US 2015O132280A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0132280 A1 Lopez et al. (43) Pub. Date: May 14, 2015

(54) THEACRINE-BASED SUPPLEMENT AND Publication Classification METHOD OF USE THEREOF (51) Int. Cl. (71) Applicant: Ortho-Nutra, LLC. Morganville, NJ A613 L/522 (2006.01) (US) A6II 45/06 (2006.01) (52) U.S. Cl. (72) Inventors: Hector L. Lopez, Cream Ridge, NJ (US); CPC ...... A61 K3I/522 (2013.01); A61K 45/06 Shawn Wells, Lewisville, TX (US); Tim (2013.01) N. Ziegenfuss, Chardon, OH (US) (73) Assignee: ORTHO-NUTRA, LLC, Morganville, NJ (US) (57) ABSTRACT (21) Appl. No.: 14/539,726 A human dietary Supplement comprises theacrine and option (22) Filed: Nov. 12, 2014 ally other compounds that modulate the effects of theacrine. Related U.S. Application Data Uses for the theacrine-containing Supplement include improvement of at least one of mood, energy, focus, concen (60) Provisional application No. 61/903,362, filed on Nov. tration or sexual desire or a reduction of at least one of anxiety 12, 2013. or fatigue. Patent Application Publication May 14, 2015 Sheet 1 of 7 US 201S/O132280 A1

Patent Application Publication May 14, 2015 Sheet 2 of 7 US 2015/0132280 A1

Covariate Fear: ENERGY Baselite Energy; 7.0 Wilks lambdas,734.74, F(3,283-3,8086, p2.04914 {Computed for covariates at their means) Wertical bars denote 8.95 confidence intervais 9.5 mmum-m-maan-a-

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8.5

8.8

7.5

70

6.0 55 ------sa-a-- 1 hr Energy 5. 2hr Energy 3hr Energy

4. Pacebo eaCrine ria: Units for vertical axis are Visual Analogue Scale (in cm). FGRE 2 Patent Application Publication May 14, 2015 Sheet 3 of 7 US 2015/0132280 A1

FACE Current effect: F(3,28)s:4.5696, p=0.04 Effective hypothesis decomposition Vertical bats denote 0.95 confidence intervais

I

3: Placebo : TeaCrire Onir 68 rif five

Units for vertical axis are Visual Analogue Scale (in cm). FGURE 3 Patent Application Publication May 14, 2015 Sheet 4 of 7 US 2015/O132280 A1

Systoic Blood Pressure Current effect: F(6, 68}:1.2115, p=0.30 Effective hypothesis decomposition Wertical bats denote (.95 confidence intervais 136 34 132 30 128 26 24 22 20 18 6 114 Kx Placebo 12 10 0 in 3} if 80 nir 98 rif 28 rif 80 in 80 nir id: FGRE 4 Patent Application Publication May 14, 2015 Sheet 5 of 7 US 2015/0132280 A1

Biastoic Blood Pressure Current effect F(6, 68)-.90829, p=0.49 Effective hypothesis decomposition Wertical bars denote 0.95 confidence intervals

f

3. Placebo 3. TeaCrine {rrin 3 in 68 min 90 fir 120 min 80 in 88 rif ME

FGRE 5 Patent Application Publication May 14, 2015 Sheet 6 of 7 US 2015/0132280 A1

FGFRS 6 1 o. o

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O.O Fatigue Anxiety Libido

Units for vertical axis are Visual Analogue Scale (in cin), Effect. Size of 200 gag dose ofTC (Ver rise of 7- apeated dose stady relative to baseline on: Fatigue: 0.64, Anxiety: -0.59, Libido: 0.71. Patent Application Publication May 14, 2015 Sheet 7 of 7 US 201S/O132280 A1

g x 6 hr

Units for vertical axis are Visual Analogue Scale (in cm). Effect Size of 200 Eng dose of TC (Ves course of 7 day repeated dose Study relative to baseline on: Energy: (.63, Motivation to Exercise: 0.58, Concentration: 0.60 US 2015/O 132280 A1 May 14, 2015

