The Ergogenic Effect of Caffeine in Rodents: A Systematic Review and Meta-Analysis, with a Narrative Synthesis of Adenosine A2A Receptor Mechanisms

Caffeine is a widely consumed ergogenic aid and a nonselective antagonist of adenosine receptors, including the facilitatory A2A subtype (A2AR), yet the magnitude of its performance-enhancing effect in rodents has not been formally quantified. We conducted a systematic review and meta-analysis of rodent studies administering caffeine before exercise, with risk of bias assessed using the SYRCLE tool (PROSPERO CRD420250653223). Fourteen studies met the eligibility criteria. Six studies of a single systemic dose preceding an aerobic task, comprising 71 animals were pooled using a restricted maximum likelihood random-effects model with a Hartung–Knapp interval, yielding a large ergogenic estimate with wide uncertainty (Hedges’ g = +1.31; 95% CI + 0.29 to +2.32; I2 = 71%). Prespecified rules, applied independently of the observed effects, precluded pooling of the two anaerobic studies, which measured different performance constructs, and of the three chronic-exposure studies, whose dosing regimens and exercise modalities were not comparable; these are reported descriptively, as are the intracerebral administration experiments. Risk of bias was frequently unclear or high in the randomization and blinding domains. Receptor-level evidence is reported separately as a narrative synthesis, because the search was not constructed to retrieve mechanistic studies: the ergogenic response was abolished in global and forebrain A2AR-knockout mice and reproduced by the selective antagonist SCH 58261, whereas A2AR agonism with NECA was ergolytic and reversed by caffeine, and deletion of CD73, which depletes the extracellular adenosine pool preferentially supplying A2AR, recapitulated the ergogenic phenotype. The rodent evidence provides preclinical support for A2AR involvement in exercise-induced fatigue on an evidence base too small and too heterogeneous to support therapeutic or performance translation.