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Paraxanthine

Paraxanthine, chemically known as 1,7-dimethylxanthine, is a naturally occurring methylxanthine alkaloid and the predominant metabolite of caffeine in humans, accounting for approximately 70–80% of caffeine's hepatic metabolism.^[1]^[2] With the molecular formula C₇H₈N₄O₂ and a molecular weight of 180.16 g/mol, it appears as faint yellow fine crystals and functions as a central nervous system stimulant by antagonizing adenosine receptors.^[1]^[3] Paraxanthine is primarily formed through N-demethylation of caffeine by the cytochrome P450 1A2 (CYP1A2) enzyme in the liver, with smaller contributions from the metabolism of theobromine.^[2] In humans, it reaches plasma concentrations up to ten times higher than other caffeine metabolites like theophylline or theobromine, and its levels can exceed those of caffeine itself 8–10 hours after ingestion due to slower clearance.^[2] The half-life of paraxanthine is influenced by genetic factors affecting CYP1A2 activity, as well as physiological states such as pregnancy, where it may triple in later trimesters. It is further metabolized to 1,7-dimethyluric acid and 1-methylxanthine, primarily in the liver and kidney, and excreted in urine.^[1] Pharmacologically, paraxanthine exhibits psychostimulant effects comparable to or stronger than caffeine, including enhanced locomotor activity, cognition, short-term memory, attention, and physical endurance in preclinical and human studies.^[5]^[3]^[6] It acts as an equipotent adenosine A1 receptor antagonist to caffeine in vitro and may additionally inhibit cGMP-preferring phosphodiesterases (e.g., PDE9), leading to increased striatal cGMP and extracellular dopamine release via nitric oxide-cGMP signaling pathways.^[2]^[5] In rat models, paraxanthine demonstrates greater locomotor activation than caffeine at equivalent doses (e.g., 30 mg/kg), though it shows limited generalization in caffeine discrimination tasks.^[5] With chronic caffeine consumption, paraxanthine accumulation contributes significantly to tolerance, withdrawal symptoms, and sustained effects like lipolysis and increased epinephrine.^[2] Compared to caffeine, paraxanthine appears to have a more favorable safety profile based on preclinical toxicity data, with an acute oral LD50 of 829 mg/kg in rats and no observed adverse effect levels (NOAEL) up to 185 mg/kg body weight in 90-day studies, versus caffeine's lower NOAEL of 150 mg/kg and associated mortality at higher doses.^[3] It shows no mutagenicity, genotoxicity, or clastogenicity in standard assays and lacks the teratogenic effects observed with caffeine at high doses in mice.^[3] While naturally present in trace amounts in green coffee beans and certain citrus flowers, paraxanthine is available as a standalone supplement for cognitive and performance enhancement as of 2025, supported by recent human studies showing reduced side effects such as less jitteriness.^[3]^[7]

Chemical properties

Molecular structure

Paraxanthine, also known as 1,7-dimethylxanthine or 1,7-dimethyl-3H-purine-2,6-dione, is a xanthine derivative with the molecular formula C₇H₈N₄O₂.^[1] This compound features a purine ring system consisting of a fused pyrimidine and imidazole ring, with carbonyl groups at positions 2 and 6 of the pyrimidine ring. Methyl groups are attached to the nitrogen atoms at positions 1 (in the pyrimidine ring) and 7 (in the imidazole ring), distinguishing it from the parent xanthine molecule, which lacks these substituents.^[1] The standard numbering of the purine ring atoms in paraxanthine follows the conventional purine nomenclature: nitrogens at positions 1, 3, 7, and 9; carbons at 2, 4, 5, 6, and 8; with the methyl groups specifically on N1 and N7, and a hydrogen on N3 and N9. This arrangement can be textually represented as a bicyclic structure where the six-membered pyrimidine ring (positions 1–6) shares the C4–C5 bond with the five-membered imidazole ring (positions 4, 5, 7–9), including the oxo functionalities at C2 and C6.^[1] Paraxanthine is a positional isomer of theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine), differing in the placement of their methyl groups on the purine nitrogens.^[8]^[9] In comparison to caffeine (1,3,7-trimethylxanthine), paraxanthine lacks a methyl group at the N3 position.^[10] Paraxanthine belongs to the broader methylxanthine family of purine alkaloids.^[1]

Physical and chemical properties

Paraxanthine appears as an off-white to pale yellow crystalline solid.^[11]^[12] Its molecular formula is C₇H₈N₄O₂, with a molecular weight of 180.16 g/mol.^[1] The compound has a melting point of 294–296 °C.^[12] Paraxanthine exhibits low solubility in water, approximately 1 g/L at room temperature, and is more soluble in hot water (up to several grams per liter), ethanol (0.6 g/L), and chloroform.^[13]^[12] It is stable under standard laboratory conditions but decomposes upon heating above its melting point.^[12] The pKa values are approximately 8.5 for the imidazole ring acidity and 0.5 for the pyrimidine ring, influencing its behavior in acidic or basic environments.^[12] Spectroscopically, paraxanthine shows a UV absorption maximum at around 269 nm in aqueous solution, useful for detection in analytical methods.^[14] Basic NMR data include ¹H NMR signals at δ 3.32 (s, 3H, N-CH₃), 4.03 (s, 3H, N-CH₃), and 8.34 (s, 1H, CH) in D₂O at pH 7.0; ¹³C NMR reveals carbonyl carbons around 150–155 ppm. IR spectroscopy features characteristic peaks at 1690–1650 cm⁻¹ for C=O stretches and 3100–3000 cm⁻¹ for N-H.^[1]

Occurrence and production

Natural occurrence

Paraxanthine occurs naturally in trace amounts in several caffeine-containing plants, including coffee beans of Coffea species, tea leaves of Camellia sinensis, and cocoa beans of Theobroma cacao, where it serves as a demethylated derivative of caffeine.^[15]^[16] These concentrations are vestigial, representing a minor fraction of the total methylxanthines in the respective plant materials.^[16] It has also been detected in small quantities in guarana seeds (Paullinia cupana) and yerba mate leaves (Ilex paraguariensis).^[17] Similar to other methylxanthines, paraxanthine may contribute to the plant's chemical defense mechanisms against herbivorous insects and other predators.^[18] Due to its low natural abundance, paraxanthine is rarely isolated directly from plant sources and is instead typically identified through analytical studies of caffeine-derived alkaloids in these materials.^[17]