THEACRINE-BASED SUPPLEMENT AND ture. Recent experiments have shown that theacrine exhibits a METHOD OF USE THEREOF variety of activities. Some of which seem inconsistent. 0007. In the past several years, there has been a substantial 0001. This application claims priority to U.S. Provisional shift in public opinion toward using naturally occurring Application Ser. No. 61/903,362, filed Nov. 12, 2013, which chemical compounds for a variety of purposes, instead of is incorporated by reference as if fully set forth herein. synthetic chemicals. For example, a wide variety of natural chemicals are now commonly used as sedatives, e.g. FIELD OF THE INVENTION root and chamomile, anti-depressants, e.g. St. John’s wort, 0002 The present invention relates to systems and meth Stimulants, e.g. , and concentration, e.g. ginseng. In ods for utilizing theacrine alone and in combination for use in general, naturally occurring compounds may be easier for the providing physiological benefits. More particularly, the body to digest and interact with and may include minimal and invention relates to theacrine and other naturally occurring less severe side effects. compounds, whether produced synthetically or harvested 0008. It is therefore desirable to identify naturally occur from natural sources, and use of these chemical compounds to ring chemical compounds and mixtures thereofthat may pro provide physiological benefits, which may vary according to vide benefits. It is also desirable to provide chemical com theacrine concentration and the presence of synergists and pounds and mixtures thereof that may be used to provide a antagonists. variety of benefits, varying by concentration, thus requiring production or harvesting of fewer materials. BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION 0003) Tea is one of the most widely consumed products in the world. Tea and the different varieties of tea have been 0009. Accordingly, the primary object of the present extensively studied. Many epidemiologic and preclinical invention is to provide a chemical composition comprising studies suggest that drinking tea may reduce the risk of cancer theacrine, either naturally or synthetically produced, and and cardiovascular disease. Theacrine, an optionally other chemicals, including theacrine congeners or similar to caffeine, is relatively rare and only found in a few analogs, to provide a plurality of desirable effects. Theacrine varieties oftea (kuchatea, genus Camelia), the fruit cupuaçu, analogs may include, but are not limited to, caffeine, methyl and other plants related to coffee and cacao (genera Coffea caffeine, , , liberine and methyl and Theobroma), such as Coffea liberica, Coffea dewevrei, liberine, and their variants. Other suitable actives may include Coffea abeokutae and . one or more ergogenic or nootropic compounds such as CDP 0004) 1,3,7,9 tetramethyluric acid, commonly known as choline, alpha-GPC, choline bitartrate, St John's Wort, sul theacrine, was not studied until around 1975. However, it has butiamine, and the like. been known of since about 1937, when it was detected in dry, 0010. Theacrine exhibits a wide variety of effects depend decaffeinated Camelia Sinensis tea leaves. At this time, the ing on dosage. The presence of other ingredients may also Camellia assamica var. kucha variety of tea is the primary modulate its effects. It may be used to promote calm or focus Source of naturally occurring theacrine and produces the and to relax, but also may be used to enhance energy and chemical in higher concentrations than other known plants. stamina. It may also serve as an antioxidant and an anti Interestingly, theacrine has not been detected at all in more inflammatory. traditional teas strains. It is believed to be formed by methy 0011. In one embodiment, theacrine may be used to modu lation of caffeine and may be an intermediary in the produc late stimulants, to provide heightened energy without height tion of liberine or other . Its natural function, if any, ened anxiety or nervousness. There may be variability among remains unknown. Theacrine has garnered attention only individuals, as described herein. relatively recently, and often only as a secondary consider 0012. In another embodiment theacrine may be used as a ation when analyzing other compounds. Some studies Sug mild sedative or relaxant. gest it may have beneficial qualities, such as serving as an 0013. In a further embodiment, theacrine may be used to effective antioxidant, anti-inflammatory and may have anti promote weight loss, act as an antioxidant and as an anti obesity properties. inflammatory. Theacrine may be used transdermally to 0005. In the studies involving theacrine, beneficial effects enhance one or more of these effects. may be at least partially attributable to an assortment of 0014. In one embodiment, a dietary supplement compris purine and phenolic compounds. The more com ing about 5 mg to about 850 mg theacrine, either natural or mon tea-related purine alkaloids include caffeine, theobro synthetic, is provided. mine, theophyline and theacrine. The major tea phenolic 0015. In another embodiment, a method of treatment for compounds are gallic acid and eight naturally occurring tea improving physical performance or energy in an individual is catechins, including (+)-catechin (C). (-)-epicatechin (EC), provided. Said method involves providing the individual with (+)-gallocatechin (GC). (-)-epigallocatechin (EGC), (-)-cat a composition comprising about 5 mg to about 850 mg of echin gallate (CG), (-)-gallocatechingallate (GCG), (-)-epi theacrine, either natural or synthetic, wherein upon adminis catechin gallate (ECG) and (-)-epigallocatechin gallate tration of the composition the individual experiences (EGCG). improvement of at least one of mood, energy, focus, concen 0006. Many different biologic and physiologic activities tration or sexual desire or a reduction of at least one of anxiety have been attributed to tea and its various components. How or fatigue. In another embodiment, a second compound Such ever, only a few of its components have been studied in depth. as caffeine may also be administered in the composition. Caffeine is by far the most studied, and the most commonly 0016. It is therefore an object of the present invention to used stimulant found in tea. Theacrine appears to have an provide compositions including theacrine capable of impart opposite effect, despite being very similar in chemical struc ing a plurality of positive effects. US 2015/O 132280 A1 May 14, 2015

