Deuterated caffeine and uses thereof

Abstract

To provide compounds and compositions that utilize positive properties of caffeine without negative effects, that is, with pharmacokinetic profiles exhibiting lower Cmax values, longer half-life, and / or longer Tmax values than caffeine.SOLUTION: Provided is a composition comprising deuterated caffeine represented by formula (I). The composition is used in pharmaceutical compositions, nutraceutical supplement compositions, foods, beverages, cosmetic compositions, diet supplements, and the like. Formula (I): [where, each Y is independently hydrogen or deuterium; and at least one Y is deuterium.]SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 120 to U.S. patent application 16 / 752,407, filed January 24, 2020, which claims priority to U.S. Provisional Patent Application Serial No. 62 / 861,517, filed June 14, 2019, which claims priority to U.S. Patent Application Serial No. 16 / 452,316, filed June 14, 2019 (now issued as U.S. Patent No. 10,582,716); and claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Serial No. 62 / 861,517, filed June 14, 2019, the entire contents of which are incorporated herein by reference. The present invention relates to compositions comprising deuterated caffeine. [Background technology]

[0002] Caffeine is a central nervous system (CNS) stimulant that belongs to the methylxanthine chemical class. It is the most widely consumed psychoactive drug in the world. Caffeine affects several biological processes. Most notably, it reversibly blocks the action of adenosine on adenosine receptors, thereby preventing the development of adenosine-induced drowsiness and fatigue. It is also known that caffeine stimulates parts of the autonomic nervous system. In addition to its anti-drowsiness effects, caffeine has also been shown to positively affect learning, memory, reaction time, alertness, concentration, and motor coordination. In addition to reducing language and cognitive delays, caffeine is also useful in treating bronchopulmonary dysplasia in premature infants, enhancing weight gain during treatment, and reducing the incidence of cerebral palsy. Furthermore, caffeine has shown promising results in treating orthostatic hypotension, hypoxic-ischemic encephalopathy (HIE), and slowing the progression of Alzheimer's disease. In addition, caffeine citrate, sold under the brand name CAFCIT™, is approved by the FDA for the treatment of apnea of ​​prematurity in newborns.

[0003] However, despite the positive properties listed above, caffeine is associated with several significant physical and psychological adverse effects that limit its use. Caffeine increases blood pressure, affects gastrointestinal motility and gastric secretion, causes palpitations, can cause and exacerbate anxiety and insomnia, and is addictive. It is believed that some or all of the above side effects may be attributable to the pharmacokinetic and metabolic profile of caffeine. Caffeine intake increases the maximum plasma concentration (plasma C), primarily through hepatic cytochrome P450 (CYP450) demethylation to produce paraxanthine, theobromine, and theophylline. max ), time to maximum plasma concentration after short ingestion (T max ), short half-life (t 1 / 2 ), and rapid clearance. In other words, caffeine intake results in a short T max ) with a large "spike" in caffeine plasma concentration (i.e., a large C max ), followed by a "crash" in caffeine plasma concentration due to rapid metabolism and clearance. The magnitude of this "spike" and the rapidity of this "crash" are believed to be responsible, at least in part, for the side effects described above. Thus, one approach to mitigating these side effects is to develop compounds and compositions that utilize the positive properties of caffeine without the negative effects (i.e., compounds with a pharmacokinetic profile that exhibits a lower C max value, long half-life, and / or long T max The aim of the project is to develop a system that demonstrates the value of the technology. Summary of the Invention

[0004] The present invention relates to compositions (e.g., pharmaceutical compositions, nutraceutical compositions, foods, beverages, cosmetic compositions, dietary supplements) comprising deuterated caffeine. In certain embodiments, the compositions are suitable for oral administration. In certain embodiments, the compositions are suitable for intravenous (IV) administration. In certain embodiments, the compositions are suitable for topical administration. In certain embodiments, the compositions are suitable for pulmonary delivery. In certain embodiments, the compositions are administered using an electronic cigarette or other vapor inhalation device, a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI). In certain embodiments, the composition is a solid dose composition (e.g., a tablet, capsule, granules, powder, sachet, or chewable), a solution, gel, suspension, emulsion, shampoo, conditioner, cream, foam, gel, lotion, ointment, transdermal patch, tincture, or paste. Also provided herein is a kit comprising the composition and instructions for use. Further provided herein is the use of the compositions described herein for the treatment of disease, the prevention of disease, the treatment of disease, and / or the prevention of disease.

[0005] The compositions described herein include deuterated caffeine (i.e., caffeine in which at least one of the hydrogen atoms has been replaced with deuterium). In certain embodiments, the compositions comprise a compound represented by formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0006] The compounds of formula (I) may contain stable isotopes of carbon, nitrogen, and oxygen in amounts greater than their natural abundance. For example, one or more carbon atoms may contain more than about 1.1% (e.g., 1.2-1.5%, 1.5-2%, 2-10%, or more than 10%). 13 C may be enriched. One or more nitrogen atoms may be enriched in an amount greater than about 0.4% (e.g., 0.5-1%, 1-2%, 2-10%, or greater than 10%). 15 Similarly, one or more oxygen atoms may be enriched in an amount greater than about 0.24% (e.g., 0.25-0.5%, 0.5-1%, 1-2%, 2-10%, or greater than 10%). 16 O can be concentrated.

[0007] In certain embodiments, the composition comprises about 1 mg to about 10,000 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In certain embodiments, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, or prodrug thereof, relative to the total amount of caffeine present in the composition, ranges from about 5% to about 99%. In certain embodiments, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, or prodrug thereof, relative to the total amount of caffeine present in the composition, ranges from about 5% to about 100%. In another embodiment, the composition is an oral composition. In another embodiment, the composition is a solid dose composition (e.g., tablet, capsule, granule, powder, sachet, or chewable). In another embodiment, the composition is suitable for intravenous (IV) administration. In another embodiment, the composition is a topical composition. In another embodiment, the composition is a shampoo, conditioner, cream, foam, gel, lotion, ointment, transdermal patch, tincture, or paste.In another embodiment, the composition is suitable for inhalation.In another embodiment, the composition is administered using an electronic cigarette or other vapor inhalation device, a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).In another embodiment, the composition is suitable for buccal administration.

[0008] The present disclosure further provides food products comprising deuterated caffeine (e.g., a compound of formula (I)).

[0009] The present disclosure further provides beverages (eg, energy drinks, vitamin waters) comprising deuterated caffeine (eg, a compound of formula (I)).

[0010] The present disclosure further provides kits comprising one or more of the compositions described herein and instructions for using the compositions.

[0011] The present disclosure further provides a method of delivering a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof, to a subject in need thereof, comprising administering to a subject in need thereof a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof.

[0012] The present disclosure further provides a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof. In certain embodiments, the method comprises administering a compound of formula (I), wherein each Y is deuterium.

[0013] The present disclosure further provides a method of preventing a disease in a subject in need thereof, comprising administering to a subject in need thereof a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof. In certain embodiments, the method comprises administering a compound of formula (I), wherein each Y is deuterium.

[0014] The disclosure further provides a method of treating a disease in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof. In certain embodiments, the method comprises administering a compound of formula (I), wherein each Y is deuterium.

[0015] The present disclosure further provides a method of preventing a disease in a subject in need thereof, comprising administering to a subject in need thereof a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof. In certain embodiments, the method comprises administering a compound of formula (I), wherein each Y is deuterium.

[0016] In certain embodiments, the subject is a human. In certain embodiments, the subject is an animal.

[0017] In another embodiment, the side effects experienced after administration of a compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salts, hydrates, solvates, compositions, or prodrugs are reduced compared to administration of an equivalent dose of caffeine. In another embodiment, the side effects are anxiety, insomnia, gastrointestinal disorders (e.g., loose stools, diarrhea, gastric ulcers, gastroesophageal reflux, etc.), rhabdomyolysis, dependency, hypertension, increased heart rate, atrial fibrillation, fatigue, irritability, nervousness, restlessness, nausea, or muscle tremors.

[0018] In another aspect, administration of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof, results in increased duration of action, reduced dosing frequency, improved patient compliance, and / or improved ease of use, as compared to administration of an equivalent dose of caffeine.

[0019] In another embodiment, administration of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof, provides a similar relative magnitude of exposure in plasma and the central nervous system compared to administration of an equivalent dose of non-isotopically enriched caffeine.

[0020] The details of one or more embodiments of the disclosure are described herein. Other features, objects, and advantages of the disclosure will become apparent from the description, examples, and claims. [Brief description of the drawings]

[0021] The invention is further described below with reference to the following non-limiting examples and by reference to the following figures.

[0022] [Figure 1]FIG. 1 shows the mean (+SD) concentrations of caffeine and D9-caffeine (Compound 14) in plasma and brain over 14 hours following oral administration (gavage) of caffeine or D9-caffeine (Compound 14) at a dose of 2 mg / kg to fasted male Sprague-Dawley rats.

[0023] [Diagram 2] Figure 2 shows the class and subclass analysis of compound 14. Doses are reported in mg / kg.

[0024] [Figure 3-1] Figure 3 shows a legend of classes and subclasses, of which Figure 3-1 is a part. [Figure 3-2] Figure 3-2 is a continuation of Figure 3-1. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] definition Before further describing the present invention, and in order that the invention may be more readily understood, certain terms are first defined and collected here for convenience.

[0026] The terms "administering," "administering," or "administration" refer to injecting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein or a composition thereof into a subject. In certain embodiments, administration is oral. In certain embodiments, oral administration includes consumption, such as eating, drinking, swallowing, gavage, etc.

[0027] The terms "composition" and "formulation" are used interchangeably.

[0028] The term "total caffeine" refers to the combined total of deuterated caffeine and non-isotopically enriched caffeine.

[0029] The amount of active agent (e.g., deuterated caffeine) or combination of active agents contained in the provided compositions, foods, beverages, or dietary supplements described herein will depend on the target population. In some embodiments, the provided compositions, foods, beverages, or dietary supplements contain an effective amount of active agent (e.g., deuterated caffeine). As used herein, the term "effective amount" refers to an amount of active agent (e.g., deuterated caffeine) sufficient to produce a desired result. The exact amount required will vary from subject to subject, depending on the species, age, general condition, and symptoms of the subject. As used herein, the term "therapeutically effective amount" refers to an amount of drug or dietary supplement (e.g., deuterated caffeine) sufficient to achieve the intended purpose, such as causing a reduction in symptoms of a disease or disorder. A "prophylactically effective amount" refers to an amount of drug or dietary supplement (e.g., deuterated caffeine) sufficient to achieve the intended purpose, such as preventing a disease or disorder, one or more symptoms associated with a disease or disorder, and / or its recurrence. In certain embodiments, the effective amount of a composition, food, beverage, or dietary supplement is the effective amount of an active agent (e.g., deuterated caffeine) contained in the composition, food, beverage, or dietary supplement.

[0030] The term "energy drink" refers to a type of beverage that contains one or more stimulating compounds (e.g., caffeine) and optionally contains sugar or artificial sweeteners that provide mental and / or physical stimulation.

[0031] The term "vitamin water" means water to which vitamins or minerals have been added, and optionally to which natural or artificial flavors, sugars, or sweeteners have been added.

[0032] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, and the like, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, and the like, or obtained by using other methods known in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-type salts such as hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. + (C 1-4Alkyl)4 - Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. In certain particular embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a citrate salt. In other particular embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a hydrochloride salt. In other particular embodiments, the pharmaceutically acceptable salt of the compound of formula (I) is a salicylate salt.

[0033] Detailed Description of Certain Embodiments of the Invention The present invention relates to compositions comprising deuterated caffeine (e.g., a compound of formula (I)). Also provided herein are kits comprising the compositions and instructions for use. Further provided herein are uses of any of the compounds or compositions described herein for treating a disease, preventing a disease, treating a condition, preventing a condition, and / or causing an effect.

[0034] Compositions, Kits, and Administration In one aspect, the present invention provides a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically acceptable salt, hydrate, or solvate thereof.

[0035] In another aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a nutraceutical acceptable salt, hydrate, solvate, or prodrug thereof.

[0036] In another aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a dietary supplement acceptable salt, hydrate, solvate, or prodrug thereof.

[0037] In another aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a dietary supplement acceptable salt, hydrate, solvate, or prodrug thereof.

[0038] In another aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a dietary supplement acceptable salt, hydrate, solvate, or prodrug thereof.

[0039] In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least two to eight of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least two of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least three of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least four of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least five of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least six of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least seven of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, at least eight of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, nine of the Y's in the compound of formula (I) are deuterium. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, each Y in the compound of formula (I) is deuterium.

[0040] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (IA), (IB), or (IC): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0041] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (ID), (IE), or (IF): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0042] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (IG), (IH), (II), (IJ), (IK), or (IL): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0043] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (IM), (IN), (IO), (IP), (IQ), or (IR): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0044] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (IS), (IT), or (IU): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0045] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (II-A), (II-B), or (II-C): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0046] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (II-D), (II-E), or (II-F): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0047] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof has the formula (II-G), (II-H), or (II-I): [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0048] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] and pharma- ceutically or nutraceutical acceptable salts, hydrates, or solvates thereof.

[0049] In another embodiment, a salt of the compound of formula (I) is provided. In another embodiment, the salt is HCl, sulfate, acetate, phosphate, diphosphate, maleate, citrate, mesylate, nitrate, tartrate, or gluconate. In another embodiment, the salt is citrate.

[0050] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] [ka] [ka] is selected from the group consisting of:

[0051] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0052] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0053] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0054] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0055] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0056] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0057] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0058] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0059] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0060] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0061] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0062] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0063] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0064] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0065] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0066] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0067] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0068] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0069] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0070] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0071] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0072] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0073] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0074] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0075] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0076] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0077] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0078] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0079] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0080] In another embodiment, the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof is [ka] It is.

[0081] In another embodiment, the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate has an isotopic purity of at least 50.0%, 60.0%, 70.0%, 75.0%, 80.0%, 85.0%, 90.0%, 95.0%, 97.0%, 98.0%, 99.0%, 99.5%, 99.7%, 99.8%, or 99.9%. More specifically, a "compound of formula (I)" can be considered to refer to a plurality of molecules. For example, a compound of formula (I) can be present in an amount measured in micrograms, milligrams, grams, or kilograms, and as such can contain a large number of individual molecules. In the case of such isotopically labeled molecules, isotopic enrichment can be described as a percentage indicating the percentage of isotopic atoms at a particular site of the molecule. The percentage can be referred to as the "isotopic purity" of the isotopically labeled compound. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salts, hydrates, or solvates has an isotopic purity of at least 50.0%. In another embodiment, the compound of formula (I) or its pharma-ceutically or nutraceutical acceptable salts, hydrates, or solvates has an isotopic purity of at least 60.0%. In another embodiment, the compound of formula (I) or its pharma-ceutically or nutraceutical acceptable salts, hydrates, or solvates has an isotopic purity of at least 70.0%. In another embodiment, the compound of formula (I) or its pharma-ceutically or nutraceutical acceptable salts, hydrates, or solvates has an isotopic purity of at least 75.0%. In another embodiment, the compound of formula (I) or its pharma-ceutically or nutraceutical acceptable salts, hydrates, or solvates has an isotopic purity of at least 80.0%. In another embodiment, the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, has an isotopic purity of at least 85.0%. In another embodiment, the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, has an isotopic purity of at least 90.0%.In another embodiment, the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate has an isotopic purity of at least 95.0%. In another embodiment, the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate has an isotopic purity of at least 97.0%. In another embodiment, the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate has an isotopic purity of at least 98.0%. In another embodiment, the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate has an isotopic purity of at least 99.0%. In another embodiment, the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate has an isotopic purity of at least 99.5%. In another embodiment, the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, has an isotopic purity of at least 99.7%. In another embodiment, the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, has an isotopic purity of at least 99.9%. In another embodiment, the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is suitable for administration to humans or animals. In another embodiment, the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is manufactured and tested in accordance with Good Manufacturing Practice (GMP) requirements.

[0082] In another embodiment, any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein contain about 1 mg to about 10,000 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein contain about 1 mg to about 5,000 mg of a compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein contain about 1 mg to about 1000 mg of a compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg to about 800 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg to about 600 mg of a compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg to about 400 mg of a compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises from about 1 mg to about 300 mg of a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises from about 1 mg to about 250 mg of a compound of formula (I), or a pharma-ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof.In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg to about 125 mg of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 5 mg to about 75 mg of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 10 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 10 mg to about 150 mg of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 10 mg to about 100 mg of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises from about 10 mg to about 75 mg of a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises from about 10 mg to about 50 mg of a compound of formula (I), or a pharma-ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof.In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 20 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 20 mg to about 150 mg of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 20 mg to about 100 mg of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises from about 20 mg to about 75 mg of a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises from about 20 mg to about 50 mg of a compound of formula (I), or a pharma-ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof.

