THETWO TORTOITUMIAUS 20180104248A1ULTIMATE TATLI HIMIN ( 19) United States ( 12) Patent Application Publication ( 10 ) Pub . No. : US 2018 /0104248 A1 Lopez et al. (43 ) Pub . Date : Apr . 19 , 2018

(54 ) THEACRINE -BASED SUPPLEMENT AND Publication Classification METHOD OF USE THEREOF IN A (51 ) Int. Cl. SYNERGISTIC COMBINATION WITH A61K 31/ 522 ( 2006 . 01 ) C07D 487/ 04 (2006 . 01) (52 ) U . S . CI. @(71 ) Applicant : Ortho - Nutra, LLC , Morganville , NJ CPC ...... A61K 31/ 522 ( 2013 .01 ); C07D 487 /04 (US ) (2013 . 01 ) @(72 ) Inventors : Hector L Lopez , Cream Ridge , NJ (US ); Shawn Wells , Lewisville , TX (US ); Tim N . Ziegenfuss , Chardon , OH (57 ) ABSTRACT (US ) A human dietary supplement comprises theacrine and @( 73 ) Assignee : Ortho -Nutra , LLC , Morganville , NJ optionally other compounds that modulate the effects of theacrine . Uses for the theacrine -containing supplement (US ) include improvement of at least one ofmood , energy, focus, concentration or sexual desire or a reduction of at least one (21 ) Appl. No. : 15 /600 , 371 of anxiety or fatigue. A synergistic composition comprises ( 22) Filed : May 19 , 2017 co -administration of theacrine and caffeine , wherein the co - administered caffeine reduces theacrine oral clearance Related U .S . Application Data (CL / F ) and oral volume of distribution (Vd / F ) . In addition , the co - administered caffeine increases area under the plasma (63 ) Continuation - in -part of application No. 14 / 539, 726 , concentration time curve ( AUC ) of theacrine , and increases filed on Nov. 12 , 2014 . theacrine maximum plasma concentration ( Cmax ) in com (60 ) Provisional application No .61 / 903 ,362 , filed on Nov . parison with the corresponding pharmacokinetic parameters 12 , 2013 . when theacrine is administered alone .

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THEACRINE -BASED SUPPLEMENT AND depth . Caffeine is by far the most studied , and the most METHOD OF USE THEREOF IN A commonly used stimulant found in tea . Theacrine appears to SYNERGISTIC COMBINATION WITH have an opposite effect, despite being very similar in chemi CAFFEINE cal structure . Recent experiments have shown that theacrine [0001 ] This application is a continuation - in -part of U . S . exhibits a variety of activities, some of which seem incon patent application Ser . No . 14 / 539, 726 , filed Nov. 12 , 2014 , sistent. which claims the benefit of U . S . Provisional Application Ser. 10007 ]. In the past several years , there has been a substan No. 61 /903 ,362 , filed Nov. 12 , 2013 , each of which are tial shift in public opinion toward using naturally occurring hereby incorporated by reference herein . chemical compounds for a variety of purposes , instead of synthetic chemicals . For example , a wide variety of natural FIELD OF THE INVENTION chemicals are now commonly used as sedatives, e . g . valer ian root and chamomile , anti - depressants , e . g . St. John ' s [0002 ] The present invention relates to systems and meth wort , stimulants , e . g . caffeine , and concentration , e . g . gin ods for utilizing theacrine alone and in combination for use seng . In general , naturally occurring compounds may be in providing physiological benefits . More particularly , the easier for the body to digest and interact with and may invention relates to theacrine and other naturally occurring include minimal and 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 ring chemical compounds and mixtures thereof that may to provide physiological benefits , which may vary according provide benefits . It is also desirable to provide chemical to theacrine concentration and the presence of synergists and compounds and mixtures thereof that may be used to pro antagonists . vide a variety of benefits , varying by concentration , thus BACKGROUND OF THE INVENTION requiring production or harvesting of fewer materials . [0003 ] Tea is one of the most widely consumed products SUMMARY OF THE INVENTION in the world . Tea and the different varieties of tea have been extensively studied . Many epidemiologic and preclinical [0009 ] Accordingly , the primary object of the present studies suggest that drinking tea may reduce the risk of invention is to provide a chemical composition comprising cancer and cardiovascular disease. Theacrine , an theacrine , either naturally or synthetically produced , and similar to caffeine, is relatively rare and only found optionally other chemicals , including theacrine congeners or in a few varieties of tea (kucha tea , genus Camellia ), the fruit analogs, to provide a plurality of desirable effects . Theacrine cupuaçu , and other plants related to coffee and cacao ( genera analogs may include , but are not limited to , caffeine , methyl Coffea and Theobroma ), such as Coffea liberica , Coffea caffeine , , , liberine and methyl dewevrei, Coffea abeokutae and . liberine , and their variants . Other suitable actives may [ 0004 ) 1 , 3 , 7 , 9 tetramethyluric acid , commonly known as include one or more ergogenic or nootropic compounds such theacrine, was not studied until around 1975 . However, it as CDP choline , alpha -GPC , choline bitartrate , St John ' s has been known of since about 1937 , when it was detected Wort , sulbutiamine , and the like . in dry , decaffeinated Camellia sinensis tea leaves. At this 100101 Theacrine exhibits a wide variety of effects time, the Camellia assamica var. kucha variety of tea is the depending on dosage . The presence of other ingredients may primary source of naturally occurring theacrine and pro also modulate its effects . It may be used to promote calm or duces the chemical in higher concentrations than other focus and to relax , but also may be used to enhance energy known plants . Interestingly , theacrine has not been detected and stamina . It may also serve as an antioxidant and an at all in more traditional teas strains. It is believed to be anti - inflammatory . formed by methylation of caffeine and may be an interme [0011 ]. In one embodiment, theacrine may be used to diary in the production of liberine or other . Its modulate stimulants , to provide heightened energy without natural function , if any, remains unknown . Theacrine has heightened anxiety or nervousness. There may be variability garnered attention only relatively recently , and often only as among individuals , as described herein . a secondary consideration when analyzing other com [0012 ] In another embodiment theacrinemay be used as a pounds. Some studies suggest it may have beneficial quali mild sedative or relaxant. ties , such as serving as an effective anti- oxidant , anti inflammatory and may have anti -obesity properties. [0013 ] In a further embodiment, theacrine may be used to [0005 ] In the studies involving theacrine , beneficial effects promote weight loss , act as an antioxidant and as an anti may be at least partially attributable to an assortment of inflammatory . Theacrine may be used transdermally to purine and phenolic compounds . The more com enhance one or more of these effects . mon tea - related purine alkaloids include caffeine , theobro [0014 ] In one embodiment, a dietary supplement compris mine , theophyline and theacrine . The major tea phenolic ing about 5 mg to about 850 mg theacrine, either natural or compounds are gallic acid and eight naturally occurring tea synthetic , is provided . catechins , including ( + ) - catechin ( C ) , ( - ) -epicatechin ( EC ) , [0015 ] In another embodiment, a method of treatment for ( + ) - gallocatechin (GC ) , ( - ) - epigallocatechin (EGC ) , ( - ) improving physical performance or energy in an individual catechin gallate (CG ) , ( - ) - gallocatechin gallate (GCG ) , ( - ) is provided . Said method involves providing the individual epicatechin gallate ( ECG ) and ( - ) - epigallocatechin gallate with a composition comprising about 5 mg to about 850 mg ( EGCG ) . of theacrine , either natural or synthetic , wherein upon [0006 ] Many different biologic and physiologic activities administration of the composition the individual experiences have been attributed to tea and its various components . improvement of at least one of mood , energy , focus , con However, only a few of its components have been studied in c entration or sexual desire or a reduction of at least one of US 2018 /0104248 A1 Apr. 19 , 2018