0017. It is another object of the present invention to pro fied to 95% or greater. Optionally, less purification may be vide congeners, derivatives and iterations of theacrine and used such that theacrine accounts for 50%, or even less, of the synthetic chemical equivalents of theacrine. material. In some embodiments, it may be preferable to uti 0018. It is another object of the present invention to pro lize theacrine isolated from a natural Source which may vide agglomerated theacrine, theacrine salts, microencapsu include other congeners of theacrine typically found in the lated, liposomal or esterified theacrine. acrine isolates. 0019. It is another object of the present invention to pro 0030. In one embodiment, theacrine may be combined vide theacrine combined with glycerides, propylene glycol, with other chemical compounds to provide a plurality of polyethylene glycol (PEG), lauroyl macrogol, lauroyl mac positive effects on a human or other animal. By altering the rogolderivatives and co-crystallization products of theacrine. dosage of theacrine and/or chemical compounds it is com 0020. These and other objects and advantages of the bined with, various physiological effects may be selected for. present invention will become apparent from a reading of the The compositions may provide primarily a single benefit, or attached specification and appended claims. There has thus may provide multiple benefits simultaneously. been outlined, rather broadly, the more important features of 0031. In another embodiment, theacrine may be used at the invention in order that the detailed description thereofthat lower dosage levels and/or in conjunction with compounds follows may be better understood, and in order that the that modulate or antagonize its activity. Such compositions present contribution to the art may be better appreciated. may induce an improved mood, higher energy, a reduction in There are features of the invention that will be described fatigue, increased focus, increased concentration, increased hereinafter and which will form the subject matter of the mobility, decreased appetite, and increased stamina. claims appended hereto. 0032. An advantage of using the invention may be the reduced likelihood that a person develops a tolerance to BRIEF DESCRIPTION OF THE DRAWINGS chemical compositions in accordance with the principles of 0021 FIG. 1 is a molecular diagram of theacrine in accor the invention. That is, a person may not become desensitized dance with the principles of the invention. to the effects induced. 0022 FIG. 2 is a graph of results of a trial showing per 0033. In another embodiment, theacrine may be used at ceived energy on a VAS scale (0 to 10 cm) at 1, 2 and 3 hours higher dosage levels and/or with Synergistic compounds. after administration of theacrine or placebo. These compositions may increase a person's basal/resting 0023 FIG. 3 is a graph of results of a trial showing per metabolic rate, increase thermogenesis, decrease appetite, ceived fatigue on a VAS scale (0 to 10 cm) at 0 minutes and 60 enhance cognitive performance, increase Alpha wave brain minutes after administration of theacrine or placebo. activity, and/or induce euphoria. Without being bound by 0024 FIG. 4 is a graph of results of a trial showing systolic theory, the inventors believe that at higher dosage levels, blood pressure at various time intervals after administration theacrine may be noradrenergic and dopaminergic, and may of theacrine or placebo. exhibit increased inhibition. 0034. In another embodiment of the invention, theacrine 0025 FIG. 5 is a graph of results of a trial showing dias may be combined with ephedrine, caffeine, salicylic acid or tolic blood pressure at various time intervals after adminis the like. These may be used to either modulate the more tration of theacrine or placebo. sedative effects of theacrine or optionally to interact syner 0026 FIG. 6 shows the results of a 7 day repeated dose gistically with the more stimulating effects of theacrine. For study of 200 mg theacrine relative to baseline of fatigue, example, theacrine may be combined with caffeine in order to anxiety and libido at various intervals after dosages (at Ohr, 1 modulate the excessive stimulatory effects of caffeine, hr, 4 hr, 6 hr., bars left to right for each measured category). thereby stabilizing heart rate and other metabolic activity. 