[0083] In another aspect, any of the pharmaceutical compositions, nutraceutical compositions, foods, beverages, or nutraceutical supplements described herein comprise an amount of isotopically enriched caffeine, or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, where the isotopically enriched caffeine has a higher proportion of the compound of formula (I) than occurs in nature, e.g., as a result of the natural abundance of deuterium. For example, the percentage of the compound of formula (I) in the caffeine can be at least 0.1%, at least 0.5%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 10.0%, at least 20.0%, at least 30.0%, at least 40.0%, at least 50.0%, at least 60.0%, at least 70.0%, at least 75.0%, at least 80.0%, at least 85.0%, at least 90.0%, at least 95.0%, at least 97.0%, at least 98.0%, at least 99.0%, at least 99.5%, at least 99.7%, at least 99.8%, at least 99.9%, or at least 100%. In certain embodiments of such pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements, the amount of caffeine, or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, is from about 1 mg to about 10,000 mg. In certain embodiments, the amount is from about 1 mg to about 5,000 mg. In certain embodiments, the amount is from about 1 mg to about 1000 mg. In certain embodiments, the amount is from about 1 mg to about 800 mg. In certain embodiments, the amount is from about 1 mg to about 600 mg. In certain embodiments, the amount is from about 1 mg to about 400 mg. In certain embodiments, the amount is from about 1 mg to about 300 mg. In certain embodiments, the amount is from about 1 mg to about 250 mg. In certain embodiments, the amount is from about 1 mg to about 200 mg. In certain embodiments, the amount is from about 1 mg to about 125 mg. In certain embodiments, the amount is from about 5 mg to about 75 mg. In certain embodiments, the amount is from about 10 mg to about 200 mg.In certain embodiments, the amount is about 10 mg to about 150 mg. In certain embodiments, the amount is about 10 mg to about 100 mg. In certain embodiments, the amount is about 10 mg to about 75 mg. In certain embodiments, the amount is about 10 mg to about 50 mg. In certain embodiments, the amount is about 20 mg to about 200 mg. In certain embodiments, the amount is about 20 mg to about 150 mg. In certain embodiments, the amount is about 20 mg to about 100 mg. In certain embodiments, the amount is about 20 mg to about 75 mg. In certain embodiments, the amount is about 20 mg to about 50 mg. In another aspect, any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein contain about 1 mg / ml to about 100 mg / ml of a compound of formula (I), or a pharmaceutical or dietary supplement salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 1 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, nutraceutical composition, food, beverage, or dietary supplement comprises from about 2 mg / ml to about 100 mg / ml of a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, nutraceutical composition, food, beverage, or dietary supplement comprises from about 2 mg / ml to about 75 mg / ml of a compound of formula (I), or a pharma-ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof.In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement contains about 2 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement contains about 2 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement contains about 2 mg / ml to about 15 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 5 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 5 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, dietary supplement composition, food, beverage, or dietary supplement comprises about 5 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, nutraceutical composition, food, beverage, or dietary supplement comprises from about 5 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical composition, nutraceutical composition, food, beverage, or dietary supplement comprises from about 5 mg / ml to about 15 mg / ml of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof.In another embodiment, the pharmaceutical or nutraceutical composition may contain about 10 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical or nutraceutical composition may contain about 10 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical or nutraceutical composition may contain about 10 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof. In another embodiment, the pharmaceutical or nutraceutical composition may contain about 10 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof.

[0084] In another aspect, any of the pharmaceutical compositions, nutraceutical compositions, foods, beverages, or nutraceutical supplements described herein comprise a concentration of isotopically enriched caffeine, or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, where the isotopically enriched caffeine has a higher proportion of the compound of formula (I) than occurs in nature, e.g., as a result of the natural abundance of deuterium. For example, the percentage of the compound of formula (I) in the caffeine can be at least 0.1%, at least 0.5%, at least 1.0, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 10.0%, at least 20.0%, at least 30.0%, at least 40.0%, at least 50.0%, at least 60.0%, at least 70.0%, at least 75.0%, at least 80.0%, at least 85.0%, at least 90.0%, at least 95.0%, at least 97.0%, at least 98.0%, at least 99.0%, at least 99.5%, at least 99.7%, at least 99.8%, at least 99.9%, or at least 100%. In certain embodiments of such pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements, the concentration of the isotopically enriched caffeine, or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, is from about 1 mg / ml to about 100 mg / ml. In certain embodiments, the concentration is from about 1 mg / ml to about 75 mg / ml. In certain embodiments, the concentration is from about 1 mg / ml to about 50 mg / ml. In certain embodiments, the concentration is from about 1 mg / ml to about 25 mg / ml. In certain embodiments, the concentration is from about 1 mg / ml to about 75 mg / ml. In certain embodiments, the concentration is from about 2 mg / ml to about 100 mg / ml. In certain embodiments, the concentration is from about 2 mg / ml to about 75 mg / ml. In certain embodiments, the concentration is from about 2 mg / ml to about 50 mg / ml. In certain embodiments, the concentration is from about 2 mg / ml to about 25 mg / ml. In certain embodiments, the concentration is from about 2 mg / ml to about 15 mg / ml.In certain embodiments, the concentration is about 5 mg / ml to about 100 mg / ml. In certain embodiments, the concentration is about 5 mg / ml to about 75 mg / ml. In certain embodiments, the concentration is about 5 mg / ml to about 50 mg / ml. In certain embodiments, the concentration is about 5 mg / ml to about 25 mg / ml. In certain embodiments, the concentration is about 5 mg / ml to about 15 mg / ml. In certain embodiments, the concentration is about 10 mg / ml to about 100 mg / ml. In certain embodiments, the concentration is about 10 mg / ml to about 75 mg / ml. In certain embodiments, the concentration is about 10 mg / ml to about 50 mg / ml. In certain embodiments, the concentration is about 10 mg / ml to about 25 mg / ml.

[0085] The following aspects of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein are provided. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, the percentage of the amount of the compound of formula (I), or its pharma- ceutically or dietary acceptable salt, hydrate, or solvate, is in the range of about 1% to about 99% based on the total amount of caffeine present in the composition, food, beverage, or dietary supplement. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, the percentage of the amount of the compound of formula (I), or its pharma-ceutically or dietary acceptable salt, hydrate, or solvate, is in the range of about 1% to about 99.99% based on the total amount of caffeine present in the composition, food, beverage, or dietary supplement. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement, ranges from about 1% to about 100%. In any of the pharmaceutical compositions, dietary supplement compositions, foods, beverages, or dietary supplements described herein, the compound of formula (I), or a pharma-ceutically or dietary acceptable salt, hydrate, or solvate thereof, represents more than 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5%, 99.7%, or 99.9% of the total amount of caffeine present in the composition, food, beverage, or dietary supplement. In any of the pharmaceutical compositions, nutraceutical compositions, foods, beverages, or dietary supplements described herein, the compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, represents 100% of the total amount of caffeine present in the composition.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 1% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 10% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 10% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 10% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 10% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 10% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 10% to about 60%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 10% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 10% to about 40%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 10% to about 25%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 25% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 25% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 25% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 25% to about 80%.In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement, ranges from about 25% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement, ranges from about 25% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 25% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 25% to about 40%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 30% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 30% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 30% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 30% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 30% to about 70%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 30% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 30% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 40% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 40% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 40% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 40% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 40% to about 70%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 40% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 40% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 50% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 50% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 50% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement is in the range of about 50% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 50% to about 70%.In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the composition, food, beverage, or dietary supplement ranges from about 50% to about 60%.

[0086] In another embodiment, the compound of formula (I) or its pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate is present in an amount of about 0.001% to 50% based on the weight of all components of the composition, food, beverage, or dietary supplement. In certain embodiments, the compound of formula (I) or its pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate is present in an amount of about 0.1% to 5% (e.g., 0.1% to 1%, 1% to 5%) based on the weight of all components of the composition, food, beverage, or dietary supplement. In certain embodiments, the compound of formula (I) or its pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate is present in an amount of about 5% to 20% based on the weight of all components of the composition, food, beverage, or dietary supplement. In certain embodiments, the compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof, is included in an amount of about 20%-50% by weight of all components of the composition, food, beverage, or dietary supplement.

[0087] The total daily dose of pharmaceutical compositions described herein can be determined by the attending physician within the scope of sound medical judgment, and it is understood that it depends on the safety and toxicity profile of the components of pharmaceutical compositions.The specific therapeutically effective dose level for a specific patient or organism will depend on various factors, including the disorder being treated and the severity of the disorder; the results of clinical trials, the activity of the specific compound used; the specific pharmaceutical composition used; the age, weight, general health, sex, diet of the patient; the time of administration, route of administration and the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination with or simultaneously with the specific compound used; and similar factors well known in the medical field (see, for example, Goodman and Gilman's, The Pharmacological Basis of Therapeutics, Tenth Edition, A. Gilman, J. Hardman, and L. Limbird, eds., McGraw-Hill Press, 155-173, 2001).

[0088] In another embodiment, any of the pharmaceutical compositions described herein may be suitable for oral administration, parenteral (e.g., intravenous (IV)) administration, topical administration, inhalation, buccal administration, or pulmonary delivery. In another embodiment, the pharmaceutical composition is suitable for oral administration. In another embodiment, the pharmaceutical composition is suitable for parenteral administration. In another embodiment, the pharmaceutical composition is suitable for intravenous (IV) administration. In another embodiment, the pharmaceutical composition is suitable for topical administration. In another embodiment, the pharmaceutical composition is suitable for pulmonary delivery.

[0089] In another embodiment, any of the dietary supplement compositions described herein may be suitable for oral administration.

[0090] In another embodiment, the composition is a cosmetic composition. In another embodiment, the cosmetic composition is suitable for topical administration.

[0091] In another embodiment, any of the pharmaceutical or dietary supplement compositions described herein suitable for oral administration may be a solid dose composition. In another embodiment, the solid dose composition may be a tablet, capsule, granule, powder, sachet, or chewable.

[0092] In another aspect, any of the pharmaceutical, nutraceutical, or cosmetic compositions described herein suitable for topical administration can be a shampoo, conditioner, cream, foam, gel, lotion, ointment, transdermal patch, tincture, or paste.

[0093] In another embodiment, any of the pharmaceutical compositions described herein suitable for pulmonary delivery may be administered using an electronic cigarette or other vapor inhalation device, a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).

[0094] In another aspect, any of the pharmaceutical, nutraceutical, or cosmetic compositions described herein may further comprise a pharma- ceutically or nutraceutically acceptable carrier.

[0095] In another aspect, any of the pharmaceutical compositions, nutraceutical compositions, or cosmetic compositions described herein may further comprise an additional agent. In another aspect, an additional agent refers to a natural or synthetic compound capable of active or other direct action in the diagnosis, cure, mitigation, treatment, or prevention of disease, or affecting the structure and function of the body. In any of the above embodiments, the provided composition may comprise one or more additional active agents, including, but not limited to, agents belonging to different Biopharmaceutics Classification Systems (BCS), such as those in BCS class I, II, III, or IV, and / or peptides, and / or vaccines, and / or nucleic acid-based products, and / or immune agents, and / or botanicals, and / or nutraceuticals, and / or cosmetic agents, and / or supplements, etc. In certain embodiments, the additional active agent is a small molecule (e.g., when the molecular weight is less than 500, 800, 1000, or 1500 g / mol). In certain embodiments, the additional active agent is a drug approved by the US Food and Drug Administration and / or the European Medicines Agency.

[0096] In the present invention, each additional drug can be incorporated into the composition.Depending on the qualitative and quantitative composition of the selected formulation, the additional drug can be released from the composition over a period of time (i.e., sustained release) or immediately.The present invention can be used for the treatment of both humans and animals.

[0097] In another embodiment, the additional agent is an ergotamine, an anti-inflammatory agent, a steroid, a barbiturate, an opioid analgesic, or a combination thereof. In another embodiment, any of the hydrogen atoms of the ergotamine, the anti-inflammatory agent, the steroid, the barbiturate, or the opioid analgesic may be replaced with deuterium. In another embodiment, the anti-inflammatory agent is a cyclooxygenase-3 (COX-3) inhibitor, a nonsteroidal anti-inflammatory drug (NSAID), or a cyclooxygenase-2 (COX-2) inhibitor.

[0098] In another embodiment, the NSAID is ibuprofen, naproxen, sulindac, ketoprofen, tolmetin, etodolac, fenoprofen, diclofenac, flurbiprofen, piroxicam, ketorolac, indomethacin, nabumetone, oxaprozin, mefanamic acid, or diflunisal.

[0099] In another embodiment, the opioid analgesic is codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, or oxycodone.

[0100] In another embodiment, the barbiturate is secobarbital, mephobarbital, pentobarbital, butabarbital, phenobarbital, or amobarbital.

[0101] In another embodiment, the COX-2 inhibitor is celecoxib, valdecoxib, rofecoxib, or etoricoxib.

[0102] In another embodiment, the COX-3 inhibitor is acetaminophen, phenacetin, antipyrine, or dipyrone.

[0103] In another embodiment, the percentage of deuterium (i.e., the percentage of hydrogen atoms replaced with deuterium atoms) in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 0.1%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 0.5%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 1%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 5%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 10%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 15%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 20%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 25%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 30%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 40%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 50%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 60%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 70%.In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 80%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 90%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 95%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 97%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 98%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory drug, steroid, barbiturate, or opioid analgesic is at least 99%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory drug, steroid, barbiturate, or opioid analgesic is at least 99.5%. In another embodiment, the percentage of deuterium in the ergotamine, anti-inflammatory drug, steroid, barbiturate, or opioid analgesic is 100%.

[0104] In certain embodiments, the composition further comprises a sweetener. Sweeteners can be used to improve palatability and are usually classified as natural or artificial. Sweeteners can be natural or artificial. Natural sweeteners include, but are not limited to, dextrose, fructose, glucose, liquid glucose, maltose, rebiana, glycyrrhizin, thaumatin, sorbitol, mannitol, isomalt, glycerol, maltitol, xylitol, and erythritol. Artificial sweeteners include, but are not limited to, saccharin, cyclamate, aspartame, acesulfame K, sucralose, alitame, and neotame. In certain embodiments, sucralose is used as the sweetener. In certain embodiments, one or a combination of neohesperidine dihydrochalcone, glycerol, and / or sucralose is used as the sweetener. In some embodiments, the concentration of the sweetener in the composition is 0.01% to 5% by weight. In some embodiments, the concentration of the sweetener in the composition is 0.01% to 1% by weight. In some embodiments, the concentration of the sweetener in the composition is 0.5% to 1% by weight. In certain embodiments, the composition further comprises sucralose. In certain embodiments, the composition further comprises about 0.01 to 0.25% by weight of sucralose, based on the dry weight of all components of the composition.

[0105] In certain embodiments, the composition further comprises a coloring agent.In particular, when formulation components or drugs are provided in a form other than a solution, coloring agent can be added to improve the appearance of the composition.Generally, any coloring agent can be added, such as FD&C dyes (e.g., Blue No. 1, Blue No. 2, Red No. 3, Red No. 40, Yellow No. 5, or Yellow No. 6). Colorants include, but are not limited to, annatto extract, dehydrated beets (beet powder), canthaxanthin, caramel, β-apo-8'-carotenal, β-carotene, cochineal extract, carmine, sodium copper chlorophyllin, toasted partially defatted cooked cottonseed flour, ferrous gluconate, ferrous lactate, grape color extract, grape skin extract (enocyanina), synthetic iron oxide, fruit juice, vegetable juice, carrot oil, paprika, paprika oleoresin, mica-based pearlescent pigments, riboflavin, saffron, spirulina extract, titanium dioxide, tomato lycopene extract; tomato lycopene concentrate, turmeric, turmeric oleoresin, alumina (dried aluminum hydroxide), calcium carbonate, potassium sodium copper chlorophyllin (chlorophyllin-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, diferric ferrocyanide Iron, Chromium Hydroxide Green, Chromium Oxide Green, Guanine, Pyrophyllite, Mica, Talc, Aluminum Powder, Bronze Powder, Copper Powder, Zinc Oxide, Bismuth Citrate, Disodium Copper EDTA, Guaiazulene, Henna, Lead Acetate, Pyrophyllite, Silver, Ultramarine, Manganese Violet, Luminescent Zinc Sulfide, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Green No. 3, Orange B, Citrus Red No. 2, FD&C Red No.3, FD&C Red No.40, FD&C Yellow No.5, FD&C Yellow No.6, D&C Blue No.4, D&C Green No.5, D&C Green No.6, D&C Green No.8, D&C Orange No.4, D&C Orange No.5, D&C Orange No.10, D&C Orange No.11, FD&C Red No.4, D&C Red No.6, D&C Red No.7, D&C Red No.17, D&C Red No.21, D&C Red No. 22, D&C Red No. 27, D&C Red No. 28, D&C Red No. 30, D&C Red No. 31, D&C Red No. 33, D&C Red No. 34, D&C Red No. 36, D&C Red No. 39, D&C Violet No. 2, D&C Yellow No. 7, Ext. D&C Yellow No. 7, D&C Yellow No. 8, D&C Yellow No. 10, D&C Yellow No. 11, D&C Black No. 2, D&C Black No. 3, D&C Brown No. 1, and Ext. D&C Violet No. 2. In certain embodiments, the colorant represents 0.001% to about 0.5% based on the weight of all components of the composition. In some embodiments, the concentration of the colorant in the composition is 0.001% to 5% by weight. In some embodiments, the concentration of the colorant in the composition is from 0.001% to 1% by weight.