anxiety or fatigue . In another embodiment, a second com [ 0026 ] FIG . 2 depicts , in one embodiment, a graph of pound such as caffeine may also be administered in the results of a trial showing perceived energy on a VAS scale composition . ( 0 to 10 cm ) at 1 , 2 and 3 hours after administration of [ 0016 ] It is therefore an object of the present invention to theacrine or placebo . provide compositions including theacrine capable of impart [0027 ] FIG . 3 depicts , in one embodiment, a graph of ing a plurality of positive effects . results of a trial showing perceived fatigue on a VAS scale ( 0 to 10 cm ) at 0 minutes and 60 minutes after administration [0017 ] It is another object of the present invention to of theacrine or placebo . provide congeners , derivatives and iterations of theacrine [0028 ] FIG . 4 depicts , in one embodiment, a graph of and synthetic chemical equivalents of theacrine . results of a trial showing systolic blood pressure at various [ 0018 ] It is another object of the present invention to time intervals after administration of theacrine or placebo . provide agglomerated theacrine , theacrine salts , microen 100291. FIG . 5 depicts , in one embodiment, a graph of capsulated , liposomal or esterified theacrine . results of a trial showing diastolic blood pressure at various [0019 ] It is another object of the present invention to time intervals after administration of theacrine or placebo . provide theacrine combined with glycerides, propylene gly (0030 ). FIG . 6 shows, in one embodiment, the results of a col, polyethylene glycol (PEG ) , lauroyl macrogol, lauroyl 7 day repeated dose study of 200 mg theacrine relative to macrogol derivatives and co -crystallization products of baseline of fatigue , anxiety and libido at various intervals theacrine . after dosages ( at 0 hr, 1 hr, 4 hr, 6 hr; bars left to right for [0020 ] These and other objects and advantages of the each measured category ) . present invention will become apparent from a reading of [0031 ] FIG . 7 shows, in one embodiment, the results of a the attached specification and appended claims. There has 7 day repeated dose study of 200 mg theacrine relative to thus been outlined , rather broadly , the more important baseline of energy , motivation to exercise , and concentration features of the invention in order that the detailed descrip at various intervals after dosages (at Ohr , 1 hr, 4 hr , 6 hr ; bars tion thereof that follows may be better understood , and in left to right for each measured category ) . order that the present contribution to the art may be better [ 0032 ] FIG . 8 ( A ) depicts , in one embodiment , individual appreciated . There are features of the invention that will be plasma concentrations of theacrine after single oral dose of described hereinafter and which will form the subject matter theacrine 25 mg. of the claims appended hereto . [0033 ] FIG . 8 ( B ) depicts , in one embodiment, individual [0021 ] In one embodiment, theacrine may be co - adminis plasma concentrations of theacrine after single oral dose of tered with caffeine to produce a synergistic composition , theacrine 125 mg. wherein the co -administered caffeine reduces theacrine oral [0034 ] FIG . 8 ( C ) depicts , in one embodiment, individual clearance and oral volume of distribution . The co - adminis plasma concentrations of theacrine after single oral dose of tered caffeine in the synergistic composition increases the theacrine 125 mg plus caffeine 150 mg . bioavailability and maximum plasma concentration of [0035 ] FIG . 9 depicts , in one embodiment, Forest plot theacrine in comparison with the corresponding pharma illustrating the probability of interaction magnitude between cokinetic parameters when theacrine is administered alone . theacrine and caffeine using 90 % confidence intervals about [0022 ] In one embodiment, a synergistic composition may the geometric mean ratio of the observed pharmacokinetic comprise theacrine and caffeine having a weight to weight parameters following a single theacrine dose ( - 25 mg ratio about 1 : 1 . 2 . Said synergistic composition may com theacrine and 1 - 125 mg theacrine in combination with 150 prise about 125 mg theacrine and about 150 mg caffeine . mg caffeine ) . Said synergistic composition may be administered once [0036 ] FIG . 10 ( A ) depicts , in one embodiment, individual daily . plasma concentrations of caffeine after single oral dose of [0023 ] In one embodiment , a method of enhancing the caffeine 150 mg . intensity and duration of theacrine ’s neurocognitive efficacy [0037 ] FIG . 10 (B ) depicts , in one embodiment, individual beyond a systemic concentration threshold . Said method plasma concentrations of caffeine after single oral dose of involves providing an individual with a synergistic compo theacrine 125 mg plus caffeine 150 mg . sition comprising co - administration of theacrine and caf [0038 ] FIG . 11 depicts , in one embodiment, Forest plot feine . illustrating the probability of interaction magnitude between 10024 ] In one embodiment, a method of treatment for caffeine and theacrine using 90 % confidence intervals about improving physical or mental performance in an individual the geometric mean ratio of the observed pharmacokinetic is provided . Said method involves providing the individual parameters following a single caffeine dose ( 150 mg) alone with a synergistic composition comprising about 5 mg to or in combination with theacrine ( 125 mg) . about 850 mg of theacrine and about 25 mg to about 650 mg [0039 ] FIG . 12 ( A ) depicts , in one embodiment, mean of caffeine . Upon administration of the synergistic compo values in heart rate after single dose theacrine 25 mg ( -- - ) , sition , the individual experiences improvement of at least theacrine 125 mg ( - 1 -) , caffeine 150 mg ( - - ) , or theacrine one of mood , energy , focus , concentration , cognitive func 125 mg plus caffeine 150 mg ( - A - ) . tion , or sexual desire or a reduction of at least one of anxiety [0040 ] FIG . 12 (B ) depicts , in one embodiment, mean or fatigue . values in systolic blood pressure after single dose theacrine 25 mg ( - . - ) , theacrine 125 mg ( - 1 - ) , caffeine 150 mg ( - - ) , or theacrine 125 mg plus caffeine 150 mg ( - A -) . BRIEF DESCRIPTION OF THE DRAWINGS [ 0041 ] FIG . 12 ( C ) depicts , in one embodiment, mean [0025 ] FIG . 1 depicts , in one embodiment, a molecular values in diastolic blood pressure after single dose theacrine diagram of theacrine in accordance with the principles of the 25 mg ( - - - ) , theacrine 125 mg ( - 1 - ) , caffeine 150 mg ( - - ) , invention . or theacrine 125 mg plus caffeine 150 mg ( - A - ). US 2018 /0104248 A1 Apr. 19 , 2018

[0042 ] FIG . 12 ( D ) depicts , in one embodiment , mean thereby stabilizing heart rate and other metabolic activity . values in rate pressure product after single dose theacrine 25 That is , a combination of theacrine and caffeine may result mg ( - - - ) , theacrine 125 mg ( - - ) , caffeine 150 mg ( - - ) , or in a composition that imparts the increased focus and energy theacrine 125 mg plus caffeine 150 mg ( - A - ) . induced by caffeine , but without the higher heart rate and blood pressure due to modulation of caffeine by theacrine . DETAILED DESCRIPTION OF THE Thus the combination may result in heightened awareness INVENTION and calmness without the jitters caffeine may cause . [ 0043] Before explaining at least one embodiment of the [0050 ] Theacrine and caffeine administered in combina invention in detail , it is to be understood that the invention tion has unexpected effects . Indeed , it has been unexpectedly is not limited in its application to the details of construction found that a combination of theacrine and caffeine admin and to the arrangements of the components set forth in the istered to human subjects results in increased levels of focus , following description or illustrated in the drawings. The concentration and energy as measured by 100 mm VAS invention is