0027 FIG. 7 shows the results of a 7 day repeated dose That is, a combination of theacrine and caffeine may result in study of 200 mg theacrine relative to baseline of energy, a composition that imparts the increased focus and energy motivation to exercise, and concentration at various intervals induced by caffeine, but without the higher heart rate and after dosages (at Ohr, 1 hr, 4 hr, 6 hr; bars left to right for each blood pressure due to modulation of caffeine by theacrine. measured category). Thus the combination may result in heightened awareness DETAILED DESCRIPTION OF THE INVENTION and calmness without the jitters caffeine may cause. 0035. Theacrine and caffeine administered in combination 0028 Before explaining at least one embodiment of the has unexpected effects. Indeed, it has been unexpectedly invention in detail, it is to be understood that the invention is found that a combination of theacrine and caffeine adminis not limited in its application to the details of construction and tered to human Subjects results in increased levels of focus, to the arrangements of the components set forth in the fol concentration and energy as measured by 100mm VAS Scales lowing description or illustrated in the drawings. The inven while also decreasing measures of anxiety, irritability or feel tion is capable of other embodiments and of being practiced ings of overstimulation. Such decrease in anxiety, irritability, and carried out in various ways. Also, it is to be understood jitters and/or feelings of overstimulation is reflected by that the phraseology and terminology employed hereinare for patients on standardized 100 mm VAS at durations of 30 the purpose of description and should not be regarded as minutes, 60 minutes, 120 minutes and 180 minutes as com limiting. pared with administration of caffeine alone. The combination 0029 Disclosed is an invention relating to uses of the also exhibits a prolonged duration of action in increased acrine, also known as 1.3.7.9-tetramethyluric acid, Temurin, energy, focus and/or concentration as compared to either Temorine, Tetramethyluric acid, Tetramethyl and caffeine or theacrine alone. 1.3.7.9-tetramethylpurine-2,6,8-trione. Theacrine may be 0036 Furthermore, theacrine also has unexpected effects produced synthetically or may be isolated from a natural on the development of tolerance and habituation of caffeine. Source. Theacrine isolated from a natural source may be puri In a fourteen day study of repetitive dosing of theacrine and US 2015/O 132280 A1 May 14, 2015 caffeine, it was found that the Subjects maintained heightened Mangifera indica L. (Anacardiaceae), Lagenaria breviflora, psychometric indices of energy, focus, concentration, moti and/or Zingiber officinale (ginger & gingerols/shogaols). Vation to exercise, motivation to accomplish and finished Such a combination may be used in, for example, methods of tasks, and improved mood at Day 14 as compared to caffeine augmenting and enhancing pain modulation, and controlling alone, and absolute levels of energy and motivation were the inflammatory response. greater than with theacrine alone. Those taking theacrine 0044. In another embodiment of the invention, theacrine alone still maintained elevated Subjective energy, focus, con may be combined with one or more metabolic enhancers centration, motivation to exercise, motivation to accomplish including hoodia gordonii, caffeine, yohimbine, Synephrine, and finish tasks, sexual desire and improved mood with theobromine, flavonoids, flavanone glycosides such as marin decreased anxiety as compared to Day 1. Subjects taking gin and hesperidin, tocopherols, theophylline, alpha-yohim caffeine alone saw decreasing levels of energy, focus and bine, conjugated linoleic acid (CLA), octopamine, evodi concentration by Day 5 of the study and had increased anxiety amine, passion flower, red pepper, cayenne, raspberry ketone, scores throughout the study. guggul, green tea, guarana, kola nut, any beta-phenethy 0037. In another embodiment of the invention, theacrine lamines, Acacia rigidula, and/or forskolin (Coleus for may be combined with one or more bioavailability enhancers, Skohli). Such a combination may be used in, for example, including for example bioperine, piperine, black pepper, ber methods of enhancing 1) thermogenesis/fat and carbohydrate gamottin, dihydroxybergamottin (CYP3A4 inhibitors), fla metabolism; 2) fat loss, weight management and improving vonoids (including hesperidin, naringin, tangeritin, body composition (loss of body fat, while retaining or sparing and nobiletin both in isolation and in combination), pteros lean body mass/fat free mass/muscle); and/or 3) appetite con tilbenes, fisetin, nanoencapsulation, microencapsulation, trol/appetite modulation. liposomes and/or phytosomes. Which enhancers are com bined with theacrine may depend on which qualities of the 0045 Combinations of theacrine and, for example, caf acrine are desired for a