IngredientsMethylliberine (CAS RN 51168-26-4; O(2),1,7,9-tetramethylurate) is a purine alkaloid of the methoxiuric acid group having the molecular formula C9H12N4O3 and a molecular weight of 224.22 g/mol. Its IUPAC name is 2-methoxy-1,7,9-trimethyl-6,7,8,9-tetrahydro-1H-purine-6,8-dione. The compound is also referred to in the literature as a methoxiuric acid and, less precisely, as dimethylguanidine. Commercially, it is almost exclusively encountered under the proprietary trade name Dynamine®, a brand owned by Compound Solutions, Inc. (Carlsbad, California, USA).
In general, methoxiuric acids are metabolic derivatives of methylxanthines (e.g., caffeine, theobromine). Specifically, methylliberine is found at low levels in plants of the genus Coffea and is a metabolite of caffeine, via a theacrine intermediate, that is likely further metabolized to liberine as an end product.
Structurally related to theacrine and other methylxanthines found in the Coffea and Camellia genera, methylliberine serves as a key intermediate in the biosynthesis of more complex purine alkaloids. While it shares a purine backbone with caffeine, its distinct methylation pattern suggests differential interactions with adenosine receptors and other neurological targets.
Methylliberine (CAS 51168-26-4), a methoxiuric acid, is a caffeine metabolite present at low levels in various Coffea plants. It is a naturally occurring purine alkaloid and a metabolite of caffeine, present at low levels in various species of the genus Coffea, including Coffea dewevrei and Coffea liberica, as well as in kucha tea (Camellia assamica var. kucha).
It is also reported as a caffeine metabolite in other genera such as Theobroma (cocoa plants) and Ilex (yerba mate). Concentrations of methylliberine in these sources are typically very low, often less than 0.1% of the plant's dry weight, corresponding to low micrograms per gram, and can vary based on species, growth conditions, and developmental stage. For instance, in C. liberica leaves during vegetative development, concentrations are below 0.1% dry weight. In Coffea leaves, it appears sporadically at these trace levels during vegetative and mature phases.
Methylliberine biosynthesis intersects with caffeine metabolism in Coffea species. The primary pathway involves sequential demethylation of caffeine, yielding methylliberine as a minor metabolite. In Camellia species, methylliberine is synthesized via methyluric acid intermediates, distinct from the xanthine-based caffeine pathway. This bifurcation underscores the complexity of purine alkaloid metabolism.
Methylliberine is commercially available as the branded ingredient Dynamine™ and is incorporated into dietary supplements and functional foods for its potential stimulant properties. The toxicological investigation conducted by Murbach et al. (2019) was undertaken on a pure, synthetic form of methylliberine in order to evaluate its potential health hazards as a food ingredient. The commercially manufactured ingredient is thus a synthetically produced equivalent of the naturally occurring compound, not a botanical extract. The test item evaluated in the pivotal toxicology study was Dynamine® (Compound Solutions, Inc., Carlsbad, California, USA), a ≥98.0% pure methylliberine.
In supplement products, methylliberine typically appears in capsule or powder form, either as a standalone ingredient or, far more commonly, combined with caffeine and/or theacrine (TeaCrine®). Following on the heels of theacrine's commercial success in the dietary supplement arena, methylliberine has been granted new dietary ingredient (NDI) status following completion of a 90-day repeated-dose oral toxicity study as required by the Dietary Supplement Health Education Act.
Methylliberine as an isolated compound has no documented history of traditional use in any culture or healing system. It is a trace constituent of plants that have themselves been used traditionally — principally tea plants and coffee species — but it was not identified as a distinct chemical entity until modern analytical chemistry methods were applied to metabolic profiling of Coffea species. The compound's presence was first documented in metabolic profiles of coffee plants in the early 1980s, with isolation achieved through extraction and chromatographic methods.
The plant from which it is most reliably sourced in supplement contexts, kucha tea (Camellia assamica var. kucha), occurs naturally in kucha tea, a specialty tea variety grown primarily in southern China. Kucha tea has traditional regional use in parts of Yunnan Province, China, but any physiological effects attributed historically to kucha tea in traditional contexts would be attributable to its overall alkaloid complex — not to methylliberine specifically, which was not known as an isolated entity to traditional practitioners. No traditional monograph, pharmacopeia, or authoritative ethnobotanical source attributes any specific historical therapeutic or ritual role to methylliberine as a distinct substance.