[0106] In certain embodiments, the provided composition further comprises a flavoring agent. In certain embodiments, the selection of the appropriate flavoring agent to be added depends on the original taste of the composition, including metallic, acidic, alkaline, salty, sweet, bitter, and sour tastes. Certain flavoring agents, alone or in combination, mask certain tastes. For example, metallic tastes can be masked with flavoring agents based on berry fruit, grape, and / or peppermint, including but not limited to these. For example, acidic tastes can be masked with flavoring agents based on lemon, lime, grapefruit, orange, cherry, and / or strawberry, including but not limited to these. For example, alkaline tastes can be masked with flavoring agents based on aniseed, caramel, passion fruit, peach, and / or banana, including but not limited to these. For example, salty taste can be masked with flavors based on, but not limited to, butterscotch, caramel, hazelnut, spicy, maple, apricot, apple, peach, vanilla, and / or wintergreen mint. For example, bitter taste can be masked with flavors based on, but not limited to, licorice, passion fruit, coffee, chocolate, peppermint, grapefruit, cherry, peach, raspberry, wild cherry, walnut, mint, and / or anise. For example, sweet taste can be masked with flavors based on, but not limited to, grape, cream, caramel, banana, vanilla, and / or fruit berry. For example, sour taste can be masked with flavors based on, but not limited to, citrus flavor, licorice, root, bear, and / or raspberry. Flavoring agents can be used alone or in combination, the choice of which also depends on the target population and other substances (e.g., drugs or nutritional supplements) that are incorporated into the composition. Flavoring perceptions vary from person to person and with age, with older people typically preferring mint or orange flavors, while younger people tend to prefer flavors such as fruit punch, raspberry, etc.Generally, the amount of flavor required to mask unpleasant tastes or improve overall taste will depend on the type and strength of the flavor as well as the composition of the formulation.

[0107] In certain embodiments, the flavoring agent is a pleasant-tasting flavoring agent that has a long shelf life and does not crystallize or precipitate from the composition upon storage. In certain embodiments, the flavoring agent may be a natural flavoring agent derived from various parts of plants such as leaves, fruits, and flowers, or may be a synthetic flavor oil or powder. Flavoring oils that can be used in or as flavoring agents include, but are not limited to, peppermint oil, cinnamon oil, spearmint oil, and oil of nutmeg. Fruity flavors that can be used in or as flavoring agents include, but are not limited to, vanilla, cocoa, coffee, chocolate, and citrus. Fruit essence flavors that can be used in or as flavoring agents include, but are not limited to, apple, raspberry, cherry, and pineapple. The amount of flavoring agent added varies depending on the flavor used. In some embodiments, the concentration of flavoring agent in the composition is about 0% to 5% by weight. In some embodiments, the concentration of the flavoring in the composition is from 0.001% to 5% by weight. In some embodiments, the concentration of the flavoring in the composition is from 0.1% to 1% by weight. In some embodiments, the concentration of the flavoring in the composition is from 0.5% to 1% by weight.

[0108] In certain embodiments, the provided compositions further include a taste masking agent. A taste masking agent can be added to improve the general sensory properties of the composition. In certain embodiments, the taste masking agent can be used to mask the unpleasant taste of some ingredients. The main tastes include metallic, acidic, alkaline, salty, sweet, bitter, and sour. Taste masking agents include, but are not limited to, menthol, peppermint oil, L-menthol, cyclodextrin, glycerol, maltodextrin, ion exchange resins, amino acids, gelatin, gelatinized starch, liposomes, lecithin, or lecithin-like substances and salts. The amount of taste masking added can vary depending on the taste masking agent used. In certain embodiments, the taste masking agent comprises about 0% to about 50% based on the dry weight of all ingredients of the composition. In certain embodiments, the taste masking agent represents 0% to about 5% based on the dry weight of all ingredients of the composition.

[0109] In another aspect, the composition provided further comprises a cooling agent. A cooling agent can also be added to improve the aftertaste of the composition. Cooling agents include, but are not limited to, neohesperidin dihydrochalcone, menthol flavor, L-menthol, and some polyol sugars that are widely used for this purpose. Other ingredients that should compete with the sensory stimuli, such as Cremophor (used to coat surface protein receptors), or saline (e.g., sodium chloride, which competes with bitter stimuli in channel receptors to reduce the overall bitterness perception), can also be added. In certain embodiments, the cooling agent in the composition is one or a combination of neohesperidin dihydrochalcone, menthol, and / or polyol sugar. In certain embodiments, the mucoadhesive composition further comprises about 0% to about 5% of a cooling agent, based on the weight of all components of the composition. In certain embodiments, the mucoadhesive composition further comprises about 0.001% to about 2.5% of a cooling agent, based on the weight of all components of the composition.

[0110] In certain embodiments, the compositions provided further comprise one or more preservatives. The preservatives used in the present invention can be any preservative as long as they do not adversely affect other desirable properties of the composition. An example of a preservative is an antimicrobial preservative used to prevent or inhibit the growth of microorganisms in the composition. Preservatives include, but are not limited to, for example, C3-C8 alcohols, phenylethyl alcohol, chlorbutanol, p-hydroxybenzoic acid esters, benzethonium chloride and benzalkonium chloride, benzoic acid, propyl gallate, methylparaben, propylparaben, sorbic acid, sodium benzoate, and / or potassium sorbate. The amount of preservative added can vary depending on the preservative used. In certain embodiments, the preservative represents about 0% to about 45% based on the weight of all components of the composition. In certain embodiments, the preservative represents about 0% to about 1% (e.g., 0.025% to 0.2%) based on the weight of all components of the composition.

[0111] In certain embodiments, the provided compositions (e.g., cosmetic or pharmaceutical compositions) further comprise a penetration enhancing additive. The penetration enhancing agent effectively increases the permeability of the active agent and / or the composition excipients. Preferably, the penetration enhancing additive is compatible with the active agent and other formulation excipients, pharmacologically inert, non-toxic, and inexpensive. Examples of the penetration enhancing additive include, but are not limited to, bile salts, surfactants, fatty acids and their derivatives, glycerides, chelating agents, salicylates, polymers, or other compounds. Examples of the bile salts that act as penetration enhancing additives include, but are not limited to, sodium glycocholate, sodium deoxycholate, sodium taurocholate, sodium fusidate, sodium glycodeoxycholate, and sodium taurodihydrofusidate. Examples of surfactants that act as penetration enhancing additives include, but are not limited to, sodium lauryl sulfate, brij1-35, lysophosphatidylcholine, dioctyl sodium sulfosuccinate, laureth-9, polysorbate-80, polyethylene glycol-8-laurate, and glyceryl monolaurate. Examples of fatty acids and their derivatives that act as penetration enhancing additives include, but are not limited to, sorbitan laurate, sodium caprate, sucrose palmitate, lauroylcholine, sodium myristate, and palmitoyl carnitine. Examples of glycerides that act as penetration enhancing additives include, but are not limited to, phospholipids, monohexanoin, and medium-chain glycerides. Examples of chelating agents that act as penetration enhancing additives include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), and disodium EDTA. Salicylates that act as penetration enhancing additives include, but are not limited to, salicylic acid, sodium methoxysalicylate, acetylsalicylic acid, etc. Polymers that act as penetration enhancing additives include, but are not limited to, chitosan, polycarbophil, sodium carboxymethylcellulose and their derivatives.Other compounds that act as penetration enhancing additives include, but are not limited to, cyclodextrin, benzalkonium chloride, phenothiazines, nitrate donors, menthol, zonula occluden toxin, poly-L-arginine, soy-derived glucosides, citicoline, alpha-acid derivatives, etc. The amount of penetration enhancing additive added may vary depending on the penetration enhancing additive used.

[0112] In one embodiment, the present invention provides a beverage comprising deuterated caffeine. In another embodiment, the beverage comprises one or more of water, flavorings, sweeteners, vitamins, minerals, cofactors, proteins, lipids, peptides, and amino acids.

[0113] In another aspect, the present invention provides a method for producing a compound comprising water and a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0114] In another embodiment, the beverage further comprises one or more of a flavoring agent and a sweetener.

[0115] In another embodiment, the beverage further comprises one or more of vitamins, minerals, cofactors, proteins, lipids, peptides, and amino acids.

[0116] In another embodiment, the beverage is an energy drink. In another embodiment, the energy drink further comprises one or more of water, taurine, citicoline, vitamin B6, vitamin B12, folic acid, niacinamide, glucuronolactone, N-acetyl-L-tyrosine, L-phenylalanine, and malic acid.

[0117] In another embodiment, the beverage is vitamin water. In another embodiment, the vitamin water further comprises one or more of water, vitamin C, vitamin B5, vitamin B6, vitamin B12, magnesium, and pantothenic acid.

[0118] In another embodiment, the beverage is coffee (decaffeinated, or non-isotopically enriched caffeine-containing) that has been enhanced or "spiked" with a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof.

[0119] In another embodiment, the beverage is a chocolate-containing beverage (decaffeinated, or non-isotopically enriched caffeine-containing) that has been fortified or "spiked" with a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0120] In another embodiment, the beverage contains about 1 mg to about 10,000 mg of the compound of formula (I), or a pharma- ceutically or dietary acceptable salt, hydrate, or solvate thereof. For example, the beverage may contain about 1 mg to about 9000 mg, about 1 mg to about 8000 mg, about 1 mg to about 7000 mg, about 1 mg to about 6000 mg, about 1 mg to about 5000 mg, about 1 mg to about 4000 mg, about 1 mg to about 3000 mg, or about 1 mg to about 2000 mg of the compound of formula (I), or a pharma-ceutically or dietary acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage contains about 1 mg to about 1000 mg of the compound of formula (I), or a pharma-ceutically or dietary acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 1 mg to about 800 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 1 mg to about 600 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 1 mg to about 400 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 1 mg to about 300 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 1 mg to about 250 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 1 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 1 mg to about 125 mg of the compound of formula (I), or a pharma-ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 5 mg to about 75 mg of the compound of formula (I), or a pharma-ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.In another embodiment, the beverage comprises about 10 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 10 mg to about 150 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 10 mg to about 100 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 10 mg to about 75 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 10 mg to about 50 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 20 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 20 mg to about 150 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 20 mg to about 100 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 20 mg to about 75 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 20 mg to about 50 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0121] In another embodiment, the beverages contain about 0.005 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.01 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.05 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.1 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.5 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.In another embodiment, any of the beverages contains from about 1 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma-ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0122] In another embodiment, the beverages contain from about 0.005 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.01 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.05 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.1 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.5 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage contains from about 1 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0123] In another embodiment, the beverages contain from about 0.005 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.01 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.05 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.1 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.5 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverages contain from about 1 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0124] In another embodiment, the beverages contain about 0.005 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.01 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.05 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.1 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.5 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverages contain from about 1 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma-ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0125] In another embodiment, the beverage comprises about 2 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 2 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 2 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 2 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 2 mg / ml to about 15 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 5 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 5 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 5 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 5 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 5 mg / ml to about 15 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 10 mg / ml to about 100 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the beverage comprises about 10 mg / ml to about 75 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.In another embodiment, the beverage comprises from about 10 mg / ml to about 50 mg / ml of the compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.In another embodiment, the beverage comprises from about 10 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma-ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0126] In another embodiment, the beverages contain from about 0.005 mg / ml to about 0.1 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.01 mg / ml to about 0.1 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.05 mg / ml to about 0.1 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0127] In another embodiment, the beverages contain about 0.005 mg / ml to about 0.25 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.01 mg / ml to about 0.25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.05 mg / ml to about 0.25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.1 mg / ml to about 0.25 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0128] In another embodiment, the beverages contain about 0.005 mg / ml to about 0.5 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.01 mg / ml to about 0.5 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.05 mg / ml to about 0.5 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.1 mg / ml to about 0.5 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains from about 0.25 mg / ml to about 0.5 mg / ml of a compound of formula (I), or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0129] In another embodiment, the beverages contain about 0.005 mg / ml to about 1.0 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.01 mg / ml to about 1.0 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.05 mg / ml to about 1.0 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.1 mg / ml to about 1.0 mg / ml of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, any of the beverages contains about 0.5 mg / ml to about 1.0 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In one embodiment, the percentage (i.e., weight percent) of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 1% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 1% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 10% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 10% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 10% to about 90%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 10% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 10% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 10% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 10% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 10% to about 40%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 10% to about 25%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 25% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 25% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 25% to about 90%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 25% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 25% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 25% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 25% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 25% to about 40%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 30% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 30% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 30% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 30% to about 80%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 30% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 30% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 30% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 40% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 40% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 40% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 40% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 40% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the beverage ranges from about 40% to about 60%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 40% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 50% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 50% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 50% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 50% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 50% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the beverage ranges from about 50% to about 60%.

[0130] In another embodiment, the beverage is provided in a container having a volume of about 1 ounce, 2 ounces, 4 ounces, 6 ounces, 8 ounces, 10 ounces, 12 ounces, 14 ounces, 16 ounces, 18 ounces, 20 ounces, 22 ounces, 24 ounces, 26 ounces, 28 ounces, 30 ounces, 32 ounces, ½ liter, 1 liter, ½ gallon, 1 gallon, 2 gallons, 3 gallons, 4 gallons, 5 gallons, or 6 gallons or more of the beverages described herein. In another embodiment, the beverage is provided in a container having a volume of about 1-4 ounces, 4-12 ounces, 12-20 ounces, 20-32 ounces, ½ liter to 1 liter, 1 liter to ½ gallon, ½ gallon to 6 gallons of the beverages described herein. In another embodiment, the container is a can (eg, an aluminum can), a plastic or glass bottle, a plastic or glass jug, or a tank (eg, a stainless steel tank).

[0131] Numerous processes, methods, and equipment for producing beverages are known to those skilled in the art. For example, see Production and Management of Beverages, Eds. Grumezescu and Holban, Woodhead Publishing, December 2018, which is incorporated herein by reference. In certain embodiments, a method for producing a beverage comprising a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is provided. In one embodiment, the method comprises adding a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a liquid comprising water to produce a beverage. In one embodiment, the liquid comprises carbonated water. In one embodiment, the method comprises adding 1 mg to 10,000 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a liquid. In one embodiment, the method includes adding 1 mg to 1,000 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method includes adding 1 mg to 8,000 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method includes adding 1 mg to 600 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method includes adding 1 mg to 400 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method includes adding 1 mg to 300 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding between 1 mg and 250 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to the liquid.In one embodiment, the method comprises adding 1 mg to 200 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 150 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 100 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 75 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 50 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 25 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 20 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 10 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid. In one embodiment, the method comprises adding 1 mg to 5 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, to the liquid.

[0132] In another embodiment, a method for producing a beverage comprising a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is provided. In one embodiment, the method comprises mixing a composition comprising a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid comprising water to produce a beverage. In one embodiment, the composition comprises a syrup comprising a natural or artificial sweetener. In one embodiment, the liquid comprises carbonated water. In one embodiment, the method comprises mixing 1 mg to 10,000 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method comprises mixing 1 mg to 1,000 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 8,000 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 600 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 400 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 300 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method comprises mixing 1 mg to 250 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method comprises mixing 1 mg to 200 mg of a compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid.In one embodiment, the method includes mixing 1 mg to 150 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 100 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 75 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 50 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method includes mixing 1 mg to 25 mg of a compound of formula (I), or a pharma- ceutically or nutraceutically acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method comprises mixing 1 mg to 20 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method comprises mixing 1 mg to 10 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid. In one embodiment, the method comprises mixing 1 mg to 5 mg of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, with a liquid.

