or dosing regimen is modified if a desired effect is not produced in a subject.

[0581]

[0569] In embodiments, a dose amount administered to a subject is increased or decreased. For example, a subject may be administered a dose amount according to a dosing regimen for a period of time, after which the dose amount is increased or decreased. In embodiments, a dose amount is increased where a desired effect is not produced in a subject, or is not produced to a sufficient degree. In embodiments, a dose amount is decreased where an effect is produced that is too strong (e.g., a psychedelic effect) or an adverse effect or side effect is produced that is unexpected or larger than expected, or not commensurate with a benefit achieved. Other bases for increasing (e.g., escalating) or decreasing (e.g., de-escalating) a dose amount will be known in view of the teachings herein and the skill in the art. In embodiments, a dose amount, such as a dose amount of LSD, is increased or decreased in an amount of between about 0.01 g and 50 pg. In some exemplary embodiments, a dose amount, such as a dose amount of LSD, is increased by about 1 pg, about 2.5 pg, about 5 pg, or about 10 pg. For example, In embodiments, a subject is administered a dose of 10 pg, which may be a starting dose for example. If a desired effect is not produced in the subject, such as a desired subjective effect, or for example an increase in feelings of or performance of cognitive ability, the dose amount administered to the subject is increased to 15 pg, which then may be maintained at that dose amount, or may be increased again to 20 pg, for example. Other like embodiments will be readily appreciated in view of the teachings of the disclosure, including dose amounts for other disclosed agents.

[0582]

[0570] In embodiments, a dose amount, such as a dose amount of LSD, is increased or decreased in an amount of between about 1 and 50%. In some exemplary embodiments, a dose amount, such as a dose amount of LSD, is increased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 50%, or about 100%. For example, In embodiments, a subject is administered a dose of 10 pig, which may be a starting dose or a modified dose for example. If a desired effect is not produced in the subject, the dose amount administered to the subject is increased to 11 pig (i.e., a 10% increase in dose amount). In some exemplary embodiments, a dose amount, such as a dose amount of LSD, is decreased by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, or about 50%.

[0583]

[0571] In embodiments, where a combination is administered more than once, the dose of one or more agents is adjusted (e.g., increased, decreased). In embodiments, the dose of one or more agents is adjusted without adjusting the dose of any other agents. In embodiments, the dose of each of the agents is adjusted.

[0584]

[0572] In embodiments, a subject is administered a combination through a first administration and a second administration, where the first administration and the second administration are not the same means of administration. In embodiments, multiple administrations are advantageous in situations where the serotonergic psychedelic has varying durations of action. For example, a long-acting serotonergic psychedelic (e.g., LSD) can be administered once per day, with other agents in a combination adminisatered multiple times per day. In embodiments, other agents in a combination may be long-acting, either by nature of the agent, or by its formulation (e.g., timed-release vitamin C). In embodiments, one of skill will determine the proper means of administration, and the order and timing thereof, given the agents in the combination, and indication sought to be treated, and / or desired improvement in cognitive function / general wellness.

[0585]

[0573] In embodiments, a metabolic coenzyme, metabolic cofactor, or glucose regulator is administered separately from a serotonergic psychedelic. In embodiments, a metabolic coenzyme, metabolic cofactor, or glucose regulator is administered sequentially with a serotonergic psychedelic. In embodiments, a metabolic coenzyme, metabolic cofactor, or glucose regulator is administered simultaneously with a serotonergic psychedelic. In embodiments, the timing of administering the metabolic coenzyme, metabolic cofactor, or glucose regulator, and the serotonergic psychedelic (including whether or not more than one administration of the metabolic coenzymes, cofactors, and glucose regulators is necessary) will be such that the combination will increase available ATP and prevent mitochondrial oxidative damage for the full duration of action of the serotonergic psychedelic. As will be appreciated by one of skill, such will depend on the specific metabolic coenzymes, cofactors, glucose regulators, and serotonergic psychedelics administered, the indications sought to be treated, and / or the improvements to cognitive function and general wellness sought, among other factors known in the art, and will be understood by those of skill in view of the teachings herein. d. Pharmaceutical Kits

[0586]

[0574] In another aspect of this disclosure are pharmaceutical kits or “kits of parts” (together as shorthand, “kits”) comprising the disclosed combinations. In embodiments, a kit comprises the agents in a combination.

[0587]

[0575] In embodiments, a kit further comprises a suitable container. In embodiments, a kit is a single-dose kit comprising the agents in a combination, as one or more pharmaceutical compositions, such as in one or more individual unit dosage forms, or as pharmaceutical compositions comprising one or more agents. In embodiments, a kit is a multi-dose kit comprising the agents in a combination, as one or more pharmaceutical compositions, such as in a plurality of individual unit dosage forms (e.g., one or more blister packs comprising multiple tablets or capsules), as multiple-dosage forms (e.g., a liquid dosage form comprising multiple doses), or a combination thereof (e.g., one or more blister packs and one or more liquid dosage forms). It will be appreciated that combinations can be formulated and packaged in a variety of ways.

[0588]

[0576] In embodiments, a kit further comprises administration guidelines or prescribing information.

[0589]

[0577] In an exemplary pharmaceutical kit, capsules, tablets, caplets, or other unit dosage forms are packaged in blister packs. “Blister pack” refers to any of several types of pre-formed container, especially plastic packaging, that contains separate receptacles (e.g., cavities or pockets) for single unit doses, where such separate receptacles are individually sealed and can be opened individually. Blister packs thus include such pharmaceutical blister packs known to those of ordinary skill, including Aclar® Rx160, Rx20e, SupRx, and UltRx 2000, 3000, 4000, and 6000 (Honeywell). Within the definition of multi-dose containers, and also often referred to as blister packs, are blister trays, blister cards, strip packs, push-through packs, and the like. Preferably, information pertaining to dosing and proper administration (if needed) will be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding the disclosed combinations); however, disclosed kits can further contain package inserts and other printed instructions (e.g., on exterior packaging) for administering the disclosed combinations and for their appropriate therapeutic use.

[0590]

[0578] In embodiments, a subject will have the option of using online software such as a website, or downloadable software such as a mobile application, to assist with compliance or to provide data relating to treatment. Software can be used to, e.g., keep track of the last dose taken or total doses taken, provide reminders and alerts for upcoming doses, discourage taking doses outside of set schedules, and allow for recording of specific subjective effects, or provide means for unstructured journaling. Data collection can assist with individual subject compliance and can be used to improve or tailor individual subject care plans.

[0591] H. Methods of Using the Disclosed Combinations Including for Treatment

[0592]

[0579] In some aspects are provided methods of use, such as methods of treatment, by administering a combination or composition. In some aspects, the methods are used to treat nervous system disorders, to promote general wellness, to increase energy, and to maintain glucose levels. In embodiments, administering a combination or composition (which herein as shorthand may be jointly referred to with either term) provides certain beneficial effects, including, as examples, increasing blood supply, increasing levels of glucose and oxygen, increasing production of ATP, increasing cellular energy, and increasing the energy level of the brain. a. Beneficial Effects of Disclosed Combinations

[0593]

[0580] In embodiments, administering a disclosed combination has one or more beneficial effects. In embodiments, a beneficial effect of administering a combination is that the combination improves, enhances, or increases (all used interchangeably, unless context indicates otherwise) any one or more of adenosine triphosphate (ATP) production, energy, mitochondrial biogenesis, mitochondrial function, and NAD levels.

[0594]

[0581] In embodiments, administering a combination increases ATP production, which may be any of an increase in intracellular ATP production, astrocyte ATP production, neurosphere ATP production, and / or neuronal ATP production. In embodiments, administering a combination increases ATP production by increasing the blood supply to neurons. In embodiments, a combination increases ATP production by activating intracellular pathways that enhance mitochondrial function. In embodiments, a combination increases ATP production by promoting the efficiency of enzymes. In embodiments, a combination increases ATP production by increasing the ability of mitochondria to produce ATP, or by enhancing the efficiency of mitochondrial ATP production. In embodiments, a combination increases glucose and oxygen supply to the cells by increasing capillary volume and increasing mitochondrial biogenesis, thus increasing ATP production.

[0595]

[0582] In embodiments, a combination increases energy. In embodiments, an increase in energy is an increase in energy production and / or an increase in energy metabolism. In embodiments, an increase in energy is an increase in any of mitochondrial energy, cellular energy, brain energy, and body energy.

[0596]

[0583] In embodiments, administering a combination increases cellular energy production. In embodiments, a combination increases cellular energy production by increasing the biogenesis of new mitochondria. In embodiments, a combination increases cellular energy production by enhancing mitochondrial functioning. In embodiments, a combination increases cellular energy production by increasing the availability of NAD+ to power new mitochondria. In embodiments, a combination increases cellular energy production by increasing the amount of glucose. In embodiments, a combination increases cellular energy production by increasing the availability of acetyl CoA for the Krebs cycle. In embodiments, a combination increases cellular energy production by increasing the amount of oxygen available for the mitochondrial electron transporter chain. In embodiments, a combination increases cellular energy production by increasing the blood supply to the cells. In embodiments, a combination increases such blood supply by the vasoconstriction of veins. In embodiments, a combination increases such blood supply by the vasoconstriction of arteries.

[0597]

[0584] In embodiments, administering a combination increases brain energy, i.e. , energy levels in the brain. In embodiments, a combination increases energy levels in the brain by increasing cellular energy production. In embodiments, a combination increases energy levels in the brain by increasing blood volume in the capillaries of the brain. In embodiments, a combination increases blood volume in the capillaries of the brain through the vasoconstrictive effects it exerts on the veins in the brain when a serotonergic psychedelic binds to 5-HT2Areceptors, causing the capillaries to dilate, increasing the amount of glucose and oxygen that reaches the neurons. In embodiments, a combination increases mitochondrial energy in the brain and body.

[0598]

[0585] In embodiments, administering a combination increases mitochondrial biogenesis, increasing the number of mitochondria. In embodiments, the number of mitochondria is increased in nerve and / or muscle cells. In embodiments, a combination increases mitochondrial biogenesis by activating an intracellular pathway that leads to the activation of genes involved in mitochondrial biogenesis.

[0599]

[0586] In embodiments, a combination protects cells from oxidative damage. In embodiments, a combination increases the production of the antioxidant enzymes catalase (CAT) and superoxide dismutase 2 (SOD2). Assessing production of CAT and SOD2 can be performed according to methods in the art, e.g., UV-vis spectrophotometry or cell-based bioassays (see, e.g., Engelbrecht et al. MethodsX. 2023:102395).

[0587] In embodiments an increase in energy production or metabolism is enhanced, such as synergistically enhanced, by administration of a glucose regulator (e.g., ascorbic acid) to maintain optimal glucose levels. In embodiments, a combination prevents a glucose decrease during heightened cellular activity.

[0600]

[0588] In embodiments, the agents in a combination synergistically provide and enhance any above effects.

[0601]

[0589] FIG. 1 illustrates certain exemplary proposed synergistic effects of a disclosed combination. In brief, and without being bound by theory, administration of a combination comprising LSD (as an exemplary serotonergic psychedelic) together with any of NAD, an NAD+ precursor, and a compound that results in an increase in NAD concentrations in the brain and body, can increase the overall amount of energy in the brain and body by increasing ATP production. The exemplary mechanism illustrated in FIG. 1 comprises increasing mitochondrial biogenesis through the SIRT1 pathway, thereby increasing the amount of ATP that the cells can use; increasing the supply of glucose and oxygen to cells by increasing capillary volume. For example, when a serotonergic psychedelic such as LSD binds to the cellular or neuronal 5-HT2Areceptors, it may activate sirtuins. The sirtuins, in turn, may promote mitochondrial function and biogenesis and increase the production of antioxidants. Furthermore, but without being bound by theory, when a serotonergic psychedelic such as LSD binds to 5-HT2Areceptors on the veins, there is a vasoconstrictive force exerted that causes the capillaries to dilate, thus increasing the amount of glucose and oxygen that reaches the neurons. In embodiments, a combination increases the overall number of mitochondria, which produce more total ATP. b. Methods of Treatment Using Disclosed Combinations

[0602]

[0590] In some aspects are disclosed methods of treating a medical condition, which broadly refers to any disease, disorder, or other condition for which administration of a disclosed combination or composition will be useful, using a disclosed combination or composition (together as shorthand, a combination). In embodiments, a combination is administered to a subject having a medical condition, treating the condition. In embodiments, a combination is used in the manufacture of a medicament to treat a medical condition.