Methylliberine is a purine alkaloid — part of the same chemical family that includes caffeine, theacrine (TeaCrine), theobromine, and theophylline. Structurally similar to other methylxanthines like caffeine and theacrine, methylliberine is hypothesized to exhibit a shorter half-life and faster onset of action compared to related compounds.
Based on its structural similarity to caffeine and theacrine, methylliberine is widely believed to be an adenosine receptor antagonist, although as of 2023 no scientific studies have been done to confirm this action. This is an important qualification: the adenosine-blocking mechanism attributed to methylliberine in much marketing and popular literature is a hypothesis grounded in structural analogy with caffeine, not in direct receptor-binding or functional studies specific to methylliberine.
Based on its structural similarity to caffeine and theacrine, methylliberine is widely believed to be an adenosine receptor antagonist. The proposed mechanism suggests that, like caffeine, methylliberine may occupy adenosine A1 and/or A2A receptors without activating them, thereby blocking adenosine's inhibitory (pro-sedative) signaling in the brain. However, this remains speculative for methylliberine specifically.
There is no evidence that methylliberine augments dopamine receptors in a way that is distinct from caffeine, contrary to claims made by the manufacturer. Some sources propose that, by potentially antagonizing adenosine A2A receptors — which are co-localized with dopamine D2 receptors in striatal circuits — methylliberine could indirectly enhance dopamine D2 receptor signaling, but this mechanism has not been demonstrated experimentally for methylliberine specifically. Studies have shown that theacrine, similar to caffeine, exerts psychostimulatory action via modulation of the adenosinergic and dopaminergic pathways. Unlike caffeine, however, theacrine does not appear to be associated with tolerance, nor does it negatively affect the cardiovascular system. Whether the same holds true for methylliberine has not been established in direct experimental work.
A pharmacokinetically relevant mechanism that has been demonstrated in human research is methylliberine's apparent inhibition of the cytochrome P450 1A2 (CYP1A2) enzyme. Methylliberine, a methylurate analog of caffeine, increased plasma exposure and half-life of caffeine following concomitant oral administration. The mechanism underlying this pharmacokinetic interaction is likely attributable to methylliberine inhibition of CYP1A2, which is a major determinant of intrinsic clearance, and thus hepatic clearance, of caffeine. Several important consequences, with regard to herb-drug interaction potential, can be inferred from the data assuming reproducibility in larger, more diverse populations. Caffeine is commonly used as a probe drug to examine CYP1A2-mediated drug interactions. Consequently, these data demonstrate that methylliberine has the potential to interact with other drugs whose elimination depends on CYP1A2.
Purine alkaloids, including methylliberine, caffeine, and theacrine, evolved independently in distinct plant lineages through convergent evolution. This process involved the expansion and functional diversification of N-methyltransferase (NMT) gene families, which catalyze methyl group transfers to purine precursors. Methylliberine, chemically known as 2-methoxy-1,7,9-trimethyluric acid, is biosynthesized in select plant species as a downstream metabolite in the purine alkaloid pathway, primarily through modifications of caffeine involving oxidation and methylation reactions. This process occurs in limited caffeine-producing plants such as certain Coffea species, where methylliberine serves as an intermediate in the conversion of caffeine to other methylurates like liberine.
Human pharmacokinetic data for methylliberine are derived from a dedicated study conducted at the University of Memphis and published in the Journal of Exercise and Nutrition (2022). The researchers conducted a double-blind, placebo-controlled pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberine's pharmacokinetic interaction potential with either caffeine or theacrine. Subjects received an oral dose of either methylliberine, caffeine, methylliberine plus caffeine, or methylliberine plus theacrine using a randomized, double-blind, crossover design. Blood samples were analyzed using UPLC-MS/MS.