[0133] In another aspect, the present invention relates to a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or dietary supplement acceptable salt, hydrate, or solvate thereof.

[0134] In another aspect, the food is any item that is processed, partially processed, or unprocessed for consumption. In another aspect, the food is an energy bar, energy gel, pre-exercise supplement, or other performance enhancing supplement. In a particular embodiment, the performance enhancing supplement is an energy gel. In a particular embodiment, the performance enhancing supplement is a pre-exercise supplement. In another aspect, the food is a food additive. In another aspect, the food is an edible supplement. In another aspect, the food is an energy bar. In another aspect, the energy bar further comprises one or more of sugar, cocoa butter, chocolate liquor, whole milk powder, soy lecithin, vanilla extract, caramel, peanuts, peanut butter, almonds, oats, molasses, cinnamon, salt, and soybean oil.

[0135] In another embodiment, the food may contain about 1 mg to about 10,000 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 5,000 mg of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 2000 mg of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 1,000 mg of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 800 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 600 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 400 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 300 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 1 mg to about 250 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food product may contain about 1 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food product may contain about 1 mg to about 125 mg of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food product may contain about 5 mg to about 75 mg of the compound of formula (I), or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.In another embodiment, the food may contain about 10 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 10 mg to about 150 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 10 mg to about 100 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 10 mg to about 75 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 10 mg to about 50 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 20 mg to about 200 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 20 mg to about 150 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 20 mg to about 100 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 20 mg to about 75 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another embodiment, the food may contain about 20 mg to about 50 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0136] In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 1% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 1% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 10% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 10% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 10% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 10% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 10% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 10% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the food product ranges from about 10% to about 50%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 10% to about 40%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 10% to about 25%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 25% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 25% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 25% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 25% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 25% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 25% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the food product ranges from about 25% to about 50%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 25% to about 40%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 30% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 30% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food product ranges from about 30% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 30% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 30% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 30% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 30% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the food product ranges from about 40% to about 100%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 40% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 40% to about 90%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 40% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 40% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 40% to about 60%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 40% to about 50%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 50% to about 100%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 50% to about 99%. In another embodiment, the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, relative to the total amount of caffeine present in the food product ranges from about 50% to about 90%.In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 50% to about 80%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 50% to about 70%. In another embodiment, the percentage of the amount of the compound of formula (I) or its pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate relative to the total amount of caffeine present in the food is in the range of about 50% to about 60%.

[0137] Where a range is recited in this application, the ends of the range are understood to be specifically disclosed as if specifically recited, for example, a range from about 19% to about 99% specifically includes the disclosure of the 19% portion and the disclosure of the 99% portion.

[0138] The present disclosure also includes a kit (e.g., a pharmaceutical or nutraceutical pack). In certain embodiments, the kit includes a pharmaceutical or nutraceutical composition described herein and instructions for using the pharmaceutical or nutraceutical composition. In certain embodiments, the kit includes a first container, the first container includes the pharmaceutical or nutraceutical composition. In some embodiments, the kit further includes a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for diluting or suspending the pharmaceutical or nutraceutical composition). In certain embodiments, the second container includes an additional agent. In some embodiments, the kit further includes a third container. In certain embodiments, the third container includes an additional agent. In some embodiments, the pharmaceutical or nutraceutical composition included in the first container and the excipient or additional agent included in the second container are combined to form a unit dosage form. In some embodiments, the pharmaceutical or nutraceutical composition contained in the first container, the excipient contained in the second container, and the additional drug contained in the third container are combined to form one unit dosage form.In certain embodiments, each of the first, second, and third containers is independently a vial, an ampoule, a bottle, a syringe, a dispenser package, a tube, a nebulizer, or an inhaler.In certain embodiments, at least one of the first, second, and third containers is a nebulizer.

[0139] In certain embodiments, the instructions are for administering the pharmaceutical composition or nutraceutical composition to a subject in need thereof.In certain embodiments, the instructions include information required by regulatory authorities, such as the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA).In certain embodiments, the instructions include prescription information.

[0140] In certain embodiments, the compositions (e.g., cosmetic compositions, pharmaceutical compositions, or dietary supplement compositions), foods, beverages, or dietary supplements described herein are safe for human use (e.g., consumption) 1-5 times per day. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use once per day. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use twice per day. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use three times per day. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use four times per day. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use five times per day.

[0141] In certain embodiments, the compositions (e.g., cosmetic compositions, pharmaceutical compositions, or dietary supplement compositions), foods, beverages, or dietary supplements described herein are safe for human use (e.g., consumption) 1-5 times per week. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use once per week. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use twice per week. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use three times per week. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use four times per week. In certain embodiments, the compositions, foods, beverages, or dietary supplements are safe for human use five times per week. In certain embodiments, a composition (e.g., a cosmetic composition, a pharmaceutical composition, or a dietary supplement), food, beverage, or dietary supplement described herein is safe for human use (e.g., consumption) 1-5 times per month. In certain embodiments, a composition, food, beverage, or dietary supplement is safe for human use once per month. In certain embodiments, a composition, food, beverage, or dietary supplement is safe for human use twice per month. In certain embodiments, a composition, food, beverage, or dietary supplement is safe for human use three times per month. In certain embodiments, a composition, food, beverage, or dietary supplement is safe for human use four times per month. In certain embodiments, a composition, food, beverage, or dietary supplement is safe for human use five times per month.

[0142] Instructions and Use Various factors contribute to the usefulness or efficacy of the disclosed compounds, compositions, beverages, and foods in the methods described herein. Such factors include the pharmacokinetics of deuterated caffeine (such as d9-caffeine), the pharmacokinetics of non-deuterated caffeine, and the formation of the four major associated metabolites paraxanthine (1,7-dimethylxanthine), theobromine (3,7-dimethylxanthine), theophylline (1,3-dimethylxanthine), and TMU (1,3,7-trimethyluric acid). The pharmacokinetics of deuterated and non-deuterated caffeine can be influenced by the route of administration or means of consumption, and are manifested in physiological effects, including blood pressure, heart rate, heart rhythm, and respiratory rate. Pharmacokinetics in a particular subject may also be affected by factors such as age, body weight, body mass index, the slow metabolic properties of caffeine, prior or concomitant use or injection of other pharmacologically active substances including certain foods, beverages, alcohol, nicotine, and the physical fitness of the subject and the frequency / duration of exercise or other strenuous activity the subject engages in.

[0143] Thus, in certain embodiments, the deuterated caffeine compounds, compositions, beverages, and foods described herein have favorable or advantageous pharmacokinetic properties.Such properties include favorable metabolic profile, for example, favorable ratio of metabolite formation upon administration or consumption.In certain embodiments, favorable metabolic profile leads to reduction of undesirable effects on the subject's respiratory or cardiovascular system, such as blood pressure, heart rate, heart rhythm, and respiratory rate.

[0144] In certain embodiments, the subject is a slow metabolizer of caffeine and / or the deuterated caffeine compounds described herein. In certain embodiments, the subject is a fast metabolizer of caffeine and / or the deuterated caffeine compounds described herein. In certain embodiments, the metabolic profile of the deuterated caffeine compounds is influenced by the metabolic classification of the subject, i.e., slow metabolizer or fast metabolizer. In certain embodiments, the metabolic profile of the deuterated caffeine compounds is influenced by the health, physical fitness, sleep quality, dietary habits, and pharmacological habits of the subject.

[0145] Other factors that contribute to the usefulness or efficacy of the disclosed compounds, compositions, beverages, and foods relate to the cognitive or emotional health of the subject, including clinical conditions such as psychiatric and neurological disorders.

[0146] In certain particular embodiments, the above-mentioned favorable metabolic profile and / or characteristics are associated with d9-caffeine. In certain particular embodiments, the above-mentioned favorable metabolic profile and / or characteristics are associated with d10-caffeine.

[0147] The present disclosure also provides the method of using the compounds, compositions, beverages and foods of the present disclosure.In another aspect, the present disclosure provides the method of delivering the composition (e.g., effective amount of the composition) (e.g., pharmaceutical composition, dietary supplement composition, cosmetic composition, dietary supplement) of the present disclosure to a subject in need thereof.

[0148] In certain particular embodiments of this method, the compound of formula (I) is compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In other particular embodiments of this method, the compound of formula (I) is compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0149] In another aspect, the disclosure provides a method of treating a disease in a subject, comprising administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound or composition (e.g., a pharmaceutical or nutraceutical composition) of the disclosure.

[0150] In another aspect, the disclosure provides a method of preventing a disease in a subject, comprising administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound or composition (e.g., a pharmaceutical or nutraceutical composition) of the disclosure.

[0151] In another aspect, provided herein is the use of a compound or composition of the present disclosure in the manufacture of a medicament for use in a method of the present disclosure (e.g., a method of delivering an active agent to a subject in need thereof, a method of treating a disease in a subject in need thereof, a method of preventing a disease in a subject in need thereof).

[0152] In another aspect, provided herein is the use of a compound or composition of the present disclosure in a method of the present disclosure (e.g., a method of delivering an active agent to a subject in need thereof, a method of treating a disease in a subject in need thereof, a method of preventing a disease in a subject in need thereof).

[0153] In certain embodiments, the subject is an animal. The animal may be of either sex and at any stage of development. In certain embodiments, the subject described herein is a human. The human may be a child or an adult. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domestic animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a dog. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically modified animal. In certain embodiments, the animal is a transgenic animal (e.g., a transgenic mouse, a transgenic pig). In certain embodiments, the subject in need thereof is a subject in need of delivery of an active agent or composition, a subject in need of treatment of a disease, or a subject in need of prevention of a disease.

[0154] In certain embodiments, the effective amount is effective to treat a disease. In certain embodiments, the effective amount is effective to prevent a disease.

[0155] In certain embodiments, the disease is an inflammatory disease.The term "inflammatory disease" refers to a disease caused by, resulting from, or resulting in inflammation.The term "inflammatory disease" can also refer to a dysregulated inflammatory response that causes an exaggerated response by macrophages, granulocytes, and / or T lymphocytes, leading to abnormal tissue damage and / or cell death.Inflammatory disease can be either acute or chronic inflammatory disease, and can result from infectious or non-infectious causes.Inflammatory diseases include atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthritis, rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes mellitus (e.g., type I), myasthenia gravis, Hashimoto's thyroiditis, Graves' disease, Goodpaschaft's disease, and osteoporosis. pulmonary circulation disorders, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, pernicious anemia, inflammatory dermatitis, usual interstitial pneumonia (UIP), asbestosis, silicosis, bronchiectasis, beryllium pulmonary disease, talc pulmonary disease, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphocytic interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener's granulomatosis and related forms of vasculitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatitis, hepatitis, delayed hypercalcaemia, and pulmonary edema. Hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, airway inflammation, adult respiratory distress syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hay fever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, sepsis These include epididymitis, fasciitis, fibromyalgia, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, orchitis, tonsillitis, urethritis, cystitis cystica, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, vasculitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enteritis. Eye inflammatory diseases include postoperative inflammation.

[0156] In certain aspects, the disease is a neurological disease. In certain embodiments, the disease is a neurological disease. The term "neurological disease" refers to any disease of the nervous system, including diseases involving the central nervous system (brain, brainstem, and cerebellum), the peripheral nervous system (including cranial nerves), and the autonomic nervous system (parts of both the central and peripheral nervous systems). Neurodegenerative disease refers to a class of neurological diseases characterized by loss of nerve cells, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, tauopathies (including frontotemporal dementia), and Huntington's disease. Neurological diseases include, for example, headaches, stupor and coma, dementia, seizures, sleep disorders, trauma, infections, neoplasms, neuro-ophthalmology, movement disorders, demyelinating diseases, spinal cord disorders, and disorders of the peripheral nerves, muscles, and neuromuscular junctions. Addiction and psychiatric disorders, including bipolar disorder and schizophrenia, are also included in the definition of neurological disease. Neurological disorders include, for example, acquired epileptic aphasia, acute disseminated encephalomyelitis, adrenoleukodystrophy, agenesis of the corpus callosum, agnosia, Aicardi syndrome, Alexander disease, Alper's disease, alternating hemiplegia, Alzheimer's disease, amyotrophic lateral sclerosis, anencephaly, Angelman syndrome, hemangiomatosis, anoxia, aphasia, apraxia, arachnoid cysts, arachnoiditis, Arnold-Chiari malformation, arteriovenous malformations, Asperger's syndrome, ataxia-telangiectasia, attention-deficit hyperactivity disorder, autism, autonomic dysfunction, lower back pain, Batten disease, Behçet's disease, Bell's palsy, benign essential blepharospasm, benign focal muscular atrophy, benign intracranial hypertension, Binswanger's disease, blepharospasm, Bloch-Sulzberger's disease, syndrome;brachial plexus injury;brain abscess;brain injury;brain tumor (including glioblastoma multiforme);spinal tumor;Brown-Séquard syndrome;Canavan disease;carpal tunnel syndrome (CTS);causalgia;central pain syndromes;central pontine myelinolysis;head injury;cerebral aneurysm;cerebral arteriosclerosis;cerebral atrophy;cerebral gigantism;cerebral palsy;Charcot-Marie-Tooth disease;chemotherapy-induced neuropathy and neuropathic pain;Chiari malformation;chorea;chronic inflammatory demyelinating polyradiculoneuropathy (CIDP);chronic pain;chronic regional pain syndrome;Coffin-Lowry syndrome;coma including persistent vegetative state;congenital diplegia of the face;corticobasal degeneration;cranial arteritis;craniosynostosis;Creutzfeldt-Jakob disease;cumulative trauma disorder;Cushing's syndrome;Cytomegalic inclusion disease (CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome; Dandy-Walker syndrome; Dawson's disease; Domorsia syndrome; Dejerine-Krampke palsy; dementia; dermatomyositis; diabetic neuropathy; diffuse sclerosis; autonomic dysfunction; dysgraphia; dyslexia; dystonia; early infantile epileptic encephalopathy; Empty-Sella syndrome; encephalitis; encephalocele; trigeminal region angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry disease; Fahr's syndrome; syncope; familial spastic paraplegia; Febrile seizures; Fisher syndrome; Friedreich's ataxia; frontotemporal dementia and other "tauopathies"; Gaucher disease; Gerstmann's syndrome; giant cell arteritis; giant cell inclusion disease; globoid cell leukodystrophy; Guillain-Barré syndrome; HTLV-1-associated myelopathy; Hallervorden-Spatz disease; head trauma; headache; hemifacial spasms; hereditary spastic paraplegia; hereditary polyneuropathic ataxia; herpes zoster oticus; herpes zoster; Hirayama syndrome; HIV-associated dementia and neuropathy (see also Neurological symptoms of AIDS). Holoprosencephaly;Huntington's disease and other polyglutamine repeat disorders;Hydranencephaly;Hydrocephalus;Hypercortisolism;Hypoxia;Immune-mediated encephalomyelitis;Inclusion body myositis;Ataxia pigmenti;Childhood diseases;Phytanic acid storage disease;Infantile Refsum disease;Infantile spasms;Inflammatory myopathy;Intracranial cysts;Intracranial hypertension;Joubert syndrome;Kerns-Sayre syndrome;Kennedy disease;Kinsbone syndrome;Klippel-Feil syndrome;Krabbe disease;Kugelberg-Welander disease;Kuru;Lafora disease;Lambert-Eaton myasthenic syndrome;Landau-Klefna -Syndrome;Lateral medullary (Wallenberg) syndrome;Learning disabilities;Leigh's disease;Lennox-Gastaut syndrome;Lesch-Nyhan syndrome;Leukodystrophy;Dementia with Lewy bodies;Lissencephaly;Locked-in syndrome;Lou Gehrig's disease (also known as motor neuron disease or amyotrophic lateral sclerosis);Lyme disease - neurological sequelae;Machado-Joseph disease;Megalencephaly;Megalencephaly;Melkersson-Rosenthal syndrome;Ménière's disease;Meningitis;Menkes disease;Metachromatic leukodystrophy;Microcephaly;Migraine;Miller Fisher syndrome;Minor stroke;Mitochondrial myopathy;Moebius syndrome;Juvenile unilateral upper limb muscular atrophy;Motor neuron disease;Moyamoya disease;Mucopolysaccharidosis;Multi-infarct dementia;Multifocal motor neuropathy;Multiple sclerosis and other demyelinating disorders;Multiple system atrophy with orthostatic hypotension;Muscular dystrophy;Myasthenia gravis;Diffuse demyelinating sclerosis;Infantile myoclonic encephalopathy;Myoclonus;Myopathy;Congenital myotonia;Narcolepsy;Neurofibromatosis;Neuroleptic malignant syndrome;Neurological manifestations of AIDS;Neurological sequelae of lupus;Neuromyotonia;Neuronal ceroid lipofuscinosis;Neuronal migration disorder;Niemann-Pick disease;O'Sullivan-McLeod syndrome;Occipital neuralgia;Secondary to latent spinal dysraphism;Otawara syndrome;olivopontocerebellar atrophy;opsoclonus-myoclonus;optic neuritis;orthostatic hypotension;overuse syndrome;paresthesia;Parkinson's disease;congenital paramyotonia;paraneoplastic disorders;acute seizures;Parry-Romberg syndrome;Pelizaeus-Merzbacher disease;periodic paralysis;peripheral neuropathy;painful neuropathy and neuropathic pain;persistent vegetative state;pervasive developmental disorder;photic sneeze reflex;phytanic acid storage disease;Pick's disease;compressed nerve;pituitary tumor;polymyositis;porencephaly;post-polio syndrome;postherpetic neuralgia (PHN);postinfectious encephalomyelitis; Orthostatic hypotension;Prader-Willi syndrome;Primary lateral sclerosis;Prion disease;Progressive disease;Facial hemimetrophy;Progressive multifocal leukoencephalopathy;Progressive sclerosing polydystrophy;Progressive supranuclear palsy;Pseudotumor cerebri;Ramsay Hunt syndrome (types I and II);Rasmussen encephalitis;Reflex sympathetic dystrophy syndrome;Refsum disease;Repetitive movement disorder;Repetitive strain injury;Restless legs syndrome;Retroviral-associated myelopathy;Rett syndrome;Reye syndrome;St. Vitus chorea;Sandhoff disease;Schilder's disease;Schisencephaly;Septo-optic dysplasia;Shaken baby syndrome;Valveolar varicella ;Shy-Drager syndrome;Sjogren's syndrome;Sleep apnea;Sotos syndrome;Spasticity;Spina bifida;Spinal cord injury;Spinal tumor;Spinal muscular atrophy;Stiff-person syndrome;Stroke;Sturge-Weber syndrome;Subacute sclerosing panencephalitis;Subarachnoid hemorrhage;Subcortical arteriosclerotic encephalopathy;Sydenham chorea;Syncope;Syringomyelia;Tardive dyskinesia;Tay-Sachs disease;Temporal arteritis;Tethered spinal cord syndrome;Thomsen's disease;Thoracic outlet syndrome;Trigeminal neuralgia;Todd's palsy;Tourette's syndrome;Transient ischemic attack;Transmitting spongiform encephalopathy;Transverse myelitis;Traumatic brain injury;Tremor;Trigeminal neuralgia;Tropical spastic paraparesis; tuberous sclerosis; vascular dementia (multi-infarct dementia); vasculitis including temporal arteritis; von Hippel-Lindau disease (VHL); Wallenberg syndrome; Werdnig-Hoffmann disease; West syndrome; whiplash injury; Williams syndrome; Wilson's disease; and Zellweger syndrome.