capable of other embodiments and of being scales while also decreasing measures of anxiety , irritability practiced and carried out in various ways. Also , it is to be or feelings of overstimulation . Such decrease in anxiety , understood that the phraseology and terminology employed irritability , jitters and /or feelings of overstimulation is herein are for the purpose of description and should not be reflected by patients on standardized 100 mm VAS at regarded as limiting. durations of 30 minutes , 60 minutes , 120 minutes and 180 10044 ] Disclosed is an invention relating to uses of minutes as compared with administration of caffeine alone . theacrine, also known as 1 , 3 , 7 , 9 - tetramethyluric acid , Temu The combination also exhibits a prolonged duration of rin , Temorine , Tetramethylurie acid , Tetramethyl action in increased energy , focus and / or concentration as and 1 , 3 , 7 , 9 -tetramethylpurine - 2 , 6 , 8 - trione . Theacrine may compared to either caffeine or theacrine alone . be produced synthetically or may be isolated from a natural 10051 ]. Furthermore , theacrine also has unexpected effects source . Theaerine isolated from a natural source may be on the development of tolerance and habituation of caffeine . purified to 95 % or greater . Optionally , less purification may In a fourteen day study of repetitive dosing of theacrine and be used such that theacrine accounts for 50 % , or even less , caffeine , it was found that the subjects maintained height of the material. In some embodiments , it may be preferable ened psychometric indices of energy , focus , concentration , to utilize theacrine isolated from a natural source which may motivation to exercise , motivation to accomplish and fin include other congeners of theacrine typically found in ished tasks, and improved mood at Day 14 as compared to theacrine isolates . caffeine alone , and absolute levels of energy and motivation [ 0045 ] In one embodiment, theacrine may be combined were greater than with theacrine alone. Those taking with other chemical compounds to provide a plurality of theacrine alone still maintained elevated subjective energy , positive effects on a human or other animal. By altering the focus , concentration , motivation to exercise , motivation to dosage of theacrine and / or chemical compounds it is com accomplish and finish tasks , sexual desire and improved bined with , various physiological effects may be selected mood with decreased anxiety as compared to Day 1 . Sub for . The compositions may provide primarily a single ben jects taking caffeine alone saw decreasing levels of energy , efit , or may provide multiple benefits simultaneously . focus and concentration by Day 5 of the study and had [0046 ] In another embodiment, theacrine may be used at increased anxiety scores throughout the study . lower dosage levels and / or in conjunction with compounds [0052 ] In another embodiment of the invention , theacrine that modulate or antagonize its activity . Such compositions may be combined with one or more bioavailability enhanc may induce an improved mood , higher energy , a reduction ers , including for example bioperine, piperine , black pepper, in fatigue , increased focus , increased concentration , bergamottin , dihydroxybergamottin (CYP3A4 inhibitors ), increased mobility , decreased appetite , and increased flavonoids ( including hesperidin , naringin , tangeritin , quer stamina . cetin and nobiletin both in isolation and in combination ) , [ 0047 ] An advantage of using the invention may be the pterostilbenes, fisetin , nanoencapsulation , microencapsula reduced likelihood that a person develops a tolerance to tion , liposomes and / or phytosomes . Which enhancers are chemical compositions in accordance with the principles of combined with theacrine may depend on which qualities of the invention . That is , a person may not become desensitized theacrine are desired for a particular use . to the effects induced . [0053 ] In another embodiment of the invention , theacrine [ 0048 ] In another embodiment, theacrine may be used at may be introduced using one or more delivery methods, higher dosage levels and / or with synergistic compounds . including , for example transdermal patches and / or creams, These compositions may increase a person ' s basal/ resting ready to mix powders , intravenous methods, capsules, tab metabolic rate , increase thermogenesis , decrease appetite , lets , liquid ( including liquids for mixing with other bever enhance cognitive performance, increase Alpha wave brain ages ) , softgels , shot format , and / or cosmetic applications activity , and /or induce euphoria . Without being bound by including soaps , lotions and shampoos . Theacrine ' s anti theory , the inventors believe that at higher dosage levels, inflammatory qualities may be desired for a variety of theacrine may be noradrenergic and dopaminergic , and may topical applications. exhibit increased inhibition . [0054 In another embodiment of the invention , theacrine [ 0049 ] In another embodiment of the invention , theacrine may be used to provide sports performance enhancers that may be combined with ephedrine, caffeine , salicylic acid or may reduce fatigue , improve mobility , and improve alert the like . These may be used to either modulate the more ness . sedative effects of theacrine or optionally to interact syner [0055 ] In another embodiment of the invention , theacrine gistically with the more stimulating effects of theacrine . For may be used as a topical agent for incorporation into body example , theacrine may be combined with caffeine in order creams or lotions to produce a cream or lotion for lightening to modulate the excessive stimulatory effects of caffeine , skin , firming skin , and /or improving skin elasticity . A US 2018 /0104248 A1 Apr. 19 , 2018 theacrine topical agent may also be used to promote local tone , taurine , choline , CDP -choline , alpha -GPC , acetyl- L ized transdermal fat loss . Theacrine may also be used in a carnitine, 5 -hydroxytryptophan , tryptophan , any beta -phen cream or lotion to promote localized enhanced metabolism ethylamines , Sceletium tortuosum ( and Mesembrine and / or enhanced thermogenesis . alkaloids ), Dendrobium sp . , Acacia rigidula , PQQ (Pyrolo [0056 ] In another embodiment of the invention , theacrine quinoline quinone ) , Ubiquinone (ol ) nicotinamide riboside , may be combined with one or more of an analgesic , for picamilon , Huperzine A (Chinese clubmoss ) or Huperzia example ibuprofen or salicylic acid , anti - inflammatory serrata , L - dopa , Mucuna pruriens, forskolin ( Coleus fors agents , salicin , fish oil ( omega - 3 fatty acids and specialized , kohlli ) . Such a combination may be used in , for example , small lipid pro -resolving derivatives ) , tart cherry , krill oil, methods for enhancing cognitive function , including focus , astaxanthin , proteolytic , glucosamine sulfate , concentration , sustained attention , working memory , choice chondroitin sulfate , MSM (methylsulfonylmethane ) , SAMe and non - choice reaction time, executive function , verbal and ( S - adenosylmethionine ), ASU ( avocado - soybean unsap non - verbal learning , visuospatial memory and verbal flu ponifiable fraction ), cetyl myristoleate , Dolichos falcate ency . and/ or triterpenoids . [0062 ] In a further embodiment, theacrine may be com [0057 ] Theacrine itself can reduce biomarkers of inflam bined with a nutritional cholinergic ingredient such as 2 - di mation in humans in response to acute inflammatory stress methylamino ) (DMAE ) , DMAE bitartrate , choline ors ( e . g . , intense exercise ) or chronic consumption . bitartrate , alpha -GPC (alpha - glycerophosphorylcholine ) , Theacrine is shown to decrease C - reactive protein (CRP ) , Huperzine A , CDP choline , or combinations thereof. One of Erythrocyte sedimentation rate ( ESR ) , interleukin - 6 ( IL - 6 ) skill in the art will recognize that these are merely examples and TNF -alpha . of cholinergic ingredients and that other such cholinergic [0058 ] In another embodiment of the invention , theacrine ingredients not listed are also contemplated by the present