particular use. feine, theobromine, or flavanone glycosides such as maringin 0038. In another embodiment of the invention, theacrine or hesperidin, upon administration to Subjects show may be introduced using one or more delivery methods, decreased VAS 100 mm ratings of perceived physical exertion including, for example transdermal patches and/or creams, with exercise as compared to ingredients alone. Theobromine ready to mix powders, intravenous methods, capsules, tablets, is used by Some for improvement of breathing or a Subjective liquid (including liquids for mixing with other beverages), feeling of improved breathing, but is also known to increase softgels, shot format, and/or cosmetic applications including feelings of anxiety, jitters and an elevated heart rate in some Soaps, lotions and shampoos. Theacrine's anti-inflammatory subjects. A combination of theobromine and theacrine retains qualities may be desired for a variety of topical applications. the beneficial effects while reducing the unwanted anxiety, 0039. In another embodiment of the invention, theacrine jitters and/or elevated heart rate effects. may be used to provide sports performance enhancers that 0046. In another embodiment of the invention, theacrine may reduce fatigue, improve mobility, and improve alertness. may be combined with anti-fatigue, focusing and/or energy 0040. In another embodiment of the invention, theacrine enhancing ingredients including caffeine, theobromine, theo may be used as a topical agent for incorporation into body phylline, Synephrine, yohimbine, rhodiola, ashwagandha, creams or lotions to produce a cream or lotion for lightening ginseng, ginkgo biloba, Siberianginseng, astragalus, licorice, skin, firming skin, and/or improving skin elasticity. A the green tea, reishi, dehydroepiandrosterone (DHEA), preg acrine topical agent may also be used to promote localized nenolone, tyrosine, N-acetyl-tyrosine, glucuronolactone, tau transdermal fat loss. Theacrine may also be used in a cream or rine, choline, CDP-choline, alpha-GPC, acetyl-L-carnitine, lotion to promote localized enhanced metabolism and/or 5-hydroxytryptophan, tryptophan, any beta-phenethy enhanced thermogenesis. lamines, Sceletium tortuosum (and Mesembrine alkaloids), 0041. In another embodiment of the invention, theacrine Dendrobium sp., Acacia rigidula, PQQ (Pyroloquinoline may be combined with one or more of an analgesic, for quinone), Ubiquinone(ol), nicotinamide riboside, picamilon, example ibuprofen or salicylic acid, anti-inflammatory Huperzine A (Chinese clubmoss) or Huperzia serrata, agents, salicin, fish oil (omega-3 fatty acids and specialized, L-dopa, Mucuna pruriens, forskolin (Coleus forskohli). small lipid pro-resolving derivatives), tart cherry, krill oil, Such a combination may be used in, for example, methods for astaxanthin, proteolytic , glucosamine Sulfate, chon enhancing cognitive function, including focus, concentra droitin sulfate, MSM (methylsulfonylmethane), SAMe tion, Sustained attention, working memory, choice and non (S-adenosylmethionine), ASU (avocado-Soybean unsapponi choice reaction time, executive function, Verbal and non fiable fraction), cetyl myristoleate, Dolichos falcate and/or Verbal learning, visuospatial memory and Verbal fluency. triterpenoids. 0047. In a further embodiment, theacrine may be com 0042. Theacrine itself can reduce biomarkers of inflam bined with a nutritional cholinergic ingredient such as mation in humans in response to acute inflammatory stressors 2-(dimethylamino) (DMAE), DMAE bitartrate, cho (e.g., intense exercise) or chronic consumption. Theacrine is line bitartrate, alpha-GPC (alpha-glycerophosphorylcho shown to decrease C-reactive protein (CRP), Erythrocyte line), Huperzine A, CDP choline, or combinations thereof. sedimentation rate (ESR), interleukin-6 (IL-6) and TNF-al One of skill in the art will recognize that these are merely pha. examples of cholinergic ingredients and that other such cho 0043. In another embodiment of the invention, theacrine linergic ingredients not listed are also contemplated by the may be combined with extracts from one or more of Acacia present invention. The combination of a nutritional cholin catechu, Andrographis paniculata, Scutalleria baicalensis, ergic ingredient with theacrine can result in a synergistic agmatine Sulfate, Stinging Nettle, Sea Buckthorn, curcumin, effect of increased psychometric measures for attention, Cissus Quadrilangularis, Boswellia Serrata, Wasabia focus and concentration beyond either the theacrine alone or japonica (wasabi extract for Tea Tree Oil), Emu Oil, Arnica, cholinergic ingredient alone. US 2015/O 132280 A1 May 14, 2015