[0157] In certain embodiments, the disease is a painful condition. "Pain conditions" include, but are not limited to, neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferented pain, chronic pain (e.g., chronic nociceptive pain and other forms of chronic pain such as postoperative pain (e.g., pain occurring after hip, knee or other replacement surgery)), preoperative pain, stimulation of nociceptive receptors (nociceptive pain), acute pain (e.g., hallucinations and episodic acute pain), noninflammatory pain, inflammatory pain, cancer-related pain, wound pain, burn pain, postoperative pain, pain associated with a medical procedure, pain due to pruritus, bladder pain syndrome, pain associated with premenstrual dysphoric disorder and / or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with preterm labor, pain associated with withdrawal from a drug addiction, joint pain, arthritis pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, or Reiter's arthritis), lower back pain (lumbosacral Pain conditions include pain, musculoskeletal pain, headache, migraine, muscle pain, lower back pain, neck pain, dental pain, dental / maxillofacial pain, visceral pain, etc. One or more painful conditions contemplated herein can include a mixture of various types of pain as described above and provided herein (e.g., nociceptive pain, inflammatory pain, neuropathic pain, etc.). In some embodiments, a particular pain may predominate. In other embodiments, a painful condition includes two or more types of pain, where no one predominates. A skilled clinician can determine the dosage to achieve a therapeutically effective amount for a particular subject based on the painful condition.

[0158] In certain embodiments, the disease is a mental disorder. The term "mental disorder" refers to mental illness and includes diseases and disorders listed in the Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV), published by the American Psychiatric Association, Washington, DC (1994). Mental disorders include anxiety disorders (e.g., acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, and specific phobias), childhood disorders (e.g., attention-deficit / hyperactivity disorder, conduct disorder, and oppositional defiant disorder), eating disorders (e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g., depression, bipolar disorder, cyclothymic disorder, dysthymic disorder, and major depressive disorder), personality disorders (e.g., antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, narcissistic personality disorder, obsessive-compulsive disorder, and psychiatric disorders), and personality disorders (e.g., anxiety disorder, anxiety disorder, and psychiatric disorders). personality disorder, paranoid personality disorder, schizotypal personality disorder, schizophreniform personality disorder), psychotic disorders (e.g., brief psychotic disorder, delusional disorder, schizoaffective disorder, schizophreniform disorder, schizophrenia, and shared psychotic disorder), substance-related disorders (e.g., alcoholism, amphetamine dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, opioid dependence, phencyclidine dependence, and sedative dependence), adjustment disorder, autism, delirium, dementia, multi-infarct dementia, learning and memory disorders (e.g., amnesia and age-related memory loss), and Tourette's disorder.

[0159] In certain embodiments, the disease is a metabolic disorder. The term "metabolic disorder" refers to any disorder involving changes in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or combinations thereof. Metabolic disorders are associated with either deficiencies or excesses in metabolic pathways, resulting in imbalances in the metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Factors that affect metabolism include endocrine (hormonal) control systems (e.g., insulin pathway, enteroendocrine hormones including GLP-1, PYY, etc.), neural control systems (e.g., GLP-1 in the brain), etc. Metabolic disorders include, for example, diabetes (e.g., type I diabetes, type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0160] In certain embodiments, the disease is cardiovascular disease. In certain embodiments, the disease is cardiovascular disease. In certain embodiments, the disease is atherogenesis or atherosclerosis. In certain embodiments, the disease is arterial stent occlusion, heart failure (e.g., congestive heart failure), coronary artery disease, myocarditis, pericarditis, valvular heart disease, stenosis, restenosis, in-stent stenosis, angina pectoris, myocardial infarction, acute coronary syndrome, coronary artery bypass graft, cardiopulmonary bypass procedure, endotoxemia, ischemia-reperfusion injury, cerebrovascular ischemia (stroke), renal reperfusion injury, embolism (e.g., pulmonary, renal, hepatic, gastrointestinal, or peripheral embolism), or myocardial ischemia.

[0161] In certain embodiments, the method further comprises administering an additional therapeutic agent to the subject in need thereof. In certain embodiments, the additional therapeutic agent is an additional pharmaceutical agent. In certain embodiments, the additional therapeutic agent is an additional dietary supplement. The pharmaceutical and dietary supplement compositions of the present disclosure and the additional therapeutic agent may exhibit synergistic effects in the methods and uses of the present disclosure.

[0162] In another aspect, the present invention provides a method for increasing energy levels in a subject, for reducing fatigue or sleepiness in a subject, or for increasing alertness in a subject, comprising administering to a subject a composition as described herein or a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0163] In certain embodiments, the method for increasing energy levels comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, the method for increasing energy levels comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0164] In another aspect, the present invention provides a method for treating obesity in a subject, for causing weight loss in a subject, for increasing metabolic rate in a subject, for reducing appetite in a subject, or for increasing energy expenditure in a subject, comprising administering to a subject a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0165] In certain embodiments, a method for treating obesity comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for treating obesity comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0166] In another aspect, the present invention provides a method for increasing urinary excretion in a subject, increasing sodium excretion in a subject, or reducing edema in a subject, comprising administering to a subject a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0167] In certain embodiments, a method for increasing urinary output comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for increasing urinary output comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0168] In another aspect, the present invention provides a method for treating a pain disorder in a subject, comprising administering to a subject a compound of formula (I); [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0169] In certain embodiments, a method for treating a pain disorder comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for treating a pain disorder comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0170] In another embodiment, the pain disorder is migraine, arthritis, headache, back pain, bursitis, chronic pain, acute pain, musculoskeletal pain, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, or sciatica. In another embodiment, the pain disorder is migraine. In another embodiment, the pain disorder is arthritis. In another embodiment, the pain disorder is headache. In another embodiment, the pain disorder is back pain. In another embodiment, the pain disorder is bursitis. In another embodiment, the pain disorder is chronic pain. In another embodiment, the pain disorder is acute pain. In another embodiment, the pain disorder is musculoskeletal pain. In another embodiment, the pain disorder is osteoarthritis. In another embodiment, the pain disorder is psoriatic arthritis. In another embodiment, the pain disorder is rheumatoid arthritis. In another embodiment, the pain disorder is sciatica. In another embodiment, the pain disorder is migraine or headache.

[0171] In another aspect, the present invention provides a method for treating apnea in a subject, comprising administering to a subject a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0172] In certain embodiments, a method for treating apnea comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for treating apnea comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0173] In another embodiment, the apnea is sleep apnea. In another embodiment, the sleep apnea is obstructive sleep apnea, central sleep apnea, apnea of ​​prematurity, or complex sleep apnea syndrome. In another embodiment, the apnea is apnea of ​​prematurity. In another embodiment, the subject is a newborn, a premature infant, a premature infant, or a low birth weight infant. In another embodiment, the subject is an adult.

[0174] In another aspect, the present invention provides a method for treating hypotension in a subject, comprising administering to a subject a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0175] In certain embodiments, a method for treating hypotension comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for treating hypotension comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0176] In another embodiment, the hypotension is orthostatic hypotension, prandial hypotension, or multiple system atrophy with orthostatic hypotension. In another embodiment, the hypotension is orthostatic hypotension. In another embodiment, the hypotension is multiple system atrophy with orthostatic hypotension.

[0177] In another aspect, the present invention provides a method for treating encephalopathy in a subject, comprising administering to a subject a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0178] In certain embodiments, a method for treating encephalopathy comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for treating encephalopathy comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0179] In another embodiment, the encephalopathy is chronic traumatic encephalopathy, glycine encephalopathy, Hashimoto's encephalopathy, hepatic encephalopathy, hypertensive encephalopathy, hypoxic-ischemic encephalopathy, toxic metabolic encephalopathy, infectious encephalopathy, uremic encephalopathy, or Wernicke's encephalopathy. In another embodiment, the encephalopathy is chronic traumatic encephalopathy. In another embodiment, the encephalopathy is glycine encephalopathy. In another embodiment, the encephalopathy is Hashimoto's encephalopathy. In another embodiment, the encephalopathy is hepatic encephalopathy. In another embodiment, the encephalopathy is hypertensive encephalopathy. In another embodiment, the encephalopathy is hypoxic-ischemic encephalopathy. In another embodiment, the encephalopathy is toxic metabolic encephalopathy. In another embodiment, the encephalopathy is infectious encephalopathy. In another embodiment, the encephalopathy is uremic encephalopathy. In another embodiment, the encephalopathy is Wernicke's encephalopathy.

[0180] In another aspect, the present invention provides a method for treating a neurological or psychiatric disorder in a subject, comprising administering to a subject a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0181] In certain embodiments, a method for treating a neurological or psychiatric disorder comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for treating a neurological or psychiatric disorder comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0182] In another embodiment, the neurological or psychiatric disorder is narcolepsy, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), schizophrenia, Parkinson's disease, or depression. In another embodiment, the neurological or psychiatric disorder is narcolepsy. In another embodiment, the neurological or psychiatric disorder is Alzheimer's disease. In another embodiment, the neurological or psychiatric disorder is attention deficit hyperactivity disorder (ADHD). In another embodiment, the neurological or psychiatric disorder is schizophrenia. In another embodiment, the neurological or psychiatric disorder is Parkinson's disease. In another embodiment, the neurological or psychiatric disorder is depression.

[0183] In certain embodiments, the neurological or psychiatric disorder is narcolepsy.In certain embodiments, the method for treating narcolepsy comprises administering to a subject compound 14, or its pharmaceutically or nutraceutical acceptable salt, hydrate, or solvate.In another particular embodiment, the method for treating narcolepsy comprises administering to a subject compound 15, or its pharmaceutically or nutraceutical acceptable salt, hydrate, or solvate. In certain embodiments, the neurological or psychiatric disorder is ADHD.In certain embodiments, the method for treating ADHD comprises administering to a subject compound 14, or its pharmaceutically or nutraceutical acceptable salt, hydrate, or solvate.In another particular embodiment, the method for treating ADHD comprises administering to a subject compound 15, or its pharmaceutically or nutraceutical acceptable salt, hydrate, or solvate.

[0184] In another aspect, the present invention provides a method for treating an inflammatory disorder in a subject, comprising administering to a subject a compound of formula (I): [ka] [In the formula, each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, to a subject.

[0185] In certain embodiments, a method for treating an inflammatory disorder comprises administering to a subject compound 14, or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof. In another particular embodiment, a method for treating an inflammatory disorder comprises administering to a subject compound 15, or a pharma-ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof.

[0186] In another embodiment, the inflammatory disorder is a pulmonary inflammatory disorder. In another embodiment, the inflammatory disorder is asthma, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis, or interstitial lung disease. In another embodiment, the inflammatory disorder is asthma. In another embodiment, the inflammatory disorder is chronic obstructive pulmonary disorder (COPD). In another embodiment, the inflammatory disorder is pulmonary fibrosis. In another embodiment, the inflammatory disorder is interstitial lung disease.

[0187] In any of the methods described herein, the maximum plasma concentration (C) of the compound of formula (I) after administration of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is determined. max ) is substantially similar to that of an equivalent dose of non-isotopically enriched caffeine.

[0188] In another embodiment, the maximum plasma concentration (C) of the compound of formula (I) after administration of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is max ) is lower than that of an equivalent dose of non-isotopically enriched caffeine. In another embodiment, the maximum plasma concentration (C) of the compound of formula (I) after administration of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, is max) is at least 5%, 10%, 25%, or 50% lower than that of an equivalent dose of non-isotopically enriched caffeine.

[0189] In any of the methods described herein, the time to maximum plasma concentration (T) of the compound of formula (I) after administration of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is determined. max ) is longer than that of a comparable dose of non-isotopically enriched caffeine.

[0190] In another embodiment, the time to maximum plasma concentration (T) of the compound of formula (I) after administration of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is max ) is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

[0191] In another embodiment, the plasma half-life (t 1 / 2 ) is longer than that of a comparable dose of non-isotopically enriched caffeine.

[0192] In any of the methods described herein, the plasma half-life (t 1 / 2 ) is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

[0193] In any of the methods described herein, the maximum concentration (C) of a compound of formula (I) in the central nervous system (CNS) of a subject following administration of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is determined. max) is substantially similar to that of an equivalent dose of non-isotopically enriched caffeine.

[0194] In another embodiment, the maximum concentration (C) of a compound of formula (I) in the central nervous system (CNS) of a subject following administration of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is max ) is at least 5%, 10%, 25%, or 50% lower than that of an equivalent dose of non-isotopically enriched caffeine.

[0195] In any of the methods described herein, the time to maximum concentration (T) of a compound of formula (I) in the central nervous system (CNS) of a subject following administration of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is determined. max ) is longer than that of a comparable dose of non-isotopically enriched caffeine.

[0196] In another embodiment, the time to maximum concentration (T) of a compound of formula (I) in the central nervous system (CNS) of a subject following administration of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is max ) is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

[0197] In any of the methods described herein, the total systemic exposure (AUC) in plasma following administration of a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, is at least 5%, 10%, 25%, 50%, 100%, or 200% greater than that of an equivalent dose of non-isotopically enriched caffeine.

[0198] In another embodiment, the total systemic exposure (AUC) in plasma of the compound of formula (I) following administration of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, or solvate thereof, is greater than that of an equivalent dose of non-isotopically enriched caffeine.

[0199] In any of the methods described herein, the total systemic exposure (AUC) in the central nervous system of the compound of formula (I) following administration of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, is at least 5%, 10%, 25%, 50%, 100%, or 200% greater than that of an equivalent dose of non-isotopically enriched caffeine.

[0200] In another embodiment, the total systemic exposure (AUC) in the central nervous system of the compound of formula (I) following administration of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, is greater than that of an equivalent dose of non-isotopically enriched caffeine.

