This article is part of our May 2023 Immune Health special issue. Download the full issue here.
Tosato M, Calvani R, Picca A. 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. Nutrients. 2022;14(23):4984.
To determine the effects of supplementation with oral L-arginine and vitamin C on exercise capacity, measured by a 6-minute walk test, in subjects with long Covid (per World Health Organization [WHO] criteria). Secondary outcomes included assessment of muscle strength, endothelial function, and fatigue in relation to supplementation with these 2 nutrients.
Oral supplementation with 3.2 g L-arginine and 1 g liposomal vitamin C for 28 days significantly improved exercise capacity, muscle strength, endothelial function, and fatigue in adults with long Covid.
Single-center, single-blind, placebo-controlled, randomized clinical trial
The study was conducted in an outpatient clinic in Rome, Italy. Participants were adults with prior SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection confirmed by polymerase chain reaction (PCR) testing, negative swab test for at least 4 weeks prior to enrollment, and with long Covid symptoms (per WHO criteria for long Covid).
The median age of participants was 50.5 years (20–60 years), and 65.2% were women. The median time from Covid-19 diagnosis to start of study was 254 days. Approximately half of the participants were hospitalized when they had active Covid, and 8.7% were in the intensive care unit.
Investigators enrolled 50 patients in the study and randomized them equally between the intervention and placebo arms. Two participants withdrew from each arm prior to the start of the intervention. At baseline, the intervention and placebo groups were similar in terms of anthropometric, clinical, and functional characteristics.
The intervention consisted of 1.66 g L-arginine and 500 mg liposomal vitamin C taken orally 2 times daily (Bioarginina® C, Farmaceutici Damor, Naples, Italy). The same manufacturer made the placebo. The form of the supplement and placebo was unclear (ie, power, capsule, other).
Study Parameters Assessed
To assess the primary outcome of exercise capacity, investigators measured the distance walked on a 6-minute walk test. They conducted this test on a marked indoor hallway at baseline and on day 28.
To assess the secondary outcome of muscle strength, investigators used a hydraulic, hand-held dynameter to measure handgrip strength.
To assess the secondary measure of endothelial function, they conducted a flow-mediated dilation test, essentially measuring the change in brachial artery dilation after 5 minutes of forearm ischemia generated by a blood pressure cuff.
Investigators measured the final secondary outcome of fatigue persistence with the question "I felt that everything I did was an effort." A response of "most or all the time" indicated persistence of fatigue. This is item 7 of the Center for Epidemiological Studies Depression Scale1 and is used to measure physical frailty2 as it relates to fatigue more than depression.3
The primary outcome of this interventional study was to determine the effect of oral supplementation of L-arginine with liposomal vitamin C on distance walked during the 6-minute walk test as a measure of exercise capacity.
This study was 80% powered to detect a difference of at least 35 meters on the 6-minute walk test. This difference corresponds to a minimally clinically significant difference.
The effects of the intervention were measured at day 28. The median serum L-arginine concentration increased in the intervention group over placebo (+60.2 μM vs +11.0 μM; P=0.02).
The primary outcome, the median distance on the 6-minute walk test, increased 30 meters in the intervention group, whereas there was no change in the placebo group (P=0.001). The mean difference between groups was 50 meters (95% CI: 20.0–80.0 m; effect size=0.56).
There were also statistically significant differences in secondary outcomes.
Handgrip strength increased by 3.4 kg compared with an increase of 1.0 kg for placebo (P=0.03). The mean difference was 3.4 kg (95% CI: 0.5–9.4 kg; effect size=0.37). Flow-mediated dilation in the intervention group increased 14.3% compared to 9.4% in the placebo group (P=0.03). The mean difference was 3.4% (95% CI: 0.4–6.5; effect size=0.66).
On day 28, 8.7% of the intervention group reported fatigue compared to 80.1% of the placebo group (P≤0.0001). There was a high degree of correlation between the primary outcome and all secondary outcomes.
The authors received no external funding for this study, and the authors declared no conflicts of interest. The supplement was donated by the manufacturer who had no role in the study design or interpretation.
Practice Implications & Limitations
According to the Centers for Disease Control and Prevention, 1 in 5 American adults who have had Covid-19 develop long Covid.4 The toll of long Covid is significant in terms of diminished quality of life, lowered work productivity, and increased risk of chronic diseases.
While the pathophysiology of long Covid is not fully understood, there are several findings that support the hypothesis that alterations in L-arginine metabolism underlie some long Covid symptoms. L-arginine is metabolized by both nitric oxide synthase and by arginase. Nitric oxide synthase metabolism generates nitric oxide (NO). NO is integral to endothelial function, the dysfunction of which compromises vascular tone, increases thrombosis, and leads to inflammation.5 When L-arginine is preferentially metabolized by arginase, less is available to generate NO. As a result, there is compromised endothelial function, increased thrombosis, and inflammation. Previous studies have found that Covid-19 infection results in decreased L-arginine with upregulated arginase activity.6,7 Based on these findings, there is logic to the idea of supplementing L-arginine to make more of it available for metabolism to NO. Furthermore, cosupplementation with vitamin C increases intracellular tetrahydrobiopterin, which is, in turn, required by nitric oxide synthase to generate NO.8
Consistent with this underlying hypothesis, this trial demonstrated that oral supplementation with L-arginine and liposomal vitamin C improved endothelial function. Not surprisingly, investigators saw improvements in the associated clinical outcomes of improved exercise capacity (6-minute walking distance), increased muscle strength, and reduced fatigue in adults with long Covid. Particularly encouraging is that these clinically significant results were obtained in a relatively short period of time, specifically 1 month, and with moderate doses. The investigators note that L-arginine supplementation has been shown in other trials to improve aerobic and anaerobic fitness, especially in untrained individuals.9 This uniquely describes the demographic of those with long Covid.
With the favorable safety profile for both L-arginine and vitamin C, in the context of the significant morbidity associated with long Covid, this relatively simple supplementation strategy deserves clinical consideration. This study is limited by the relatively small number of participants and the fact that the study was conducted at a single center. However, even though these findings should be considered preliminary, these results offer a clinically viable strategy for a group of patients for whom few validated options exist.