This investigation determined whether variation in the HTR2A (serotonin receptor) gene modifies the ergogenic effects of caffeine on endurance and further modifies performance by the CYP1A2 genotype. Male athletes (n = 100; 25 ± 4 years) completed 10-km cycling time trials under 3 conditions as follows: 0, 2, or 4 mg of caffeine per kg body mass. Using a randomized, double-blinded, placebo-controlled design, data were analyzed using analysis of covariance to compare changes in cycling time between placebo (0 mg·kg-1) and each caffeine dose and adjusted for the placebo trial and order of treatment. A significance of p = 0.05 was used. Subjects were genotyped for HTR2A (rs6313) and CYP1A2 (rs762551). A significant caffeine-HTR2A interaction (p = 0.003) was observed; however, after adjustment for placebo trials, the interaction was no longer significant (p = 0.37). Because of the strong caffeine-CYP1A2 interaction (p < 0.0001) previously reported in these subjects, where the 4-mg dose resulted in divergent effects (slower and faster) on the 10-km cycling time, we conducted a simplified model to examine these same factors by the HTR2A genotype. The post hoc analysis excluded HTR2A CT heterozygotes and 2-mg·kg-1 caffeine trials. Among CYP1A2 fast metabolizers alone, a significant difference (1.7 minutes; p = 0.006) was observed when comparing (4- vs. 0-mg·kg-1 caffeine trials) between the HTR2A CC (n = 16; 2.4 minutes) and TT (n = 7; 0.7 minutes) genotypes. Our results show that 4-mg·kg-1 caffeine improves performance in individuals with the HTR2A CC genotype but only in those who are also CYP1A2 AA fast metabolizers. This study was registered with clinicaltrials.gov (NCT 02109783).
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