[0201] In any of the methods described herein, following administration of a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, the ratio of total systemic exposure in plasma (AUC) of the compound of formula (I) to the total systemic exposure in the central nervous system (AUC) of the compound is substantially similar to that of an equivalent dose of non-isotopically enriched caffeine.

[0202] In another embodiment, following administration of a compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, or solvate thereof, the ratio of the total systemic exposure (AUC) in plasma of the compound of formula (I) to the total systemic exposure (AUC) of the compound in the central nervous system is within 20%, 15%, 10%, 5%, 2%, or 1% of that of an equivalent dose of non-isotopically enriched caffeine.

[0203] In another embodiment, the side effects experienced after administration of a compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt, hydrate, solvate, composition, or prodrug thereof, are reduced compared to administration of an equivalent dose of non-isotopically enriched caffeine. In another embodiment, the side effects are anxiety, insomnia, gastrointestinal disorders (e.g., loose stools, diarrhea, gastric ulcers, gastroesophageal reflux, etc.), rhabdomyolysis, dependency, hypertension, increased heart rate, atrial fibrillation, fatigue, irritability, nervousness, restlessness, nausea, or muscle tremors.

[0204] In any of the methods described herein, side effects are reduced compared to administration of equivalent doses of non-isotopically enriched caffeine.In another embodiment, side effects are anxiety, insomnia, gastrointestinal disorders (e.g., loose stools, diarrhea, gastric ulcers, gastroesophageal reflux, etc.), rhabdomyolysis, dependence, hypertension, increased heart rate, atrial fibrillation, fatigue, irritability, nervousness, restlessness, nausea, or muscle tremors.

[0205] In another embodiment, the rate or frequency of consumption of a beverage comprising water and a compound of Formula (I), or a pharma- ceutically or dietary supplementally acceptable salt, hydrate, solvate, composition, or prodrug thereof, is decreased as compared to the rate of consumption of a beverage comprising an equivalent dose of non-isotopically enriched caffeine. In certain embodiments, the rate or frequency of consumption of the beverage is decreased by about 10% to about 80% per unit of time (e.g., day, week, or month) as compared to the rate of consumption of a beverage comprising an equivalent dose of non-isotopically enriched caffeine. In certain embodiments, the rate or frequency of consumption of the beverage is decreased by about 10% per unit of time. In certain embodiments, the rate or frequency of consumption of the beverage is decreased by about 20% per unit of time. In certain embodiments, the rate or frequency of consumption of the beverage is decreased by about 30% per unit of time. In certain embodiments, the rate or frequency of consumption of the beverage is decreased by about 40% per unit of time. In certain embodiments, the rate or frequency of consumption of the beverage is decreased by about 50% per unit of time. In certain embodiments, the rate or frequency of beverage consumption is reduced by about 60% per unit of time. In certain embodiments, the rate or frequency of beverage consumption is reduced by about 70% per unit of time. In certain embodiments, the rate or frequency of beverage consumption is reduced by about 80% per unit of time. In certain embodiments, the unit of time is a day. In certain embodiments, the unit of time is a week. In certain embodiments, the unit of time is a month. The following representative examples are intended to help illustrate the present invention, and are not intended to limit the scope of the present invention, and should not be interpreted as such. Indeed, in addition to those shown and described herein, various modifications of the present invention, and many further embodiments thereof, will become apparent to those skilled in the art from the entire contents of this document, including the following examples and the scientific references and patent documents cited herein. Furthermore, unless otherwise indicated, it should be understood that the entire contents of each reference cited herein are incorporated herein by reference to help describe the state of the art. The following examples contain important additional information, exemplification and guidance that can be adapted to the practice of the present invention in its various embodiments and equivalents thereof.

[0206] These and other aspects of the present invention will be further understood in light of the following examples, which are intended to illustrate certain embodiments of the invention and are not intended to limit the scope defined by the claims. EXAMPLES

[0207] In order that the disclosure set forth herein may be more fully understood, the following examples are set forth: The synthetic and biological examples described in this application are provided to illustrate the compounds, compositions, foods, beverages, and methods provided herein, and should not be construed in any way as limiting the scope thereof. Abbreviation AUC inf : Area under the concentration-time curve from time zero to infinity AUC last : Area under the concentration-time curve from time zero to the final quantifiable concentration BQL: Below quantification limit C max : Maximum observed concentration CV: Coefficient of variation Hr: time LC-MS / MS: Liquid chromatography tandem mass spectrometry LLOQ: Lower limit of quantification Min: Minutes n: number of samples NA: Not applicable No. : Number NR : Not Reported QC: Quality control rpm: revolutions per minute SD: standard deviation Sec: seconds Std : Standard T 1 / 2 Terminal half-life T max : Time of maximum observed concentration ULOQ: Upper limit of quantification v : volume

[0208] compound The compounds described herein include their salts, hydrates and solvates, including all compounds depicted in the schemes herein, whether intermediate or final compounds in a process.

[0209] The compounds of the invention can be obtained from natural sources or can be prepared or modified by means known in the art of organic synthesis. For example, 1-trideuteromethyl-3,7-dimethylxanthine (1-CD3-caffeine), 3-trideuteromethyl-1,7-dimethylxanthine (3-CD3-caffeine), and 7-trideuteromethyl-1,3-dimethylxanthine (7-CDs-caffeine) can be synthesized from theobromine, 1,7-dimethylxanthine, and theophylline, respectively, and 1,3,7-tri-trideuteromethylxanthine (1,3,7-[CD3]3-caffeine) can be synthesized from xanthine by the following general method. To a stirred solution of 100 mg of xanthine or dimethylxanthine in 5 mL of acetone:water (1:1), 5 mL of 0.5 N sodium hydroxide and 50 μL of trideuteromethyl iodide are added. After 1 and 2 hours, an additional 50 μL of trideuteromethyl iodide is added. The solution is left at room temperature for 4-6 hours. The acetone is then removed (nitrogen stream) and 10 mL of water is added. The product is extracted from the aqueous solution with ethyl acetate and recrystallized three times from ethanol. See MG Horning, J. Nowlin, JP. Thenot, and OJ Bouwsma, "Effect of Deuterium Substitution on the Rate of Caffeine Metabolism", Stable Isotopes, Proceedings of the Third International Conference, 1979, 379.See also JB Falconnet, JL Brazier and M. Desage, J Label Compd Radiopharm, 1986, 23, 267.

[0210] Methods for optimizing reaction conditions, if necessary to minimize competition with products, are known in the art. Reaction optimization and scale-up can advantageously utilize high speed parallel synthesis equipment and computer-controlled microreactors (see, for example, Design And Optimization in Organic Synthesis, 2001). nd (Ed., Carlson R, Ed, 2005; Elsevier Science Ltd.; Jahnisch, K et al., Angew. Chem. Int. Ed. Engl. 2004 43:406; and references therein). Additional reaction schemes and protocols can be determined by those skilled in the art using commercially available structure-searchable database software, such as SciFinder™ (CAS division of the American Chemical Society), and CrossFire Beilstein™ (Elsevier MDL), or by appropriate keyword searches using Internet search engines such as Google™, or keyword databases such as the United States Patent and Trademark Office text database.

[0211] Caffeine and D9-caffeine (compound 14) were purchased from Sigma-Aldrich and stored at room temperature upon receipt.

[0212] Example 1 Pharmacokinetic (PK) Study Design Two groups of fasted male Sprague-Dawley rats (12 animals per group) were administered a single oral dose of caffeine in deionized water (group 1) or D9-caffeine in deionized water (group 2) at a target dose level of 2 mg / kg.

[0213] Serial blood samples were collected from three animals per group at pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 14 hours post-dose. No more than three blood samples were collected from each animal, with the last sample being the terminal bleed. Terminal brain samples were collected from three animals per group at 1, 4, 8, and 14 hours post-dose. Blood samples were collected into tubes containing sodium heparin, processed for plasma, and stored frozen until bioanalysis. Brain samples were taken after the terminal bleed, rinsed with saline, and stored frozen until bioanalysis.

[0214] Plasma and brain samples were analyzed for caffeine and D9-caffeine (compound 14) concentrations using a liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Noncompartmental pharmacokinetic parameter estimates were calculated from the mean plasma concentration-time data.

[0215] The results demonstrate that D9-caffeine (compound 14) provides higher systemic exposure (as measured by AUC) and a longer half-life in vivo than a corresponding dose of caffeine.

[0216] Extraction methods, LC and MS conditions, and data analysis Table 1 summarizes the extraction methods, liquid chromatography (LC) and mass spectrometry (MS) conditions, and data analysis methods used. [Table 1]

[0217] Preparation of dosage forms Dosage formulations were prepared on the day of dosing.

[0218] For Group 1, the dosage formulation was prepared at a target concentration of 0.2 mg / mL by adding caffeine (10.00 mg) to deionized water (49.778 g), vortex mixing and sonication.

[0219] For Group 2, the dosage formulation was prepared at a target concentration of 0.2 mg / mL by adding D9-caffeine (10.04 mg) to deionized water (49.792 g), vortex mixing and sonication.

[0220] After administration, the formulations were stored in a -80°C freezer.

[0221] Rat acclimation and housing Male Sprague-Dawley rats were received from Envigo RMS on March 18, 2019. After a 3-day acclimation period, 24 males were assigned to studies based on acceptable health status. Animals assigned to studies were individually identified by tail markings (indelible ink) and cage cards.

[0222] Animals were housed in Innovive™ disposable microisolator cages (1–3 animals per cage). Teklad GlobalDiets TM (Envigo) 18% Protein Rodent Diet 2018, and tap water were provided ad libitum until the evening before dosing. Animals were fasted overnight before dose administration.

[0223] The animal quarters were maintained at temperatures between 20°C and 26°C (68°F and 79°F), relative humidity between 30% and 70%, and airflow with at least 10 changes per hour. A light / dark cycle was set with 12-h intervals, with the cycle interrupted for the performance of test procedures.

[0224] After collection of the final blood sample, the test animals were euthanized by carbon dioxide asphyxiation according to the American Veterinary Medical Association guidelines for euthanasia (current edition).

[0225] Dose Administration Animals were fasted overnight prior to dose administration. Water was provided ad libitum. Food was restored after 4-h samples were collected. Two groups of male Sprague-Dawley rats (12 animals per group) received a single dose of caffeine in deionized water (group 1) or D9-caffeine (compound 14) in deionized water (group 2) at a target dose level of 2 mg / kg.

[0226] Prior to dosing, the body weight of each animal was recorded. The dose (rounded to the nearest 0.001 mL) was calculated based on the pretreatment body weight (kg) and a dosing volume of 10 mL / kg. Oral dosing was performed using a ball-tip feeding needle. Just before and immediately after dosing each animal, the dosing syringe was weighed and the amount of formulation administered to each animal was determined from the difference in syringe weight.

[0227] Sample collection and processing Serial blood samples (~300 μL) were collected in tubes containing sodium heparin from three animals per group per time point at pre-dose and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 14 hours post-dose. Blood was collected three times from each animal, with the last blood collection occurring at the time of animal sacrifice. Blood samples were stored on wet ice and processed for plasma by centrifugation (3500 g, 10 minutes at 5°C) within 30 minutes of collection. Plasma samples were transferred to matrix tubes and stored in a freezer set to maintain a temperature of -80°C until analysis.

[0228] Immediately after 1, 4, 8, and 14 h of blood collection, three animals / group were euthanized and brains were dissected from each rat. Brains were rinsed with saline, dried, placed in pre-weighed conical tubes, and flash frozen in liquid nitrogen. Brain weight was calculated for each sample. Brains were stored in a freezer set to maintain a temperature of -80 °C.

[0229] Bioanalysis Rat plasma and brain samples were analyzed for caffeine and D9-caffeine (compound 14) concentrations using a validated LC-MS / MS method. Table 1 shows the details of the extraction procedure and analytical method.

[0230] Pharmacokinetic analysis Pharmacokinetic parameter estimates were calculated from plasma concentration-time data for caffeine and D9-caffeine (compound 14) generated from the combined animal plasma data using nominal sampling times and noncompartmental methods. Concentration-time data were analyzed and fitted to an extravascular (gavage) dose plasma analysis model (200) using the software WinNonlin Phoenix version 6.3 (Pharsight). Pharmacokinetic parameters evaluated included, where appropriate, T 1 / 2 (Terminal half-life);T max (time to peak concentration); C max (peak or maximum concentration); AUC last (calculated from time zero to the time of the last positive Y value), and AUC INF (area under the analyte concentration-time line calculated from zero to infinity).

[0231] The area under the plasma concentration-time curve (AUC) was estimated using the linear trapezoidal rule. last ) time (T last ) is the area under last The AUC extrapolated to infinity (AUC INF ) is the AUC last and C. last / λ z It was estimated by adding the ratio of z is the terminal rate constant. Apparent T 1 / 2 was calculated using the slope of the log-linear terminal phase of the concentration-time curve, defined by a minimum of three plasma concentration-time points. Half-lives are reported if the correlation of the regression line, as measured by r-squared, was estimated to be ≥ 0.9.

[0232] result Dose Administration Two groups of male Sprague-Dawley rats (12 animals per group) received a single dose of caffeine in deionized water (group 1) or D9-caffeine in deionized water (group 2) at a target dose level of 2 mg / kg.

[0233] In rats treated with caffeine (group 1), the administered doses were determined gravimetrically and based on nominal concentrations and ranged from 1.970 to 2.023 mg / kg (dose variation of -1.48% to 1.21%). In rats treated with D9-caffeine (group 2), the administered doses were determined gravimetrically and based on nominal concentrations and ranged from 1.971 to 2.017 mg / kg (dose variation of -1.43 to 0.85%). Dose administration data are reported in Table 2. [Table 2]

[0234] Sample collection and processing With the following exceptions, samples were obtained within 5% of the planned time: a 0.5-h blood sample from animal No. 1 (11.61%) and a 1-h brain sample from animals No. 1 (8.19%), No. 2 (7.47%), No. 3 (7.06%), No. 4 (7.39%), No. 5 (8.00%), and No. 6 (6.72%).

[0235] Plasma concentration Table 3 summarizes the mean caffeine concentrations in plasma following oral (gavage) administration of caffeine to male Sprague-Dawley rats, and Table 4 reports individual animal data. Table 5 summarizes the mean D9-caffeine (compound 14) concentrations in plasma following oral (gavage) administration of D9-caffeine (compound 14) to male Sprague-Dawley rats. Table 6 reports individual animal data. The mean plasma concentration-time profiles of caffeine and D9-caffeine are plotted in Figure 1.

[0236] Following administration of 2 mg / kg of caffeine or D9-caffeine (Compound 14), measurable plasma concentrations of caffeine or D9-caffeine (Compound 14) were detected in all animals evaluated at each time point up to 14 hours post-dose. Table 3 - Group 1: Mean (n=3 / time point) caffeine concentrations in plasma following oral (gavage) administration of caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 3] Table 4 - Group 1: Plasma caffeine concentrations following oral (gavage) administration of caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 4] Table 5 - Group 2: Mean (n=3 / time point) D9-caffeine concentrations in plasma following oral (gavage) administration of D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 5] Table 6 - Group 2: Plasma D9-caffeine concentrations following oral (gavage) administration of D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 6]

[0237] Brain concentration Table 7 summarizes the mean caffeine concentrations in the brain following oral (gavage) administration of caffeine to male Sprague-Dawley rats. Individual animal data are reported in Table 8. Table 9 summarizes the mean D9-caffeine (compound 14) concentrations in the brain following oral (gavage) administration of D9 caffeine (compound 14) to male Sprague-Dawley rats. Individual animal data are reported in Table 10. The mean brain concentration-time profiles of caffeine and D9-caffeine (compound 14) are shown in Figure 1.

[0238] Following administration of 2 mg / kg of caffeine or D9-caffeine (Compound 14), measurable brain concentrations of caffeine or D9-caffeine (Compound 14) were detected in all animals evaluated at each time point up to 14 hours post-dose. Table 7 - Group 1: Mean (n=3 / time point) caffeine concentrations in the brain following oral (gavage) administration of caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 7] Table 8 - Group 1: Caffeine concentrations in the brain following oral (gavage) administration of caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 8] Table 9 - Group 2: Mean (n=3 / time point) D9-caffeine concentrations in the brain following oral (gavage) administration of D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 9] Table 10 - Group 2: D9-caffeine concentrations in the brain following oral (gavage) administration of D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 10]

[0239] Pharmacokinetics Mean pharmacokinetic parameter estimates for caffeine and D9-caffeine (Compound 14) following oral administration of caffeine or D9-caffeine (Compound 14) to male Sprague-Dawley rats are reported in Table 11 for plasma and in Table 12 for brain.