0048. In another embodiment, any of the above combina Sub-acute repetitive dosing protocol, and acquire preliminary tions may be used with an isomer of congener of derivative data on various biomarkers of safety and tolerability, an of and/or a metabolite of theacrine such as, for example, experiment was performed. liberine or methylliberine. Other suitable examples include 0054 15 healthy subjects (meant-SD age, height, wgt, methylated theacrine, nitrate salts of theacrine, oxidized the BMI: 28.3+6.1 y, 175.7+11.5 cm, 89.8+21.7 kg, 29.1+4.7) acrine, reduced theacrine and/or theacrine salts. Agglomer ingested 200 mg of TeaCrineTM (Compound Solutions, Inc., ated theacrine, microencapsulated theacrine, liposomal the Carlsbad, Calif.) (TC) or Placebo (PLA). Anchored VAS acrine, esterified theacrine, theacrine glycerides, and questionnaires were used to detect changes in various aspects mixtures of theacrine with propylene glycol, lauroyl Mac of physical and mental energy and performance; side effect rogol, polyethylene glycol, theacrine derivatives, and/or the profiles, hemodynamics and biochemical markers of safety acrine co-crystallization products may also be used in accor were also collected overa 3-hr post-dosing period. A subset of dance with the principles of the invention. Such use of these, 6 subjects underwent a separate 7-day, open-label, repeated as well as co-crystals or other conjugates (such as quercetin or dose study comparing 100 mg, 200 mg and 400 mg of TC. pterostilbenoids), theacrine salts including citrate, Salicylate, 0055. The experiment was a randomized, placebo-con malate, tartrate, fumarate. Succinate, nitrate, Sulfate, phos trolled, double-blind, within-subject crossover clinical trial phate and the like, or PEG-ylated (Macrogol) preparations (for N=15 study). A further subset study was open-label, may increase the functional efficacy of the theacrine. sub-acute (7-day), repetitive dosing trial (for N=6 subset). 0049. In another embodiment, congeners of theacrine, for 0056 Six (6) subjects provided written and dated example catechins and other flavonoids, may be used an informed consent to participate in the 7-day repetitive dosing isolated, either independently or in combination with the study between Dec. 15, 2012 and Feb. 21, 2013. A separate acrine-based compositions. cohort of fifteen (15) subjects provided written and dated 0050. The dosage of theacrine may range from about 5 mg informed consent for the acute dose, placebo-controlled, to about 850 mg. In another embodiment, the range may be crossover clinical trial. All Subjects were in good health as from about 65 mg to about 300 mg. In relation to the weight determined by physical examination and medical history, of the human Subject, in one embodiment the dosage may be between the ages of 18 and 45 (inclusive). Subjects caffeine expressed as about 0.75 mg/kg of body weight to about 3 intake from foods/beverages was limited to <300 mg daily. mg/kg of body weight. In initial trials the human ED90 Subjects were willing and able to comply with the experimen appears to be about 1 mg/kg to about 3 mg/kg. tal and Supplement protocol. 0051. In one aspect of the invention, the theacrine may be 0057 Excluded subjects included subjects who were preg administered with caffeine. When administered with caf nant or lactating, Subjects with a history of hepatorenal, mus feine, the ratio of caffeine to theacrine, weight to weight, may culoskeletal, autoimmune, or neurologic disease, diabetes, range from about 0.5:1 to about 50:1, and in another embodi thyroid disease, adrenal disease, hypogonadism, inborn error ment, from about 1:1 to about 10:1, and in a further embodi of metabolism, personal history of heart disease, high blood ment, from about 2:1 to about 4:1. In administration, the pressure (systolic-140 mm Hg & diastolic-90 mm Hg), psy theacrine may be administered in an amount of about 5 mg to chiatric disorders, cancer, benign prostate hypertrophy, caf about 800 mg with caffeine amounts ranging from about 25 feine sensitivity, gastric ulcer, reflux disease, or any other mg to about 650 mg. In another embodiment the theacrine medical condition deemed exclusionary by the medical staff, may be administered in an amount of about 5 mg to about 650 Subjects currently taking thyroid, hyperlipidemic, hypogly mg with the caffeine, and in other embodiments may be any cemic, anti-hypertensive, anti-coagulant medications or OTC amount in that range. Such administration provides an products containing pseudoephedrine or other stimulants, increase, as measured by 100 mm VAS scales, in at least one Subjects who had used any weight-loss Supplements within of focus, concentration and energy, while also providing a 30-days prior to the study, subjects who had gained or lost decrease in at least one of anxiety, irritability, and feelings of more than 10 lbs within the past 30 days, subjects who drank overstimulation. Recommended dosages expressed in terms more than one cup of percolated coffee or 2 cups of tea per of amount per body weight can range from about 0.75 mg/kg day, Subjects who Smoked or had quit Smoking within the past to about 3 mg/kg of theacrine when administered in combi six months, Subjects who had a known allergy to any of the nation with caffeine, although theacrine may be administered ingredients in the Supplement or the placebo, and Subjects in the ranges described above up to about 850 mg regardless who did not demonstrate a verbal understanding of the of whether it is administered in combination with caffeine. Informed Consent document. 0052. The invention may be used for the treatment of a 0058. The study did not incorporate a dietary intervention variety of conditions. Such as improvement of mood, energy, (other than Supplement/placebo ingestion). Subjects were focus, or concentration. The invention may also promote a instructed to complete a 24-hr diet record prior to their first reduced appetite, reduce the perceived exertion from exer laboratory visit, and duplicate that 24-hr diet prior to each cise, decrease the discomfort associated with intense exer Subsequent laboratory visit. The study also did not incorpo cise, and may also improve sexual desire. rate any physical activity intervention. Subjects refrained from exercise and/or heavy physical activity the day prior to EXAMPLES each laboratory visit. 0059) Physical activity levels and health history were Example 1 determined using standardized questionnaires. Heart rate and blood pressure were measured using an Omron HEM-780. 0053. In order to examine the beneficial experiential Standing height was determined using a wall-mounted Stadi effects and psychometric properties of theacrine Supplemen ometer. Body weight was measured using a Seca 767TM tation in healthy Subjects, explore optimal dosing and poten Medical Scale. A 100 mm anchored VAS questionnaire for tial cumulative effects in a healthy human cohort with a 7-day, energy, fatigue, and concentration was distributed at each US 2015/O 132280 A1 May 14, 2015

