Effects of serotonergic pharmacological manipulation on exercise performance and central fatigue: a systematic review and three-level meta-analysis

BACKGROUND: Exercise-induced fatigue is a complex, non-pathological state that acutely limits physical performance, and the serotonergic (5-HT) system has been proposed as an important modulator of its central components. This systematic review and meta-analysis aimed to clarify the effects of serotonergic pharmacological manipulation on exercise-related outcomes. METHODS: Following PRISMA guidelines, we systematically searched PubMed, Scopus, Web of Science, Cochrane Central, and SportDiscus from inception to August 2025. Randomized controlled trials examining the effects of serotonergic pharmacological manipulation on exercise-related outcomes in healthy adults were included. Study selection, data extraction, and risk-of-bias assessment using RoB 2.0 were conducted independently. Pooled effects were synthesized using three-level random-effects models, and the certainty and robustness of the evidence were examined in additional analyses. RESULTS: Twenty-one randomized controlled trials involving 248 healthy adults were included in the systematic review, of which 19 studies involving 229 participants were included in the meta-analysis. In the primary models, serotonergic pharmacological manipulation was associated with small reductions in evoked motor response (Hedges' g = -0.24, 95% CI -0.46 to -0.02), time-domain EMG (Hedges' g = -0.18, 95% CI -0.33 to -0.02), heart rate (Hedges' g = -0.17, 95% CI -0.34 to -0.01), and blood glucose (Hedges' g = -0.50, 95% CI -0.89 to -0.11). Voluntary activation showed a borderline negative pooled estimate (Hedges' g = -0.20, 95% CI -0.40 to 0), whereas ratings of perceived exertion showed a positive but statistically uncertain pooled estimate (Hedges' g = 0.63, 95% CI -0.01 to 1.28). Resting twitch torque showed a small positive pooled effect (Hedges' g = 0.12, 95% CI 0.04 to 0.19), whereas superimposed twitch torque, maximal voluntary contraction, prolactin, lactic acid, and time to task failure did not show clear overall effects. CONCLUSIONS: Overall, this meta-analysis indicates that serotonergic pharmacological manipulation has outcome-specific effects on exercise-related fatigue rather than a single uniform influence across domains. The most consistent primary-model signals were found for evoked motor response, time-domain EMG, heart rate, and blood glucose, whereas overt performance and perceptual outcomes remained more variable. By integrating evidence across different serotonergic interventions and exercise paradigms, these findings improve our understanding of how 5-HT-related mechanisms may contribute to central fatigue during exercise.