may be combined with extracts from one or more of Acacia invention . The combination of a nutritional cholinergic catechu , Andrographis paniculata , Scutalleria baicalensis , ingredient with theacrine can result in a synergistic effect of agmatine sulfate , Stinging Nettle , Sea Buckthorn , curcumin , increased psychometric measures for attention , focus and Cissus Quadrilangularis , Boswellia Serrata , Wasabia concentration beyond either the theacrine alone or cholin japonica (wasabi extract for Tea Tree Oil ) , Emu Oil, Arnica , ergic ingredient alone . Mangifera indica L . ( Anacardiaceae ) , Lagenaria breviflora , 10063 ]. In another embodiment , any of the above combi and / or Zingiber officinale ( ginger & gingerols / shogaols ) . nations may be used with an isomer of , congener of, Such a combination may be used in , for example , methods derivative of and /or a metabolite of theacrine such as , for of augmenting and enhancing pain modulation , and control example, liberine or methylliberine . Other suitable examples ling the inflammatory response . include methylated theacrine , nitrate salts of theacrine , oxi [0059 ] In another embodiment of the invention , theacrine dized theacrine , reduced theacrine and / or theacrine salts . may be combined with one or more metabolic enhancers Agglomerated theacrine, microencapsulated theacrine , lipo including hoodia gordonii , caffeine, yohimbine , synephrine , somal theacrine , esterified theacrine, theacrine glycerides , theobromine , flavonoids, flavanone glycosides such as nar and mixtures of theacrine with propylene glycol, lauroyl ingin and hesperidin , tocopherols , theophylline , alpha -yo Macrogol, polyethylene glycol, theacrine derivatives, and /or himbine, conjugated linoleic acid (CLA ) , octopamine , evo theacrine co - crystallization products may also be used in diamine , passion flower, red pepper, cayenne, raspberry accordance with the principles of the invention . Such use of ketone , guggul, green tea , guarana , kola nut , any beta these , as well as co - crystals or other conjugates ( such as phenethylamines , Acacia rigidula , and /or forskolin (Coleus or pterostilbenoids) , theacrine salts including cit forskohlli ) . Such a combination may be used in , for example , rate , salicylate , malate , tartrate , fumarate , succinate , nitrate , methods of enhancing 1 ) thermogenesis / fat and carbohy sulfate , phosphate and the like, or PEG - ylated (Macrogol ) drate metabolism ; 2 ) fat loss, weight management and preparations may increase the functional efficacy of the improving body composition ( loss of body fat , while retain theacrine . ing or sparing lean body mass /fat free mass /muscle ) ; and / or [0064 ] In another embodiment, congeners of theacrine , for 3 ) appetite control/ appetite modulation . example catechins and other flavonoids , may be used an [0060 ] Combinations of theacrine and , for example , caf isolated , either independently or in combination with feine , theobromine, or flavanone glycosides such as naringin theacrine -based compositions . or hesperidin , upon administration to subjects show [0065 ] The dosage of theacrine may range from about 5 decreased VAS 100 mm ratings of perceived physical exer mg to about 850 mg. In another embodiment, the range may tion with exercise as compared to ingredients alone . Theo be from about 65 mg to about 300 mg. In relation to the bromine is used by some for improvement of breathing or a weight of the human subject, in one embodiment the dosage subjective feeling of improved breathing , but is also known may be expressed as about 0 . 75 mg/ kg of body weight to to increase feelings of anxiety , jitters and an elevated heart about 3 mg/ kg of body weight. In initial trials the human rate in some subjects . A combination of theobromine and ED90 appears to be about 1 mg/ kg to about 3 mg/ kg . theacrine retains the beneficial effects while reducing the 10066 ] In one aspect of the invention , the theacrine may be unwanted anxiety , jitters and / or elevated heart rate effects . administered with caffeine. When administered with caf [0061 ] In another embodiment of the invention , theacrine feine , the ratio of caffeine to theacrine, weight to weight, may be combined with anti - fatigue , focusing and / or energy may range from about 0 . 5 : 1 to about 50 : 1 , and in another enhancing ingredients including caffeine, theobromine, the embodiment, from about 1: 1 to about 10 : 1, and in a further ophylline , synephrine , yohimbine , rhodiola , ashwagandha , embodiment, from about 2 : 1 to about 4 : 1 . In administration , ginseng , ginkgo biloba , siberian ginseng, astragalus , lico the theacrine may be administered in an amount of about 5 rice , green tea, reishi, dehydroepiandrosterone (DHEA ) , mg to about 800 mg with caffeine amounts ranging from pregnenolone, tyrosine, N - acetyl- tyrosine , glucuronolac about 25 mg to about 650 mg. In another embodiment the US 2018 /0104248 A1 Apr. 19 , 2018 theacrine may be administered in an amount of about 5 mg other medical condition deemed exclusionary by the medical to about 650 mg with the caffeine , and in other embodiments staff , subjects currently taking thyroid , hyperlipidemic , may be any amount in that range . Such administration hypoglycemic , anti -hypertensive , anti - coagulant medica provides an increase , as measured by 100 mm VAS scales, tions or OTC products containing pseudoephedrine or other in at least one of focus, concentration and energy , while also stimulants, subjects who had used any weight- loss supple providing a decrease in at least one of anxiety , irritability, ments within 30 - days prior to the study, subjects who had and feelings of overstimulation . Recommended dosages gained or lost more than 10 lbs within the past 30 days , expressed in terms of amount per body weight can range subjects who drank more than one cup of percolated coffee from about 0 .75 mg/ kg to about 3 mg /kg of theacrine when or 2 cups of tea per day , subjects who smoked or had quit administered in combination with caffeine , although smoking within the past six months , subjects who had a theacrine may be administered in the ranges described above known allergy to any of the ingredients in the supplement or up to about 850 mg regardless of whether it is administered the placebo , and subjects who did not demonstrate a verbal in combination with caffeine . understanding of the Informed Consent document. [0067 ] The invention may be used for the treatment of a [0073 ] The study did not incorporate a dietary intervention variety of conditions, such as improvement ofmood , 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 . 10074 ] Physical activity levels and health history were Example 1 determined using standardized questionnaires. Heart rate [0068 ] In order to examine the beneficial experiential and blood pressure were measured using an Omron HEM effects and psychometric properties of theacrine supplemen 780 . Standing height was determined using a wall -mounted tation in healthy subjects , explore optimal dosing and poten stadiometer . Body weightwas measured using a Seca 767TM tial cumulative effects in a healthy human cohort with a Medical Scale . A 100 mm anchored VAS questionnaire for 7 - day, sub -acute repetitive dosing protocol, and acquire energy , fatigue , and concentration was distributed at each preliminary data on various biomarkers of safety and toler acute lab session ; additional VAS questionnaires were dis ability , an experiment was performed . tributed for the daily assessment over a 6 -hour period during [0069 ] 15 healthy subjects (mean + SD age , height, wgt, the 7 -day subset study . Quest Diagnostics (Pittsburgh , Pa . ) BMI: 28. 3 : 6 . 1 y , 175 .7 : 11. 5 cm , 89. 8 + 21. 7 kg , 29 . 104 . 