Methylliberine was rapidly absorbed from oral administration, with Cmax reached on average at 0.6 and 0.9 hours following low (25 mg) and high (100 mg) doses of methylliberine, respectively. Thereafter, methylliberine was eliminated with a half-life averaging 1 to 1.4 hours. For comparison, methylliberine has a short half-life of only 1.5 hours compared to the 5- to 7-hour half-life of caffeine.
Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. However, the same study found a significant effect in the reverse direction: methylliberine co-administration resulted in decreased oral clearance (41.9 ± 19.5 vs. 17.1 ± 7.80 L/hr) and increased half-life (7.2 ± 5.6 versus 15 ± 5.8 hrs) of caffeine. Methylliberine had no impact on caffeine's maximum concentration (440 ± 140 vs. 458 ± 93.5 ng/mL) or oral volume of distribution (351 ± 148 vs. 316 ± 76.4 L).
In the context of supplement combinations involving all three compounds (caffeine, methylliberine, and theacrine), their divergent peak times are pharmacologically relevant. Pharmacokinetic data for a combination of 100 mg methylliberine, 150 mg caffeine, and 50 mg theacrine showed peak plasma concentration times of 0.8, 1.1, and 1.4 hours with half-lives of 1.5, 21, and 30 hours, respectively. This shows the potential synergistic effect of supplementation with these compounds as the differential peak times allow for the stimulatory actions to be maximized over a longer period.
The most directly relevant human trial examining methylliberine as a standalone supplement was published in Nutrients in 2023 (Cintineo et al. / Raub et al., MDPI). This study assessed the acute effects of oral methylliberine (Dynamine™) supplementation on cognitive function and indices of well-being. It was a double-blind, randomized, within-subject crossover trial. In total, 25 healthy men and women (33.5 ± 10.7 yr, 172.7 ± 8.6 cm, 73.3 ± 11.0 kg) underwent pretesting before ingesting methylliberine (100 mg) or a placebo (PLA) for 3 days. On the fourth day, the participants were tested before their fourth dose (baseline) and every hour post-ingestion for 3 hours. After a one-week washout period, the participants repeated testing with the alternate investigational product. The testing battery consisted of vitals, Stroop test, Trail Making Test-B, and visual analog scales that assessed various indices of well-being.
There were significant (p ≤ 0.050) interactions in terms of concentration, motivation, and mood. More specifically, methylliberine significantly improved subjective feelings of energy, concentration, motivation, and mood, but not cognitive function. Placebo improved motivation and mood at hours 1 and 2, while methylliberine sustained these benefits for longer. Methylliberine also improved concentration, well-being, and the ability to tolerate stress to a greater degree than placebo, while having no detrimental effects on vital signs. Methylliberine also seemed to have a positive impact on sustained energy in women.
Evidence strength: This is a single, relatively small (n=25) crossover trial. The subjective outcomes are meaningful but susceptible to expectation effects even in blinded designs. No significant improvement in objective cognitive test performance was detected on the Stroop test or Trail Making Test-B, indicating that the observed benefits were confined to subjective affect rather than measurable neurocognitive task performance.
A few studies have examined the impact of the combination of caffeine, theacrine (as TeaCrine®), and methylliberine (CMT) on cognitive tasks, but investigations examining methylliberine independently are scarce. To date, only two investigations have analyzed independent methylliberine ingestion in humans.
Both human studies of methylliberine as a standalone supplement (Bloomer et al., 2020; VanDusseldorp et al., 2020) were primarily safety-focused and did not include objective cognitive outcome measures as primary endpoints. Within the two studies that have investigated the independent ingestion of methylliberine, neither one reported any influence on vital signs, respiratory rate, body temperature, or mood in men and women, nor did it negatively affect markers of health.
The 2023 crossover trial specifically targeting cognitive endpoints found that methylliberine had a negligible influence on cognitive function and vitals (p > 0.050), and no adverse events were reported. Thus, at 100 mg acutely, methylliberine does not appear to produce measurable improvements in standardized objective cognitive testing instruments such as the Stroop test or Trail Making Test.
Evidence strength: Weak for objective cognitive enhancement with standalone methylliberine. The absence of an effect on objective measures is consistent across available human trials.