acute lab session; additional VAS questionnaires were distrib 0069. Routes of Administration uted for the daily assessment over a 6-hour period during the 0070 The compounds may be administered by any route, 7-day subset study. Quest Diagnostics (Pittsburgh, Pa.) was including but not limited to oral, Sublingual, buccal, ocular, utilized to transport and analyze all blood samples. For each pulmonary, rectal, and parenteral administration, or as an oral laboratory session, subjects reported to the lab well hydrated, or nasal spray (e.g. inhalation of nebulized vapors, droplets, 10-12 hours postprandial, and at least 24-hours after their last or solid particles). Parenteral administration includes, for exercise session. example, intravenous, intramuscular, intraarterial, intraperi 0060 Statistical Analyses: toneal, intranasal, intravaginal, intravesical (e.g., to the blad 0061. Descriptive statistics (mean, median, SD, 95% CIs) der), intradermal, transdermal, topical, or Subcutaneous were used to quantify Subjects physical characteristics. RM administration. Also contemplated within the scope of the ANOVA, as well analyses of co-variance (ANCOVA), using invention is the instillation of theacrine in the body of the baseline scores as the co-variate (respectively), were used to patient in a controlled formulation, with systemic or local analyze between trial differences. Alpha was set to 0.05 (Ps0. release of the drug to occur at a later time. For example, the 05) for statistical significance, and <0.10 for trends. Effect drug may be localized in a depot for controlled release to the sizes were also calculated. Upon arrival for the first testing circulation. session, Subjects were randomly assigned to receive their 0071. The pharmaceutical compositions of the present respective Supplement/placebo. Each Subject ingested the invention may be administered in combination with a phar sponsor recommended dosage of their respective Supplement maceutically acceptable carrier. The active ingredients in (1 capsule prior to schedule of assessments). Supplements such formulations may comprise from 1% by weight to 99% were prepared in capsule form and packaged in coded generic by weight, or alternatively, 0.1% by weight to 99.9% by containers for double-blind administration. weight. “Pharmaceutically acceptable carrier” means any 0062 Results: carrier, diluent or excipient that is compatible with the other 0063. The 200 mg dose of TC caused significant improve ingredients of the formulation and not deleterious to the user. ments in energy (TC: +8.6% vs. PLA: -5.7%, P=0.049) and Useful excipients include microcrystalline cellulose, magne reductions in fatigue (TC: -6.7% vs. PLA: +5.8%, P=0.04). A sium Stearate, Stearate, any acceptable Sugar (e.g., trend for improved concentration was also noted (TC: +2.4% mannitol. Xylitol), and for cosmetic use an oil-base is pre vs. PLA: -1.3%, P=0.07). No changes in systemic hemody ferred. namics or side effect profiles were noted. The N-6 cohort 0072 The nutraceutical compositions of the present study demonstrated moderate to large effect sizes (0.50 to invention may be administered in combination with a nutra 0.71) with the 200 mg dose of TC over a 7-day period of ceutically acceptable carrier. The active ingredients in Such assessment for the following Subjective measures: energy, formulations may comprise from 1% by weight to 99% by fatigue, concentration, anxiety, motivation to exercise and weight, or alternatively, 0.1% by weight to 99.9% by weight. libido. “Nutraceutically acceptable carrier’ means any carrier, dilu 0064. The results of the experiment are also shown graphi ent or excipient that is compatible with the other ingredients cally in FIGS. 2 through 7. of the formulation and not deleterious to the user. Useful 0065. As shown in FIG. 2, individuals who were admin excipients include microcrystalline cellulose, istered theacrine reported higher levels of energy at each time Stearate, calcium Stearate, any acceptable Sugar (e.g., manni increment measured. FIG. 3 shows that while individuals tol. Xylitol), and for cosmetic use an oil-base is preferred. given the placebo reported higher fatigue at 60 minutes after 0073. Whereas, the present invention has been described administration, those administered theacrine reported lower in relation to certain embodiments thereof, and many details levels of fatigue. FIGS. 4 and 5 show that no substantial have been put forth in its illustration, it should be understood change in Systemic hemodynamics occurred. that other and further modifications, apart from those shown 0066 FIGS. 6 and 7 show the results of the N=6 cohort or Suggested herein, may be made within the spirit and scope study. With a 200 mg dose of theacrine over a 7 day period of of this invention. Descriptions of the embodiments shown in assessment, it was observed that theacrine has a positive the drawings should not be construed as limiting or defining effect on each of energy, fatigue, concentration, anxiety, the ordinary and plain meanings of the terms of the claims motivation to exercise, and libido. That is, fatigue and anxiety unless Such is explicitly indicated. were decreased substantially, while energy, concentration, 0074 As such, those skilled in the art will appreciate that motivation to exercise and libido were increased Substan the conception, upon which this disclosure is based, may tially. readily be utilized as a basis for the designing of other struc 0067 Thus, the experimental data shows that theacrine tures, methods and system for carrying out the several pur Supplementation appears to favorably impact several Subjec poses of the present invention. It is important, therefore, that tive and psychometric indices of energy and fatigue. These the claims be regarded as including Such equivalent construc findings, as well as the potential cumulative effects on focus, tions insofar as they do not depart from the spirit and scope of concentration, and libido are worthy of future study. the present invention. 0068 Although previously published animal data sug 0075 All references cited herein are incorporated by ref gested much larger doses of “TC” would be necessary to exert erence in their entirety. The present invention may be embod its neurophysiological effects, this first-in-human data Sug ied in other specific forms without departing from the spirit or gests much lower doses of 1.5 mg to 2.5 mg/kg bodyweight essential attributes thereofand, accordingly, reference should (for example, approximately 200 mg in a 100 kg individual) be made to the appended claims, rather than to the foregoing provide optimal benefit. Follow-up studies should confirm specification, as indicating the scope of the invention. these results, explore other objective measures of physical What is claimed is: and cognitive function, and clarify the mechanisms by which 1. A dietary Supplement comprising about 5 mg to about theacrine exerts the observed salutary effects. 850 mg theacrine, either natural or synthetic. US 2015/O 132280 A1 May 14, 2015