7 ) was utilized to transport and analyze all blood samples . For ingested 200 mg of TeaCrineTM (Compound Solutions, Inc . , each laboratory session , subjects reported to the lab well Carlsbad , Calif. ) ( TC ) or Placebo (PLA ). Anchored VAS hydrated , 10 - 12 hours postprandial, and at least 24 -hours questionnaires were used to detect changes in various after their last exercise session . aspects of physical and mental energy and performance ; side [0075 ] Statistical Analyses : effect profiles , hemodynamics and biochemical markers of [0076 ] Descriptive statistics (mean ,median , SD , 95 % CIS ) safety were also collected over a 3 - hr post - dosing period . A were used to quantify subjects physical characteristics . RM subset of 6 subjects underwent a separate 7 -day , open - label, ANOVA , as well analyses of co - variance ( ANCOVA ), using repeated dose study comparing 100 mg, 200 mg and 400 mg baseline scores as the co - variate ( respectively ) , were used to of TC . analyze between trial differences . Alpha was set to 0 . 05 [0070 ] The experiment was a randomized , placebo - con ( P < 0 .05 ) for statistical significance , and < 0 . 10 for trends . trolled , double -blind , within - subject crossover clinical trial Effect sizes were also calculated . Upon arrival for the first ( for N = 15 study ) . A further subset study was open - label , testing session , subjects were randomly assigned to receive sub - acute ( 7 - day ) , repetitive dosing trial ( for N = 6 subset ) . their respective supplement/ placebo . Each subject ingested [0071 ] Six (6 ) subjects provided written and dated the sponsor recommended dosage of their respective supple informed consent to participate in the 7 - day repetitive dos ment (1 capsule prior to schedule of assessments ). Supple ing study between Dec . 15 , 2012 and Feb . 21 , 2013 . A ments were prepared in capsule form and packaged in coded separate cohort of fifteen (15 ) subjects provided written and dated informed consent for the acute dose , placebo - con generic containers for double -blind administration . trolled , crossover clinical trial . All subjects were in good 10077 ] Results : health as determined by physical examination and medical [0078 ] The 200 mg dose of TC caused significant history , between the ages of 18 and 45 ( inclusive ). Subjects ' improvements in energy ( TC : + 8 .6 % vs . PLA : - 5 . 7 % , caffeine intake from foods/ beverages was limited to < 300 P = 0 .049 ) and reductions in fatigue ( TC : - 6 .7 % vs. PLA : mg daily . Subjects were willing and able to comply with the + 5 . 8 % , P = 0 .04 ) . A trend for improved concentration was experimental and supplement protocol. also noted ( TC : + 2 . 4 % vs . PLA : - 1 . 3 % , P = 0 . 07 ) . No [ 0072) Excluded subjects included subjects who were changes in systemic hemodynamics or side effect profiles pregnant or lactating , subjects with a history of hepatorenal, were noted . The N = 6 cohort study demonstrated moderate to musculoskeletal, autoimmune, or neurologic disease , diabe large effect sizes (0 . 50 to 0 . 71) with the 200 mg dose of TC tes , thyroid disease , adrenal disease, hypogonadism , inborn over a 7 -day period of assessment for the following subjec error of metabolism , personal history of heart disease , high tive measures: energy, fatigue , concentration , anxiety , moti blood pressure ( systolic > 140 mm Hg & diastolic > 90 mm vation to exercise and libido . Hg ) , psychiatric disorders , cancer, benign prostate hypertro [0079 ] The results of the experiment are also shown phy, caffeine sensitivity , gastric ulcer , reflux disease , or any graphically in FIGS. 2 through 7 . US 2018 /0104248 A1 Apr. 19 , 2018

[0080 ] As shown in FIG . 2 , individuals who were admin or caffeine (72 -hours ) and strenuous physical exer istered theacrine reported higher levels of energy at each cise ( 24 -hours ) . A catheter was inserted into the forearm vein time increment measured . FIG . 3 shows that while individu for blood sampling . Duplicate measurements of resting heart als given the placebo reported higher fatigue at 60 minutes rate and blood pressure were taken pre -dose and prior to after administration , those administered theacrine reported each timed blood sample . In addition , respiratory rate was lower levels of fatigue . FIGS. 4 and 5 show that no sub counted in one minute and body temperature was measured stantial change in systemic hemodynamics occurred . using an ear scanning thermometer (dual readings taken at 10081 ] FIGS . 6 and 7 show the results of the N = 6 cohort each time) . Atapproximately 8 : 00 am , each subject received study . With a 200 mg dose of theacrine over a 7 day period a single oral dose of a theacrine , caffeine , or combined of assessment, it was observed that theacrine has a positive theacrine - caffeine composition accompanied by water. effect on each of energy , fatigue , concentration , anxiety , Blood samples at 0 minute ( 5 samples obtained for baseline motivation to exercise, and libido . That is , fatigue and prior to administration of the oral compositions ) , 15 min anxiety were decreased substantially , while energy , concen utes, 30 minutes , 60 minutes, and 90 minutes , and 2 , 4 , 6 , 8 , tration , motivation to exercise and libido were increased and 24 hours post- administration . Collected samples were substantially . processed and stored in multiple aliquots ( ~ 500 UL , - 70° C .) [0082 ] Thus, the experimental data shows that theacrine until analyzed for theacrine , caffeine , and supplementation appears to favorably impact several sub using LC -MS / MS . jective and psychometric indices of energy and fatigue . [0091 ] All subjects were instructed to consume their usual These findings , as well as the potential cumulative effects on diet throughout the study period , with the exception of the focus , concentration , and libido are worthy of future study. actual days of testing . During the two days prior to each test [ 0083] Although previously published animal data sug day , subjects recorded all food and drink consumed and gested much larger doses of “ TC ” would be necessary to attempted to mimic this intake for the two - day period prior exert its neurophysiological effects , this first - in -human data to subsequent visits . Diet records were analyzed using suggests much lower doses of 1 . 5 mg to 2 . 5 mg/ kg body nutrient analysis software ( Food Processor SQL , version 99 ; weight ( for example , approximately 200 mg in a 100 kg ESHA Research , Salem , Oreg . ). For the actual test days , individual) provide optimal benefit . Follow -up studies standardized meals (meal replacement food bars [Clif should confirm these results , explore other objective mea “ Builder ' s 20 g Protein Bar ” ) and ready - to - drink shakes sures of physical and cognitive function , and clarify the [Orgain Organic NutritionTM ]) were provided to the subjects mechanismsby which theacrine exerts the observed salutary after sample collection at hour 2 and hour 6 (one shake and effects. one -half bar at each time) . Subjects were also provided with adequate meal replacement bars and shakes to consume Example 2 following the 8 hour sample collection . (during their time [0084 ] Assessment of the drug -drug interaction potential outside the lab ) . Each bar contained 280 calories , 10 grams between theacrine and caffeine in humans of fat , 29 grams of carbohydrate , and 20 grams of protein . [0085 ] Theacrine pharmacokinetics in humans has not Each shake contained 250 calories, 7 grams of fat, 32 grams been systematically characterized . Therefore , one purpose of of carbohydrate , and 16 grams of protein . No food other than this study, among others , was to determine theacrine phar what was provided to the subjects was allowed during each macokinetics and dose -linearity following oral administra study day , including both time spent in the lab and outside tion in humans. Another purpose ofthis study is to determine the lab . The only beverage that the subjects were allowed to whether or not caffeine alters theacrine pharmacokinetics consume was water and the volume consumed while in the and / or pharmacodynamics , when both ingredients are lab was matched for each test day (men : 94 + 25 ounces ; ingested together . women : 78 - 17 ounces ) . The subjects returned the following [0086 ] Eight healthy nonsmokers , including 4 men and 4 morning for the 24 hour blood collection , again in a 10 hour women , were recruited for the experiment. The test subjects fasted state . The same volume of meal replacement bars or regularly consumed stimulants ( i. e ., caffeine , 50 - 400 shakes was consumed by each subject during each visit mg/ day ) with beverages or nutritional supplements. The (both in lab and outside lab ) . All the subjects except one same test subjects did not have a history of adverse reactions female consumed 3 shakes and 3 bars during the period of to caffeine or other stimulants . time outside the lab . Said female subject only consumed 2 [0087 ] Study Design and Procedures bars and 2 shakes. Physical activity remained similar for all [0088 ] This study was a randomized , double -blind , 4 -arm the subjects throughout the study period , with the exception crossover design with each subject receiving 4 treatments of refraining from strenuous physical activity during the consisting of theacrine (25 mg) , theacrine (125 mg) , caffeine 24 -hour period prior to each test day and for the actual test ( 150 mg ) , and theacrine ( 125 mg) plus caffeine ( 150 mg) , day itself, respectively . Theacrine , administered as iTeaCrine® , was [0092 ] Pharmacokinetic Study provided by Compound Solutions (Carlsbad , Calif .) . Caf [0093 ] Plasma concentration -time data were evaluated feine , administered as caffeine anhydrous, was obtained using noncompartmental methods in Phoenix WinNonlin from Nutravative Ingredients (Allen , Tex .) . Treatment (version 7 . 0 ; Pharsight Corporation , Mountain View , Calif .) sequence was randomized using a 4x4 Latin square . There with adjustment for lag time after oral administration . The was an approximate 1 -week washout period between treat maximum concentration (Cmax ) , lag time ( tiag ) , and time of ments for all subjects . maximum concentration (tmar ) were determined from the [ 0089 ) Test Visit Procedures plasma concentration versus time data . The area under the [ 0090 ] Each study day, subjects reported to the lab plasma concentration - time curve from time 0 to infinity (was between 6 : 00 and 7 : 00 am after a 10 - hour fast and absti- calculated using the trapezoidal rule extrapolated to time nence from beverages , drugs , or supplements containing infinity ) . The terminal half -life ( t12) was calculated using US 2018 /0104248 A1 Apr. 19 , 2018 7 the following function : 112 = 0 .693 / k , wherein k is the con TABLE 1- continued stant of terminal rate elimination estimated from the slope of the linear portion of the log plasma concentration versus Theacrine Pharmacokinetics time curve . The oral clearance (CL / F ) was calculated by dividing the oral dose by AUCO- 00 . The apparent volume of Parameter Condition 15 Condition 2° Condition 4d distribution during the terminal elimination phase (VZ / F ) AUC ( hr×ng 111g , 809 + 923 736 = 312 1 ,242 + 1 , 129 CL / F ( L /hr ) 2 . 0 + 0 . 9 1 . 6 + 0 . 5 1 . 2 + 0 . 6 was calculated by dividing CL / F by k . Vd / F ( L ) 48 . 1 + 23 . 4 51. 0 + 8 . 5 35 . 4 12 . 4 10094 ] Statistical Analysis 41. 7 = 38 . 8 [0095 ] Differences between treatment group values were MRT ( hours ) 24 . 9 + 3 . 5 36 . 8 18 . 9 " Tmax values are expressed as median (range ). All other values are expressed as mean + SD determined for systolic blood pressure (SBP ) , diastolic and represent dose -adjusted pharmacokinetic parameters. blood pressure (DBP ) , rate pressure product, and heart rate . " Theacrine 25 mg Parametric data were analyzed by paired Student' s t tests of Theacrine 125 mg mean differences in values between treatment groups . Sta dTheacrine 125 mg + Caffeine 150 mg tistical significance was defined a priori as a 2 -sided or < 0 . 05 . The probability of interaction magnitude between TABLE 2 theacrine and caffeine was determined using 90 % confi dence intervals about the geometric mean ratio of the Caffeine Pharmacokinetics observed pharmacokinetic parameters . [0096 ] Results Parameter Condition 36 Condition 4° [0097 ] Subject Characteristics. Cmax (ng / mL ) 33. 4 + 9 . 5 37 .4 11. 8 10098 ] Eight physically active and healthy men ( n = 4 ; age Tmax (hours ) 0 . 8 ( 0 . 5 - 1 . 5 ) 1 . 0 ( 0 . 3 - 1 . 5 ) t1 /2 (hours ) 6 . 2 + 3 . 8 5 . 5 = 2 . 2 34 . 5 + 7 . 0 years ; weight 94 . 3 + 13 . 1 kg ) and women ( n = 4 ; age AUC ( hr* ng/ mL/ mg ) 262 . 0 + 74. 1 323 209 22 . 5 + 3 . 9 years ; weight 66 . 4 - 10 . 1 kg ) completed this study. CL / F ( L /hr ) 4 . 1 + 1 . 1 4 . 3 + 2 . 0 Men ingested a daily amount of caffeine equal to 143 . ?d/ F { L ) 33 . 5 + 13. 7 30 . 2 + 12 . 4 8 : 168. 7 mg, while women ingested 144 . 3 + 139. 7 mg. All the MRT (hours ) 8 . 4 + 4 . 3 8 . 0 + 3 . 2 subjects tolerated the treatments well and no adverse events Tmox values are expressed as median ( range ) . All other values are expressed as mean + SD were noted . Dietary intake was not different across treatment and represent dose -adjusted pharmacokinetic parameters . conditions for calories , macronutrients, or micronutrients ( p bCaffeine 150 mg > 0 .05 ). " Theacrine 125 mg + Caffeine 150 mg [ 0099 ] Pharmacokinetics [0100 ] Mean plasma concentration time profiles for TABLE 3 theacrine , caffeine , and paraxanthine are shown in FIGS . 8 , 9 , and 10 . Theacrine is well absorbed following oral admin Paraxanthine Pharmacokinetics istration of theacrine alone reaching maximal concentration Parameter Condition 35 Condition 4° within approximately 2 hours . Dose -adjusted theacrine phar Cmax (ng / mL ) 7 . 3 + 1 . 5 8 . 4 + 3 . 5 macokinetic parameters were not significantly different Tmax (hours ) 5 . 0 ( 4 . 0 - 8 . 0 ) 7 . 0 ( 1 . 5 - 8 . 0 ) ( Table 1 ) . Theacrine absorption rate ( Thor ) and half - life t12 (hours ) 12 . 5 + 12 . 7 14 . 8 : 17 . 7 ( t12 ) were unaffected by caffeine co -administration . How AUC (hr * ng mL/ / ing ) 174 + 152 209 + 202 ever , caffeine co - administration significantly increased both MRT (hours ) 19 . 1 + 18 . 6 22 . 7 + 26 . 2 mean theacrine exposure parameters Cmore ( 38 . 6 : 16 . 6 ver " Tmor values are expressed as median ( range ) . All other values are expressed as mean + SD sus 25 . 6 + 5 . 5 ng /mL ) and AUC ( 1 . 2 : 1 . 1 versus 0 .74 + 0 . 31 and represent dose - adjusted pharmacokinetic parameters . hr * ug /mL /mg ) as well as geometric mean ratios ( 1. 1 + 0 . 06 Caffeine 150 mg and 1 . 1 + 0 .03 ) ( Table 2 ) . Moreover , caffeine decreased both " Theaerine 125 mg + Caffeine 150 mg theacrine oral clearance (CL / F , 1 . 6 + 0 .49 versus 1 . 2 + 0 .56 [0101 ] Pharmacodynamics L / hr ) and oral volume of distribution (Vd / F , 50 . 5 + 0 .49 10102 ] Hemodynamic parameters such as blood pressure versus 35 . 4 - 12 .4 L ) by approximately 30 % . Of note , and heart rate are elevated following co -administration of theacrine exposure (AUC ) was consistently higher in Sub caffeine and other stimulants such as ephedrine . To deter ject 8 than all other subjects in all treatment arms. However, mine the potential for a pharmacodynamics interaction caffeine pharmacokinetics in Subject 8 was similar to the between theacrine and caffeine , we evaluated systolic and other seven subjects . Caffeine pharmacokinetics is similar diastolic blood pressure , heart rate , and rate pressure product following caffeine alone or caffeine plus theacrine co - inges following administration of both theacrine ( 25 mg and 125 tion (FIGS . 10 and 11 and Table 2) . Likewise , theacrine mg) and caffeine ( 150 mg) alone and in combination co - ingestion did not alter paraxanthine exposure parameters ( theacrine 125 mg plus caffeine 150 mg) . Heart rate suggesting caffeine metabolism was unaffected by theacrine decreased slightly over the first two hours following admin ( Table 3 ). istration for each of the four conditions returning to baseline by 24 hours post - ingestion ( FIG . 12A ). Systolic diastolic TABLE 1 blood pressure and rate pressure product remained relatively constant across the 24 hour evaluation period for each of the Theacrine Pharmacokinetics four conditions ( FIGS. 12B , 12C , and 12D ) : Parametera Condition 15 Condition 20 Condition 4d [0103 ] The experimental results reveal that the pharma Cmax (ng / mL ) 34 . 1 + 38 . 9 25 . 6 + 5 . 5 37 . 7 + 16 . 5 cokinetics of theacrine , when ingested alone , were similar Tmax (hours ) 1 . 