A more robust body of evidence exists for the combination of caffeine, methylliberine, and theacrine (CMT). A preprint study by La Monica et al. (2021), published in the Journal of Exercise and Nutrition, used a placebo-controlled crossover design. Using a placebo-controlled crossover design, nine healthy men (23.4 ± 5.7 yr, 178.9 ± 5.8 cm, 86.0 ± 17.1 kg) completed four 20-minute gaming sessions designed to assess cognitive, motor, and perceptual skills via an AI-driven battery of tasks (Aim Lab). Participants ingested either a placebo (PL), caffeine (CAFF), or caffeine + methylliberine (Dynamine™) + theacrine (TeaCrine®) (CMT).
Comparing placebo (PLA), caffeine, and CMT on gaming performance in a first-person shooter, the study showed that CMT, not caffeine alone, improved the time it took to eliminate a target vs. PLA. Simultaneously, caffeine increased jitteriness relative to baseline and was not able to maintain cognitive control vs. CMT and PLA. The overall conclusion was that acute CMT supplementation improved cognitive and motor abilities in recreational gamers, and that the addition of theacrine and methylliberine to caffeine may lessen some undesirable effects of isolated caffeine ingestion on cognitive control and jitteriness.
A larger randomized controlled trial by Cintineo et al. published in the Journal of the International Society of Sports Nutrition (2022) investigated CMT in tactical personnel. A between-subjects, randomized, placebo-controlled design was used to test the effects of placebo (PLA), 300 mg caffeine (CAF), and a combination of 150 mg caffeine, 100 mg methylliberine, and 50 mg theacrine (CMT) on RT and marksmanship along with hemodynamic and arousal measures following a sustained vigilance task in tactical personnel (n = 48). Following consumption of the supplement, participants underwent a 150-min protocol consisting of two rounds.
These findings suggest similar benefits on reaction time during a vigilance task between CAF (containing 300 mg caffeine) and CMT above PLA, though CAF resulted in slightly less favorable hemodynamic changes. This study was the first to provide data showing similar efficacy of combined caffeine, methylliberine, and theacrine compared to double the caffeine dose consumed alone on vigilance RT but without a significant rise in diastolic blood pressure above PLA in tactical personnel.
Importantly, Cintineo et al. (2022) compared CMT, caffeine, and PLA on reaction time and marksmanship in tactical athletes and found that caffeine and CMT (as opposed to PLA) were able to improve reaction time on a vigilance task; however, there were no differences in accuracy or reaction time between treatments within a marksmanship task.
Evidence strength: Moderate for CMT combinations as a class. A critical limitation of all CMT studies is that methylliberine cannot be isolated as the active driver of any observed effects; the combination always includes caffeine, which is an established, well-documented cognitive stimulant. The contribution of methylliberine itself to the CMT combination's effects on performance cannot be determined from these designs.
One of the most consistent findings across the available human literature is methylliberine's apparent lack of effect on cardiovascular parameters when administered without caffeine. Human adverse event potential studies using methylliberine alone, and in combination with theacrine, found no effect of methylliberine on heart rhythm (electrocardiogram; ECG), resting heart rate, or blood pressure.
The VanDusseldorp et al. (2020) four-week safety trial enrolled 125 participants. One-hundred twenty-five men and women (mean age 23.0 yrs, height 169.7 cm, body mass 72.1 kg; n = 25/group) were randomly assigned to one of five groups: low-dose DYM (100 mg), high-dose DYM (150 mg), low-dose DYM with TCR (100 mg + 50 mg), high-dose DYM with TCR (150 mg + 25 mg), and placebo. This investigation corroborated previous findings showing no effect on hemodynamics with methylliberine ingestion (Bloomer et al., 2020; VanDusseldorp et al., 2020). Likewise, TeaCrine® did not impact hemodynamics over 8 weeks or in combination with methylliberine under acute or chronic conditions.
When caffeine is added to the combination, blood pressure effects attributable to caffeine become detectable. An investigation assessing methylliberine, TeaCrine®, caffeine, and various combinations of the three observed higher blood pressure only when caffeine was included in the treatment. However, it should be noted that the observed increases were small, transient, and within normal clinical limits.
