DHM is a naturally occurring flavonoid found in plants such as Hovenia dulcis and Ampelopsis grossedentata and has anti-alcohol intoxication properties via its interactions with the GABAA receptor, a main mediator of the symptoms of alcohol consumption. Pharmacokinetics of DHM have not been studied in humans. However, intravenous (i.v) (2 mg/kg) or oral (p.o) administration (20 mg/kg) in rats resulted in Cmax of 166 and 22 ng/mL, respectively. As shown in rats, p.o administration of DHM has poor bioavailability. It is distributed rapidly within 15 mins post dose in rats and metabolized into 7 metabolites: Glucuronide-dihydromyricetin (Glc-DHM), 3ˊ-O-methyl-dihydromyricetin, 4ˊ-Me-DHM, 4ˊ-DeOH-DHM), glucuronide-3ˊ-O-methoxy- dihydromyricetin (Glc-3ˊ-Me-DHM), glucuronide-3ˊ-O-methoxy-dihydromyriceitn (Glc-4ˊ-Me-DHM) and glucuronide-dehydroxy-dihydromyricetin (Glc-DeOH-DHM).

DHM has been studied in context of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). DHM was associated with significant improvements in markers of liver injury (ALT, AST, GGT) and lipid metabolism in patients with NAFLD, and significant improvements in measures of insulin resistance in patients with T2DM. In both studies, participants were provided daily p.o doses of DHM with NAFLD patients taking 600 mg daily for three months and T2DM patients taking 970 mg daily for one month. There were no reported adverse events (AEs) in either study.

Methylliberine is a synthetic purine alkaloid that has been shown to improve alertness alone and in combination with caffeine and theacrine. Based on its structural similarity to caffeine, methylliberine is believed to be an adenosine receptor antagonist. In humans, a single p.o administration of 100 mg of methylliberine resulted in a Cmax of 365 ng/mL, Tmax of 0.8 hours, and AUC of 10.3 ng·h/mL. Although there are no reports of absorption, distribution, metabolism, and excretion studies conducted in animals, methylliberine’s safety and toxicology have been well described in humans.

Methylliberine has been studied in humans and it was found to be safe and well tolerated when taken orally for up to 150 mg once daily for up to four weeks in healthy volunteers. In these clinical studies, methylliberine was used in combination with caffeine and theacrine. The combination of methylxanthines in these studies helps to justify using lower doses of caffeine in combination with methylliberine to elicit the same effects on mental alertness and cognitive performance while limiting the cardiovascular side effects from caffeine.

Caffeine, a methylxanthine compound, is a potent adenosine receptor antagonist. Several human and animal species degrade caffeine using slightly different pathways, resulting in different metabolite profiles of plasma and urine. Paraxanthine and 1-methyluric acid were found to be the major metabolites in the human plasma and urine, respectively. 5-acetylamino-6-amino-3-methyluracil was found exclusively in human urine. In Macaca cynomolgus monkeys, two significant metabolites are identified: theophylline and 1,3-dimethyluric acid. In contrast, paraxanthine is the predominant metabolite detected in both the blood and urine of rabbits. Additionally, 6-Amino-5-[N-formylmethylamino]-1,3-dimethyluracil is a major metabolite present in rat urine, but it is not found in the urine samples from either mice or rabbits.

As described above, paraxanthine is the major plasma metabolite of caffeine in humans. Likewise, caffeine, paraxanthine is an adenosine receptor antagonist with central nervous system activating activity. In a human study, paraxanthine was shown to have similar sympathomimetic effects (increases in diastolic blood pressure, plasma epinephrine levels, and free fatty acids) as caffeine at a dose of 4 mg/kg. Compared with caffeine, paraxanthine may have greater effects on mental alertness. In a study in rats, paraxanthine was shown to have a stronger locomotor activating effect than caffeine. This effect was attributed to paraxanthine blocking cGMP phosphodiesterase in addition to adenosine receptors.

Caffeine has been shown to be effective in improving cognitive performance, alertness and wakefulness, mental sharpness, physical energy, and motor performance. A comprehensive review of the effects of caffeine consumption on human health concluded that for healthy adults, moderate chronic intakes of caffeine up to 400 mg/day are not associated with AEs on cardiovascular health, behavior, cancer risk, or male fertility. As per the USFDA, up to 400 mg of caffeine a day in healthy adults is considered to be a dose not likely to be associated with any potentially dangerous effects.

Huperzine A, a compound isolated from Huperzia serrata, is a selective, reversible inhibitor of acetylcholine esterase (AChE) with neuroprotective and memory enhancing properties. The PK of a single p.o dose (0.4 mg) of Huperzine A was evaluated in 12 healthy volunteers and the following parameters were observed: Cmax of 2.6 ng/mL, Tmax of 58 min, and AUC of 2450 µg·min/L. The results suggest a two-compartment model: initial distribution of Huperzine A followed by a slower, overall elimination rate from the rest of the body compartments. A larger study with 24 healthy male volunteers demonstrated a similar result using a single p.o dose (0.2 mg) of Huperzine A. In this study following parameters were observed: Cmax of 1.550 ± 0.528 ng/mL, Tmax of 0.946 ± 1.021 hour, t1/2 of 725.52 ± 124.08 min, and AUC0-72 of 1053 ± 228 µg·min/L.