[0603]

[0591] In some aspects are disclosed methods of treating and / or preventing a condition in a mammal, the method comprising administering to the mammal a therapeutically effective amount of a combination. In embodiments, “treating” or “treatment” refers to treating a condition in a mammal, and preferably in a human, and includes causing a desired biological or pharmacological effect, such as: (a) preventing a condition from occurring in a subject who may be predisposed to the condition but has not yet been diagnosed with it; (b) inhibiting a condition, i.e. arresting its development; (c) relieving a condition, i.e., causing regression thereof; (d) protecting from or relieving a symptom or pathology caused by or related to a condition; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency or probability of one or more symptoms or pathologies associated with a condition; and (f) preventing or inhibiting of a worsening or progression of symptoms or pathologies associated with a condition or comorbid with a condition. Other relevant measurements, benefits, and clinical or surrogate endpoints, alone or in combination, will be understood to one of skill in view of the disclosure and the general knowledge in the art.

[0604]

[0592] In embodiments, a combination treats a central nervous system (CNS) disorder, include diseases of the nervous system (e.g., movement disorders, neurodegenerative disorders), and mental, behavioral, and neurodevelopmental disorders, such as characterized by the DSM-5, Merck Manual, ICD-11, or the like. i. Subjects For Which Disclosed Combinations and Compositions Are Useful

[0605]

[0593] In embodiments, a combination is useful for improving mitochondrial energy in a subject, such as a human subject. Herein, “a subject” will include in some embodiments a human subject.

[0606]

[0594] In embodiments, a combination is useful for treating a subject having mitochondrial dysfunction. In embodiments, a combination is useful for treating a subject having reduced cellular energy metabolism. In embodiments, a combination is useful for treating a subject having reduced mitochondrial biosynthesis. In embodiments, a combination is useful for treating a subject having reduced ATP production. In embodiments, a combination is useful for treating a subject having reduced NAD, NADH, and / or NAD+ levels.

[0607]

[0595] “Reduced,” as in “reduced cellular energy metabolism,” “reduced mitochondrial biosynthesis,” “reduced ATP production,” and “reduced NAD, NADH, and / or NAD+” refers to a decrease in biological activity or process compared to a standard or control, a baseline value in a subject, or a baseline value for a population, and which may be measured directly, or known by a correlation with a condition in a subject, such as where the subject has a medical condition caused by or associated with such reduction.

[0608]

[0596] In embodiments, a combination is useful for treating a subject having a medical condition caused by or associated with any of reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, and / or NAD+ levels. The assessment of a subject, including a human, can be performed according to methods disclosed herein or known in the art.

[0609]

[0597] In embodiments, a combination is useful to treat a subject to improve overall health and wellness. An improvement in overall health and wellness will be as known in the art.

[0610]

[0598] In embodiments, a subject is selected for treatment, such as by a disclosed method. In embodiments, a subject is selected for treatment if the subject meets certain inclusion criteria, does not meet certain exclusion criteria, and does not meet any withdrawal criteria before or during the course of treatment.

[0611]

[0599] In embodiments, selecting a subject for treatment comprises measuring any of a subject’s mitochondrial function, metabolic enzyme activity, adenosine triphosphate (ATP) production, intracellular ATP levels, astrocyte ATP levels, neurosphere ATP levels, neuron ATP levels, nicotinamide adenine dinucleotide (NAD+, NADH, and NAD) levels, maximal oxygen uptake, mitochondrial respiration, mitochondrial membrane potential, mitochondrial health index (MHI), bioenergetic health index (BHI), mitochondrial oncobioenergetic index (MOBI), antioxidant levels, antioxidant enzyme activity, glucose levels, ability to sustain concentration, consciousness (i.e., state of alertness), one or more biomarkers of a mitochondrial disorder, and one or more biomarkers related to aging. Measuring any of the foregoing will be according to procedures known in the art.

[0612]

[0600] In embodiments, selecting a subject for treatment comprises an assessment. An “assessment” refers to any means or method used with a subject, before, during, after, or unrelated in time to administering a combination, to measure, estimate, or evaluate a nature, ability, symptom, disorder, or other characteristic, trait, or behavior of the subject, whether qualitatively or quantitatively, and whether performed by a clinician (e.g. , an interview), by the subject his or herself (e.g., a self-reported questionnaire), by a third-party, or by a computer, including a medical device (e.g., as such as defined by FDA or other regulatory body) or other device (e.g., medical sensor, biosensor, smartphone, watch, fitness tracker, “wearable”), and whether graded by a human decision-maker or by an artificial intelligence (Al), machine learning (ML), or computer algorithm. An assessment may be computer-assisted. A “computer-assisted” assessment includes any assessment comprising the use of a computer, device, and / or electronic tool such as an online tool or an app, such as a health app, and including any assessment contributing to or comprising the use of a digital phenotype.

[0613]

[0601] In embodiments, an assessment is a clinical assessment performed by a medical professional and / or a subject’s self-assessment of symptoms they wish to reduce or aspects of their general health and wellbeing they wish to improve. In embodiments, a subject is selected for treatment if an assessment indicates that the subject would benefit from treatment. Assessments may vary depending on the subject, including the medical condition(s) sought to be treated, or the aspects of health and wellbeing sought to be improved.

[0614]

[0602] In embodiments, a subject is selected for treatment if the subject has a condition, for example which the combinations and compositions are useful to treat. In embodiments, a subject is selected for treatment if the subject is at risk of a condition, for example which the combinations and compositions are useful to treat.

[0615]

[0603] A subject “at risk of’ a condition, such as a disease or a disorder, includes a subject with an increased risk of developing the condition, such as a 5%, 10%, 15%, 20% 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 700%, 800%, 900%, 1 ,000%, and greater than 1,000% increased risk, such as an increased relative risk, of developing the condition, of developing symptoms of the condition, or of being diagnosed with the condition. Exemplary methods of determining an increased risk, such as an increased relative risk, will be known in the art as they relate to a specific condition, such as a disclosed condition for which the disclosed combinations are useful.

[0616]

[0604] In embodiments, a combination is useful to treat a subject, e.g., to treat a subject with a condition.

[0617]

[0605] In embodiments, a combination is useful to treat a subject with a condition, where the condition is caused by or associated with any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels.

[0618]

[0606] In embodiments, the subject has mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels but does not have a condition caused thereby or associated therewith.

[0619]

[0607] In embodiments, a subject is selected for treatment if the subject has a medical condition. In embodiments, a subject is selected for treatment if the subject is at risk of a medical condition. In embodiments, a subject is selected for treatment if the subject has, or if the subject is at risk of, a medical condition, and the subject has any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels.

[0620]

[0608] “A medical condition,” for which a subject is, in embodiments, selected for treatment if the subject has, is at risk of, or has or is at risk of and also has any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels, can include any of, as non-limiting examples, as well as such other medical conditions described herein and known to be useful in disclosed embodiments by those in the art: (1) a mental, behavioral, or neurodevelopmental disorder; (2) a neurodegenerative disorder; (3) a mitochondrial disorder; (4) reduced cellular energy metabolism; (5) a mental health disorder; (6) Alzheimer’s disease.

[0621]

[0609] In embodiments, a subject is selected for treatment if she has a symptom, condition, or complication caused by or associated with any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels. In embodiments, a subject is selected for treatment if at risk of a symptom, condition, or complication caused by or associated with any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels.

[0622]

[0610] In embodiments, a subject is selected for treatment to improve a subject’s cognitive functioning. In embodiments, a subject is selected for treatment if the subject desires to improve their cognitive functioning and the subject has any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels.

[0623]

[0611] In embodiments, a subject is selected for treatment to increase the efficacy of another intervention. In embodiments, a subject is selected for treatment if the subject desires to increase the efficacy of another intervention and the subject has any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels.

[0624]

[0612] In embodiments, a subject is selected for treatment to slow the progression of aging. In embodiments, a subject is selected for treatment if the subject desires to to slow the progression of aging and the subject has any of mitochondrial dysfunction, reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, or NAD+ levels.

[0625]

[0613] In embodiments, a combination is useful to improve the health, healthspan, or lifespan of a subject. In embodiments, the improvement in the health, healthspan, or lifespan of the subject is caused by, or contributed to by, an increase in the overall mitochondrial energy of a subject, as a result of treatment. ii. Mental, Behavioral, and Neurodevelopmental Disorders

[0626]

[0614] In embodiments, a combination treats (in alternative embodiments, “treats” may be “is used to treat” or “is useful to treat”) a mental, behavioral, or neurodevelopmental disorder. In embodiments, a combination is administered (“administered” will be understood herein to also include “administered in a therapeutically effective amount”), to a subject having a mental, behavioral, or neurodevelopmental disorder, thereby treating the mental, behavioral, or neurodevelopmental disorder. In some methods herein, a combination, when administered, provides beneficial effects to treat a mental, behavioral, or neurodevelopmental disorder.

[0627]

[0615] The ICD-11, which is incorporated by reference herein in its entirety, defines “mental, behavioral, or neurodevelopmental disorders” as syndromes characterized by clinically significant disturbance in a subject's cognition, emotional regulation, or behavior that reflects a dysfunction in the psychological, biological, or developmental processes that underlie mental and behavioral functioning. Such disorders include, and in different embodiments a disclosed combination will be useful to treat, any of neurodevelopmental disorders, schizophrenia or other primary psychotic disorders, catatonia, mood disorders, anxiety or fear-related disorders, obsessive-compulsive or related disorders, disorders specifically associated with stress, dissociative disorders, feeding (or eating) disorders, elimination disorders, disorders of bodily distress or bodily experience, disorders due to substance use or addictive behaviors, impulse control disorders, disruptive behavior or dissocial disorders, personality disorders (and related traits), paraphilic disorders, factitious disorders, neurocognitive disorders, mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, sleep-wake disorders, sexual dysfunctions, and gender incongruence.

[0628]

[0616] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and / or behavior. Broadly, such disorders can be characterized by clinically significant disturbances in a subject's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering. Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11, or a subject with a diagnosis based thereon, it will be appreciated that disclosed methods are also applicable to subjects having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11 , ICD-10, DSM-5, or DSM-IV (all incorporated by reference herein in their entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the subject has not yet had a formal clinical diagnosis.

[0629]

[0617] In embodiments, a combination treats a mental health disorder. In embodiments, a combination is administered, such as in a therapeutically effective amount (meaning as shorthand that the agents are each administered in a therapeutically effective amount), to a subject having a mental health disorder, treating the mental health disorder. In embodiments, a combination, when administered in a therapeutically effective amount, provides beneficial therapeutic effects for the treatment of a mental health disorder. In embodiments, a combination is used to reduce the symptoms of a mental health disorder. Such symptoms will be able to be determined by one of skill, by reference to the general understanding in the art regarding any such disorder.

[0630]

[0618] In embodiments, the mental health disorder is any of disruptive mood dysregulation disorder, major depressive disorder (MDD), treatment resistant depression (TRD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, substance or medication-induced depressive disorder, post-partum depression, depressive disorder due to another medical condition, separation anxiety disorder, selective mutism, specific phobia, social anxiety disorder (social phobia), panic disorder, panic attack, agoraphobia, generalized anxiety disorder, substance-medication-induced anxiety disorder, anxiety disorder due to another medical condition, somatic symptom disorder, illness anxiety disorder (hypochondria), conversion disorder (functional neurological symptom disorder), factitious disorder, post-traumatic stress disorder (PTSD), adjustment disorders, trauma and stressor-related disorders, acute distress disorder, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania (hair-pulling) disorder, excoriation (skin-picking) disorder, substance or medication-induced obsessive-compulsive and related disorder, obsessive- compulsive and related disorder due to another medical condition, substance-related disorders, alcohol-related disorders, cannabis-related disorders, hallucinogen-related disorders, inhalant-related disorders, cocaine-related disorders, opioid-related disorders, sedative-, hypnotic-, or anxiolytic-related disorders, stimulant-related disorders, tobacco-related disorders, non-substance-related disorders (gambling disorder, gaming disorder, and other behavioral addictions), migraines, cluster headaches such as chronic cluster headaches, cyclical vomiting, tension-type headache, dysphasia, pica, anorexia nervosa, bulimia nervosa, binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, conduct disorder, antisocial personality disorder, psychopathy, pyromania, and kleptomania.