2. The dietary supplement of claim 1, where the supple 5. The dietary supplement of claim 1, wherein the supple ment further comprises at least one additional active ingredi ment is in a solid oral dosage form. ent. 6. The dietary supplement of claim 1, wherein the supple 3. The dietary supplement of claim 2, wherein said active ment is in a topical form for administration. ingredient is selected from the group consisting of gallic acid, 7. The dietary supplement of claim 2, wherein said addi (+)-catechin (C), (-)-epicatechin (EC), (+)-gallocatechin tional active ingredient is a theacrine congener or theacrine (GC), (-)-epigallocatechin (EGC), (-)-catechingallate (CG), analog. (-)-gallocatechin gallate (GCG), (-)-epicatechin gallate 8. The dietary supplement of claim 7, wherein said the (ECG) and (-)-epigallocatechin gallate (EGCG), glycerides, acrine congener or analog is selected from the group consist propylene glycol, lauroyl macrogol, lauroyl macrogolderiva ing of caffeine, methyl caffeine, theobromine, theophylline, tives, co-crystallization products of theacrine, bioperine, pip erine, black pepper, bergamottin, dihydroxybergamottin liberine, methylliberine, and combinations thereof. (CYP3A4), flavonoids (naringin, hesperidin, nobiletin, tan 9. The dietary supplement of claim8, wherein the theacrine geretin, quercetin), pterostilbene, fisetin, phytosomes, Sali congener or analog is caffeine. cin, fish oil (omega-3 fatty acids and specialized, Small lipid 10. A method of treatment for improving physical perfor pro-resolving epoxide derivatives), oxylipins, tart cherry, mance or energy in an individual, comprising: krill oil, astaxanthin, proteolytic enzymes, glucosamine Sul providing the individual with a composition comprising fate, chondroitin sulfate, MSM (methylsulfonylmethane), about 5 mg to about 850 mg of theacrine, either natural SAMe (S-adenosylmethionine), ASU (avocado-soybean or synthetic, unsapponifiable fraction), cetyl myristoleate, Dolichos fal wherein upon administration of the composition the indi cate, triterpenoids, acacia catechu, Andrographispaniculata, vidual experiences improvement of at least one of mood, Scutalleria baicalensis, Agmatine Sulfate, Stinging Nettle, energy, focus, concentration or sexual desire or a reduc Sea Buckthorn, Curcumin, Cissus Ouadrilangularis, tion of at least one of anxiety or fatigue. Boswellia Serrata, Wasabia japonica (wasabi extract for Tea 11. The method of claim 10, wherein the amount of the Tree Oil), Emu Oil, Arnica, Mangifera indica L. (Anacardi acrine provided is about 65 mg to about 300 mg. aceae), Lagenaria breviflora, Zingiber officinale (ginger & 12. The method of claim 10, wherein the patient experi gingerols/shogaols), hoodia gordonii, caffeine, yohimbine, ences a decrease in fatigue of at least about 6 percent. methylsynephrine, Synephrine, theobromine, flavenoids, 13. The method of claim 10, wherein the patient experi tocopherols, theophylline, alpha-yohimbine, conjugated ences an increase in energy of at least about 8 percent. linoleic acid (CLA), octopamine, evodiamine, passion 14. The method of claim 10, wherein the composition flower, red pepper, cayenne, raspberry ketone, guggul, green provided to the individual further comprises at least one tea, guarana, kola nut, beta-Phenethylamines, Acacia ingredient selected from the group consisting of caffeine, rigidula, forskolin (Coleus forskohli), theophylline, Syneph theobromine, naringin, hesperidin, 2-(dimethylamino)etha rine, yohimbine, rhodiola, ashwagandha, ginseng, ginkgo nol (DMAE), DMAE bitaritrate, choline bitartrate, alpha biloba, Siberianginseng, astragalus, licorice, green tea, reishi, GPC, huperzine A, and CDP choline. dehydroepiandrosterone (DHEA), pregnenolone, tyrosine, 15. The method of claim 14, wherein the at least one N-acetyl-tyrosine, glucuronolactone, taurine, choline, CDP ingredient is caffeine. choline, alpha-GPC, Acetyl-L-carnitine, 5-hydroxytryp 16. The method of claim 15, wherein the caffeine is present tophan, tryptophan, Phenethylamines, Sceletium tortuosum in the composition in the amount of about 25 mg to about 650 (and Mesembrine alkaloids), Dendrobium sp., Acacia rigidula, PQQ (Pyroloquinoline quinone), Ubiquinone(01), ng. Nicotinamide riboside, picamilon, Huperzine A (Chinese 17. The method of claim 15, wherein the weight to weight clubmoss or Huperzia serrata, L-dopa, Mucuna pruriens, and ratio of theacrine to caffeine is from about 0.5:1 to about 50:1. forskolin (Coleus forskohli), 2-(dimethylamino)ethanol 18. The method of claim 15, wherein the weight to weight (DMAE), DMAE bitartrate, cholinebitartrate, and combina ratio of theacrine to caffeine is from about 1:1 to about 10:1. tions thereof. 19. The method of claim 15, wherein the weight to weight 4. The dietary Supplement of claim 1, further comprising a ratio of theacrine to caffeine is from about 2:1 to about 4:1. pharmaceutically acceptable carrier. k k k k k