Biosynthesis in humans

Paraxanthine is primarily biosynthesized in humans through the metabolism of dietary caffeine, obtained from sources such as coffee, tea, and chocolate. Caffeine, a trimethylxanthine, undergoes hepatic demethylation where the cytochrome P450 1A2 (CYP1A2) enzyme catalyzes the removal of the methyl group at the N-3 position, yielding paraxanthine (1,7-dimethylxanthine) as the dominant product.^[19] This process represents the major pathway for caffeine clearance, accounting for approximately 70-80% of its initial metabolism in the liver.^[20] The rate of this biosynthetic conversion is highly variable among individuals due to genetic polymorphisms in the CYP1A2 gene, which classify people as slow or fast metabolizers. Slow metabolizers exhibit reduced enzyme activity, leading to prolonged caffeine half-life and lower paraxanthine production rates, while fast metabolizers process caffeine more rapidly, resulting in higher paraxanthine yields.^[21] Following oral caffeine ingestion, paraxanthine reaches peak plasma concentrations approximately 3-5 hours later, reflecting the time course of CYP1A2-mediated demethylation.^[22] Direct biosynthesis of paraxanthine from xanthine precursors is negligible in humans, as endogenous purine metabolism does not significantly incorporate methylation to form this dimethylxanthine; production is overwhelmingly derived from exogenous caffeine.^[23] Compared to rodents, human CYP1A2 shows greater specificity for producing paraxanthine from caffeine, whereas murine orthologs favor alternative demethylation routes yielding more theophylline and other metabolites.^[24]

Industrial production

Paraxanthine is produced industrially through synthetic chemical methods or biocatalytic processes using genetically engineered microorganisms, such as Escherichia coli, to convert caffeine into paraxanthine. These methods enable the manufacture of paraxanthine for use as a dietary supplement, bypassing direct extraction from natural sources due to its low abundance. As of 2023, biocatalytic approaches have been developed to achieve high yields for commercial applications.^[25]

Metabolism

Metabolism of caffeine to paraxanthine

Paraxanthine is the primary metabolite of caffeine in humans, formed through N-3 demethylation catalyzed by the cytochrome P450 1A2 (CYP1A2) enzyme in the liver, accounting for 75-80% of caffeine's biotransformation.^[2] This pathway involves the removal of the methyl group at the N-3 position of caffeine (1,3,7-trimethylxanthine), yielding paraxanthine (1,7-dimethylxanthine). Minor alternative routes include N-1 demethylation to theobromine (approximately 10-12%) and N-7 demethylation to theophylline (approximately 4-5%), both also primarily mediated by CYP1A2.^[26]^[27] The enzyme kinetics of CYP1A2 follow Michaelis-Menten parameters, with a reported Km value of approximately 0.66 mM for caffeine N-3 demethylation in human liver microsomes.^[28] This indicates moderate substrate affinity, allowing efficient metabolism at typical physiological concentrations of caffeine following moderate intake. Several factors influence the rate of this metabolic conversion. Smoking induces CYP1A2 activity through polycyclic aromatic hydrocarbons, accelerating caffeine clearance by up to 50%.^[2] Conversely, oral contraceptives inhibit CYP1A2, potentially doubling caffeine's half-life and reducing paraxanthine formation.^[2] Consumption of cruciferous vegetables, such as broccoli, also induces CYP1A2 via isothiocyanates, enhancing demethylation efficiency.^[29] Caffeine's plasma half-life in adults typically ranges from 3 to 7 hours, with a mean of about 5 hours, leading to gradual accumulation of paraxanthine as the primary circulating metabolite over time with repeated dosing.^[2] Following a 200 mg oral dose of caffeine, plasma paraxanthine concentrations typically peak at 5-9 μM several hours post-ingestion, reflecting the enzyme's predominant role in caffeine clearance.^[30] Genetic polymorphisms in the CYP1A2 gene significantly affect this metabolism; carriers of the CYP1A2*1F allele (rs762551 A allele) exhibit slower demethylation rates compared to homozygous CYP1A2*1A individuals, resulting in prolonged caffeine exposure and reduced paraxanthine production.^[31] While paraxanthine is further metabolized to downstream products like 1-methylxanthine and 1-methyluric acid, ultimate excretion of caffeine-derived compounds occurs primarily via the kidneys, with less than 3% of unchanged caffeine appearing in urine.^[2]^[27]

Further metabolism of paraxanthine

Paraxanthine, the principal metabolite of caffeine, undergoes further hepatic metabolism primarily through N-demethylation and subsequent oxidation pathways. The major route involves 7-demethylation catalyzed by the cytochrome P450 enzyme CYP1A2, yielding 1-methylxanthine, which accounts for approximately 67% of paraxanthine clearance.^[32] This process occurs predominantly in the liver, where CYP1A2 activity determines the rate of conversion. A minor demethylation pathway, also mediated by CYP1A2, removes the methyl group at the N1 position to form 7-methylxanthine, representing about 6% of clearance.^[32] Following demethylation to 1-methylxanthine, further biotransformation leads to the formation of 1-methyluric acid via oxidation by xanthine oxidase (XO), with additional involvement of aldehyde oxidase in intermediate steps such as the conversion to 5-acetylamino-6-formylamino-3-methyluracil (AFMU).^[32] Approximately 8% of paraxanthine is directly oxidized to 1,7-dimethyluric acid, likely through XO-mediated pathways without prior demethylation. The primary urinary metabolites are 1-methylxanthine and 1-methyluric acid, which serve as endpoints of these catabolic processes.^[32] An additional 9% of paraxanthine is excreted unchanged in the urine.^[32] The plasma half-life of paraxanthine in healthy adults is approximately 3.1 hours, similar to but slightly shorter than that of caffeine.^[33] Clearance is heavily dependent on hepatic function, with reduced CYP1A2 activity in liver disease leading to decreased metabolism and potential prolongation of effects, akin to observations in caffeine pharmacokinetics.^[34] Renal function influences the excretion of unchanged paraxanthine and metabolites, though the small renal clearance fraction limits significant accumulation in mild impairment; hydration status can modulate urinary metabolite concentrations by affecting urine volume.^[32]