[0631]

[0619] Whether a subject has a condition, such as a mental health disorder, can be determined according to ordinary skill. A condition may be diagnosed after symptoms present. Examples of methods used to diagnose conditions include conducting a psychological evaluation (e.g., the Structured Clinical Interview for DSM-5); genetic testing (e.g., DNA testing) to detect known abnormalities that may be indicative of a disorder; a laboratory test (e.g., performing a blood test, a thyroid test); imaging (e.g., an X-ray, a MRI, a CT scan, an ultrasound); a trial of condition-specific medication useful in alleviating a symptom of a condition; a physical examination; family history information; observance of present symptoms; subject history information; and additional testing to exclude one or more similar conditions. Because a variety of conditions have overlapping or ambiguous symptoms, diagnosis may include a combination of these methods, and may include additional methods known in the art. The severity of a condition (mild, moderate, severe) is determined by ordinary skill.

[0632]

[0620] In embodiments, measures of therapeutic efficacy include reports by a subject or an observer. In embodiments, measures of therapeutic efficacy include responses to a questionnaire. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.

[0633]

[0621] In embodiments, a combination treats a neurodevelopmental disorder. In embodiments, a “neurodevelopmental disorder” is a neurological and / or cognitive disorder arising during the developmental period that involves significant difficulties in the acquisition and execution of specific neurological functions (e.g., intellectual, motor, language, or social functions). In embodiments, the neurodevelopmental disorder is a disorder of intellectual development, a developmental speech or language disorder, autism spectrum disorder, a developmental learning disorder, a developmental motor coordination disorder, attention deficit hyperactivity disorder, or stereotypic movement disorder. In embodiments, the neurodevelopmental disorder is autism spectrum disorder (ASD); cerebral palsy (CP); epilepsy; bipolar disorder; obsessive compulsive disorder (OCD); a disorder of communication, speech, or language; fetal alcohol syndrome / fetal alcohol effects (FAS / FAE); fragile X syndrome (FXS); William’s syndrome; or Down syndrome.

[0634]

[0622] In embodiments, a combination treats schizophrenia or another primary psychotic disorder. Broadly, such disorders can be characterized by significant impairments in reality and alterations in behavior manifest in positive symptoms like persistent delusions, persistent hallucinations, disorganized thinking and speech, grossly disorganized behavior, as well as experience of negative symptoms such as blunted or flat affect and avolition and psychomotor disturbances. In embodiments, a combination treats schizophrenia, schizoaffective disorder, schizotypal disorder, acute and transient psychotic disorder, delusional disorder, or a substance-induced psychotic disorder.

[0635]

[0623] In embodiments, a combination treats catatonia. In embodiments, “catatonia” refers to a category of syndromes characterized by the co-occurrence of several symptoms of decreased, increased, or abnormal psychomotor activity. In embodiments, the catatonia is associated with another mental disorder. In embodiments, the catatonia is induced by substances or medications.

[0636]

[0624] In embodiments, a combination treats a mood disorder. In the ICD-11, mood disorders are categorized by the specific types of mood episodes, and their pattern over time. The primary types of mood episodes are depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder. In embodiments, the mood disorder is a depressive disorder. In embodiments, the depressive disorder is single-episode depressive disorder, major depressive episode disorder, persistent depressive disorder (formally known as dysthymia), disruptive mood dysregulation disorder, premenstrual dysphoric disorder, postpartum depression, substance / medication-induced depressive disorder, depressive disorder due to another medical condition, seasonal affective disorder, mixed depressive and anxiety disorder, or an unspecified depressive disorder.

[0637]

[0625] In embodiments, a combination treats an anxiety or fear-related disorder. Broadly, such disorders can be characterized by excessive or abnormal fear, dread, or worry. In embodiments, the anxiety disorder is any of generalized anxiety disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, and a substance-induced anxiety disorder.

[0638]

[0626] In embodiments, a combination treats an obsessive-compulsive or related disorder. Broadly, such disorders can be characterized by repetitive thoughts and behaviors, such as cognitive phenomena (obsessions, intrusive thoughts and preoccupations). In embodiments, the disorder is characterized by a compulsive need to accumulate possessions and distress related to discarding them (hoarding disorder). In embodiments, the disorder is body-focused and can be characterized by recurrent and habitual actions (hair-pulling, skin-picking). In embodiments, the disorder is obsessive-compulsive disorder (OCD), body dysmorphic disorder, olfactory reference disorder, hypochondriasis, hoarding disorder, a body-focused repetitive behavior disorder, or a substance-induced OCD.

[0639]

[0627] In embodiments, a combination treats a disorder associated with stress. A disorder associated with stress generally has an identifiable stressor that is a causal factor, like exposure to a stressful or traumatic event, or a series of such events or adverse experiences. Stressors may be within the normal range of life experiences (e.g., divorce, socio economic problems), or from a threatening or traumatizing experience. In general, the nature and duration of the symptoms that arise in response to the stressor can distinguish the disorder from everyday stress. In embodiments, a combination treats PTSD, complex PTSD, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.

[0640]

[0628] In embodiments, a combination treats a dissociative disorder. Broadly, such disorders can be characterized by involuntary disruption or discontinuity in the normal integration of one or more of the following: identity, sensations, perceptions, affects, thoughts, memories, control over body movements, or behavior. Dissociative disorder symptoms can be severe, and may result in impairment in personal, social, educational, occupational or other areas of functioning. In embodiments, a combination treats dissociative neurological symptom disorder, dissociative amnesia (including amnesia with dissociative fugue and without dissociative fugue), trance disorder, possession trance disorder, dissociative identity disorder, partial dissociative identity disorder, or depersonalization-derealization disorder.

[0641]

[0629] In embodiments, a combination treats a feeding or eating disorder. Broadly, such disorders can be characterized abnormal eating or feeding behaviors that are not explained by another health condition, and are not developmentally appropriate or culturally sanctioned. These disorders can involve preoccupation with food as well as body weight and shape concerns. In embodiments, a combination treats anorexia nervosa (including anorexia with significantly low body weight, anorexia with dangerously low body weight, or anorexia in recovery with normal body weight), bulimia nervosa, binge eating disorder, avoidant-restrictive food intake disorder, pica, or rumination-regurgitation disorder.

[0642]

[0630] In embodiments, a combination treats an elimination disorder. Elimination disorders include, for example, the repeated voiding of urine into clothes or bed, and the repeated passage of feces in inappropriate places once the subject has reached a developmental age when continence is ordinarily expected. In embodiments, a combination treats enuresis (including nocturnal enuresis, diurnal enuresis, and nocturnal and diurnal enuresis) or encopresis (including both with encopresis constipation or overflow incontinence, and encopresis without constipation or overflow incontinence).

[0643]

[0631] In embodiments, a combination treats a disorder of bodily distress or bodily experience. Broadly, such disorders can be characterized by bodily symptoms a subject finds distressing and to which the subject devotes excessive attention, including disturbances in the subject’s experience of the body manifested by persistent discomfort or intense feelings of body configuration. In embodiments, a combination treats a bodily distress disorder (including mild, moderate, and severe bodily distress disorder) or body integrity dysphoria.

[0644]

[0632] In embodiments, a combination treats a disorder due to substance use or addictive behaviors. Disorders due to substance use or addictive behaviors are mental and / or behavioral disorders that develop predominantly as a result of the use of psychoactive substances (including medications and illegal or illicit substances), or specific repetitive rewarding and reinforcing behaviors. In embodiments, a combination treats disorders due to substance use (i.e., a substance use disorder, or SUD). In embodiments, the substance use disorder (SUD) is associated with alcohol, cannabis, synthetic cannabinoids, opioids, sedatives, hypnotics or anxiolytics, cocaine, stimulants (e.g., amphetamines, methamphetamines, methcathinone, synthetic cathinones, caffeine), hallucinogens, nicotine, volatile inhalants, MDMA or MDA, dissociative drugs like ketamine and phencyclidine, or another substance (including medications and non-psychoactive substances). In embodiments, the SUD is selected from alcohol use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalants use disorder, opioids use disorder, sedatives use disorder, hypnotics use disorder, anxiolytics use disorder, stimulants use disorder, and tobacco use disorder. In embodiments, the SUD is alcohol use disorder, wherein the alcohol use disorder is selected from alcohol abuse, alcohol dependence, and alcoholism. In embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder). In embodiments, a SUD can be screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OUD (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS).

[0645]

[0633] In embodiments, a combination treats an impulse control disorder. Broadly, such disorders can be characterized by the repeated failure to resist an impulse, drive, or urge to perform an act that is rewarding to the subject despite negative long-term consequences, such as harm to the subject or a significant impairment in important areas of the subject’s functioning. In embodiments, impulse control behaviors include fire-setting, stealing, inappropriate sexual behavior, and explosive outbursts. In embodiments, a combination treats pyromania, kleptomania, compulsive sexual behavior disorder, or intermittent explosive disorder.

[0646]

[0634] In embodiments, a combination treats a disruptive behavior disorder or a dissocial disorder. Broadly, such disorders can be characterized by persistent behavior problems ranging from persistently defiant, disobedient, provocative or spiteful behaviors to behaviors violating the rights of others or norms, rules, or laws. In embodiments, a combination treats oppositional defiant disorder, oppositional defiant disorder with chronic irritability-anger, oppositional defiant disorder without chronic irritability-anger, conduct-dissocial disorder, childhood-onset conduct-dissocial disorder, or adolescent-onset conduct-dissocial disorder.

[0647]

[0635] In embodiments, a combination treats a personality disorder. Broadly, such disorders can be characterized by problems in perceiving one’s identity, self-worth, accuracy of self-view, and self- discretion manifest in patterns of cognition, emotional experience, emotional expression, and maladaptive behavior. In embodiments, a combination treats a mild, moderate, or severe personality disorder. In embodiments, a combination treats a prominent personality trait or patterns (e.g., negative affectivity, detachment, dissociality, disinhibition, anankastia, borderline pattern). In embodiments, the personality disorder is antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.

[0648]

[0636] In embodiments, a combination treats a paraphilic disorder. Broadly, such disorders can be characterized by persistent and intense patterns of atypical sexual arousal, the focus of which involves others whose age or status renders them unwilling or unable to consent. In embodiments, a combination treats exhibitionistic disorder, voyeuristic disorder, pedophilic disorder, coercive sexual sadism disorder, frotteuristic disorder, other paraphilic disorders involving non-consenting individuals, or paraphilic disorders involving solitary behavior or consenting individuals.

[0649]

[0637] In embodiments, a combination treats a factitious disorder. Broadly, such disorders can be characterized by intentionally feigning, falsifying, inducing or aggravating medical, psychological, or behavior signs and symptoms or injury in oneself or in another person. Subjects with factitious disorders may seek treatment or otherwise present themselves or another person as ill, injured, or impaired. In embodiments, a combination treats factitious disorder imposed on self or a factitious disorder imposed on another.

[0650]

[0638] In embodiments, a combination treats a neurocognitive disorder. Broadly, such disorders can be characterized by primary clinical defects in cognitive functioning that are acquired (rather than developmental), and thus the subject experiences a decline from a previously attained level of functioning. In embodiments, a combination treats delirium. In embodiments, the delirium is associated with another disease or disorder. In embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a combination treats mild neurocognitive disorder. In embodiments, a combination treats an amnestic disorder. In embodiments, the amnestic disorder is associated with another disease or disorder. In embodiments, the delirium is associated with a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a combination treats dementia. In embodiments, the dementia is associated with Alzheimer’s disease (AD), Parkinson’s disease, cerebrovascular disease, Lewy body disease, a psychoactive substance (including medications and illicit or illegal substances). In embodiments, a combination treats a behavioral or psychological disturbance associated with dementia. In embodiments, dementia is assessed using a Functional Activities Questionnaire (FAQ), Ascertain Dementia 8 (AD8), Mini-Cog, Mini-Mental State Exam (MMSE), the Montreal Cognitive Assessment (MoCA), and the Neuropsychiatric Inventory Questionnaire (NPI-Q).