In the Cintineo et al. (2022) CMT trial, Group main effects for systolic (SBP; P = 0.001) and diastolic blood pressure (DBP; P = 0.028) indicated higher SBP in CAF (P = 0.003, d = 0.84) and CMT (P = 0.007, d = 0.79) compared to PLA, but only higher DBP in CAF (P = 0.025, d = 0.74). This pattern suggests that the SBP rise in the CMT group is driven by its caffeine content, while DBP remained unaffected by CMT.
Evidence strength: Moderate. Consistent across multiple controlled trials that standalone methylliberine and methylliberine combined with theacrine (without caffeine) do not elevate heart rate or blood pressure.
Methylliberine's primary investigated domain is the central nervous system, specifically in relation to alertness, energy perception, and mood. Methylliberine (trademark name Dynamine™) is a purine alkaloid metabolite of caffeine which may provide similar cognitive enhancements as caffeine with none of the hemodynamic effects (i.e., elevated blood pressure and jitteriness). This comparison with caffeine is a hypothesis that remains partially validated: human data do support mood and subjective energy improvements, but do not yet confirm equivalent cognitive task performance enhancement.
Multiple human trials report no significant standalone effect on heart rate, blood pressure, or ECG parameters. A four-week study evaluating the daily intake of 100 mg methylliberine and 50 mg theacrine found no clinically relevant effects on key health parameters such as heart rate, systolic blood pressure, high-density lipoproteins, mean corpuscular haemoglobin, basophils, absolute eosinophils, creatinine, or estimated glomerular filtration rate.
As noted in the pharmacokinetics section, methylliberine appears to inhibit CYP1A2 activity, a hepatic enzyme responsible for metabolism of caffeine and numerous pharmaceutical drugs. This positions hepatic drug metabolism as a relevant body system when methylliberine is used concurrently with CYP1A2-dependent compounds.
The following doses are those that appear in the peer-reviewed and preprint clinical literature. No dosing recommendations should be inferred from these figures.
Across all human trials, 100 mg of methylliberine has been the most commonly studied acute dose for standalone administration. In CMT combination formulas, 100 mg methylliberine co-dosed with varying amounts of caffeine (150 mg) and theacrine (50 mg) is the most consistently reported combination.
The foundational safety work on methylliberine was conducted by Murbach et al. (2019), published in the Journal of Toxicology. A bacterial reverse mutation test, in vitro mammalian chromosomal aberration test, in vivo mammalian micronucleus test, and 90-day repeated-dose oral toxicity study in rats with a 28-day recovery period were conducted.
Genotoxicity: Based on the unequivocally negative results, it is concluded that methylliberine is not mutagenic or clastogenic under the conditions of the conducted in vitro studies and does not cause in vivo genetic toxicity in the bone marrow of mice under the applied conditions. No genotoxicity was observed in the mammalian micronucleus study up to the highest dose tested of 700 mg/kg bw.
90-Day Sub-Chronic Toxicity: In the 90-day study, methylliberine was administered to Han:WIST rats at doses of 0, 75, 112, 150, 187, and 225 mg/kg bw/day. No mortality or morbidity was observed and no toxicologically relevant clinical effects or effects on clinical pathology parameters were observed. In male animals, test item-related effects on body weight and sexual organs, which were not reversible after a 28-day recovery period without treatment, were observed in the high-dose group.
More specifically, in the 90-day study in rats, body weight development was depressed at 187 and 225 mg/kg bw/day and testicular atrophy and inhibition of spermatogenesis were observed at 225 mg/kg bw/day in male animals (testes weights were also reduced compared to controls at 187 mg/kg bw/day but were not grossly atrophic). These effects were not recovered in the high-dose animals 28 days after the final treatment. In female animals, no adverse effects were observed following repeated administration of the test item for 91 consecutive days. Thus, the NOAEL for Dynamine was determined to be 150 and 225 mg/kg bw/day, respectively, in male and female Han:WIST rats.
The male reproductive toxicity signal observed at high doses in rats is a specific and notable finding. It has not been investigated or replicated in human studies, and no human data exist on the reproductive safety of methylliberine supplementation.