Pharmacology

Pharmacodynamics

Paraxanthine exerts its biological effects primarily through antagonism of adenosine receptors and inhibition of phosphodiesterases, with additional modulation of intracellular calcium signaling. It acts as a competitive antagonist at adenosine A1 and A2A receptors, binding with IC50 values of 40–65 μM at A1 receptors and 40–90 μM at A2 subtypes in rat brain membranes and striatal slices.^[35] These affinities are comparable to or slightly higher than those of caffeine (IC50 90–110 μM), and paraxanthine demonstrates effectiveness in counteracting A1 receptor-mediated locomotor depression more potently than A2A-mediated effects in rodent models.^[35]^[5] Paraxanthine also inhibits phosphodiesterases (PDEs), particularly the cGMP-preferring PDE9 isoform, leading to accumulation of cGMP in rat striatum and enhanced locomotor activation at doses of 30 mg/kg.^[5] It modestly inhibits cAMP-specific PDE isoforms (types 3–5).^[16]^[35] Regarding structure-activity relationships among methylxanthines, the 1,7-dimethyl substitution in paraxanthine results in weaker PDE inhibition compared to the 1,3-dimethyl pattern of theophylline (IC50 ~55 μM), highlighting how N-methylation position influences potency.^[36] In terms of calcium signaling, paraxanthine promotes intracellular Ca²⁺ mobilization by stimulating ryanodine receptor (RyR) channels in the endoplasmic reticulum, producing moderate increases in cytosolic Ca²⁺ independent of adenosine antagonism or cAMP elevation.^[37] This effect is neuroprotective against dopaminergic cell death in culture models and occurs dose-dependently in skeletal muscle fibers starting at 0.01 mM (10 μM), a concentration aligning with peak plasma levels (8–10 μM) observed 4 hours after 270 mg caffeine ingestion in humans.^[37]^[38] Paraxanthine exhibits weak inhibition of monoamine oxidase (MAO), partially impairing tyramine oxidation in human adipose tissue at high concentrations (up to 2.5 mM, <75% inhibition), less effectively than caffeine.^[39] Human studies with direct oral administration (200–300 mg) have shown enhanced cognition, short-term memory, and attention, supporting its psychostimulant profile.^[40]^[41] Overall, dose-response thresholds for these pharmacodynamic effects, including receptor antagonism and calcium release, begin at plasma levels of 10–50 μM.^[38]

Pharmacokinetics

Paraxanthine is rapidly absorbed from the gastrointestinal tract when administered orally as a supplement, with high bioavailability similar to that of caffeine due to its structural homology.^[42] As the primary metabolite of caffeine, paraxanthine exhibits high systemic availability following caffeine ingestion, with peak plasma concentrations typically occurring within 1-2 hours post-absorption.^[34] The compound distributes widely throughout the body, with a volume of distribution of approximately 0.6 L/kg, reflecting its hydrophilic nature and equilibration into total body water.^[33] Paraxanthine efficiently crosses the blood-brain barrier, achieving a cerebrospinal fluid-to-plasma concentration ratio of about 0.8, enabling central nervous system exposure comparable to peripheral levels.^[2] Protein binding is low, with 30-40% of paraxanthine reversibly bound to plasma albumin, leaving the majority unbound and pharmacologically active.^[43] Metabolism of paraxanthine occurs primarily in the liver via cytochrome P450 enzymes, with minimal hepatic first-pass effect observed upon oral administration, consistent with patterns seen in related methylxanthines. Detailed metabolic pathways, including further demethylation and oxidation, are addressed in dedicated sections.^[2] Excretion of paraxanthine is predominantly renal, with approximately 20% eliminated unchanged in urine and the remainder as metabolites; renal clearance averages 8.4 mL/min, while total plasma clearance is around 100 mL/min, indicating hepatic metabolism as the primary elimination route.^[32] Pharmacokinetic parameters of paraxanthine are influenced by several factors. Clearance decreases with age, resulting in slower elimination and prolonged half-life in the elderly due to reduced hepatic function.^[34] In pregnancy, paraxanthine clearance is reduced across trimesters, attributed to decreased CYP1A2 activity, leading to higher plasma concentrations.^[44] Drug interactions, such as inhibition by fluvoxamine—a potent CYP1A2 inhibitor—can significantly impair metabolism and increase exposure.^[43]

