Toxicology of caffeine poisoning: molecular mechanisms, toxicokinetic profiles, and clinical implications

Caffeine toxicity represents a growing public health challenge due to the widespread availability of highly potent formulations. Ingestions of 3-10 g can be fatal, with serious toxicity occurring at plasma concentrations 15 mg/L or greater. This review provides a framework explaining its diverse clinical consequences.

A comprehensive literature search was conducted across PubMed, Scopus, and Google Scholar using AI-assisted tools, prioritizing clinical, forensic, toxicokinetic, and molecular mechanism studies while excluding chronic moderate consumption.

Caffeine toxicity is dose-dependent, progressing from adenosine receptor antagonism to phosphodiesterase inhibition, intracellular calcium release, and GABA-A antagonism. In overdose, these mechanisms interact synergistically to cause severe neurological, cardiovascular, and metabolic complications. Furthermore, the CYP1A2 metabolic system becomes saturated, prolonging the elimination half-life up to 27 h and causing a disproportionate rise in plasma concentrations. Interactions with drugs like mexiletine drastically reduce clearance.

Severe poisoning stems from complex, synergistic molecular interactions. Hypokalemia serves as a promising, actionable clinical biomarker for severity assessment. When massive ingestions saturate endogenous detoxification, hemodialysis becomes essential for survival. Unregulated markets for pure caffeine require stricter regulatory interventions and intensified clinical surveillance.