No additive effect of acetaminophen when co-ingested with caffeine on cycling performance in well-trained young men

We investigated the effect of caffeine and acetaminophen on power output during a 6-min performance test, peripheral fatigue, and muscle protein kinase A (PKA) substrate phosphorylation. Fourteen men [age (means ± SD): 26 ± 6 yr; V̇o_2max: 63.9 ± 5.0 mL·min^-1·kg^-1] completed four randomized trials with acetaminophen (1,500 mg), caffeine (5 mg·kg body wt^-1), combined caffeine and acetaminophen (caffeine + acetaminophen), or placebo. Mean power output during the 6-min performance test (placebo mean: 312 ± 41 W) was higher with caffeine (+5 W; 95% CI: 1 to 9; P = 0.017) and caffeine + acetaminophen (+6 W; 95% CI: 0 to 12; P = 0.049) than placebo, but not with acetaminophen (+1 W; 95% CI: -4 to 7; P = 0.529). Decline in quadriceps maximal isometric voluntary torque immediately after the performance test was lower (treatment × time; P = 0.035) with acetaminophen (-40 N·m; 95% CI: -53 to -30; P < 0.001) and caffeine + acetaminophen (-44 N·m; 95% CI: -58 to -30; P < 0.001) than placebo (-53 N·m; 95% CI: -71 to -39; P < 0.001) but was similar with caffeine (-54 N·m; 95% CI: -69 to -38; P < 0.001). Muscle phosphocreatine content decreased more during the performance test (treatment × time; P = 0.036) with caffeine + acetaminophen (-55 mmol·kg dry wt^-1; 95% CI: -65 to -46; P < 0.001) than placebo (-40 mmol·kg dry wt^-1; 95% CI: -52 to -24; P < 0.001). Muscle net lactate accumulation was not different from placebo (+85 mmol·kg dry wt^-1; 95% CI: 60 to 110; P < 0.001) for any treatment (treatment × time; P = 0.066), being +75 mmol·kg dry wt^-1 (95% CI: 51 to 99; P < 0.001) with caffeine, +76 mmol·kg dry wt^-1 (95% CI: 58 to 96; P < 0.001) with acetaminophen, and +103 mmol·kg dry wt^-1 (95% CI: 89 to 115; P < 0.001) with caffeine + acetaminophen. Decline in muscle ATP and glycogen content and increase in PKA substrate phosphorylation was not different between treatments (treatment × time; P > 0.1). Thus, acetaminophen provides no additive performance enhancing effect to caffeine during 6-min maximal cycling. In addition, change in PKA activity is likely not a major mechanism of performance improvement with caffeine.NEW & NOTEWORTHY Here, we show that acetaminophen does not provide additive performance improvement to caffeine during a 6-min cycling ergometer performance test, and that acetaminophen does not improve performance on its own. Neither substance affects peripheral fatigue, muscle glycolytic energy production, or phosphorylation of muscle proteins of importance for ion handling. In contrast to previous suggestions, increased epinephrine action on muscle cells does not appear to be a major contributor to the performance enhancement with caffeine.