Physiological effects

Central nervous system effects

Paraxanthine exerts stimulant effects on the central nervous system primarily through antagonism of adenosine receptors, similar to caffeine but with potentially distinct potency profiles.^[45] In preclinical models, paraxanthine enhances cognitive functions such as memory consolidation and attention more effectively than caffeine. A 2024 rat study using the Morris water maze demonstrated that high-dose paraxanthine significantly reduced escape latency in both young and aged animals, indicating improved spatial memory, with greater effects than equivalent caffeine doses (P < 0.001 in young rats).^[46] This cognitive enhancement is linked to increased levels of neurotransmitters including acetylcholine, dopamine, and GABA, as well as neurochemicals like brain-derived neurotrophic factor (BDNF), which supports synaptic plasticity.^[46] Human randomized trials further support paraxanthine's nootropic benefits, particularly in demanding conditions. In a 2024 double-blind study of trained runners, a 200 mg dose of paraxanthine improved prefrontal cortex function and reduced cognitive fatigue post-10 km run, increasing correct responses on the Berg-Wisconsin Card Sorting Test by 6.8% (P = 0.012) and decreasing perseverative errors by 26.9% compared to caffeine (P = 0.026).^[47] Reaction time on the Psychomotor Vigilance Task also improved by 23.2% versus placebo (P = 0.029), outperforming caffeine without additional benefits from combining the two.^[47] Regarding neuroprotection, paraxanthine shows promise in models of neurodegenerative diseases. It reduces neurodegeneration in Parkinson's disease models, potentially lowering disease risk independently of caffeine metabolism speed, as evidenced by epidemiological data linking higher paraxanthine levels to reduced odds of onset (OR 0.47 for high caffeine consumers).^[48] In Alzheimer's disease models, paraxanthine promotes neuronal cysteine uptake via the excitatory amino acid carrier 1 (EAAC1), elevating glutathione levels to mitigate oxidative stress and cell damage, similar to caffeine.^[49] As a stimulant, paraxanthine increases alertness and reduces fatigue more potently than caffeine in animal models, with stronger locomotor activation and reversal of adenosine-induced depression at equivalent doses.^[45] It also modulates dopamine release in the striatum, contributing to enhanced executive function and reasoning in human trials.^[45]^[47] Paraxanthine disrupts sleep patterns akin to caffeine by promoting wakefulness and delaying onset, though with longer-lasting effects in mice; both compounds proportionally suppress REM sleep, but paraxanthine demonstrates higher wake-promoting potency at 100 mg/kg.^[50] Paraxanthine elevates striatal dopamine levels more effectively than caffeine in preclinical assays.^[45]

Cardiovascular and other effects

Paraxanthine exerts cardiovascular effects primarily through its inhibition of phosphodiesterase (PDE), which elevates intracellular cyclic adenosine monophosphate (cAMP) levels, potentially enhancing cardiac contractility. However, human studies indicate that paraxanthine has milder impacts on heart rate and blood pressure compared to caffeine, with doses of 100-300 mg often decreasing heart rate rather than increasing it. For instance, a 100 mg dose reduced heart rate by approximately 6 bpm at 60 minutes and 5 bpm at 180 minutes post-ingestion, while showing no significant changes in systolic or diastolic blood pressure. In contrast to caffeine's more pronounced sympathomimetic actions, paraxanthine produces a smaller elevation in diastolic blood pressure and plasma epinephrine, alongside comparable increases in free fatty acids.^[51]^[52] Paraxanthine also promotes lipolysis in adipose tissue by stimulating hormone-sensitive lipase via cAMP-mediated pathways, leading to elevated free fatty acid levels and increased energy expenditure. A dose-response study demonstrated that 300 mg of paraxanthine significantly raised circulating free fatty acids (AUC increase) compared to placebo and that 200 mg boosted total energy expenditure by approximately 100 kcal over three hours compared to placebo. This effect supports its potential in enhancing metabolic rate without the jitteriness associated with caffeine. Regarding respiratory effects, as a methylxanthine, paraxanthine contributes to bronchodilation through smooth muscle relaxation, though it is less potent than theophylline; elevated urinary paraxanthine levels have been linked to 53% lower odds of current asthma in adults.^[51]^[53] In renal function, paraxanthine exhibits a mild diuretic effect by increasing glomerular filtration rate and renal blood flow, similar to other methylxanthines, though direct human data is limited.^[54] Gastrointestinal effects are minimal, with paraxanthine causing fewer motility disturbances and side effects than caffeine. Endocrinologically, it shows no significant adverse impact on insulin sensitivity and may improve it, as evidenced by reduced fasting insulin and increased glucose infusion rates in obese rat models.^[55] Research indicates paraxanthine's favorable metabolic profile for weight management, including enhanced thermogenesis, improved lipid profiles (e.g., reduced triglycerides and LDL, increased HDL), and greater resting energy expenditure without cardiovascular strain.^[51]^[56]^[57] These effects are primarily observed in preclinical models and small human studies (n=12-21), with larger clinical trials needed to confirm benefits as of 2025.^[57]

Uses and applications

Role in caffeine metabolism

Paraxanthine serves as the primary metabolite of caffeine in humans, accounting for approximately 70-84% of caffeine's breakdown through N-3 demethylation by the hepatic enzyme cytochrome P450 1A2 (CYP1A2).^[3]^[58] This dominant metabolic route contributes significantly to caffeine's overall pharmacodynamics, as paraxanthine exhibits similar potency in antagonizing adenosine receptors, thereby promoting alertness, cognition, and physical endurance.^[3] Due to its comparable half-life of 3-4 hours and tendency to accumulate with repeated caffeine intake, paraxanthine contributes to caffeine's sustained stimulant effects over time.^[59]^[45] By representing the major pathway for caffeine elimination, paraxanthine facilitates the detoxification and clearance of the parent compound, reducing potential toxicity from prolonged caffeine exposure.^[2] This process helps maintain physiological homeostasis, as paraxanthine is further metabolized and excreted primarily via urine, preventing buildup of the more anxiogenic caffeine.^[58] The human metabolic preference for the paraxanthine pathway over other routes, such as those producing theobromine or theophylline, favors this major elimination route.^[45] Plasma paraxanthine levels, often assessed via the paraxanthine-to-caffeine ratio, serve as a reliable biomarker for CYP1A2 activity in phenotyping studies, enabling evaluation of individual metabolic variations and drug interactions.^[60] In clinical settings, particularly caffeine overdose cases, monitoring paraxanthine concentrations aids prognosis by estimating time elapsed since ingestion, predicting symptom duration, and guiding interventions like hemodialysis, where paraxanthine clearance informs treatment efficacy and risks such as rhabdomyolysis.^[61]^[62]