To date, only two investigations have analyzed independent methylliberine ingestion in humans. These investigations conducted a safety profile (i.e., cardiovascular function and comprehensive hematological panel) of methylliberine supplementation alone and in conjunction with TeaCrine® and/or caffeine over an acute period of 48 hours and over a period of four weeks in healthy, young men and women. Preceding human trials, methylliberine was shown to be safe in rats following chronic dosing (90 days) and after a 28-day follow-up.
Regardless of group and sex, significant main effects for time were noted for heart rate, systolic blood pressure, and QTc (p < 0.001), high-density lipoproteins (p = 0.002), mean corpuscular hemoglobin (p = 0.018), basophils (p = 0.006), absolute eosinophils (p = 0.010), creatinine (p = 0.004), estimated glomerular filtration rate (p = 0.037), chloride (p = 0.030), carbon dioxide (p = 0.023), bilirubin (p = 0.027), and alanine aminotransferase (p = 0.043), among others. Notably, these were reported as time effects across all groups including placebo, rather than group-specific adverse signals attributable to methylliberine alone.
Future studies are encouraged to corroborate the safety, and assess efficacy, of methylliberine in humans. This recommendation by the investigators of the pivotal toxicology study reflects the acknowledged limitation in the available human safety dataset.
The most important documented safety consideration is the pharmacokinetic interaction with caffeine and, by extension, other CYP1A2-metabolized substances. An interaction study showed concomitant administration of both caffeine and methylliberine increases the half-life of caffeine by about 2-fold. This is likely due to inhibition of the CYP1A2 enzyme.
The finding that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction suggests that caffeine may interact uniquely with different methylurates. Drugs whose clearance is substantially dependent on CYP1A2 include (but are not limited to) certain antipsychotics (e.g., clozapine, olanzapine), antidepressants, theophylline, and warfarin. Several important consequences, with regard to herb-drug interaction potential, can be inferred from the data assuming reproducibility in larger, more diverse populations. These potential interactions have not been studied directly in human trials involving co-administration of methylliberine with pharmaceutical CYP1A2 substrates.
The overall human safety dataset for methylliberine is limited in scope. As of the time of the pivotal toxicology publication (2019), there was a dearth of published information, including toxicological data, relating to methylliberine. Since that time, a small number of short-duration human trials have been completed, but all were conducted in healthy young adults over periods of four weeks or less. There are no long-term human safety data, no reproductive safety data in humans, no data in special populations (pregnant or lactating individuals, pediatric populations, elderly individuals, or those with chronic diseases), and no systematic pharmacovigilance database exists for methylliberine as a standalone ingredient. The reproductive toxicity signal (testicular atrophy and inhibited spermatogenesis) observed in male rats at doses of 187–225 mg/kg bw/day has not been followed up with reproductive safety studies in humans.
Methylliberine has been granted new dietary ingredient (NDI) status following completion of a 90-day repeated-dose oral toxicity study as required by the Dietary Supplement Health Education Act. NDI notification to the U.S. Food and Drug Administration (FDA) is required for dietary ingredients not marketed in the United States before October 15, 1994, but does not constitute pre-market approval by the FDA. The ingredient is marketed by Compound Solutions, Inc. under the Dynamine® brand. No European Food Safety Authority (EFSA) safety opinion, European Medicines Agency (EMA) monograph, WHO Traditional Medicine monograph, or Pharmacopeial monograph specifically addressing methylliberine has been published.
Health conditions that Methylliberine may help support.
Methylliberine (Dynamine™) is a purine alkaloid found in kucha tea that promotes mental energy, concentration, and mood with a rapid onset. Clinical trials show improvements in energy, sustained energy, concentration, and motivation within 1–3 hours of dosing.
Methylliberine (Dynamine) is a purine alkaloid in kucha tea (Camellia assamica) structurally related to theacrine and caffeine with stimulant and potential thermogenic properties. It modulates adenosine and dopamine signaling and is marketed in thermogenic supplements for faster-onset stimulant effects than theacrine. Human pharmacokinetic studies confirm its activity.
Body systems that Methylliberine may help support.
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