Huperzine A has been well-tolerated in several clinical studies with patients taking daily doses of 400 µg and 800 µg for up to 16 weeks. As a reversible inhibitor of AChE, Huperzine A has been investigated for its impact on memory in patients with Alzheimer’s disease and other forms of dementia, traumatic brain injuries, and adolescents with memory issues. It demonstrated a positive effect in cognitive function in Alzheimer’s disease and vascular dementia patients compared to placebo. Huperzine A may support next-day recovery from the effects of alcohol intoxication by improving cognition.

Fructose is a monosaccharide that has been shown experimentally to promote alcohol metabolism. The PK of fructose have been studied in humans using high-fructose corn syrup (HFCS) or sucrose. HFCS consists of 55% fructose, 42% glucose, and 3% oligosaccharides, while sucrose consists of 50% fructose and 50% glucose. The study was a prospective, randomized, single-blinded, crossover trial in 40 men and women who consumed 24 oz of HFCS or sucrose sweetened beverage. The 24 oz of HFCS sweetened beverage contained 39.2 g of fructose and 28.8 g of glucose, while the same volume of sucrose sweetened beverage contained 34.6 g of fructose and 34.8 g of glucose. The AUC, Cmax and Tmax for fructose in the HFCF group were 38,800 min⁎μmol/L, 363 μmol/L and 57 minutes, respectively. The AUC, Cmax and Tmax for fructose in the sucrose group was 32,300 min⁎μmol/L, 317 μmol/L and 60 minutes, respectively.

The effect of fructose in accelerating alcohol metabolism has been studied since the 1950’s with positive results reported. Fructose has been associated with lowering blood alcohol levels and increasing alcohol metabolism in humans at varying doses, ranging from 0.25 to 1 g/kg. Fructose is a substance that is GRAS.

Quercetin is a commonly occurring polyphenolic bioflavonoid typically found in grapes, wine, green tea, apples, onions, and green leafy vegetables. Isoquercitrin is activated and converted into quercetin in the body. Quercetin is the active compound that exerts is pharmacological effects including hepatoprotective effects on liver injury induced by alcohol consumption by increasing EtOH metabolism and/or increasing antioxidative activity. Quercetin’s PK properties have been studied in a human clinical trial. The subjects were given quercetin 500 mg three times daily(t.i.d.), leading to a Cmax of 15.4 ng/mL, Tmax of 3 hours and AUC of 62.5 ng/mL*h.

Isoquercitrin is converted into quercetin in our body. Quercetin has shown several beneficial effects in animal studies, including anti-inflammatory, anti-carcinogenic, antioxidant, and immune modulation. Preclinical study also demonstrate a protective effect on EtOH-induced acute liver injury via the upregulation of protective liver enzymes, increase of antioxidant activity against oxidative stress, and reduced expression of proinflammatory cytokines. In addition, a self-GRAS dossier, considered equivalent to a GRAS dossier, is available from the manufacturer of Isoquercetrin. This can be shared under strict confidentiality with permission from the manufacturer.

An extract called silymarin is obtained from the milk thistle plant. Silymarin contains chemicals such as silybin A and silybin B, which are active components. Silymarin acts as a free radical scavenger and modulates enzymes involved in cellular damage, fibrosis, and cirrhosis. EtOH leads to the formation of free radicals in hepatocytes, and the persistence of ROS can eventually lead to liver fibrosis. Silymarin can act as a scavenger for ROS and promote substrate availability to increase glutathione generation thus enhancing the antioxidant capacity in the liver. A study examined the PK of these substances in healthy volunteers by administering single doses of either one (175 mg), two (350 mg), or three (525 mg) of milk thistle capsules. Silybin A, one of the major components of silymarin, had a Cmax of 107, 201 and 299 ng/mL in 175, 350, and 525 mg groups, respectively. Silybin A had a Tmax of 1.5, 1.0 and 1.0 hours in 175, 350, and 525 mg groups, respectively. Silybin A had an AUC0-24h of 231, 462 and 737 ng·h/mL in 175, 350, and 525 mg groups, respectively.

Milk thistle extract is a complex mixture of phytochemicals, and silymarin is an active extract with flavonolignans extracted from the milk thistle, Silybum marianum (L.) gaernt. This mixture can function as a free radical scavenger and modulator of enzymes involved in cellular damage, fibrosis, and cirrhosis. Silymarin has been investigated for its liver-protective properties in various human diseases. When patients with chronic liver disease take silymarin or placebo daily for two or more years, the results indicate that survival rates are higher in the silymarin group. Several studies have observed that silymarin is safe when consumed daily for long periods of time, including a daily dose of 420 mg for an average of 41 months.

B vitamins are water soluble nutrients that serve important functions as cofactors in cell metabolism and energy production.

L-Phenylalanine is an essential amino acid that helps produce dopamine, tyrosine and other compounds.

Sodium Citrate, magnesium citrate, monopotassium phosphate are electrolytes that provide nutritional support.