Direct therapeutic and supplemental uses

Paraxanthine has emerged as a standalone ingredient in dietary supplements, primarily marketed for its potential cognitive-enhancing properties without the adverse effects associated with caffeine, such as jitters or crashes. Brands like Rarebird have commercialized paraxanthine-infused products, such as coffee alternatives, since 2023, positioning it as a nootropic to support mental clarity, alertness, and focus. Typical dosages in these supplements range from 100 to 300 mg per day, with studies indicating that acute ingestion of 100–200 mg can improve measures of cognition, memory, reasoning, and sustained attention.^[63]^[40]^[64] In athletic contexts, paraxanthine is incorporated into pre-workout and performance supplements to enhance endurance, strength, and recovery. A 2024 randomized controlled trial demonstrated that pre-exercise ingestion of paraxanthine improved prefrontal cortex function, reaction times, and cognitive performance during high-intensity exercise, while mitigating fatigue without the post-exercise crash seen with caffeine. These benefits stem from its ability to boost nitric oxide production and support muscle function, as evidenced in human and animal models.^[47]^[6]^[56] Preclinical research highlights paraxanthine's promise in neurodegenerative disorders, particularly Parkinson's disease, through neuroprotective mechanisms. Studies from 2024 attribute coffee's protective effects against Parkinson's to caffeine metabolites like paraxanthine, showing an inverse association between plasma paraxanthine levels and disease risk via preservation of dopaminergic neurons and reduced inflammation. Earlier models confirm paraxanthine's role in stimulating ryanodine receptors to protect against dopaminergic cell death and promoting cysteine uptake for glutathione synthesis, offering targeted neuroprotection independent of caffeine's pathways.^[65]^[66]^[67]^[68] For weight management, paraxanthine exhibits lipolytic effects, promoting fat breakdown and increasing energy expenditure in supplements. A 2024 dose-response study found that paraxanthine doses of 100–300 mg elevated lipolysis markers and reduced hunger perceptions, potentially aiding metabolic health without significant cardiovascular strain. Animal studies further support reduced body fat mass with chronic administration.^[69]^[51]^[55] Historically, paraxanthine lacked direct therapeutic applications, remaining a research-focused metabolite until its recent commercialization as a purified supplement ingredient around 2021–2023. In the United States, it is available as a dietary supplement under self-affirmed GRAS status, permitting use up to 300 mg per serving in foods and beverages, though it is not approved as a prescription drug. In the European Union, paraxanthine is under review as a novel food via an ongoing application submitted in 2022, with proposed safe intakes up to 200–400 mg daily for adults, but it awaits authorization for market placement as of November 2025.^[70]^[71]

Safety and toxicity

Toxicity profile

Paraxanthine exhibits relatively low acute toxicity compared to other methylxanthines, with an oral LD50 of 829 mg/kg body weight established in female Sprague-Dawley rats following a single dose, and no mortality or treatment-related adverse effects observed in the subsequent 14-day observation period.^[72] An independent acute oral toxicity study in rats reported a higher LD50 of 1601 mg/kg body weight, with no deaths at doses up to 990 mg/kg over 14 days.^[73] Using standard interspecies scaling factors, these rodent LD50 values translate to estimated human equivalents of approximately 9-18 g for a 70 kg adult, notably higher than caffeine's estimated lethal dose of 6-10 g.^[72]^[73] At high doses exceeding 500 mg/kg in animal models, paraxanthine can induce symptoms typical of methylxanthine overstimulation, including hyperactivity, hyperreflexia, tachycardia, tremors, and potentially seizures, though these effects are reversible within hours and occur with lower incidence than with equivalent caffeine doses.^[72] Human data on overt toxicity are limited due to paraxanthine's primary occurrence as a caffeine metabolite, but its overall toxicological potency is considered very low. Chronic exposure studies demonstrate no evidence of carcinogenicity or genotoxicity for paraxanthine; in vitro and in vivo assays, including bacterial reverse mutation, chromosomal aberration, and micronucleus tests, showed negative results up to doses of 100 mg/kg body weight, with no mutagenic potential identified.^[73]^[72] In a 90-day subchronic oral toxicity study in rats at doses up to 300 mg/kg body weight per day, the no-observed-adverse-effect level (NOAEL) was established at or above the highest tested dose, with no mortality, organ toxicity, or histopathological changes observed.^[73] Paraxanthine also shows potential for dependence similar to but milder than caffeine, with preclinical data indicating little to no abuse liability and reduced reinforcing effects in behavioral models.^[74] In vulnerable populations, caution is advised during pregnancy, as paraxanthine readily crosses the placenta and extremely high maternal serum levels (>1845 ng/mL, corresponding to heavy caffeine intake) are associated with increased risk of spontaneous abortion, though moderate exposure does not appear to elevate this risk.^[75] Individuals with pre-existing cardiac arrhythmias should avoid paraxanthine due to its stimulant properties, which may exacerbate tachycardia or irregular rhythms, consistent with methylxanthine pharmacology.^[72] Overdose management for paraxanthine is primarily supportive, focusing on monitoring vital signs, controlling seizures or agitation with benzodiazepines if needed, and addressing dehydration or electrolyte imbalances, as symptoms are generally self-limiting.^[72] Hemodialysis may be effective in severe cases owing to paraxanthine's low plasma protein binding (similar to caffeine at approximately 30-40%), facilitating rapid removal, though human case reports are scarce.^[76] As of 2025, human clinical trials, primarily acute and short-term, have shown paraxanthine to be well-tolerated at doses up to 200-300 mg, with no serious adverse events reported beyond mild, transient stimulation effects.^[77]^[6]