[0240] After oral administration of caffeine at 2 mg / kg, plasma T 1 / 2 , C max , and AUC last were 1.9 h, 2600 ng / mL, and 16000 h*ng / mL, respectively. After oral administration of D9-caffeine (compound 14) at 2 mg / kg, the plasma T 1 / 2 , C max , and AUC last were 5 h, 2400 ng / mL, and 22000 h*ng / mL, respectively. D9-caffeine (compound 14) provided a higher AUC exposure and a longer half-life than the corresponding dose of caffeine in plasma.

[0241] Due to the difference in molecular weight between caffeine (MW = 195.1) and D9-caffeine (MW = 204.1), D9-caffeine, which is a smaller molecule than caffeine, was administered at a dose level of 2 mg / kg. Table 13 shows the molecular weight-corrected C max , AUC last , and AUC inf The plasma C values ​​are shown to allow comparison of caffeine and D9-caffeine (compound 14). max The values ​​were similar between D9-caffeine (compound 14) and caffeine (C max,corr ratio 0.97), total systemic exposure (AUC inf ) was approximately 77% higher (AUC inf,corr Ratio 1.77).

[0242] After oral administration of caffeine at 2 mg / kg, the C max and AUClast were 1900 ng / mL and 11000 hr*ng / mL, respectively. After oral administration of D9-caffeine (compound 14) at 2 mg / kg, the C max and AUC last were 1600 ng / mL and 16000 hr*ng / mL, respectively. Similar to plasma, D9-caffeine (compound 14) provided a higher AUC exposure than the corresponding dose of caffeine in the brain. Brain / plasma AUC last The ratios were similar, 0.69 and 0.73 for caffeine and D9-caffeine (compound 14), respectively.

[0243] Table 14 shows the molecular weight-corrected C max and AUC last The values ​​of C in the brain are shown. max The value was slightly lower for D9-caffeine (compound 14) than for caffeine (C max,corr Ratio 0.88), and these differences were due to the small number of time points evaluated and the T max However, the total brain exposure (AUC last,corr ) was approximately 52% higher than caffeine (AUC last,corr Ratio 1.52). Table 11 - Plasma pharmacokinetic parameters of caffeine and D9-caffeine following oral (gavage) administration of caffeine or D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 11] Table 12 - Brain pharmacokinetic parameters of caffeine and D9-caffeine following oral (gavage) administration of caffeine or D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 12] Table 13 - Molecular weight corrected plasma pharmacokinetic parameters of caffeine and D9-caffeine following oral (gavage) administration of caffeine or D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 13] Table 14 - Molecular weight corrected brain pharmacokinetic parameters of caffeine and D9-caffeine following oral (gavage) administration of caffeine or D9-caffeine to fasted male Sprague-Dawley rats at a target dose level of 2 mg / kg. [Table 14]

[0244] Example 2 The following study assessed the CNS-like activity of compound 14 in naive C57 / Bl6 mice using acute oral dosing followed by the SmartCube™ assay.

[0245] Experimental design Male C57 / Bl6 mice obtained from Taconic Laboratories (Germantown, NY) were used. Upon receipt, mice were group-housed in OPTI mouse ventilated cages, with four mice per cage. Mice were acclimated to the colony room for at least 1 week prior to testing and then tested at approximately 8 weeks of age. All animals were inspected, handled, and weighed prior to the start of testing to ensure adequate health and suitability and to minimize nonspecific stress associated with manipulation. A 12 / 12 light / dark cycle was maintained throughout the course of testing. Room temperature was maintained at 20-23°C with relative humidity at 30-70%. Food and water were provided ad libitum throughout the testing period.

[0246] Compound 14 was tested at 0.3, 1, 3, 10, 20, and 30 mg / kg. Compounds were formulated in deionized water and administered orally at a dose of 10 mL / kg 60 minutes before testing. Each treatment group contained 12 animals per group. SmartCube™ test session lasted 45 minutes.

[0247] The SmartCube™ system is designed to measure multiple spontaneous behaviors and responses to challenges in the same testing environment. The hardware includes force sensors and a number of aversive stimuli to elicit behavior. Three high-resolution video cameras provide a continuous 3D view of the mouse within the SmartCube™ Apparatus (SC) throughout the entire testing period. During a 45-minute testing session, the mouse is exposed to a series of challenges. The cube is cleaned between each run.

[0248] To construct a reference dataset, drugs were injected 15 min before testing and multiple challenges were administered over the course of the test session. Digital videos of subjects were processed by a computer segmentation algorithm to fit a geometric model to the frame images of each mouse. The resulting fitted parameters were then analyzed using a behavioral classification algorithm to extract behavioral states such as rearing, locomotion, and immobility. The data thus obtained were used to define drug signatures of known reference compounds and to establish treatment class signatures against which test samples could be compared. The data mining effort utilizes several analytical techniques, including probability density Bayesian models and decision trees. The algorithm considers ~2,600 measurements, including the frequency and duration of behavioral states such as grooming, rearing, and many other features acquired during the test session.

[0249] For class and subclass analysis, a reference dataset was constructed from hundreds of drug doses in multiple drug classes, plus control groups that received different types of vehicle only. Drug classes were divided into subclasses. Each reference drug was tested in mice at multiple doses appropriate for that drug. The best performing classifiers were selected from the evaluation tests, and two additional types of classifiers were constructed, which make independent predictions at the drug class and subclass levels. The behavioral signatures of the test drugs were evaluated using these classifiers to predict potential therapeutic utility. The results of the classification are displayed as bar graphs of classes and subclasses.

[0250] result Class and subclass analysis of vehicle and all compounds is shown in Figure 2. See Figure 3 for full class and subclass legend. Compound 14 was behaviorally inactive at doses of 0.3, 1, and 3 mg / kg. The predominant class and subclass signatures at these doses were vehicle-like as seen in the white bars. The 10 mg / kg dose showed a mixed but predominantly "unknown" class and subclass signature. This unknown portion of the signature indicates that the compound is active, but the classification scheme, although detecting differences from vehicle, was unable to reliably assign specific features or patterns (either novel or changes of insufficient magnitude shown at lower doses) to a CNS class. At 20 mg / kg, the class analysis still showed a predominant "unknown" signature mixed with psychostimulant / ADHD-like signatures, but the subclasses showed a predominant psychostimulant / ADHD signature. A clear psychostimulant / ADHD signature was demonstrated at 30 mg / kg for both class and subclass. This psychostimulant / ADHD-like signature seen at 20 and 30 mg / kg was similar to that of dopamine reuptake inhibitors and modafinil.

[0251] Example 3 The following study assessed the metabolic stability and metabolite formation of caffeine and compound 14 in human hepatocytes.

[0252] Cryopreserved human hepatocytes were thawed and suspended in 50 ml of InVitro GRO HT medium. Cells were centrifuged (50 g, 5 min) and resuspended in InVitro GRO KHB medium (protein-free). Cell density and viability were determined by trypan blue exclusion. Stock solutions of test compounds (caffeine, compound 14, theophylline, theobromine, paraxanthine, D6-theophylline, and D6-theobromine) were prepared in DMSO and diluted in incubation medium before spiking into the incubations.

[0253] Instrument: Waters Acquity UPLC + Waters TQ-S Triple Quadrupole MS; Column: Phenomenex Kinetex Biphenyl (2.1 × 100 mm, 1.8 μm) column with guard filter; Software: MassLynx 4.2.

[0254] Samples were analyzed by LC / MS / MS at 0, 30, 60, 90, and 120 min (with and without hepatocytes) to monitor the reduction of substrate and the formation of metabolites theophylline, theobromine, and paraxanthine. No obvious loss of caffeine or compound 14 was observed in human hepatocytes or buffer, and the observed metabolite levels were low. The most abundant metabolite was paraxanthine, with concentrations of 26.6 nM for unlabeled caffeine and 6.3 nM for compound 14 (D6-paraxanthine) at 120 min. Similarly, theophylline was at a concentration of approximately 1.1 nM and D6-theophylline was at a concentration of approximately 0.4 nM at 120 min. Theobromine was not detected in any of the incubations. Based on this, deuterium labeling appears to slow down the metabolic reaction rate of caffeine but does not appear to affect the ratio of metabolites formed.

[0255] Example 4 Phase 1 Pharmacokinetic Evaluation of Caffeine Versus d9-Caffeine in Healthy Male and Female Subjects Following a Single Oral Dose

[0256] The study objectives included: (i) to evaluate the pharmacokinetic relationships between the plasma pharmacokinetics (PK) of caffeine and d9-caffeine and their four major metabolites: paraxanthine (1,7-dimethylxanthine), theobromine (3,7-dimethylxanthine), theophylline (1,3-dimethylxanthine), and TMU (1,3,7-trimethyluric acid); (ii) to characterize the PK of caffeine and its metabolites in plasma after oral administration; (iii) to characterize the PK of d9-caffeine and its metabolites in plasma after oral administration; and (iv) to evaluate the pharmacological effects of caffeine and d9-caffeine on blood pressure, heart rate, cardiac rhythm, and respiratory rate.

[0257] Exploratory objectives of the study include evaluating the relationship between caffeine and d9-caffeine on alertness as a measure of pharmacological effects. Exploratory objectives include a variety of behavioral measures, including (i) the trail making test (see, e.g., Bowie, CRCR; PDPD Harvey (2006) "Administration and interpretation of the trail making test" Nature Protocols. 1 (5): 2277-2281); (ii) the Stroop Color Word Test (see, e.g., Scarpina F. and Tagini S. (2017) "The Stroop Color and Word Test" Front. Psychol. 8:557); and (iii) the Stanford Sleepiness Scale (see, e.g., Hoddes E. (1972) "The development and use of the stanford sleepiness scale (SSS)" Psychophysiology. 9 (150)).

[0258] The study is a randomized, double-blind, two-part, two-period crossover study in which subjects will be randomized to the following treatment sequence: 16 subjects will be treated in two groups with approximately equal numbers for each part. Subject groups will include a reasonable distribution of male and female subjects and may include 2-3 slow metabolizers per group. Four treatments will be evaluated in the study: Part 1: caffeine 50 mg orally and d9-caffeine 50 mg orally (as molar equivalents); and, Part 2: caffeine 250 mg orally and d9-caffeine 250 mg orally (as molar equivalents).

[0259] Subjects may be selected based on criteria including: (i) CYP1A2 * 1A or CYP1A2 *(ii) consumption / use of known CYP1A2 inhibitors (e.g., artemisinin, atazanavir, cimetidine, ciprofloxacin, enoxacin, ethinyl estradiol, etc.) or known CYP1A2 inducers (e.g., barbiturates, cruciferous vegetables, grilled meats, carbamazepine, primidone, rifampin, smoking) within 48 hours prior to dosing; (ii) use of nicotine-containing products for at least 3 months prior to dosing; (iii) history of alcohol use or dependence; (iv) history of heavy caffeine intake; (v) consumption of dietary supplements, juices, herbal preparations, or other foods or beverages that may affect various drug-metabolizing enzymes and transporters (e.g., alcohol, grapefruit, grapefruit juice, grapefruit-containing foods, etc.) within 48 hours prior to dosing. (vi) intake / use of prescription or over-the-counter (OTC) medications, except for oral contraceptives, within 2 weeks prior to treatment; (vii) engagement in strenuous exercise (e.g., exercise, exercise routine, exercise routine, exercise routine) within 1 week prior to treatment; (vii) consumption of alcoholic beverages, apple or orange juice, mustard family vegetables (e.g., kale, broccoli, watercress, collard greens, kohlrabi, Brussels sprouts, mustard greens), or charbroiled meats; consumption of herbal preparations containing St. John's wort within 4 weeks prior to treatment; (vii) consumption of prescription or over-the-counter (OTC) medications, except for oral contraceptives, within 2 weeks prior to treatment; (vii) engagement in strenuous exercise (e.g., exercise routine ... (viii) a history of bleeding disorders, deep vein thrombosis, or thromboembolic disease; (ix) clinically significant abnormal screening blood test results or recurrent infections, or if any of the following are observed (regardless of the PI's assessment of clinical significance): hemoglobin <11 g / dL (women) or <13 g / dL (men) (<100 g / L), absolute neutrophil count <2000 / mm 3 , platelets < 135 × 10 9 / L, AST within research reference ranges (or 3 × ULN), ALT within research reference ranges (or 3 × ULN); (x) positive screen result for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV), or COVID-19; (xi) sitting blood pressure less than 90 / 40 mmHg or more than 140 / 90 mmHg; and (xii) estimated glomerular filtration rate (eGFR) < 80 mL / min.

[0260] Equivalents and scope In the claims, words such as "a," "an," and "the" can mean one or more unless stated otherwise or clear from the context. A claim or description including "or" between one or more members of a group is deemed to be satisfied that one, more than one, or all of the group members are present in, employed in, or relevant to a given item or method, unless stated otherwise or clear from the context. The invention includes embodiments in which exactly one member of a group is present in, employed in, or relevant to a given item or method. The invention includes embodiments in which more than one or all members of a group are present in, employed in, or relevant to a given item or method.

[0261] Moreover, the invention encompasses all variations, combinations, and arrangements in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, a claim that is dependent on another claim can be amended to include one or more limitations found in other claims that are dependent on the same base claim. When elements are presented as lists, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element can be removed from the group. In general, when the invention or aspects of the invention are described as comprising certain elements and / or features, it should be understood that the particular embodiment of the invention or aspects of the invention consist of or consist essentially of such elements and / or features. For purposes of simplicity, those embodiments have not been specifically described herein in that literal sense. It should also be noted that the terms "comprising," "including," and "containing" are intended to be open and allow for the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Furthermore, unless otherwise stated or clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can be any specific value or sub-range from within the ranges set forth in different embodiments of the invention to the unit of the lower limit of that range, unless the context clearly indicates otherwise.

[0262] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this specification, the specification shall control. Furthermore, any particular embodiment of the present invention that falls within the prior art may be expressly excluded from any one or more of the claims. Such embodiments may be excluded even if the exclusion is not expressly set forth herein, since they are deemed known to those of skill in the art. Any particular embodiment of the present invention may be excluded from the claims for any reason, whether or not related to the existence of prior art.

[0263] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above specification, but rather is set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically acceptable salt thereof.

2. Formula (I): 【Chemistry 2】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a dietary supplement acceptable salt thereof.

3. Formula (I): 【Chemistry 3】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or an acceptable salt thereof.

4. The composition of claim 1 or 2, wherein the composition is suitable for oral administration.

5. The composition of claim 1 , wherein the composition is suitable for intravenous (IV) administration.

6. The composition of claim 1 or 3, wherein the composition is suitable for topical administration.

7. The composition of claim 1 , wherein the composition is suitable for pulmonary delivery.

8. The composition of claim 1 or 2, wherein the composition is a solid dose composition.

9. The composition according to claim 1 or 2, wherein the composition is used for weight reduction.

10. The composition according to claim 1 or 2, wherein the composition is used for appetite suppression.

11. The composition according to claim 1 or 2, wherein the composition is used as a dietary supplement.

12. The composition according to claim 1 or 2, wherein the composition is used as a diuretic composition.

13. The composition of claim 1 , wherein the composition is used as an analgesic composition.

14. The composition of any one of claims 1 to 13, wherein at least two of Y are deuterium.

15. The composition of any one of claims 1 to 13, wherein at least three of the Y's are deuterium.

16. The composition of any one of claims 1 to 13, wherein at least four of the Y's are deuterium.

17. The composition of any one of claims 1 to 13, wherein at least five of the Y's are deuterium.

18. The composition of any one of claims 1 to 13, wherein at least six of the Y's are deuterium.

19. The composition of any one of claims 1 to 13, wherein at least seven of the Y's are deuterium.

20. The composition of any one of claims 1 to 12, wherein at least eight of the Y's are deuterium.

21. The composition of any one of claims 1 to 13, wherein nine of the Y's are deuterium.

22. The composition of any one of claims 1 to 13, wherein each Y is deuterium.

23. Formula (IA), (IB), or (IC): 【Chemistry 4】 23. The composition of any one of claims 1 to 22, wherein the compound is selected from the group consisting of:

24. Formula (ID), (IE), or (IF): 【Chemistry 5】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

25. Formula (IG), (I-H), (II), (I-J), (I-K), or (IL): 【Chemistry 6】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

26. Formula (IM), (IN), (IO), (IP), (IQ), or (IR): 【Chemistry 7】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

27. Formula (IS), (IT), or (IU): 【Chemistry 8】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

28. Formula (II-A), (II-B), or (II-C): 【Chemistry 9】 23. The composition of any one of claims 1 to 22, wherein the compound is selected from the group consisting of:

29. Formula (II-D), (II-E), or (II-F): 【Chemistry 10】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

30. Formula (II-G), (II-H), or (II-I): 【Chemistry 11】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

31. The compound is 【Chemistry 12】 31. The composition of any one of claims 1 to 30, which is selected from the group consisting of: or a pharma- ceutically or nutraceutical acceptable salt thereof.

