Effects of Oral L-Arginine on Everyday Persistent Fatigue, Sleep, and Post-Exercise Lactate Recovery in Community-Dwelling Working-Age Adults: A Double-Blind, Placebo-Controlled Randomized Trial

Background/Objectives: The evidence for nutritional interventions against fatigue is limited; we evaluated whether L-arginine reduces fatigue in working-age adults. Methods: In this 8-week randomized, double-blind, placebo-controlled trial, 120 community-dwelling working-age adults aged 30–59 years with persistent fatigue (Fatigue Severity Scale [FSS] total ≥ 27) received oral L-arginine 3 g/day, 6 g/day, or placebo. The primary endpoint was FSS change; secondary endpoints included the Checklist Individual Strength (CIS), Pittsburgh Sleep Quality Index (PSQI), and blood lactate kinetics during a standardized submaximal treadmill run (~70% VO2max, 30 min). Data from 119 participants were analyzed, with Holm adjustment for multiplicity. Results: At Week 8, FSS decreased more with 6 g/day than with placebo (−6.41 vs. −2.23; Holm-adjusted p = 0.024), whereas 3 g/day did not differ from placebo. The 6 g/day CIS improvement did not survive multiplicity adjustment. PSQI scores improved nominally at both doses (3 g/day, p = 0.007; 6 g/day, p = 0.045). With 6 g/day, the total lactate area under the curve (Holm-adjusted p = 0.041) and 15-min recovery lactate (Holm-adjusted p = 0.002) were lower than with the placebo, whereas the resting plasma nitrite did not differ. No serious adverse events occurred. Conclusions: L-arginine supplementation at 6 g/day for 8 weeks reduced fatigue severity relative to placebo and was well-tolerated; however, mean FSS scores remained above the enrollment threshold, indicating a reduction in, rather than resolution of, persistent fatigue.