Comparison to caffeine

Paraxanthine and caffeine share similar stimulant effects on the central nervous system, primarily through antagonism of adenosine receptors, but paraxanthine demonstrates enhanced cognitive benefits with reduced anxiogenic properties. A 2024 randomized controlled trial in healthy young men found that acute ingestion of paraxanthine (200 mg) led to greater improvements in cognitive function, including reaction time and accuracy on attention tasks, compared to an equivalent dose of caffeine, both pre- and post-exercise.^[6] This superiority is attributed to paraxanthine's ability to avoid the adenosine receptor rebound effect associated with caffeine, which can contribute to post-stimulation fatigue. Additionally, paraxanthine avoids the production of other metabolites like theobromine and theophylline, potentially leading to more targeted neurostimulation without the broader physiological interference seen with caffeine.^[78] In terms of safety, paraxanthine exhibits a more favorable toxicity profile than caffeine. Studies report oral LD50 values for paraxanthine of 829 mg/kg and 1601 mg/kg in rats, compared to approximately 192 mg/kg for caffeine.^[72]^[73]^[79] Paraxanthine also produces fewer adverse effects such as jitteriness and sleep disruption; for instance, a 2010 study on wake promotion showed paraxanthine to be more potent at promoting alertness with lower anxiogenic and cardiovascular side effects than caffeine at equimolar doses.^[80] These differences stem from paraxanthine's pharmacokinetic profile, including faster clearance and a shorter half-life (approximately 3-4 hours versus 5-6 hours for caffeine), which minimizes prolonged receptor blockade and subsequent disruptions.^[6] Metabolically, paraxanthine represents a "downstream" product of caffeine, accounting for 70-84% of caffeine's biotransformation via hepatic cytochrome P450 1A2, and it undergoes further demethylation to less active compounds like 1-methylxanthine and 1-methyluric acid.^[59] This results in a cleaner metabolic pathway with fewer minor metabolites than caffeine, which produces three primary metabolites (paraxanthine, theobromine, and theophylline), potentially reducing the risk of cumulative side effects from poly-metabolite interactions.^[6] Regarding side effects, caffeine is more prone to inducing gastrointestinal upset, tolerance development, and dependency due to its broader receptor interactions and longer persistence in the body. In contrast, paraxanthine shows reduced gastrointestinal irritation and slower tolerance buildup, making it suitable for sustained use without the escalation of doses often required with caffeine.^[6] Human studies indicate paraxanthine elicits fewer instances of anxiety and heart rate elevation, further differentiating its tolerability.^[80] Head-to-head trials from 2023 to 2025 provide evidence favoring paraxanthine for specific applications. A 2024 preclinical study in rats demonstrated that paraxanthine enhanced memory consolidation and neuroplasticity markers (e.g., BDNF levels) more effectively than caffeine, suggesting greater neuroprotective potential.^[81] Similarly, the aforementioned 2024 human trial highlighted paraxanthine's edge in exercise performance contexts, with improved cognitive recovery post-10 km run compared to caffeine.^[6] These findings align with earlier toxicity data, reinforcing paraxanthine's profile for neuroprotection and endurance.^[64] Practically, paraxanthine is increasingly preferred in dietary supplements and performance aids to circumvent caffeine's drawbacks, such as energy crashes and tolerance. By delivering caffeine-like stimulation without the associated jitteriness or metabolic baggage, it offers a more consistent option for cognitive enhancement and athletic use, as evidenced by emerging formulations in the supplement industry.^[82]