[0651]

[0639] In embodiments, a combination treats a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium. Broadly, such disorders can be characterized by significant mental and behavioral features, including depressive symptoms. In embodiments, the disorder includes psychotic symptoms. In embodiments, a combination treats mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, with psychotic symptoms. In embodiments, a combination treats mental or behavioral disorders associated with pregnancy, childbirth or the puerperium, without psychotic symptoms.

[0640] In embodiments, a combination treats a sleep-wake disorder. Broadly, such disorders can be characterized by difficulty initiating or maintaining sleep (e.g., insomnia), excessive sleepiness (e.g., hypersomnolence disorders), respiratory disturbance during sleep (e.g., sleep-related breathing disorders (SRBDs), such as obstructive sleep apnea (OSA), central sleep apnea (CSA), sleep-related hypoventilation disorders, sleep-related hypoxemia disorder, snoring, catathrenia, Cheyne-Stokes breathing, and sleep-disordered breathing), disorders of the sleep-wake schedule (e.g., circadian rhythm sleep-wake disorders), abnormal movements during sleep, or problematic behavioral or psychological events that occur while falling asleep, during sleep, or upon arousal from sleep (e.g., parasomnia disorders). In embodiments, a combination treats an insomnia disorder, a hypersomnolence disorder, a sleep-related breathing disorder, a circadian rhythm sleep-wake disorder, or a parasomnia disorder.

[0652]

[0641] In embodiments, a combination treats a sexual dysfunction. Broadly, such disorders can be characterized by the difficulty of a subject experiencing personally satisfying, non-coercive sexual activities. In embodiments, a combination treats hypoactive sexual desire disorder, sexual arousal dysfunction, orgasmic dysfunction, ejaculatory dysfunction, or sexual dysfunction associated with pelvic organ prolapse. iii. Neurodegenerative Disorders

[0653]

[0642] In embodiments, a combination treats a neurodegenerative disorder. In embodiments, a combination is administered to a subject having a neurodegenerative disorder, thereby treating the mental health disorder. In embodiments, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a neurodegenerative disorder.

[0654]

[0643] The term “neurodegenerative disorder” refers to a class of progressive, chronic, and debilitating conditions characterized by the gradual loss of structure and function of neurons within the central nervous system (CNS) or peripheral nervous system (PNS). These disorders involve the degeneration, impairment, or death of neuronal cells, leading to a decline in cognitive, motor, and / or sensory abilities.

[0655]

[0644] Neurodegenerative disorders can be classified according to primary clinical features, e.g., dementia, parkinsonism, or motor neuron disease, anatomic distribution of neurodegeneration, e.g., frontotemporal degenerations, extrapyramidal disorders, or spinocerebellar degenerations, or principal molecular abnormality (Dugger B, Dickson DW. Cold Spring Harbor Perspectives in Bio. 2017;9(7):a028035). These disorders may involve various etiologies, such as the presence of pathogenic proteins, age, environmental stressors, and genetic predisposition (Armstrong R. Folia Neuropathologica. 2020;58(2):93-112).

[0656]

[0645] In embodiments, the neurodegenerative disorder is selected from the group consisting of Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) or Charcot’s disease, chronic traumatic encephalopathy (CTE), corticobasal degeneration, dementias including vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment (MCI), multiple sclerosis (MS), a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease (PD) or parkinsonisms, prion diseases, progressive supranuclear palsy, and traumatic brain injury (TBI) or mild traumatic brain injury (mTBI).

[0657]

[0646] In embodiments, a combination treats Alzheimer’s disease (AD). AD is a neurodegenerative disease characterized by a progressive, inexorable loss of cognitive function (Francis et al. Neurosci Res. 1999;57:487-94). AD is the most common form of dementia related to age, and a serious health problem; it is a leading cause of death in the U.S.. Individuals afflicted with AD may exhibit diminished oxidative phosphorylation, a gradual decline in cerebral metabolic rates of glucose, reduced adenosine triphosphate production, and heightened generation of ROS, and generally may have compromised mitochondrial function (Lanzillota et al. CNS Drugs. 2019;33(10):857-969). In embodiments, methods that improve mitochondrial function, such as administration of disclosed combinations, are particularly efficacious for treating AD. iv. Mitochondrial Disorders

[0658]

[0647] In embodiments, a combination treats a mitochondrial disorder. A “mitochondrial disorder” is a disease caused by impairment of one or more mitochondrial functions, especially of the mitochondrial respiratory chain. Mitochondrial disorders are heterogenous (e.g., different underlying factors lead to the disease) and often multisystemic (e.g., affecting multiple body systems), as mitochondria are present in all tissues of the body, except mature red blood cells (Orsucci et al. Drugs Context. 2019;8:212588). Because mitochondria provide much of the energy for the cell, mitochondrial disorders preferentially affect tissues with high energy demand, including the brain, muscle, and heart, although any organ (including liver, nerves, kidneys, eyes, pancreas, bone marrow, etc.) can be affected (id.). Mitochondrial defects are implicated in forms of stroke, increased risk of infection, pancreatic failure, liver failure, kidney disease, blindness, deafness, dementia, cardiomyopathy, myopathy, renal dysfunction, gastrointestinal conditions, ptosis, and aging, among others (id.). Mitochondrial dysfunction also can lead to telomere shortening, oxidative stress, apoptosis and inflammasome activation (see Barnes et al. Meeh Ageing Dev. 2019; 177:37-45).

[0659]

[0648] Whether a subject has a mitochondrial disorder can be determined according to ordinary skill. Mitochondrial disorders can be diagnosed after symptoms present. Examples of methods used to diagnose mitochondrial disorders include genetic testing (e.g., DNA testing) to detect known abnormalities that may be indicative of a mitochondrial disorder; a metabolic examination, which may include testing of blood, urine, and cerebrospinal fluid; a trial of condition-specific medication useful in alleviating a symptom of a condition; nuclear imaging; an X-ray; family history information; measuring concentrations of plasma, CSF lactate, glucose, and pyruvate; a physical examination; a neurologic evaluation; a cardiac evaluation; magnetic resonance imaging (MRI) or spectroscopy (MRS) for neurological symptoms; a retinal exam or electroretinogram (ERG) for vision symptoms; an electrocardiogram (EKG) or echocardiogram (echo) for symptoms affecting the heart; an audiogram for hearing symptoms; an electroencephalogram (EEG) for seizures and related brain issues; computerized tomography (CT); neuroimaging; a biopsy; biochemical testing; neurophysiologic studies; observance of present symptoms; subject history information; and additional testing to exclude one or more similar conditions. Because a variety of diseases and conditions have symptoms characteristic of one or more mitochondrial disorders, diagnosis may include a combination of the aforementioned methods, and may include additional methods known to those of skill.

[0660]

[0649] In embodiments, the mitochondrial disorder is any of myopathy with exercise intolerance; eyelid ptosis; ophthalmoparesis; pigmentary retinopathy; sensorineural hearing loss; hypertrophic cardiomyopathy; migraine disorder; mitochondrial disease NOS; chronic fatigue immunity deficiency syndrome (CFIDS); myalgic encephalomyelitis (ME); chronic fatigue syndrome (CFS); demyelination due to mitochondrial disease; mitochondrial cytopathy; a liver disease due to a mitochondrial disorder; a disorder of mitochondrial oxidative phosphorylation; a mitochondrial DNA depletion syndrome; an unspecified disorder of mitochondrial oxidative phosphorylation; a multiple mitochondrial DNA deletion syndrome; a mitochondrial protein translation defect; a mitochondrial myopathy (e.g., an unspecified mitochondrial myopathy, an other specified mitochondrial myopathy); a glomerular disease associated with a mitochondrial disease; mitochondrial diabetes; myoclonus due to a mitochondrial cytopathy; a disorder of mitochondrial membrane transport (e.g., a mitochondrial substrate carrier disorder; an unspecified mitochondrial substrate carrier disorder; an other specified mitochondrial substrate carrier disorder, a mitochondrial protein import disorder); epilepsy due to a mitochondrial disorder; an intestinal congenital motility disorder due to a mitochondrial disease; mitochondrial ocular myopathy; congenital muscular dystrophy with mitochondrial structural abnormalities; a disorder of mitochondrial fatty acid oxidation; ataxia due to a mitochondrial mutation; mitochondrial isocitrate dehydrogenase deficiency; chorea due to mitochondriopathy; mitochondrial thiamine pyrophosphate carrier deficiency; dystonia due to a mitochondrial cytopathy; dilated cardiomyopathy due to a mitochondrial myopathy; mitochondrial disease with hypertrophic cardiomyopathy; mitochondrial myopathy with sideroblastic anemia; and mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency, potassium-stimulated.

[0661]

[0650] In embodiments, a therapeutic combination treats a secondary mitochondrial disorder. A “secondary mitochondrial disorder” includes a genetic or non-genetic disorder where: (a) a mitochondrial mechanism is a secondary feature; (b) the genetic or non-genetic disorder leads to mitochondrial dysfunction; or (c) the genetic or non-genetic disorder results from a primary mitochondrial disorder or mitochondrial dysfunction. A secondary mitochondrial disorder can be caused by genes encoding neither function nor production of the oxidative phosphorylation proteins and accompanies many hereditary non-mitochondrial diseases (Niyazov et al. Mol Syndromol. 2016 Jul; 7(3): 122-137), or may be due to non-genetic causes, such as environmental factors, which can cause oxidative stress (id.). In embodiments, the secondary mitochondrial disorder is any of Wolfram syndrome; muscular dystrophy; Alzheimer’s disease; Charcot-Marie-Tooth disease; 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome (MEGDEL); myopathic carnitine deficiency; early infantile epileptic deficiency; sensorineural hearing loss or deafness; hyperornithinemia-hyperammonemia-homocitrullinuria syndrome (HHH syndrome); 3-methylglutaconic aciduria; a carnitine palmitoyltransferase deficiency; ophthalmoplegic neuromuscular disorder with abnormal mitochondria; pyruvate carboxylase deficiency; reticular dysgenesis; cardiomyopathy; infantile mitochondrial striatonigral degeneration; retinitis pigmentosa-deafness syndrome; infantile cerebellar-retinal degeneration; muscle atrophy; a deficiency in mitochondrial import-stimulating factor; cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS) syndrome; and a mitochondrial HMG-CoA synthase-2 deficiency. v. Conditions Caused by or Associated with Mitochondrial Dysfunction

[0662]

[0651] In embodiments, a subject has a condition and a mitochondrial dysfunction. In embodiments, a subject has a condition, wherein the condition is caused by or associated with mitochondrial dysfunction.

[0663]

[0652] In embodiments, a subject has a mental, behavioral, or neurodevelopmental disorder and mitochondrial dysfunction. In embodiments, a subject has a mental health disorder and mitochondrial dysfunction. In embodiments, a subject has a neurodevelopmental disorder and mitochondrial dysfunction. In embodiments, a subject has schizophrenia or another primary psychotic disorder and mitochondrial dysfunction. In embodiments, a subject has catatonia and mitochondrial dysfunction. In embodiments, a subject has a mood disorder and mitochondrial dysfunction. In embodiments, a subject has anxiety or a fear-related disorder and mitochondrial dysfunction. In embodiments, a subject has obsessive- compulsive or related disorder and mitochondrial dysfunction. In embodiments, a subject has a disorder associated with stress and mitochondrial dysfunction. In embodiments, a subject has a dissociative disorder and mitochondrial dysfunction. In embodiments, a subject has a feeding or eating disorder and mitochondrial dysfunction. In embodiments, a subject has an elimination disorder and mitochondrial dysfunction. In embodiments, a subject has a disorder of bodily distress or bodily experience and mitochondrial dysfunction. In embodiments, a subject has a disorder due to substance use or addictive behaviors and mitochondrial dysfunction. In embodiments, a subject has an impulse control disorder and mitochondrial dysfunction. In embodiments, a subject has a disruptive behavior disorder or a dissocial disorder and mitochondrial dysfunction. In embodiments, a subject has a personality disorder and mitochondrial dysfunction. In embodiments, a subject has a paraphilic disorder and mitochondrial dysfunction. In embodiments, a subject has a factitious disorder and mitochondrial dysfunction. In embodiments, a subject has a neurocognitive disorder and mitochondrial dysfunction. In embodiments, a subject has a mental or behavioral disorder associated with pregnancy, childbirth, or the puerperium and mitochondrial dysfunction. In embodiments, a subject has a sleep-wake disorder and mitochondrial dysfunction. In embodiments, a subject has a sexual dysfunction and mitochondrial dysfunction. In embodiments, a subject has a neurodegenerative disorder and mitochondrial dysfunction. In embodiments a subject has Alzheimer’s disease and mitochondrial dysfunction.