8 ( 0 . 5 - 6 . 0 ) 1 . 8 ( 1 . 0 - 4 . 0 ) 1 . 0 ( 0 . 3 - 2 . 0 ) between the two doses tested . However , following co t12 (hours ) 16 . 5 = 2 . 4 26 . 1 + 13 . 7 29 . 2 + 25 . 3 ingestion with caffeine , theacrine disposition was signifi cantly altered . Specifically , caffeine decreased theacrine' s US 2018 /0104248 A1 Apr. 19 , 2018 oral clearance (CL / F ), which correlated with enhanced mination of individual contribution of A , and A24 AR to the theacrine exposure parameters , area under the plasma con - pharmacologic effects of theacrine . These data present a centration time curve (AUC ) and maximum concentration hypothesis that theacrine has different A , and A 4 binding (Cmar ). It is impossible to determine with certainty the exact affinities than caffeine, which permits discrimination mechanism for enhanced theacrine exposure , viz ., decreased between the Al and A24 receptors at physiologically rel CL and /or increased oral bioavailability ( F ), in the absence evaevant concentrations. Theacrine ' s preferential reliance on of intravenous data . However, the finding that theacrine ' s A24 AR antagonism would provide a mechanistic basis for elimination half - life ( t12 or Vd / CL ) was unaffected by lack of pharmacodynamic tolerance . Overall , the experi caffeine indicates that caffeine enhances theacrine ' s oral mental data suggest that the interactions between theacrine bioavailability ( F ), which is also consistent with the and adenosine receptors are complex . decreased oral volume of distribution (Vd / F ) of theacrine . Theacrine had no impact on the pharmacokinetics of caf Example 3 . Improvements in Subjective Feelings, feine or paraxanthine, which is the primary caffeine metabo Cognitive Performance , and Hemodynamics lite in humans formed via CYP1A2 -mediated 3 - N -demeth ylation . Caffeine is completely absorbed following oral [0106 ] In one clinical study, the effects of a single dose of administration . Such results indicate that theacrine would theacrine , caffeine , or their combination on subjective feel not have a reciprocal effect on caffeine bioavailability . ings, cognitive performance , and hemodynamics in men and Determination of whether or not theacrine is a CYP1A2 women were examined . In the study, 24 men and 26 women substrate will provide further insight into caffeine ' s effect on ingested a placebo , theacrine at 25 mg, theacrine at 125 mg , theacrine disposition , viz . , enhanced fraction absorbed and / caffeine at 150 mg, or combination of 125 mg theacrine and or reduced first -pass hepatic metabolism . 150 mg caffeine on five separate occasions, which were [0104 ] One study subject was found to have exaggerated separated by approximately one week . Subjects rated their theacrine exposure in all treatment arms. It is unclear, subjective feelings using a 10 cm visual analog scale at 30 however , whether the finding is genetic and /or environmen minutes, 1 , 2 , 3 , 4 , and 5 hours post ingestion and performed tal. The presence of a 5 -methyl substituent and a carbamide the trail making test ( TMT) of cognitive performance at at the 6 - position distinguish theacrine from caffeine . baseline and at hours 2 and 4 post ingestion . Subjective Because theacrine contains a 3 -methyl substituent, the pri feelings of attentiveness , sense of focus , and sense of energy mary site of caffeine metabolism via CYP1A2 -mediated improved with all active treatments . More favorable scores demethylation , it is possible that theacrine is also susceptible were generally associated with the caffeine and theacrinel to CYP1A2 -mediated metabolism . Caffeine exposure caffeine combination treatments . Self- reported motivation to ( AUC ) is controlled by both environmental, as well as exercise significantly increased in caffeine and theacrine ! genetic factors . In particular, the CYP1A2 polymorphism caffeine combination treatments . Caffeine and theacrine / ( rs2470893 ) , located in the common promoter region caffeine combination resulted in a significant increase in between CYPJA ] and CYP1A2, significantly associated subjective focus from baseline to 2 hours post - ingestion , with caffeine exposure in non - smokers, but not in smokers . while the 125 mg theacrine treatment reached statistical Non - smokers heterozygous or homozygous for the CYPJAI/ significance at 3 hours post - ingestion . Motivation to exer CYP1A2 A allele had a significantly lower caffeine exposure cise and sense of energy significantly increased from base compared to nullizygous individuals . Additional environ line to 2 hours post - ingestion in caffeine and theacrinel caffeine combination treatments . No condition effects were mental factors including oral contraceptive use mask the noted for the TMT ( p > 0 . 05 ) , although a trend was present effect of genetics on caffeine metabolism . The role of ( p - 0 .069 ) for theacrine /caffeine combination treatment, with pharmacogenetics in theacrine pharmacokinetics and phar TMT time improved at 4 hours post ingestion compared to macodynamics is of potential importance should CYP1A2 pre - ingestion . These findings indicate that theacrine , when prove to be an important theacrine elimination pathway . used alone at 125 mg or in combination with caffeine , is safe [0105 ] At the doses tested , the results reveal no effect on and effective at improving subjective feelings related to baseline hemodynamic parameters , e . g . heart rate and blood energy in healthy men and women . Moreover, the data show pressure , among the subjects receiving theacrine or caffeine that the combination of theacrine and caffeine may improve administered alone or in combination . Such data are con cognitive performance as assessed by the TMT. sistent with other studies demonstrating that theacrine supplementation ( up to 400 mg/ day for 8 weeks ) appears to Example 4 . Improvements in Cognitive be safe in humans with no adverse effects on hemodynamic parameters . It is surprised to find that in repeat dose Performance theacrine studies there is an absence of either sensitization or 101071. Another clinical study will demonstrate synergistic pharmacodynamic tolerance . Caffeine is a mixed A , A , , improvements in exercise performance and time to exhaus (AR ) antagonist . It is believed that the tion obtained from 125 mg theacrine and 150 mg caffeine acute psychostimulatory activity of caffeine is related to its combination treatment over 275 mg caffeine or 275 ability to antagonize the A , AR , which removes inhibition of theacrine administered alone . The purpose of this random the A2A AR leading to NMDA -dependent release of gluta ized , placebo - controlled , four - condition , double -blind clini mate and dopamine . Following chronic caffeine administra cal trial is to determine and compare the effects of theacrine tion , however, caffeine ' s primary effects shift from A , - de to caffeine on various measures of cognitive performance pendent to A2A -dependent antagonism in tolerant individuals under fatiguing conditions of a simulated athletic contest in due to A , AR desensitization . Administration of a cocktail high level male and female soccer players . Secondary pur containing both A , and A24 AR antagonists blocks theacrine poses are to determine whether there is a synergistic effect stimulating activity in rats . However , simultaneous admin of theacrine / caffeine combination as well as the impact on istration of A , and A24 AR antagonists prevents the deter time - to - exhaustion in an “ added time” scenario . After giving US 2018 /0104248 A1 Apr. 19 , 2018 informed consent, 20 (males n = 10 , females n = 10 ) Division [0112 ] Whereas, the present invention has been described I and professional soccer players will undergo baseline in relation to certain embodiments thereof, and many details performance testing and then randomly assigned to order of have been put forth in its illustration , it should be understood supplementation of a placebo ( P ) , caffeine ( C ) , theacrine ( T ), that other and further modifications, apart from those shown and theacrine/ caffeine combination ( TC ) . In each condition , or suggested herein , may be made within the spirit and scope subjects will undergo a 15 minutes dynamic warm -up and of this invention . Descriptions of the embodiments shown in then engage in a simulated soccer game on a high - speed the drawings should not be construed as limiting or defining treadmill . The " game” will be divided into two 45 -minute the ordinary and plain meanings of the terms of the claims halves. Simple , choice , and cognitive - load reaction time will unless such is explicitly indicated . be assessed immediately following each 45 - minute half . [0113 ] As such , those skilled in the art will appreciate that After the second assessment, subjects will immediately be the conception , upon which this disclosure is based , may put back on the treadmill and asked to run to volitional readily be utilized as a basis for the designing of other fatigue at 90 % VO2max . The experimental results indicated structures, methods and system for carrying out the several that 125 mg theacrine / 150 mg caffeine combined treatment purposes of the present invention . It is important, therefore , outperformed 275 mg pure caffeine or 275 mg pure theacrine that the claims be regarded as including such equivalent interventions . At almost half of the pure caffeine or pure constructions insofar as they do not depart from the spirit theacrine dose , the combined theacrine /caffeine treatment and scope of the present invention . resulted in a true synergistic and superior performance in 0114 ] All references cited herein are incorporated by comparison to the pure caffeine , the pure theacrine , or reference in their entirety . The present invention may be placebo group . More specifically, the combination of 125 embodied in other specific forms without departing from the mg theacrine/ 150 mg caffeine outperformed all other spirit or essential attributes thereof and , accordingly , refer groups , including 275 mg pure caffeine , 275 mg of pure ence should be made to the appended claims, rather than to theacrine , and placebo , in measures of cognitive flexibility , the foregoing specification , as indicating the scope of the attention and task switching , complex - choice reaction time invention . and information processing . What is claimed is : [ 0108 ] Routes of Administration 1 . A method of improving physical performance of a [0109 ] The compounds may be administered by any route , human comprising : including but not limited to oral, sublingual, buccal, ocular , orally administering to the human a synergistic compo pulmonary, rectal, and parenteral administration , or as an sition comprising theacrine and caffeine , oral or nasal spray ( e . g . inhalation of nebulized vapors , wherein the co - administered caffeine provides a pharma droplets , or solid particles ) . Parenteral administration cokinetic (PK ) parameter selected from the group consisting includes, for example , intravenous, intramuscular , intraarte of decreasing theacrine oral clearance (CL / F ) , decreasing rial, intraperitoneal, intranasal, intravaginal, intravesical theacrine oral volume of distribution (Vd / F ) , increasing area ( e . g . , to the bladder ) , intradermal , transdermal, topical, or under the plasma concentration time curve ( AUC ) of subcutaneous administration . Also contemplated within the theacrine , and increasing theacrine maximum plasma con scope of the invention is the instillation of theacrine in the centration (Cmor ) , in comparison with the PK parameters body of the patient in a controlled formulation , with sys when theacrine is administered alone . temic or local release of the drug to occur at a later time. For 2 . The method of claim 1 , wherein the weight to weight example , the drug may be localized in a depot for controlled ratio of theacrine to caffeine in the synergistic composition release to the circulation . is about 1 : 1 . 2 , and the dosage comprises about 125 mg [0110 ] The pharmaceutical compositions of the present theacrine and about 150 mg caffeine administered once invention may be administered in combination with a phar daily . maceutically acceptable carrier . The active ingredients in 3 . The method of claim 2 , wherein the co - administered such formulations may comprise from 1 % by weight to 99 % caffeine decreases theacrine oral clearance (CL / F ) by about by weight, or alternatively , 0 . 1 % by weight to 99. 9 % by 30 % in comparison with theacrine administered alone . weight . “ Pharmaceutically acceptable carrier" means any 4 . The method of claim 2 , wherein the co - administered carrier , diluent or excipient that is compatible with the other caffeine decreases theacrine oral volume of distribution ingredients of the formulation and not deleterious to the user. (Vd / F ) by about 30 % in comparison with theacrine admin Useful excipients include microcrystalline cellulose , mag istered alone . nesium stearate , stearate , any acceptable sugar ( e . g . , 5 . The method of claim 22 , wherein the co - administered mannitol, Xylitol) , and for cosmetic use an oil -base is caffeine increases theacrine maximum plasma concentration preferred . (Cmax ) by about 50 % in comparison with theacrine admin [ 0111] The nutraceutical compositions of the present istered alone . invention may be administered in combination with a nutra 6 . The method of claim 2 , wherein the co - administered ceutically acceptable carrier . The active ingredients in such caffeine increases area under the plasma concentration time formulations may comprise from 1 % by weight to 99 % by curve (AUC ) of theacrine by about 60 % in comparison with weight , or alternatively , 0 . 1 % by weight to 99 . 9 % by weight . theacrine administered alone. “ Nutraceutically acceptable carrier " means any carrier, 7 . The method of claim 1 , wherein the synergistic com diluent or excipient that is compatible with the other ingre position enhances the intensity and duration of theacrine ' s dients of the formulation and not deleterious to the user. neurocognitive efficacy beyond a systemic concentration Useful excipients include microcrystalline cellulose, mag threshold . nesium stearate , calcium stearate, any acceptable sugar ( e . g . , 8 . The method of claim 1 , wherein the synergistic com mannitol, Xylitol) , and for cosmetic use an oil - base is position enhances exercise performance , capacity , and preferred . extended endurance . US 2018 /0104248 A1 Apr. 19 , 2018 10

9 . The method of claim 1 , wherein the synergistic com 13 . The method of claim 12 , wherein the weight to weight position enhances fatigue - resistance to volitional exercise ratio of theacrine to caffeine is about 1 : 1 . 2 . measured at 90 % VO2max . 14 . The method of claim 10 , wherein the synergistic 10 . A method of treatment for improving physical or composition provided to the human further comprises at mental performance in a human , comprising : least one ingredient selected from the group consisting of providing the human with a synergistic composition com theobromine , theophylline , libertine, methylliberine , methyl prising about 5 mg to about 850 mg of theacrine and caffeine , naringin , hesperidin , 2 - (dimethylamino ) ethanol about 25 mg to about 650 mg of caffeine , (DMAE ), DMAE bitartrate , choline bitartrate , alpha -GPC , wherein upon administration of the composition the huperzine A , and CDP choline . human experiences improvement of at least one of 15 . The method of claim 14 , wherein the weight to weight mood , energy , focus , concentration , cognitive function , ratio of theacrine to caffeine is from about 0 . 5 : 1 to about or sexual desire or a reduction of at least one of anxiety 50 : 1 . or fatigue . 16 . The method of claim 14 , wherein the weight to weight 11 . The method of claim 10 , wherein the amount of theacrine provided is about 65 mg to about 300 mg. ratio of theacrine to caffeine is from about 1 : 1 to about 10 : 1 . 12 . The method of claim 10 , wherein the amount of 17 . The method of claim 14 , wherein the weight to weight theacrine provided is about 125 mg and the amount of ratio of theacrine to caffeine is from about 2 : 1 to about 4 : 1 . caffeine provided is about 150 mg. * * * *