Melatonin, Caffeine, or Their Combination: Effects on Sleep, Performance, Perceived Exertion in a Placebo-Controlled Crossover Study

Background/Objectives: Melatonin (MEL) promotes sleep and recovery, while caffeine (CAF) enhances alertness and performance. Despite their common use among athletes, their potential interaction remains underexplored. This study examined the effects of MEL and CAF, administered separately or in combination, on sleep, physical performance, physiological, biochemical, and perceptual responses in trained males. Methods: In a randomized double-blind placebo-controlled crossover study, fourteen trained males (22.4 ± 2.9 years) underwent four conditions, designed to isolate the effects of each substance and their interaction: (1) PLA + PLA: placebo before sleep and placebo in the morning; (2) PLA + CAF: placebo before sleep and caffeine (3 mg·kg−1) in the morning; (3) MEL + PLA: melatonin (6 mg) before sleep and placebo in the morning; and (4) MEL + CAF: melatonin before sleep followed by caffeine in the morning. One hour after the morning ingestion, participants performed the 5 m shuttle run test (5mSRT). Blood samples were collected pre- and post-exercise to assess markers of muscle damage (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase) and inflammation (C-reactive protein). Peak heart rate (HRpeak) and rating of perceived exertion (RPE) were recorded throughout the test. Sleep was assessed only during the night following melatonin or placebo ingestion. Results: No differences were observed in sleep parameters between conditions (p > 0.05). Total distance in the 5mSRT increased following MEL + CAF and PLA + CAF conditions compared with PLA + PLA. Moreover, MEL + CAF reduced muscle damage and inflammation markers compared with PLA + PLA, MEL + PLA, and PLA + CAF conditions (p < 0.05). Conclusions: The ingestion of nocturnal MEL and next-day CAF was associated with improvements in certain high-intensity exercise performance outcomes, along with changes in muscle damage and inflammation.