[0664]

[0653] In embodiments, a condition, such as any above condition, the condition of a subject for which a combination is administered to the subject to treat, or for which a combination is useful to treat, is caused by or associated with mitochondrial dysfunction. In embodiments, the condition is caused by or associated with reduced cellular energy metabolism. In embodiments, the condition is caused by or associated with reduced mitochondrial biosynthesis. In embodiments, the condition is caused by or associated with reduced ATP production. In embodiments, the condition is caused by or associated with reduced NAD / NAD-t / NADH levels. c. Improving General Wellness, Longevity, and Cognition

[0665]

[0654] In embodiments, a subject is administered a combination to improve and / or promote general wellness. In embodiments, a combination promotes general health and wellness and is administered whether or not a subject has or is diagnosed with a condition, and need not treat a condition, or any symptom thereof.

[0655] In embodiments, a subject is a healthy person who does not have a condition (e.g. , a subject without symptoms of or a diagnosis of a condition). In embodiments, a combination is administered to a healthy subject (a “healthy normal,” such as where a combination is for the betterment of the well), to improve the cognition, longevity, and / or overall wellbeing of the subject. In embodiments, a combination is administered to a subject with a condition to improve the cognition, longevity, and / or overall wellbeing of the subject.

[0666]

[0656] In embodiments, a disclosed combination is useful for improving the overall wellbeing of a subject. “Wellbeing” refers to a positive state of health or comfort, e.g., relative to a reference population. As used herein “mental wellbeing” refers to a positive mental state, as understood or as relative to a reference population. For example, in a subject experiencing depression (whether or not medically diagnosed, or rising to the level of a clinical diagnosis), low self-esteem, addiction, compulsion, or anxiety may experience an improvement in mental wellbeing in response to therapy aimed at improving mood, self-esteem, addiction, compulsion, or anxiety, respectively. Herein, “physical wellbeing” refers to one or more positive aspects of a subject's physical health. An improvement of physical wellbeing includes alleviation of somatic symptoms associated with a psychological disorder, depression, addiction, compulsion, anxiety, or sexual dysfunction, as well as chronic pain, pain disorder, relational disorder, body dysmorphia, conversion (e.g., loss of bodily function due to anxiety), hysteria, neurological conditions without identifiable cause, or psychosomatic illness.

[0667]

[0657] In embodiments, improving general health and wellness comprises improving one’s general physical and mental health, such that one has a heightened consciousness, improved mood, a more positive outlook on one’s life and personal situation, improved gut health, increased regularity, reduced joint pain, increased stamina, better social connectedness, deeper and more restive sleep, spiritual connectedness, empathy, compassion, increase pleasure, increase the desire for physical activity, promote a feeling of comfort / calm in challenging circumstances, and other general wellness improvements, as would be known to those of skill.

[0668]

[0658] In embodiments, improving general health and wellness comprises stimulation of intracellular pathways that trigger expression of genes involved in healthy longevity, such as the genes involved in the production of new mitochondria (Nrfl and Tfam) and the genes that code for antioxidants (Cat and Sod2).

[0669]

[0659] In embodiments, a subject is administered a combination to improve at least one cognitive ability, including improvements in any general mental capability such as those involving reasoning, problem solving, planning, abstract thinking, complex idea comprehension, and learning from experience, and also including, e.g., perception, such as visual and auditory perception; attention, such as focused, sustained, and divided attention; memory, such as short term, working, long-term, visual, and auditory memory; logical reasoning, such as deductive and inductive reasoning; and creativity, such as spontaneous and deliberate creativity.

[0670]

[0660] In embodiments, improving longevity and cognitive enhancement may be determined via outcome measures, endpoints, effect measures, and measures of effect within clinical or medical practice or research which can be used to assess an effect (positive and / or negative) of an intervention or treatment.

[0671]

[0661] In embodiments, administering a combination improves any of a subject’s mood, focus, creativity, performance (such as performance at one’s work), sociability, energy, or pain management. In some such embodiments, a combination is therefore “useful” without reference to the treatment of a medical condition.

[0672]

[0662] In embodiments, measures of therapeutic efficacy include reports by a subject or an observer.

[0673]

[0663] In embodiments, administering a combination enhances the benefits, including cognitive benefits, of treatment with a serotonergic psychedelic, including by providing mitochondrial energy, maintaining an optimal glucose concentration, and reducing or preventing mitochondrial oxidative damage.

[0674]

[0664] In embodiments, a treatment regimen further comprises providing a subject with a lifestyle modification. Lifestyle modifications useful in disclosed embodiments can include for a subject any one or more of, dietary changes (e.g., restricting consumption of overly processed food), product choice changes, limiting alcohol or other substances, smoking cessation, stress management, physical activity such as running, yoga, cycling, pilates, tennis, or walking (e.g., a certain number of minutes per week), flexibility work such as stretching, mindfulness, therapy, monitoring sleeping patterns, and increasing water consumption.

[0675]

[0665] In embodiments, a combination is administered together with therapy, such as psychosocial or behavioral therapy, including any of (or adapted from any of) cognitive behavioral therapy (Crits-Christoph et al, Archives Gen Psych. 1999;56(6):493-502), interpersonal therapy (Rounsaville et al., Am J Drug Alcohol Abuse. 1985; 11 (3-4): 171 -191), contingency management based therapy (Barry et ai., Psych Addictive Behav. 2009;23(1): 168-174; Petry et al., J Consult Clin Psych. 2005;73(2):354-59; Adams et al., Case Reports Psych. 2012;731638), motivational interviewing based therapy (Stotts et al. J Consult Clin Psych. 2001 ;69(5): 858-62), meditation based therapy, such as transcendental meditation based therapy (Rohsenowet al. J Consult Clin Psych. 2000;68(3):515-52), or the therapeutic approach of MAPS for PTSD subjects (Mithoefer et al. A Manual for MDMA-Assisted Psychotherapy in the Treatment of PTSD. Santa Cruz MAPS; 2017).

[0676]

[0666] In embodiments, a subject will engage in one or more therapeutically beneficial activities as an adjunct to administration of a combination, where such activities can be together with administration of the combination, including breathing exercises, meditation and concentration practices, focusing on an object or mantra, listening to music, physical exercise, stretching or bodywork, journaling, grounding techniques, positive self-talk, engaging with a pet or animal, and the like, and which may be with or without a facilitator.

[0677]

[0667] In embodiments, administration of a combination increases the benefits received by a subject engaging in therapy, including psychedelic-assisted therapy (PAT). In embodiments, administration of a combination increases the benefits received by a subject engaging in a therapeutically beneficial activity.

[0678]

[0668] In embodiments, a combination provides an ATP “brain boost,” by providing any of the benefits or enhancements above, such as by improving or promoting general wellness and cognitive enhancement. d. Outcome Measures

[0679]

[0669] In embodiments, measures of therapeutic effect include outcome measures, endpoints, effect measures, and measures of effect within clinical or medical practice or research which can be used to assess an effect (positive or negative) of an intervention or treatment, whether subject-reported (e.g., questionnaires); based on other subject data (e.g., subject monitoring); gathered through laboratory tests such as from blood or urine; through medical examination by a doctor or medical professional, or by digital means, such as using electronic tools like online tools, smartphones, wireless devices, biosensors, or apps.

[0680]

[0670] “Outcome measure” may refer to data collected that is related to the treatment of a subject. An outcome measure may include one or more physiological measures, one or more subject- or patientcentered outcome measures (either as shorthand, a PCOM), or one or more behavioral factor measures.

[0681]

[0671] A measure may be a physiological measure. A physiological measure monitors the physical reaction of a subject (e.g., reduction in a symptom of a medical condition). A measure may be a PCOM. A PCOM is an assessment of a subject’s beliefs, opinions and needs in relation to their treatment (e.g., subject-reported negative or positive effects relating to a medical condition). A measure may be a behavioral factor measure, such as a measure of specific subject behaviors (e.g., behaviors affected or caused by a medical condition).

[0682]

[0672] In embodiments, measures of therapeutic effect may be measured by monitoring or self-monitoring of a subject. In embodiments, the result of a disclosed method is measured by monitoring the number or content of paper diaries submitted by a subject. In embodiments, the result of a method is measured by monitoring the number or content of Internet-based diaries submitted by a subject. In embodiments, the result of a disclosed method is measured by monitoring the scores on a survey taken by a subject. In embodiments, the result of a disclosed method is measured by monitoring an available database wherein a subject tracks improvements related to a medical condition, or improvements related to overall health, wellness, consciousness, or cognition. In embodiments, the result of a disclosed method is measured by monitoring use of current technology, such as smartphones with applications that track improvements related to a medical condition, or improvements related to overall health, wellness, consciousness, or cognition.

[0683]

[0673] In embodiments, a measure of therapeutic effect, which may be an outcome measure, includes an assessment. “Assessment” refers to any method used with a subject, whether before, during, after, or unrelated in time to treatment, to measure, estimate, or evaluate a nature, ability, symptom, disorder, or other characteristic of the subject, qualitatively or quantitatively, and whether by a clinician (e.g., an interview), by a subject (e.g., a self-reported questionnaire), by a third-party, or by a computer, including a medical device or other device (e.g., a medical sensor or biosensor, a watch or fitness tracker, or a “wearable”), and whether graded by a human or Al decision-maker, and whether or not regulated as software as a medical device.

[0684]

[0674] An assessment may be computer-assisted, and other computer-assisted assessments may be performed besides the assessments above. “Computer-assisted” in “computer-assisted assessment” means an assessment comprising the use of an electronic tool such as an online tool, smartphone, wireless device, or health app (including any aspect of “digital phenotyping”). Computer- assisted assessments include use of an electronic psychiatric notes system, where clinical information is recorded, such as by a therapist interacting with a subject, and includes use of a computer where a therapist and a subject interact virtually (synchronously or asynchronously), and where a subject only interacts with a computer (“computer” broadly meaning any suitable electronic tool, such as desktop, laptop, and notebook computers; tablets, smartphones, and mobile devices; watches, fitness trackers, personal electronic devices; and the like).

[0685]

[0675] In embodiments, an improvement in a subject is measured, determined, and / or monitored using an outcome measure. In embodiments, the outcome measure is a comparison between a measurement at a time following initiation of treatment and a baseline (e.g., prior to treatment with a combination). A change represented in or by an outcome measure may be referred to herein as an “improvement,” and the improvement may be an increase, a reduction, a pace of change, a rate of change (e.g., a faster increase, a faster reduction, a slower increase, a slower reduction, or a higher level of stability or resistance to change), or another measurement of “improvement” as will be known in view of the art and the teachings herein.

[0686]

[0676] Several exemplary outcome measures follow, and their determination will be known in view hereof.

[0687]

[0677] In embodiments, the outcome measure is a change in the number of symptoms of a condition. In embodiments, the outcome measure is a reduction in the number of symptoms of a condition. In embodiments, the outcome measure is a reduction in one or more symptoms of the condition, such as two symptoms of the condition, three symptoms of the condition, four symptoms of the condition, five symptoms of the condition, and greater than five symptoms of the condition. In embodiments, the subject’s number of symptoms experienced are compared to their baseline number of symptoms experienced, for a period of time after administration, i.e., after administering a therapeutic combination. A “period of time after administration” herein will include a period of 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, and longer than 12 months. In embodiments, the subject’s number of symptoms is improved by at least a % amount compared to the subject's baseline number of symptoms. “By at least a % amount compared to” herein will include an amount of at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 100% compared to, for example, the subject’s baseline. “Baseline” as in “baseline number of symptoms,” may refer to, for example, a measurement or assessment taken at the start of treatment, or at a time prior to administering the therapeutic combination.

[0688]

[0678] In embodiments, the outcome measure is a change in the severity of one or more symptoms of a condition. In embodiments, the severity of one or more symptoms are compared to a subject’s baseline severity, for a period of time after administration. In embodiments, the subject’s severity of one or more symptoms is improved by at least a % amount compared to the subject's baseline severity of the symptom(s).

