Caffeine against persistent fatigue in long-COVID: a randomized clinical trial

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Background & Objective Long COVID causes persistent symptoms, such as fatigue and cognitive impairment, which caffeine may help mitigate. This study aimed to evaluate the acute effects of caffeine on these symptoms.Methods This randomized, double-blind, placebo-controlled trial with a within-subjects design was conducted between October 2021 and January 2023 in Araranguá, Brazil. Twenty-eight participants (13 caffeine, 15 placebo) received a single administration of either caffeine (3 mg/kg) or placebo capsules. Participants met the Myalgic Encephalomyelitis: International Consensus Criteria, with fatigue assessed using the Chalder Fatigue Questionnaire. The cohort was predominantly of females (64.3%), with a mean age of 44.6 ± 7.7 years. Most were sedentary (82.1%) with moderate baseline fatigue. Exclusion criteria included significant cardiovascular or respiratory diseases. Primary outcomes included the Incremental Shuttle Walk Test, Borg Scale, Short Physical Performance Battery, Stroop Test, Montreal Cognitive Assessment, and biochemical markers. Data are presented as mean (standard deviation) or median [interquartile range, IQR], with statistical analyses performed using independent t-tests, Mann–Whitney U tests, and effect size calculations according to data distribution. Statistical significance was set at p < 0.05.Results Caffeine increased walking distance (476 [70.1] m vs. 284.4 [83] m; p < 0.05) and improved executive function (Stroop test: 47.3 [IQR 43.2–54.2] vs. 68.2 [IQR 60.9–72.2]; p < 0.05). Perceived exertion decreased pre- and post-exercise (p < 0.05).Conclusion Caffeine alleviates fatigue and cognitive dysfunction in Long COVID, supporting its potential role in rehabilitation.