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[11]
Paraxanthine CAS - 1,7-Dimethylxanthine - United States Biological
Solubility: Ethanol (0.6 mg/ml), 0.1N Sodium Hydroxide (2 mg/ml), Water (1 mg/ml),. Storage and Stability. May be stored at RT for short-term only. Long-term ...
[12]
1,7-Dimethylxanthine CAS#: 611-59-6 - ChemicalBook
1,7-Dimethylxanthine ; storage temp. room temp ; solubility, ethanol: 0.6mg/mL ; form, solid ; pka, pKa 8.5 (Uncertain) ; color, white.
[13]
Absorption spectra of xanthines in aqueous solution - RSC Publishing
We present a detailed computational analysis of the UV/Vis spectra of caffeine, paraxanthine and theophylline in aqueous solution.
[14]
Paraxanthine - an overview | ScienceDirect Topics
Up to 90% of caffeine is hepatically metabolized, mostly to paraxanthine (80%) and theobromine (10%) and trivial theophylline (5%). Paraxanthine is generally ...
[15]
Paraxanthine - an overview | ScienceDirect Topics
This methylxanthine is naturally present in tea leaves and in vestigial amounts in cocoa and coffee beans (Barnes, 2013).
[16]
Minor alkaloids in caffeine containing stimulants - ResearchGate
Aug 5, 2025 · Using HPLC and a special preseparation technique quantitative values for paraxanthine in cocoa, mate and tea and for paraxanthine and theacrine ...<|control11|><|separator|>
[17]
Convergent evolution of caffeine in plants by co-option of exapted ...
We have shown that convergent caffeine production, surprisingly, has evolved by two previously unknown biochemical pathways in chocolate, citrus, and guaraná ...<|control11|><|separator|>
[18]
Genetic susceptibility to caffeine intake and metabolism
Oct 22, 2024 · The main route of caffeine metabolism in humans is via CYP1A2 catalyzed N-3 demethylation to paraxanthine (around 84%), N-1 demethylation to ...Missing: biosynthesis | Show results with:biosynthesis
[19]
Biotransformation of caffeine, paraxanthine, theobromine ... - PubMed
The metabolic profile of caffeine biotransformation by CYP1A2 averaged 81.5% for paraxanthine, 10.8% for theobromine and 5.4% for theophylline formation.
[20]
Genetics of caffeine consumption and responses to caffeine - PMC
Modeling based on twin studies reveals that genetics plays a role in individual variability in caffeine consumption and in the direct effects of caffeine.
[21]
The effect of caffeine dose on caffeine and paraxanthine changes in ...
Nov 11, 2024 · This rapid absorption is particularly relevant for athletes, as it can lead to quicker improvements in reaction time and cognitive alertness ...<|control11|><|separator|>
[22]
Pharmacokinetics of Caffeine: A Systematic Analysis of Reported ...
Caffeine is almost exclusively metabolized in the liver by the cytochrome P-450 enzyme system to the main product paraxanthine and the additional products ...
[23]
Differences in Caffeine and Paraxanthine Metabolism Between ...
In CYP1A2-null murine LM, the main paraxanthine metabolite was 7-methylxanthine. The quinolones competitively inhibited caffeine metabolism in human but not in ...Missing: biosynthesis | Show results with:biosynthesis
[24]
Biotransformation of caffeine, paraxanthine, theobromine and...
The metabolic profile of caffeine biotransformation by CYP1A2 averaged 81.5% for paraxanthine, 10.8% for theobromine and 5.4% for theophylline formation.
[25]
Caffeine Pathway, Pharmacokinetics - ClinPGx
CYP1A2 is responsible for more than 95% of the primary metabolism of caffeine [Article:8491061]. Therefore caffeine is used as a probe drug for CYP1A2 activity ...
[26]
[PDF] EFFECTS OF THEOPHYLLINE ON CYP1A2-MEDIATED CAFFEINE ...
The KM and Vmax of caffeine 3-N-demethylation were determined without adding any theophylline to the incubation; they were 0.66 ± 0.06 mM caffeine ...<|control11|><|separator|>
[27]
Effects of dietary broccoli on human in vivo caffeine metabolism
Broccoli consumption significantly induced CYP1A2 and CYP2A6 activities in both men and women, confirming the induction of CYP1A2 activity.
[28]
Coffee, CYP1A2 genotype, and risk of myocardial infarction - PubMed
Mar 8, 2006 · Individuals who are homozygous for the CYP1A2*1A allele are "rapid" caffeine metabolizers, whereas carriers of the variant CYP1A2*1F are "slow" ...
[29]
Paraxanthine metabolism in humans: determination of ... - PubMed
Formation of 7-methylxanthine (7-MX) and 1,7-dimethyluric acid and renal excretion of unchanged PX comprised 6, 8 and 9% of PX clearance, respectively.
[30]
Comparative pharmacokinetics of caffeine and its primary ... - NIH
The pharmacokinetics of caffeine (CA), paraxanthine (PX), theobromine (TB) and theophylline (TP) were studied in six healthy male volunteers.
[31]
Pharmacokinetics of Caffeine: A Systematic Analysis of Reported ...
Caffeine is almost exclusively metabolized in the liver by the cytochrome P-450 enzyme system to the main product paraxanthine and the additional products ...<|control11|><|separator|>
[32]
Subclasses of adenosine receptors in the central nervous system
... paraxanthine (IC50, 40–65µM) > caffeine (IC50, 90–110µM) > theobromine (IC50 ... In addition, the functional significance of xanthine action will depend on the ...Missing: IC50 | Show results with:IC50
[33]
Structure-Bioactivity Relationships of Methylxanthines: Trying to ...
As for paraxanthine it is also supposedly to be fairly harmless for humans [32]. 8. Conclusions. Methylxanthines have been a more or less noticeable part of ...
[34]
Paraxanthine, the primary metabolite of caffeine, provides protection ...
Paraxanthine, the primary metabolite of caffeine, provides protection against dopaminergic cell death via stimulation of ryanodine receptor channels · Abstract.
[35]
Paraxanthine, a caffeine metabolite, dose dependently increases [Ca2+]i in skeletal muscle | Journal of Applied Physiology | American Physiological Society
### Summary of Paraxanthine Plasma Levels and Calcium-Related Effects
[36]
Methylxanthines Inhibit Primary Amine Oxidase and Monoamine ...
Apr 2, 2020 · Caffeine induced almost 75% inhibition at 2.5 mM. Paraxanthine, 7-methylxanthine, and theophylline only partially impaired tyramine oxidation.3. Results · 3.6. Tyramine Oxidation By... · 4. Discussion
[37]
https://pubmed.ncbi.nlm.nih.gov/18621927/
[38]
https://journals.physiology.org/doi/full/10.1152/jappl.2000.89.6.2312
[39]
Pregnancy-Induced Changes in the Pharmacokinetics of Caffeine ...
This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy.
[40]
Psychostimulant pharmacological profile of paraxanthine, the main ...
In this study we show that in rats paraxanthine has a stronger locomotor activating effect than caffeine or the two other main metabolites of caffeine, ...
[41]
Paraxanthine enhances memory and neuroplasticity more than ...
Dec 2, 2024 · PXN supplementation has been shown to increase measures of cognition, memory, reasoning, response time, and sustained attention; however, no ...
[42]
Paraxanthine provides greater improvement in cognitive function ...
Paraxanthine provides greater improvement in cognitive function than caffeine after performing a 10-km run. J Int Soc Sports Nutr. 2024 Dec;21(1):2352779. doi: ...
[43]
Association between caffeine intake and risk of Parkinson's disease ...
Both caffeine and its main metabolite, paraxanthine, may be neuroprotective. ... Central Nervous System Stimulants / adverse effects*; Coffee / adverse ...
[44]
Glutathione-Mediated Neuroprotective Effect of Purine Derivatives
Aug 22, 2023 · Our recent study found that another purine derivative, paraxanthine, has neuroprotective effects similar to those of caffeine and UA.
[45]