[0689]

[0679] In embodiments, the outcome measure is a change in a subject’s mitochondrial function. In embodiments, the subject’s mitochondrial function is compared to their baseline mitochondrial function, for a period of time after administration. In embodiments, the subject’s mitochondrial function is improved by at least a % amount compared to the subject's baseline mitochondrial function.

[0690]

[0680] In embodiments, the outcome measure is a change in a subject’s metabolic enzyme activity. In embodiments, the subject’s metabolic enzyme activity is compared to their baseline metabolic enzyme activity, for a period of time after administration. In embodiments, the subject’s metabolic enzyme activity is improved by at least a % amount compared to the subject's baseline activity.

[0691]

[0681] In embodiments, the outcome measure is a change in a subject’s adenosine triphosphate (ATP) production. In embodiments, the subject’s ATP production is compared to their baseline ATP production, for a period of time after administration. In embodiments, the subject’s ATP production is improved by at least a % amount compared to the subject's baseline ATP production.

[0692]

[0682] In embodiments, the outcome measure is a change in a subject’s intracellular adenosine triphosphate (ATP) level. In embodiments, the subject’s intracellular ATP level is compared to their baseline intracellular ATP level, for a period of time after administration. In embodiments, the subject’s intracellular ATP level is improved by at least a % amount compared to the subject's baseline intracellular ATP level.

[0693]

[0683] In embodiments, the outcome measure is a change in a subject’s astrocyte ATP levels. In embodiments, the subject’s astrocyte ATP levels are compared to their baseline astrocyte ATP levels, for a period of time after administration. In embodiments, the subject's astrocyte ATP levels are improved by at least a % amount compared to the subject's baseline astrocyte ATP levels.

[0694]

[0684] In embodiments, the outcome measure is a change in a subject’s neurosphere ATP levels. In embodiments, the subject’s neurosphere ATP levels are compared to their baseline neurosphere ATP levels, for a period of time after administration. In embodiments, the subjects neurosphere ATP levels are improved by at least a % amount compared to the subject's baseline levels.

[0695]

[0685] In embodiments, the outcome measure is a change in a subject’s neuronal ATP levels. In embodiments, the subject’s neuronal ATP levels are compared to their baseline neuronal ATP levels, for a period of time after administration. In embodiments, the subject’s neuronal ATP levels are improved by at least a % amount compared to the subject's baseline neuronal ATP levels.

[0696]

[0686] Measuring increases in ATP production and ATP levels can be performed according to techniques known in the art, such as those described in the Examples below.

[0697]

[0687] In embodiments, the outcome measure is a change in a subject’s nicotinamide adenine dinucleotide levels (i.e., NAD, NAD+, and NADH). In embodiments, the subjects NAD, NADH, and NAD+ levels are compared to their baseline NAD, NADH, and NAD+ levels, for a period of time after administration. In embodiments, one or more of the subject’s NAD, NADH, and NAD+ levels are improved by at least a % amount compared to the subject's baseline NAD, NADH, and NAD+ levels.

[0698]

[0688] In embodiments, the outcome measure is a change in a subject’s maximal oxygen (02) uptake. In embodiments, the subject’s maximal oxygen uptake is compared to their baseline maximal oxygen uptake, for a period of time after administration. In embodiments, the subject’s maximal oxygen uptake is improved by at least a % amount compared to the subject's baseline maximal 02 uptake.

[0699]

[0689] In embodiments, the outcome measure is a change in a subject’s mitochondrial respiration. In embodiments, the subject’s mitochondrial respiration is compared to their baseline mitochondrial respiration, for a period of time after administration. In embodiments, the subject’s mitochondrial respiration is improved by at least a % amount compared to the subject's baseline mitochondrial respiration.

[0700]

[0690] In embodiments, the outcome measure is a change in a subject’s mitochondrial membrane potential (MMP). In embodiments, the subject’s MMP is compared to their baseline mitochondrial respiration, for a period of time after administration. In embodiments, the subject’s MMP is improved by at least a % amount compared to the subject's baseline MMP.

[0691] In embodiments, the outcome measure is a change in a subject’s mitochondrial health index (MHI). In embodiments, the subject’s MHI is compared to their baseline MHI, for a period of time after administration. In embodiments, the subject’s MHI is improved by at least a % amount compared to baseline.

[0701]

[0692] In embodiments, the outcome measure is a change in a subject’s bioenergetic health index (BHI). In embodiments, the subject’s BHI is compared to their baseline BHI, for a period of time after administration. In embodiments, the subject’s BHI is improved by at least a % amount compared to the subject's baseline BHI.

[0702]

[0693] In embodiments, the outcome measure is a change in a subject’s mitochondrial oncobioenergetic index (MOBI). In embodiments, the subject’s MOBI is compared to their baseline MOBI, for a period of time after administration. In embodiments, the subject’s MOBI is improved by at least a % amount compared to the subject's baseline MOBI.

[0703]

[0694] In embodiments, the outcome measure is a change in a subject’s antioxidant levels. In embodiments, the subject’s antioxidant levels are compared to their baseline antioxidant levels, for a period of time after administration. In embodiments, the subject’s antioxidant levels are improved by at least a % amount compared to the subject's baseline antioxidant levels.

[0704]

[0695] In embodiments, the outcome measure is a change in a subject’s antioxidant enzyme activity. In embodiments, the subject’s antioxidant enzyme activity is compared to their baseline antioxidant enzyme activity, for a period of time after administration. In embodiments, the subject’s antioxidant enzyme activity is improved by at least a % amount compared to the subject's baseline activity.

[0705]

[0696] In embodiments, the outcome measure is a change in a subject’s glucose levels. In embodiments, the subject’s glucose levels are compared to their baseline glucose levels, for a period of time after administration. In embodiments, the subject’s glucose levels are improved by at least a % amount compared to the subject's baseline glucose levels.

[0706]

[0697] In embodiments, the outcome measure is a change in the level of a biomarker of a mitochondrial disorder. Exemplary such biomarkers include lactate, creatine kinase, pyruvate, organic acids, amino acids, carnitines, oxidative stress markers, mitochondrial genetic defects, cell-free circulating mtDNA, fibroblast growth factor 21 (FGF21), growth / differentiation factor 15 (GDF-15), xanthine, hypoxanthine, acetone, n-pentane, and isoprene. In embodiments, the subject’s biomarker level is compared to their baseline biomarker level, for a period of time after administration. In embodiments, the subject’s biomarker levels are improved by at least a % amount compared to the subject's baseline biomarker levels. In embodiments, the biomarker level is decreased (where a decrease represents improvement) by at least about 99%, 99%, 98%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1 %, or less than 1%, including numbers in between these values. In other embodiments, the biomarker level is increased (where an increase represents improvement) by at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 200%, 300%, 400%, 500%, or 1,000%, and numbers in between.

[0707]

[0698] In embodiments, an improvement in a condition is determined using an outcome measure. In embodiments, the outcome measure is a change in the severity of one or more symptoms of the condition.

[0699] In embodiments, an improvement in a mental health disorder is determined using an outcome measure, where the outcome measure is a change in the severity of symptoms of the mental health disorder. In embodiments, the change in severity of symptoms of the mental health disorder is a reduction in at least one symptom of the mental health disorder. The reduction in at least one symptom of the mental health disorder is, for example, a reduction in any of feeling sad or down; confused thinking or reduced ability to concentrate; excessive fears or worries, or extreme feelings of guilt; extreme mood changes of highs and lows; withdrawal from friends and activities; significant tiredness, low energy or problems sleeping; detachment from reality (delusions), paranoia or hallucinations; inability to cope with daily problems or stress; trouble understanding and relating to situations and to people; problems with alcohol or drug use; major changes in eating habits; sex drive changes; excessive anger, hostility or violence; suicidal thinking; and physical pain. In embodiments, the subject’s severity of any such symptoms are compared to their baseline severity, for a period of time after administration. In embodiments, the subject’s severity of one or more symptoms is improved by at least a % amount compared to the subject's baseline severity of symptoms.

[0708]

[0700] In embodiments, one or more improvements in a mental health disorder may be measured using psychodiagnostic and psychometric tools commonly employed by those in the art. Examples of such tools include the Structured Clinical Interview for DSM-5 (SCID-5; see, e.g., Am Psych Assoc. The Structured Clinical Interview for DSM-5®. Appi.org. Published 2017; see also, e.g., Elman et al. Sci Rep. 2020;10(1):5617), the Beck Depression Inventory, the Hamilton Rating Scale for Depression, the Hamilton Rating Scale for Anxiety, the State-Trait Anxiety Inventory, the Daily Stress Inventory, the Perceived Stress Scale, the Profile of Mood States questionnaire, the Yale Food Addiction Scale, the Eating Disorder Examination Questionnaire, the Food Craving Inventory, the Yale-Brown Obsessive-Compulsive Scale, the Food Craving Questionnaires, the Three-Factor Eating Questionnaire, the Relationship Patterns Questionnaire, the Treatment Adherence Perception Questionnaire, the Reward Deficiency Syndrome Questionnaire, the Genetic Addiction Risk Severity (GARS) test (Blum et al. Psychol Res Behav Manag. 2023;16:4287-4291), the Clinician-Administered PTSD Scale, and the Civilian Mississippi Post-Traumatic Stress Disorder (PTSD) Scale, all of the foregoing known and used as will be ordinarily understood. For each of the psychodiagnostic and psychometric tools disclosed herein, it will be appreciated that such tools are generally known and employed by those in the art, and reference to such tools may be found in the art.

[0709]

[0701] In embodiments, the outcome measure is a change in a subject’s ability to sustain concentration. In embodiments, the subject’s ability to sustain concentration is compared to their baseline ability to sustain concentration, for a period of time after administering the combination. In embodiments, the subject’s ability to sustain concentration is improved by at least a % amount compared to the subject's baseline ability.

[0710]

[0702] In embodiments, the outcome measure is a change in a subject’s consciousness, such as the subject’s state of or ability to maintain attention and alertness. In embodiments, this is compared to the subject’s baseline consciousness, for a period of time after administering a combination. In embodiments, this is improved by at least a % amount compared to the subject's baseline measure of such consciousness.

[0703] In embodiments, the outcome measure is a change in one or more biomarker levels related to aging. Exemplary such biomarkers include loss of core histones (e.g., H2A, H2B, H3, and H4), histone modifications (e.g., acetylation), DNA methylation, interleukin-6, and C-reactive protein. In embodiments, one or more of a subject’s biomarker levels related to aging are compared to their baseline levels, for a period of time after administration. In embodiments, one or more of a subject’s biomarkers related to aging are improved by at least a % amount compared to one or more of the subject's baseline biomarker levels related to aging.

[0711]

[0704] In embodiments, the improvement in a symptom of a condition is a durable improvement, and lasts for at least about 1 week, including about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 36 months, about 48 months, about 60 months, and more than about 60 months, including for 10 years and longer.

[0712]

[0705] In embodiments, the reduction in the severity of at least one symptom of a condition is a durable reduction, where the reduction lasts for at least about 1 week, including about 2 weeks, about 3 weeks, about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 18 months, about 24 months, about 36 months, about 48 months, about 60 months, and more than about 60 months, when measured from baseline (as other such reductions or determinations of durability herein may be measured from). In embodiments, the reduction in severity of a symptom is durable for at least 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 6 months, 9 months, or 12 months, measured from baseline.

[0713] / . Examples

[0714] EXAMPLE 1: General Procedures for Establishing ATP Measurements in HeLa Cells

[0715]

[0706] Basic Technique: The CellTiter-Glo® 2.0 Cell Viability Assay provides a homogenous method for determining the number of viable cells in culture by quantifying the amount of ATP present, indicating the presence of metabolically active cells. This ready-to-use reagent is based on the original chemistry of the CellTiter-Glo® 2.0 Luminescent Cell Viability Assay and eliminates the need to combine buffer with lyophilized substrate when preparing the reagent. The homogenous assay procedure involves adding a single reagent (CellTiter-Glo® 2.0 Reagent) directly to cells cultured in serum-supplemented medium. Cell washing, removal of medium, and multiple pipetting steps are not required.