32. The compound is 【Chemistry 13】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

33. The compound is 【Chemistry 14】 or a pharma- ceutically or nutraceutical acceptable salt thereof.

34. The compound is 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 The composition according to any one of claims 1 to 30, which is selected from the group consisting of:

35. The compound is 【Chemistry 18】 The composition according to any one of claims 1 to 30,

36. The composition of any one of claims 1 to 35, further comprising a pharma- ceutically or nutraceutical acceptable carrier.

37. 9. The composition of claim 8, wherein the solid dose composition is a tablet, capsule, granule, powder, sachet, or chewable.

38. 7. The composition of claim 6, wherein the topical composition is a shampoo, conditioner, cream, foam, gel, lotion, ointment, transdermal patch, tincture, or paste.

39. 8. The composition of claim 7, wherein the composition is administered using a nebulizer, a pressurized metered dose inhaler (pMDI), or a dry powder inhaler (DPI).

40. The composition of any one of claims 1 to 39, further comprising an additional agent.

41. 41. The composition of claim 40, wherein the additional agent is an ergotamine, an anti-inflammatory agent, a steroid, a barbiturate, an opioid analgesic, or a combination thereof.

42. 42. The composition of claim 41, wherein the anti-inflammatory agent is a cyclooxygenase-3 (COX-3) inhibitor, a nonsteroidal anti-inflammatory drug (NSAID), or a cyclooxygenase-2 (COX-2) inhibitor.

43. 42. The composition of claim 41, wherein any of the hydrogen atoms in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic are replaced with deuterium.

44. 44. The composition of claim 43, wherein the percentage of deuterium in the ergotamine, anti-inflammatory agent, steroid, barbiturate, or opioid analgesic is at least 5%.

45. 44. The composition of claim 43, wherein the NSAID is ibuprofen, naproxen, sulindac, ketoprofen, tolmetin, etodolac, fenoprofen, diclofenac, flurbiprofen, piroxicam, ketorolac, indomethacin, nabumetone, oxaprozin, mefanamic acid, or diflunisal.

46. 44. The composition of claim 43, wherein the opioid analgesic is codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, or oxycodone.

47. 44. The composition of claim 43, wherein the barbiturate is secobarbital, mephobarbital, pentobarbital, butabarbital, phenobarbital, or amobarbital.

48. 44. The composition of claim 43, wherein the COX-2 inhibitor is celecoxib, valdecoxib, rofecoxib, or etoricoxib.

49. 44. The composition of claim 43, wherein the COX-3 inhibitor is acetaminophen, phenacetin, antipyrine, or dipyrone.

50. The composition according to any one of claims 1 to 49, wherein the composition comprises from about 1 mg to about 200 mg of the compound of formula (I) or a salt thereof.

51. 51. The composition of claim 50, wherein the composition comprises from about 1 mg to about 125 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof.

52. 51. The composition of claim 50, wherein the composition comprises from about 5 mg to about 75 mg of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof.

53. The composition of claim 1 or 5, wherein the composition comprises from about 1 mg / ml to about 25 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof.

54. 54. The composition of claim 53, wherein the composition comprises from about 2 mg / ml to about 15 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof.

55. 54. The composition of claim 53, wherein the composition comprises from about 5 mg / ml to about 15 mg / ml of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof.

56. 56. The composition according to any one of claims 1 to 55, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof, relative to the amount of caffeine present in the composition ranges from about 10% to about 99%.

57. 57. The composition of claim 56, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof, relative to the total amount of caffeine present in the composition ranges from about 10% to about 25%.

58. 57. The composition of claim 56, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof, to the total amount of caffeine present in the composition ranges from about 25% to about 100%.

59. 57. The composition of claim 56, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof, to the total amount of caffeine present in the composition ranges from about 25% to about 75%.

60. 57. The composition of claim 56, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof, relative to the total amount of caffeine present in the composition ranges from about 30% to about 70%.

61. 57. The composition of claim 56, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt thereof, to the total amount of caffeine present in the composition ranges from about 25% to about 50%.

62. 57. The composition of claim 56, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or dietary supplementally acceptable salt thereof, to the total amount of caffeine present in the composition ranges from about 40% to about 60%.

63. 57. The composition of claim 56, wherein the percentage of the amount of the compound of formula (I), or a pharma- ceutically or nutraceutical acceptable salt thereof, to the total amount of caffeine present in the composition ranges from about 50% to about 100%.

64. A method for increasing energy levels in a subject, for reducing fatigue or sleepiness in a subject, or for increasing alertness in a subject, comprising the composition of any one of claims 1 to 63; or a compound of formula (I): 【Chemistry 19】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

65. A method for treating obesity in a subject, for causing weight loss in a subject, for increasing metabolic rate in a subject, for reducing appetite in a subject, or for increasing energy expenditure in a subject, comprising a composition according to any one of claims 1 to 63; or a compound of formula (I): 【Chemistry 20】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

66. A method for increasing urinary excretion in a subject, for increasing sodium excretion in a subject, or for reducing edema in a subject, comprising a composition according to any one of claims 1 to 63; or a compound of formula (I): 【Chemistry 21】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

67. A method for treating a pain disorder in a subject, comprising administering to a subject a composition according to any one of claims 1 to 63; or to a compound of formula (I): 【Chemical 22】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

68. 68. The method of claim 67, wherein the pain disorder is migraine, arthritis, headache, back pain, bursitis, chronic pain, acute pain, musculoskeletal pain, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, or sciatica.

69. 69. The method of claim 67 or 68, wherein the pain disorder is migraine or headache.

70. A method for treating apnea in a subject, comprising administering to a subject a composition according to any one of claims 1 to 63; or to a compound of formula (I): 【Chemistry 23】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

71. 71. The method of claim 70, wherein the apnea is sleep apnea.

72. 72. The method of claim 71, wherein the sleep apnea is obstructive sleep apnea, central sleep apnea, apnea of ​​prematurity, or complex sleep apnea syndrome.

73. 73. The method of any one of claims 71 to 72, wherein the subject is a newborn, a premature infant, a premature infant, or a low birth weight infant.

74. The method of any one of claims 71 to 73, wherein the subject is an adult.

75. A method for treating hypotension in a subject, comprising administering to a subject a composition according to any one of claims 1 to 63; or to a compound of formula (I): 【Chemistry 24】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

76. 76. The method of claim 75, wherein the hypotension is orthostatic hypotension, dietary hypotension, or multiple system atrophy with orthostatic hypotension.

77. 76. The method of claim 75, wherein the hypotension is dietary hypotension.

78. A method for treating encephalopathy in a subject, comprising administering to a subject a composition according to any one of claims 1 to 63; or to a subject of formula (I): 【Chemistry 25】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

79. 79. The method of claim 78, wherein the encephalopathy is chronic traumatic encephalopathy, glycine encephalopathy, Hashimoto's encephalopathy, hepatic encephalopathy, hypertensive encephalopathy, hypoxic-ischemic encephalopathy, toxic metabolic encephalopathy, infectious encephalopathy, uremic encephalopathy, or Wernicke's encephalopathy.

80. 79. The method of claim 78, wherein the encephalopathy is hypoxic-ischemic encephalopathy.

81. A method for treating a neurological or psychiatric disorder in a subject, comprising the composition of any one of claims 1 to 63; or a compound of formula (I): 【Chemistry 26】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

82. 82. The method of claim 81, wherein the neurological or psychiatric disorder is narcolepsy, Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), schizophrenia, Parkinson's disease, or depression.

83. A method for treating an inflammatory disorder in a subject, comprising administering to a subject a composition according to any one of claims 1 to 63; or to a compound of formula (I): 【Chemistry 27】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or nutraceutical acceptable salt thereof, The method comprises administering to a subject.

84. 84. The method of claim 83, wherein the inflammatory disorder is a pulmonary inflammatory disorder.

85. 85. The method of claim 84, wherein the inflammatory disorder is asthma, chronic obstructive pulmonary disorder (COPD), pulmonary fibrosis, or interstitial lung disease.

86. The maximum plasma concentration (C) of the compound of formula (I) after administration of the composition according to any one of claims 1 to 63, or a compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64-85, wherein the duration of isotopic enrichment of caffeine is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

87. The maximum plasma concentration (C) of the compound of formula (I) after administration of the composition according to any one of claims 1 to 63, or the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64 to 85, wherein the amount of caffeine produced by isotopically enriching the caffeine is less than that of an equivalent dose of non-isotopically enriched caffeine.

88. The time to maximum plasma concentration (T) of the compound of formula (I) after administration of the composition according to any one of claims 1 to 63, or a compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64-85, wherein the duration of isotopic enrichment of caffeine is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

89. The time to maximum plasma concentration (T) of the compound of formula (I) after administration of the composition according to any one of claims 1 to 63, or a compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64 to 85, wherein the time to release is longer than that of an equivalent dose of non-isotopically enriched caffeine.

90. The plasma half-life (t １／２ 86. The method of any one of claims 64-85, wherein the duration of isotopic enrichment of caffeine is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

91. The plasma half-life (t １／２ 86. The method of any one of claims 64 to 85, wherein the time to release is longer than that of an equivalent dose of non-isotopically enriched caffeine.

92. The maximum concentration (C) of the compound of formula (I) in the central nervous system (CNS) of a subject after administration of the composition according to any one of claims 1 to 63, or a compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64-85, wherein the isotopic enrichment of caffeine is at least 5%, 10%, 25%, or 50% lower than that of an equivalent dose of non-isotopically enriched caffeine.

93. The maximum concentration (C) of the compound of formula (I) in the central nervous system (CNS) of a subject after administration of the composition according to any one of claims 1 to 63, or a compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64 to 85, wherein the amount of caffeine produced by isotopically enriching the caffeine is less than that of an equivalent dose of non-isotopically enriched caffeine.

94. The time to maximum concentration (T) of the compound of formula (I) in the central nervous system (CNS) of a subject after administration of the composition of any one of claims 1 to 63, or the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64-85, wherein the duration of isotopic enrichment of caffeine is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

95. The time to maximum concentration (T) of the compound of formula (I) in the central nervous system (CNS) of a subject after administration of the composition of any one of claims 1 to 63, or the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof. ｍａｘ 86. The method of any one of claims 64 to 85, wherein the time to release is longer than that of an equivalent dose of non-isotopically enriched caffeine.

96. 86. The method of any one of claims 64 to 85, wherein the side effects are reduced compared to administration of an equivalent dose of caffeine.

97. 97. The method of claim 96, wherein the side effect is anxiety, insomnia, gastrointestinal disorders, rhabdomyolysis, dependency, hypertension, increased heart rate, atrial fibrillation, fatigue, irritability, nervousness, restlessness, nausea, or muscle tremors.

98. The maximum plasma concentration (C ｍａｘ 64. The composition of any one of claims 1 to 63, wherein the isotopic enrichment of caffeine is at least 5%, 10%, 25%, or 50% lower than that of an equivalent dose of non-isotopically enriched caffeine.

99. The maximum plasma concentration (C ｍａｘ 64. The composition of any one of claims 1 to 63, wherein the isotopic enrichment of caffeine is less than that of an equivalent dose of non-isotopically enriched caffeine.

100. The time to maximum plasma concentration of the compound of formula (I) after administration of the composition (T ｍａｘ ) is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

101. The time to maximum plasma concentration of the compound of formula (I) after administration of the composition (T ｍａｘ 64. The composition of any one of claims 1 to 63, wherein the duration of the isotopic enrichment is longer than that of an equivalent dose of non-isotopically enriched caffeine.

102. The plasma half-life (t １／２ ) is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

103. The plasma half-life (t １／２ 64. The composition of any one of claims 1 to 63, wherein the duration of the isotopic enrichment is longer than that of an equivalent dose of non-isotopically enriched caffeine.

104. The maximum concentration (C) of the compound of formula (I) in the central nervous system (CNS) of the subject after administration of the composition ｍａｘ 64. The composition of any one of claims 1 to 63, wherein the isotopic enrichment of caffeine is at least 5%, 10%, 25%, or 50% lower than that of an equivalent dose of non-isotopically enriched caffeine.

105. The maximum concentration (C) of the compound of formula (I) in the central nervous system (CNS) of the subject after administration of the composition ｍａｘ 64. The composition of any one of claims 1 to 63, wherein the isotopic enrichment of caffeine is less than that of an equivalent dose of non-isotopically enriched caffeine.

106. The time to maximum concentration (T ｍａｘ ) is at least 5%, 10%, 25%, 50%, 100%, 200%, 300%, or 400% longer than that of an equivalent dose of non-isotopically enriched caffeine.

107. The time to maximum concentration (T ｍａｘ 64. The composition of any one of claims 1 to 63, wherein the duration of the isotopic enrichment is longer than that of an equivalent dose of non-isotopically enriched caffeine.

108. Water and a compound of formula (I): 【Chemistry 28】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or dietary supplement acceptable salt thereof.

109. A beverage comprising water and the composition of any one of claims 1 to 63.

110. 110. The beverage of claim 108 or 109, wherein the beverage further comprises one or more of a flavoring agent and a sweetener.

111. 111. The beverage of any one of claims 108-110, wherein the beverage further comprises one or more of vitamins, minerals, cofactors, proteins, lipids, peptides, and amino acids.

112. 112. The beverage of claim 111, wherein the beverage is an energy drink.

113. 112. The beverage of claim 111, wherein the beverage is a vitamin water.

114. 113. The beverage of claim 112, wherein the energy drink further comprises one or more of water, taurine, citicoline, vitamin B6, vitamin B12, folic acid, niacinamide, glucuronolactone, N-acetyl-L-tyrosine, L-phenylalanine, and malic acid.

115. 114. The beverage of claim 113, wherein the vitamin water further comprises one or more of water, vitamin C, vitamin B5, vitamin B6, vitamin B12, magnesium, and pantothenic acid.

116. 116. The beverage of any one of claims 108 to 115, wherein the beverage comprises from about 1 mg to about 200 mg of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof.

117. 116. The beverage of any one of claims 108 to 115, wherein the beverage comprises from about 1 mg to about 125 mg of the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof.

118. 116. The beverage of any one of claims 108 to 115, wherein the beverage comprises from about 5 mg to about 75 mg of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof.

119. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 10% to about 99%.

120. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 10% to about 25%.

121. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 25% to about 99%.

122. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 25% to about 75%.

123. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 30% to about 70%.

124. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 25% to about 50%.

125. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 40% to about 60%.

126. 119. The beverage according to any one of claims 108 to 118, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the beverage ranges from about 50% to about 99%.

127. Formula (I): 【Chemical 29】 [In the formula, Each Y is independently hydrogen or deuterium; and At least one Y is deuterium. or a pharma- ceutically or dietary supplement acceptable salt thereof.

128. 128. The food product of claim 127, wherein the food product is an energy bar, an energy gel, a pre-workout supplement, or other performance enhancing supplement.

129. 129. The food product of claim 128, wherein the energy bar further comprises one or more of sugar, cocoa butter, chocolate liquor, whole milk powder, soy lecithin, vanilla extract, caramel, peanuts, peanut butter, almonds, oats, molasses, cinnamon, salt, and soybean oil.

130. 130. The food product of any one of claims 127 to 129, wherein the food product comprises from about 1 mg to about 200 mg of the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof.

131. 130. The food product of any one of claims 127 to 129, wherein the food product comprises from about 1 mg to about 125 mg of the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof.

132. 130. The food product of any one of claims 127 to 129, wherein the food product comprises from about 5 mg to about 75 mg of the compound of formula (I) or a pharma- ceutically or nutraceutical acceptable salt thereof.

133. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof relative to the total amount of caffeine present in the food product ranges from about 10% to about 99%.

134. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof relative to the total amount of caffeine present in the food product ranges from about 10% to about 25%.

135. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof relative to the total amount of caffeine present in the food product ranges from about 25% to about 99%.

136. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the food product ranges from about 25% to about 75%.

137. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof relative to the total amount of caffeine present in the food product ranges from about 30% to about 70%.

138. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the food product ranges from about 25% to about 50%.

139. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof relative to the total amount of caffeine present in the food product ranges from about 40% to about 60%.

140. 130. The food product of any one of claims 127 to 129, wherein the percentage of the amount of the compound of formula (I) or a pharma- ceutically or dietary supplementally acceptable salt thereof to the total amount of caffeine present in the food product ranges from about 50% to about 100%.

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