Effects of l-Arginine Plus Vitamin C Supplementation on Physical Performance, Endothelial Function, and Persistent Fatigue in Adults with Long COVID: A Single-Blind Randomized Controlled Trial

Single-blind randomized controlled trial in adults aged 20–60 years with long COVID and persistent fatigue who attended a post-acute COVID-19 outpatient clinic in Rome, Italy. In the active arm, 25 participants were randomized and 23 were analyzed/completed; baseline mean age was 50.0 years, 65.2% were women, and mean BMI was 24.8 kg/m2.

The active arm received oral L-arginine 1.66 g plus liposomal vitamin C 500 mg twice daily for 28 days (Bioarginina C). The comparison arm received placebo.

L-arginine plus vitamin C improved walking performance, handgrip strength, endothelial function, fatigue, and serum L-arginine over 28 days in adults with long COVID. The active arm increased 6-minute walk distance by +30 (40.5) m versus +0 (75) m with placebo (p = 0.001), and handgrip strength by +3.4 (7.5) kg versus +1 (6.6) kg (p = 0.03; mean difference = 3.4 kg, 95% CI: 0.5-9.4; effect size = 0.37). Flow-mediated dilation was 14.3% (7.3) in the supplemented group versus 9.4% (5.8) with placebo (p = 0.03; mean difference = 3.4%; 95% CI: 0.4-6.5; effect size = 0.66), and serum L-arginine increased by +60.2 (85.8) µM versus +11.0 (90.8) µM (p = 0.02; mean difference = 62.4 µM; 95% CI: 11.1-113.7; effect size = 0.72). Fatigue at day 28 was reported in 2 participants (8.7%) in the active group versus 21 participants (80.1%) in placebo (p < 0.0001), and no adverse events were recorded.

Small, short-duration, single-center trial with only 23 participants analyzed in the active arm limits precision and durability of the findings. Single-blind design and the specific outpatient long-COVID population reduce generalizability. Physical activity was not reported, and the short follow-up does not establish long-term efficacy or safety.