[0716]

[0707] Methods (ATP Measurements): ATP measurements in astrocytes and neurospheres were performed with the commercially available CellTiter-Glo® 2.0 Assay (Promega). To validate the assay, a standard ATP curve and ATP measurements were performed in HeLa cell plates at different densities.

[0717]

[0708] HeLa cells were plated in a 96-well plate at the following densities in triplicates: 0, 650, 1,250, 2,500, 5,000, 10,000, and 20,000 cells per well. After 24 hours, the media of all wells was changed, adding 80 pL of the culture media DMEM / F12 + 10% SFB. Following another 24 hours, 80 pL of the CellTiter-Glo® 2.0 was incubated in each well. The plate was agitated for two minutes at room temperature and then allowed to rest for 10 minutes in the dark. Subsequently, 100 pL of each well was transferred with a multichannel pipette to a 96-well plate suitable for reading luminescence. To analyze the ATP concentration in each well through luminescence readings on the plate, a standard ATP curve was prepared. The first standard curve had the following concentrations: 10 pM, 5 pM, 1.25pM, 0.625 pM, 0.3125 pM, 0.15625 pM, and 0.078 pM.

[0718]

[0709] Starting from a 10 nM ATP stock solution, an intermediate solution at 1 mM was prepared (1 pL of ATP stock solution + 9 pL Nuclease-Free water). Then, 2 pL of the intermediate solution (1 mM) was transferred into an Eppendorf tube containing 198 pL of DMEM / F12 + 10% FBS, resulting in a concentration of 10 pM. From the 10 pM solution, 75 pL was consecutively transferred to the next Eppendorf tube containing 75 pL of medium, performing serial dilutions for the ATP standard curve with a dilution factor of 2.

[0719]

[0710] To perform the luminescence analysis, 50 pL of each concentration from the curve was transferred to a 96-well reading plate, and 50 pL of CellTiter-Glo® 2.0 was added. The plate was incubated at room temperature in the dark for 10 minutes, and relative luminescence units (RLU) were recorded using a plate reader with an integration time between 0.25 and 1 second.

[0720]

[0711] Experimental Design: The experimental planning followed good laboratory practices (GLP) to assess the variability of biological phenomena that are intrinsic to living systems. This meant a preliminary exploratory assessment in a series of tests called pilot tests. In pilot assays, the parameters were established to develop the protocols that were tested in technical and experimental replicates, called Ns (number of repetitions). Experimental replicates are independent repetitions, with samples from the same source, separated chronologically. Technical replicates are repetitions in the same test with the same sample.

[0721]

[0712] Results (ATP Standard Curve): ATP standard curves were performed according to the manufacturer’s instructions. The R2of the curves was 0.99, therefore, ATP curve measurements were suitable to be used to calculate ATP concentration in cells.

[0722]

[0713] Results (ATP Measurements in HeLa Cells): CellTiter-Glo® assay was performed in HeLa cells plated in a 96-well plate at the following densities in triplicates: 0, 650, 1,250, 2,500, 5,000, 10,000, and 20,000 cells per well. It was understood, based on preliminary results, that the number of cells influenced the production of ATP and ATP detection. Images were acquired with EVOS Cell Imaging System. Therefore, it was determined that the duration of the experiment following the cell plating impacts the results, considering that there was proliferation in the case of astrocytes and neurospheres.

[0723] EXAMPLE 2: Pilot Experiment #1 to Evaluate ATP Levels in Human Astrocytes

[0724]

[0714] Purpose: The purpose of this pilot experiment was to evaluate ATP levels after treating human astrocytes with LSD, NAD, and DOI. A monoculture of astrocytes were treated with a range of concentrations of LSD (0.1 nM-100 nM), NAD+ (0.001 pM-100 pM), a combination of LSD and NAD+, and DOI (5 pM; used as a positive control). The treatment lasted for 1 , 2, 4, and 6 days, with all six replicates for each condition. After the incubation period, the supernatant and cell lysates were gathered for ATP measurement assays. The levels of ATP were determined using commercially available kits based on the luciferase reaction.

[0725]

[0715] Methods (Cell Culture): Astrocytes were derived from neural stem cells (NSCs), as described by Yan et al. Stem Cells Transl Med. 2013;2(11). NSCs were cultured in astrocyte induction medium [(AIM - DMEM / F12 #11330-032, Thermo Fisher Scientific), N2 supplement (#17502001 , Thermo Fisher Scientific) and 1 % fetal bovine serum (FBS #12657029)] for 21 days. At the end of this period, medium was replaced to astrocyte medium (DMEM / F12 10% FBS) and astrocytes were cultured for 7-8 weeks to obtain mature cells to perform experiments. Cells were plated at a density of 3 x 103or 4 x 103cells / well on 96-well plates. After 4 days of cell seeding, treatment was performed.

[0726]

[0716] Methods (Treatment with LSD, NAD, and DOI): Medium was removed and completely replaced with each treatment condition, using the following concentrations (10-fold dilution curve or 2-fold dilution curve):

[0727]

[0717] A concentration curve of DOI was added, since the evidence of ATP increase with 5 pM concentration was conducted in rat cortical neurons and the effect in human astrocytes could be distinguished. Cells were incubated at 37 °C and 5% CO2 until ATP measurement.

[0728]

[0718] Methods (ATP Measurements): ATP measurements in astrocytes were performed with the commercially available kit CellTiter-Glo® 2.0 Cell Viability Assay (#G9242, Promega). To perform the Cell Titer Assay, 100 pL of Cell Titer Reagent was added to each well and luminescence was read after 20 minutes. The CellTiter-Glo® Assay provides a homogenous method for determining the number of viable cells in culture by quantifying the amount of ATP present, indicating the presence of metabolically active cells. This assay was previously validated using HeLa cells as described in EXAMPLE (“EX.”) 1. ATP standard curves were performed according to the manufacturer’s instructions. Relative Luminescence was obtained, and ATP concentration was calculated interpolating RLU values from the standard curve.

[0729]

[0719] Preliminary Results: After 4 days of cell seeding in a 96-well plate at a density of 4,000 cells / well, astrocytes exhibited good spindle-like morphology and reached -60% confluency. The culture was monitored daily from days 1 to 6 to assess whether a long period without changing the medium could affect viability. Indeed, after 72 hours cell viability decreased as correlated by lower ATP concentration compared to 24 hours and 48 hours (FIG. 2). Thus, treatment with LSD, DOI and NAD was carried out for a maximum time of 48 hours for the culture to maintain good viability (i.e., to avoid any interference of cell viability due to lack of nutrients after a long period without medium change) to evaluate the effects on ATP production (FIG. 3).

[0730]

[0720] Although effects on ATP levels were observed, the pattern was not as consistent; after 4 days of cell seeding, astrocytes exhibited 60% of confluency. The cell density after 48 hours may have affected the reproducibility of the treatment curve, even though cell viability was preserved. To avoid influences on cell density in the assay, the experiment was performed by plating 3,000 cells / well instead of 4,000 cells / well to avoid high confluency after 48 hours of treatment. The p-NAD concentration curve was also changed to: 100uM; 10uM; 1 uM; 0.1 uM; 0.01 uM; 0.001 uM; and the DOI concentration curve to: 10uM; 1 uM; 0.1 uM; 0.001 uM; 0.0001 uM; 0.0001 uM. The adjustment to the concentration curves considered that high NAD concentrations decreased ATP production and the DOI concentration curve was not covering the entire induction cycle (i.e., the lowest concentration in the previous curve did not appear to be the limit of effect).

[0731] EXAMPLE 3: Pilot Experiment #2 to Evaluate ATP Levels and Cell Count in Human Astrocytes

[0732]

[0721] Purpose: The purpose of this pilot experiment was to evaluate ATP levels and cell count after treating human astrocytes with LSD, NAD, and DOI.

[0733]

[0722] Methods (Cell Culture): Astrocytes cell cultures were prepared as described in EX. 2.

[0734]

[0723] Methods (Treatment with LSD. NAD, and DOI): Medium was removed and completely replaced with each treatment condition, using the following concentrations (10-fold dilution curve or 2-fold dilution curve):

[0735]

[0724] Methods (ATP Measurements): ATP measurements in astrocytes were done as described in EX. 2.

[0736]

[0725] Methods (Cell Count): Cells were incubated with Hoechst 33342 (#H1399, ThermoFisher Scientific) for 30 minutes for nuclei staining. Images were acquired using the Cytation Biotek Imaging System and the cell counting was performed using Cytation Analysis software.

[0737]

[0726] Results: After 2 days of treatment, ATP was measured according to Cell Titer 2.0 protocol. LSD, NAD and DOI revealed effects in ATP levels as plotted below in FIG. 4. Even though astrocytes are less proliferative, a cell count assay was performed to evaluate and validate the compounds’ effects on ATP production. It was observed that none of the treatments induced any change in cell number, so the increased ATP levels obtained after treatment with LSD, NAD, and DOI, are not related to an increase in cell number, but in fact to an increase in ATP production (FIG. 5).

[0738] EXAMPLE 4: Evaluation of ATP Levels, ROS Levels, and Cell Count in Human Astrocytes

[0739]

[0727] Purpose: The purpose of this experiment was to evaluate ATP levels, reactive oxygen species (ROS) levels, and cell count after treating human astrocytes with LSD, p-NAD, DOI, and LSD + p-NAD.

[0740]

[0728] Methods (Cell Culture): Astrocyte cell cultures were prepared as described in EX. 2.

[0741]

[0729] Methods (Treatment with LSD. B-NAD. DOI. LSD + B-NAD): Medium was removed and completely replaced with each treatment condition, using the following concentrations (10-fold or 2-fold dilution curve):

[0742]

[0730] Methods (ATP Measurements): ATP measurements in astrocytes were done as described in EX. 2.

[0743]

[0731] Methods (ROS Measurements): ROS measurements were performed with a commercially available ROS-Glo™ H2O2Assay (#G8820, Promega). To perform the ROS-Glo™ Assay, substrate was added to the cultivation media 6 hours before the detection reaction. For the detection reaction, 20 L of medium was removed and 20 |jL substrate was added to the medium and cells were incubated for 6 hours at 37 °C, 5% CO2. Luminescence detection was performed after incubation for 20 minutes with 100 pL ROS detection solution. H2O2standard curves were performed according to manufacturer instructions. H2O2concentration was calculated interpolating RLU values from the standard curve. The ROS-Glo™ assay mechanism for measuring H2O2involves a substrate that reacts directly with H2O2to generate a luciferin precursor. After adding ROS-Glo Detection Reagent containing Recombinant Luciferase Ultra-Gio and d-Cysteine, precursor is converted into luciferin by d-Cysteine, and produced luciferin reacts with Recombinant Luciferase Ultra Gio™ to generate a luminescent signal proportional to the concentration of H2O2.

[0744]

[0732] Methods (Cell Count): Cells were stained and counted as described in EX. 2.

[0745]

[0733] Data Analysis: Data was analyzed using GradPad Prism 10. Relative values of ATP and ROS were transformed into fold change from control samples in MS Excel. Outliers were excluded based on the Prism 10 algorithm (ROUT method). A two-way ANOVA test was applied with a confidence interval of 0.5. Post hoc t test for multiple comparison was used. Bars are standard error mean (SEM) or standard deviation (SD).

[0746]

[0734] Results (ATP Measurements): After 2 days treatment, ATP was measured according to Cell Titer 2.0 protocol. Astrocytes treated with LSD and NAD showed an increase of ATP concentration when compared to control (untreated) or vehicle treated (DMSO) (FIG. 6). LSD produced a significant (p < 0.05) increase in ATP at 0.001 nM, 0.01 nM, 0.1 nM, and 1 nM concentrations (FIG. 6A). -NAD pro...

Claims

CLAIMSThe invention claimed is:

1. A therapeutic “brain boost” combination or kit of parts for enhancing energy production, comprising: a. a serotonergic psychedelic; b. a mitochondrial energy enhancer; and c. an antioxidant or glucose regulator.

2. The combination or kit of parts of claim 1 , wherein: a. the serotonergic psychedelic is lysergic acid diethylamide (LSD); b. the mitochondrial energy enhancer is nicotinamide adenine dinucleotide as NAD+; and c. the antioxidant or glucose regulator is ascorbic acid (vitamin C).

3. The combination or kit of parts of claim 1 , wherein the serotonergic psychedelic is a tryptamine, a phenethylamine, or a lysergamide.

