Caffeine

Caffeine (1,3,7‑trimethylxanthine) is the most widely consumed psychoactive substance worldwide. It is found naturally in coffee beans, tea leaves and cacao, and is formulated pharmaceutically as caffeine citrate for the treatment of apnea of prematurity.

Beyond neonatal medicine, purified caffeine is incorporated into over‑the‑counter alertness aids and many dietary supplements. Typical adult exposure from beverages ranges from 50 mg (tea) to 150 mg (brewed coffee) per serving; total intakes above about 400 mg day^‑1 are associated with an increased risk of adverse effects such as anxiety, palpitations and sleep disturbance.

Mechanistically, caffeine acts primarily as a competitive antagonist at adenosine A₁ and A_2A receptors, resulting in increased neuronal firing and catecholamine release. At higher concentrations it inhibits phosphodiesterases and mobilises intracellular calcium, further potentiating its stimulant actions DailyMed 2024 .

CYP1A2 encodes a hepatic cytochrome P450 enzyme that catalyses more than 95 percent of caffeine clearance, converting caffeine to paraxanthine via N‑3‑demethylation PGx Background 2021 .

Transcription of CYP1A2 is inducible by polycyclic aromatic hydrocarbons (for example cigarette smoke), whereas several single‑nucleotide variants modulate basal activity. The promoter variant rs762551 (‑163C>A, star‑allele *1F) increases inducibility; the promoter variant rs2069514 (‑3860G>A, *1C) reduces constitutive expression. Allele combinations translate to clinically recognised metaboliser phenotypes that account for a substantial fraction of the inter‑individual variability in caffeine pharmacokinetics Koonrungsesomboon et al. 2018 .

Functional grouping of CYP1A2 diplotypes yields five principal metaboliser categories. Subjects with two high‑inducibility alleles (*1F/*1F or equivalent) exhibit the highest intrinsic and inducible clearance, whereas those carrying two reduced‑function alleles (*1C or null variants) show the slowest clearance. Intermediate activity is observed in heterozygous combinations.

Population studies demonstrate that caffeine oral clearance differs roughly three‑fold between the extremes of the phenotype distribution. In controlled settings, the mean caffeine half‑life is approximately 2.5 h in Ultrarapid Metabolisers and 7–8 h in Slow Metabolisers BMC Med 2024 . These pharmacokinetic differences translate to measurable differences in subjective alertness, sleep latency and, at high intakes, cardiovascular outcomes.

Ultrarapid Metaboliser (e.g. *1F/*1F)

• Effect: Accelerated clearance
• Implication: Shorter duration of stimulant effect; potential need for larger or more frequent servings to maintain efficacy
• Side effects: Low; sub‑therapeutic stimulation more common than toxicity

Rapid Metaboliser (heterozygous high‑inducibility)

• Effect: Faster than average clearance
• Implication: Reduced duration of effect; may increase consumption
• Side effects: Usually mild; monitor total intake

Normal Metaboliser

• Effect: Expected clearance
• Implication: Standard response profile
• Side effects: Follow population safety limits

Intermediate Metaboliser (one reduced‑function allele)

• Effect: Slower clearance
• Implication: Prolonged stimulant action; higher risk of sleep disruption if taken late in the day
• Side effects: Mild anxiety or insomnia at doses tolerated by Normals

Slow Metaboliser (two reduced‑function alleles or null variants)

• Effect: Markedly impaired clearance
• Implication: Plasma exposure two‑ to three‑fold higher than normal at equal dose; observational data link this phenotype to increased risk of hypertension and myocardial infarction at intakes >200 mg day^‑1 JAMA Netw Open 2023
• Side effects: Palpitations, jitteriness, insomnia; severity moderate to severe if intake is not reduced

Indeterminate / Not Available

• Effect: Unknown
• Implication: No specific guidance; follow standard dosing with clinical monitoring

CYP1A2‑Guided Caffeine Intake

The high‑inducibility *1F allele (rs762551‑A) is the most common worldwide, with allele frequencies ranging from 59 percent in South Asians to 72 percent in Europeans. The reduced‑function *1C allele is rare in Europeans (≈ 1 percent) but rises to about 27 percent in East Asian and African‑ancestry populations PGx Background 2021 .

Consequently, Slow Metabolisers are uncommon in European cohorts but may comprise up to 10 percent of some East Asian groups, influencing both habitual caffeine consumption patterns and susceptibility to dose‑related adverse effects Kazan et al. 2024 .

• DailyMed. Caffeine citrate injection, USP. 2024. Link
• Koonrungsesomboon N et al. The impact of genetic polymorphisms on CYP1A2 activity in humans: systematic review and meta‑analysis. Pharmacogenomics J. 2018. Link
• PGx Knowledge Base. General background text – CYP1A2. 2021. Link
• Ganna A et al. Genetic investigation into the broad health implications of caffeine metabolism. BMC Med. 2024. Link
• Xu S et al. CYP1A2 genetic variation, coffee intake and kidney dysfunction. JAMA Network Open. 2023. Link
• Kazan HH et al. CYP1A2 rs762551 polymorphism and athletic adaptation. Mol Biol Rep. 2024. Link
• Shabir M et al. Functional SNP rs762551 modulates coffee intake and lipid profile. Nutr Metab Cardiovasc Dis. 2022. Link