Unraveling the complexities of caffeine: metabolism, genetics, evolution, and health.

Caffeine (1,3,7-trimethylxanthine) is the most widely consumed psychoactive substance globally, yet individuals differ strikingly in their physiological and health responses. These differences arise from the combined effects of genetic variation, evolutionary history, lifestyle exposures, and cultural practices. In this review, we synthesize current knowledge on the pharmacokinetics of caffeine, emphasizing the central role of the hepatic enzyme CYP1A2 and its transcriptional regulator AHR in determining metabolic rate. We summarize functional polymorphisms, haplotypes, and genome-wide association signals that underlie the spectrum from slow to rapid metabolizers, and integrate population-genetic and ancient DNA evidence to reveal how evolutionary pressures have shaped global patterns of caffeine tolerance. We further examine non-genetic modulators—including smoking, pregnancy, diet, and commonly prescribed medications—that dynamically influence CYP1A2 activity. Finally, we discuss how genetic variation interacts with coffee and tea’s diverse bioactive components to influence cardiovascular, neurological, and metabolic outcomes. By uniting pharmacogenomics, evolutionary genetics, and epidemiology, this review highlights the need for personalized caffeine intake recommendations that account for genetic background, beverage preparation methods, and individual health status.