4. The combination or kit of parts of claim 1 , wherein the serotonergic psychedelic is any of LSD, 1 P-LSD, AL-LAD, psilocybin, psilocin, psilacetin, mescaline, DMT, DOI, 5-MeO-DMT, and ibogaine.

5. The combination or kit of parts of claim 1 , wherein the serotonergic psychedelic is LSD.

6. The combination or kit of parts of claim 1 , wherein the mitochondrial energy enhancer is a metabolic cofactor or a metabolic coenzyme.

7. The combination or kit of parts of claim 1 , wherein the mitochondrial energy enhancer is a nicotinamide adenine dinucleotide (NAD) compound.

8. The combination or kit of parts of claim 7, wherein the NAD compound is any of NAD+, NADH, a-NAD+, a-NADH, P-NAD+, -NADH, and a combination thereof.

9. The combination or kit of parts of claim 8, wherein the NAD compound is NAD+.

10. The combination or kit of parts of claim 1, wherein the mitochondrial energy enhancer is a NAD+ precursor.

11. The combination or kit of parts of claim 10, wherein the NAD+ precursor is any of nicotinic acid (NA), nicotinic acid mononucleotide (NaMN), nicotinic acid adenine dinucleotide (NAAD), nicotinic acid riboside (NaR), nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), inositol hexanicotinate (IHN), and tryptophan (Trp).

12. The combination or kit of parts of claim 1, wherein the mitochondrial energy enhancer is any of flavin adenine dinucleotide (FAD), coenzyme Q10 (CoQ10), acetyl-L-carnitine (ALC), alpha-lipoic acid (ALA), a B-complex vitamin, and a mineral.

13. The combination or kit of parts of claim 12, wherein the B-complex vitamin is vitamin B1, vitamin B2,vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, vitamin B12, or a combination thereof.

14. The combination or kit of parts of claim 12, wherein the mineral is iodine, sulfur, or magnesium.

15. The combination or kit of parts of claim 1, wherein the antioxidant or glucose regulator is ascorbic acid (vitamin C) or coenzyme Q10 (CoQ10).

16. The combination or kit of parts of claim 1, further comprising a NAD+ degradation inhibitor.

17. The combination or kit of parts of claim 16, wherein the NAD+ degradation inhibitor is any of a CD38 inhibitor, a PARP inhibitor, a SIRT inhibitor, and a SARM1 inhibitor.

18. The combination or kit of parts of claim 1, further comprising any of a SIRT activator, an agentthat increases SIRT activity, an agentthat preserves SIRT activity, an agent that enhances SIRT synthesis or protein expression, an agent that enhances the half-life of a SIRT protein, an agent that promotes NADH oxidation, an activator of AMP-activated kinase, an agent that increases expression of nicotinamide phosphoribosyltransferase (PRT), an agent that acts as a substrate for NAD+ synthesis, an agent that lessens the reduction of NAD+ mediated by glycolysis, a methyl-donor supplement, and a NAMPT activating agent.

19. The combination or kit of parts of claim 18, wherein the methyl-donor supplement is trimethylglycine.

20. The combination or kit of parts of claim 18, wherein the NAMPT activating agent is berberine, resveratrol, or P7C3.21 . The combination or kit of parts of claim 1 , further comprising an additional active agent.

22. The combination or kit of parts of claim 21 , wherein the additional active agent is selected from the group consisting of: amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic agents, antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, hypnotics, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, entactogens, psychedelics, plasticity-inducing agents, psychoplastogens, neuroplastogens, monoamine oxidase inhibitors, reversible inhibitors of monoamine oxidase-A (RIMAs), tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, and vitamins.

23. The combination or kit of parts of claim 1 , wherein each of the serotonergic psychedelic, the mitochondrial energy enhancer, and the antioxidant or glucose regulator are separately formulated as a pharmaceutical composition, each further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

24. The combination or kit of parts of claim 23, wherein the serotonergic psychedelic is LSD, the mitochondrial energy enhancer is NAD+, and the antioxidant or glucose regulator is vitamin C.

25. The combination or kit of parts of claim 24, wherein LSD is in an amount of between about 1 pg and about 50 pg, between about 5 pg and about 20 pg, less than about 50 pg, less than about 20 pg, less than about 10 pg, or about 10 pg.

26. A pharmaceutical composition for enhancing energy production, comprising: a. a serotonergic psychedelic; b. a mitochondrial energy enhancer; and c. an antioxidant or glucose regulator; and further comprising a pharmaceutically acceptable carrier, diluent, or excipient.

27. The pharmaceutical composition of claim 26, suitable for enteral or parenteral administration.

28. The pharmaceutical composition of claim 26, suitable for oral administration.

29. The pharmaceutical composition of claim 26, in unit dosage form.

30. The pharmaceutical composition of claim 26, wherein the serotonergic psychedelic is LSD, the mitochondrial energy enhancer is NAD+, and the antioxidant or glucose regulator is vitamin C.31 . A method for enhancing energy production in a subject, comprising administering to the subject the combination or kit of parts of claim 1 .

32. The method of claim 31 , wherein administration is for the treatment of a medical condition.

33. The method of claim 32, wherein the medical condition is any of a nervous system condition or disorder; a mental, behavioral, or neurodevelopmental disorder; a mental health disorder; a neurodegenerative disorder; a mitochondrial disorder; and a condition related to energy production.

34. The method of claim 33, wherein the nervous system condition or disorder is any of addiction, a substance use disorder, a depressive disorder, an anxiety disorder, Alzheimer’s disease, attention deficit hyperactivity disorder (ADHD), an autism spectrum disorder, cluster headaches, migraines, cognitive decline, dementia, an eating disorder, grief, existential distress associated with terminal illness or mortality, Parkinson’s disease, and post traumatic stress disorder (PTSD).

35. The method of claim 33, wherein the mental, behavioral, or neurodevelopmental disorder is any of a neurodevelopmental disorder, schizophrenia, a primary psychotic disorder, catatonia, a mood disorder, anxiety, a fear-related disorder, an obsessive-compulsive or related disorder, a disorder associated with stress, a dissociative disorder, a feeding or eating disorder, an elimination disorder, a disorder of bodily distress or bodily experience, a disorder due to substance use or an addictive behavior, an impulse control disorder, a disruptive behavior or dissocial disorder, a personality disorder, a paraphilic disorder, a factitious disorder, a neurocognitive disorder, a mental or behavioral disorder associated with pregnancy, childbirth or the puerperium, a sleep-wake disorder, a sexual dysfunction, and gender incongruence.

36. The method of claim 35, wherein the neurodevelopmental disorder is any of autism spectrum disorder, cerebral palsy, epilepsy, bipolar disorder, obsessive compulsive disorder, a disorder of communication, speech, or language, fetal alcohol syndrome or fetal alcohol effects (FAS / FAE), fragile X syndrome, William’s syndrome, and Down syndrome.

37. The method of claim 33, wherein the mental health disorder is any of disruptive mood dysregulation disorder, major depressive disorder (MDD), treatment resistant depression (TRD), persistent depressive disorder (dysthymia), premenstrual dysphoric disorder, a substance / medication-induced depressive disorder, post-partum depression, a depressive disorder due to another medical condition, separation anxiety disorder, selective mutism, a specific phobia, a social anxiety disorder, social phobia, a panic disorder, panic attacks, agoraphobia, generalized anxiety disorder (GAD), a substance or medication-induced anxiety disorder, an anxiety disorder due to another medical condition, a somatic symptom disorder, an illness anxiety disorder, a conversion disorder, a functional neurological symptom disorder, factitious disorder, post-traumatic stress disorder (PTSD), an adjustment disorder, a trauma or stressor-related disorder, an acute distress disorder, obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, trichotillomania, excoriation, a substance or medication-induced obsessive-compulsive or related disorder, an obsessive-compulsive or related disorder due to another medical condition, a substance-related disorder, an alcohol-related disorder, a cannabis-related disorder, a hallucinogen-related disorder, an inhalant-related disorder, a cocaine-related disorder, an opioid-related disorder, a sedative-, hypnotic-, or anxiolytic-related disorder, a stimulant-related disorder, a tobacco-related disorder, a non-substance-related disorder, a behavioral addiction, migraines, cluster headaches, cyclical vomiting, tension-type headaches, dysphasia, pica, anorexia nervosa, bulimia nervosa, a binge-eating disorder, oppositional defiant disorder, intermittent explosive disorder, a conduct disorder, antisocial personality disorder, psychopathy, pyromania, and kleptomania.

38. The method of claim 33, wherein the neurodegenerative disorder is any of Alzheimer’s disease, amyotrophic lateral sclerosis, Charcot’s disease, chronic traumatic encephalopathy, corticobasal degeneration, dementia, vascular dementia, Huntington’s disease, Lytico-Bodig disease, mild cognitive impairment, multiple sclerosis, a motor neuron disease, neuromyelitis optica spectrum disorder, Parkinson’s disease, parkinsonisms, a prion disease, progressive supranuclear palsy, traumatic brain injury, and mild traumatic brain injury.

39. The method of claim 33, wherein the mitochondrial disorder is any of myopathy with exercise intolerance, eyelid ptosis, ophthalmoparesis, pigmentary retinopathy, sensorineural hearing loss, hypertrophic cardiomyopathy, migraine disorder, mitochondrial disease not otherwise specified, chronic fatigue immunity deficiency syndrome, myalgic encephalomyelitis, chronic fatigue syndrome, demyelination due to mitochondrial disease, mitochondrial cytopathy, a liver disease due to a mitochondrial disorder, a disorder of mitochondrial oxidative phosphorylation, a mitochondrial DNA depletion syndrome, anunspecified disorder of mitochondrial oxidative phosphorylation, a multiple mitochondrial DNA deletion syndrome, a mitochondrial protein translation defect, a mitochondrial myopathy, a glomerular disease associated with a mitochondrial disease, mitochondrial diabetes, myoclonus due to a mitochondrial cytopathy, a disorder of mitochondrial membrane transport, epilepsy due to a mitochondrial disorder, an intestinal congenital motility disorder due to a mitochondrial disease, mitochondrial ocular myopathy, congenital muscular dystrophy with mitochondrial structural abnormalities, a disorder of mitochondrial fatty acid oxidation, ataxia due to a mitochondrial mutation, mitochondrial isocitrate dehydrogenase deficiency, chorea due to mitochondriopathy, mitochondrial thiamine pyrophosphate carrier deficiency, dystonia due to a mitochondrial cytopathy, dilated cardiomyopathy due to a mitochondrial myopathy, mitochondrial disease with hypertrophic cardiomyopathy, mitochondrial myopathy with sideroblastic anemia, and mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency.

40. The method of claim 33, wherein the condition related to energy production is a condition caused by or associated with any of reduced cellular energy metabolism, reduced ATP production, reduced mitochondrial biosynthesis, and reduced NAD, NADH, and / or NAD+ levels.41 . The method of claim 31 , wherein enhancing energy production in the subject improves mental health and functioning, or improves overall health and wellness.

42. The method of claim 31 , wherein the serotonergic psychedelic, the mitochondrial energy enhancer, and the antioxidant or glucose regulator are administered in separate dosage forms.

43. The method of claim 31 , wherein the serotonergic psychedelic, the mitochondrial energy enhancer, and the antioxidant or glucose regulator are administered separately, sequentially, or simultaneously.

44. The method of claim 31 , wherein the serotonergic psychedelic is LSD, the mitochondrial energy enhancer is NAD+, and the antioxidant or glucose regulator is vitamin C.

45. A method for enhancing energy production in a subject, comprising administering to the subject the pharmaceutical composition of claim 26.

46. The method of claim 45, wherein the serotonergic psychedelic is LSD, the mitochondrial energy enhancer is NAD+, and the antioxidant or glucose regulator is vitamin C.

47. Use of the combination or kit of parts of claim 1 , or the pharmaceutical composition of claim 26, for enhancing energy production, treating a medical condition, improving mental health and functioning, or improving overall health and wellness.

48. The use of the combination or kit of parts of claim 1 , or the pharmaceutical composition of claim 26, for the manufacture of a medicament for the therapeutic or prophylactic treatment of a medical condition.

49. A therapeutic “brain boost” combination or kit of parts for enhancing energy production, comprising a serotonergic psychedelic and a mitochondrial energy enhancer.

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