Effects of paraxanthine and caffeine on sleep, locomotor activity, and ...
The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher ...
[46]
A Dose-Response Study to Examine Paraxanthine's Impact on ...
May 14, 2024 · Using this, a 200 mg CAF dose is equivalent to approximately 140 mg PX. Additionally, most of the caffeine literature indicates that CAF dosages ...<|control11|><|separator|>
[47]
Sympathomimetic effects of paraxanthine and caffeine in humans
Caffeine is metabolized extensively (on average 80%) to paraxanthine. With regular caffeine consumption, average serum levels of paraxanthine are two thirds ...
[48]
Paraxanthine provides greater improvement in cognitive function ...
May 9, 2024 · Results provide some evidence that pre-exercise PX ingestion improves prefrontal cortex function, attenuates attentional decline, mitigates ...
[49]
Paraxanthine Supplementation Increases Muscle Mass, Strength ...
Feb 20, 2022 · The purpose of this study was to evaluate the potential beneficial effects of paraxanthine supplementation in mice on muscle mass, muscular ...
[50]
Urinary caffeine and caffeine metabolites, asthma, and lung function ...
Our findings for paraxanthine are novel and suggest that a high paraxanthine level is linked to lower odds of current or active asthma in adults. Although less ...
[51]
Methylxanthines and the Kidney - PMC - NIH
The focus of this chapter is a description of the renal effects of the natural methylxanthines, mainly of caffeine and theophylline, and a discussion of ...
[52]
Effect of Paraxanthine on Body Fat Reduction and Insulin Sensitivity ...
Dec 31, 2007 · These results suggest that paraxanthine exerts an anti-obesity effect and improve insulin sensitivity in rats with MSG-induced obesity.Missing: cortisol endocrine
[53]
Flurry of recent studies support paraxanthine benefits
Mar 24, 2025 · “Paraxanthine has been shown to increase resting energy expenditure and thermogenesis,” Baier said, pointing to a dose-response study that found ...
[54]
What are the effects and management of paraxanthine, a metabolite ...
Sep 18, 2025 · Cardiovascular effects: Increases diastolic blood pressure; Elevates plasma epinephrine levels; Raises free fatty acids 1. Neurological effects:.Missing: threshold | Show results with:threshold
[55]
Time to Recover From Daily Caffeine Intake - Frontiers
After an acute p.o. administration, 99% of the caffeine is rapidly absorbed within ~45 min (1), which brings the peak plasma concentration of caffeine at 1–2 h ...Introduction · Methods · Results · Discussion
[56]
Evolution of the biochemistry underpinning purine alkaloid ...
Sep 30, 2024 · Paraxanthine is the primary caffeine catabolite in humans but is rarely detected in plants. ... xanthine biosynthesis [55,56]. XMP can be directly ...
[57]
The determination of the Paraxanthine/Caffeine ratio as a metabolic ...
Nov 1, 2021 · The Paraxanthine/Caffeine ratio is a way to probe CYP1A2 activity, a central enzyme in drug metabolism, by measuring a precursor/product ratio.
[58]
Simultaneous analysis of caffeine and paraxanthine provides ...
Caffeine (CFF) is efficiently absorbed after ingestion, and approximately 80% of ingested CFF is metabolized to paraxanthine (PXT).Missing: impairment | Show results with:impairment
[59]
Pharmacokinetics of caffeine self-administered in overdose in a ...
Oct 4, 2021 · We measured the plasma concentrations of caffeine and its primary metabolite paraxanthine along with the other medicines and also generated ...
[60]
About Paraxanthine | The Science & Benefits of Px
### Summary of Paraxanthine (Px) Information
[61]
Dose-Response of Paraxanthine on Cognitive Function - NIH
Dec 15, 2021 · Paraxanthine (PXN) is a metabolite of caffeine that has recently been reported to enhance cognition at a dose of 200 mg.
[62]
Paraxanthine safety and comparison to caffeine - Frontiers
Feb 1, 2023 · The aim of this study was to evaluate the toxicity of paraxanthine (Rarebird, Inc.) relative to caffeine through a battery of toxicological studies.Missing: appearance | Show results with:appearance
[63]
Association of Coffee Consumption and Prediagnostic Caffeine ...
Mar 21, 2024 · This study demonstrates that the neuroprotection of coffee on PD is attributed to caffeine and its metabolites by detailed quantification of plasma caffeine ...
[64]
Drinking Coffee May Help Protect Against Parkinson's, Study Says
May 25, 2024 · "These neuroprotective effects align with our findings, which revealed an inverse association between caffeine, paraxanthine, and ...
[65]
Paraxanthine, the Primary Metabolite of Caffeine, Provides ...
Paraxanthine, the Primary Metabolite of Caffeine, Provides Protection against Dopaminergic Cell Death via Stimulation of Ryanodine Receptor Channels - ...<|control11|><|separator|>
[66]
A purine derivative, paraxanthine, promotes cysteine uptake for ...
Paraxanthine, a caffeine metabolite, increases cysteine uptake, leading to increased glutathione (GSH) levels, which may promote neuroprotection.<|control11|><|separator|>
[67]
A Dose-Response Study to Examine Paraxanthine's Impact on ...
May 14, 2024 · Paraxanthine 200mg increased energy expenditure and hunger ratings compared to placebo, while 300mg increased free fatty acids. Heart rate ...
[68]
Ingenious Ingredients self-affirms GRAS status for paraxanthine ...
Nov 23, 2021 · Ingenious Ingredients (Ing2) has announced it has achieved self-affirmed GRAS (generally recognized as safe) status for its Enfinity-branded ...
[69]
None
### Summary of Paraxanthine as a Novel Food in the EU
[70]
https://www.nutraingredients.com/Article/2021/11/23/Ingenious-Ingredients-self-affirms-GRAS-status-for-paraxanthine-ingredient/
[71]
https://food.ec.europa.eu/document/download/330ca889-27cc-4db5-835b-a0670180b85a_en?filename=novel-food_sum_ongoing-app_2022-90305.pdf
[72]
Effects of caffeine and its metabolite paraxanthine on intracranial ...
Each drug was tested in groups of six or seven rats. Tests with different drugs with a given rat were separated by at least two weeks, and during this inter- ...
[73]
Maternal serum paraxanthine, a caffeine metabolite, and the risk of ...
Conclusions: Only extremely high serum paraxanthine concentrations are associated with spontaneous abortion. This suggests that moderate consumption of caffeine ...
[74]
Pharmacokinetics of paraxanthine, one of the primary metabolites of ...
These findings indicate that in the rat paraxanthine is eliminated by a saturable process with an apparent Km of about 31 micrograms/ml and an apparent Vmax of ...Missing: absorption | Show results with:absorption
[75]
https://pubmed.ncbi.nlm.nih.gov/10572151/
[76]
Paraxanthine provides greater improvement in cognitive function ...
May 9, 2024 · Compared to caffeine, paraxanthine has a shorter half-life and faster clearance from the blood than caffeine, theobromine, and theophylline [15] ...
[77]
Effects of Paraxanthine and Caffeine on Sleep, Locomotor Activity ...
A recent study demonstrated that paraxanthine provides protection against dopaminergic cell death via ryanodine receptor stimulation.9 Therefore, paraxanthine ...
[78]
Paraxanthine enhances memory and neuroplasticity more than ...
Paraxanthine (PXN) is the main metabolite of caffeine (CAF). PXN supplementation has been shown to increase measures of cognition, memory, reasoning, response ...
[79]
Lasting energy with sustained release caffeine - Nutritional Outlook
Jun 17, 2025 · Sustained release provides longer-lasting energy and focus, while helping to minimize the side effects typically associated with a single high dose.