Evidence Review
Blood Pressure — 2022 Dose-Response Meta-Analysis
Shiraseb et al. (2022, PMID 34967840) conducted a systematic review and dose-response meta-analysis of 22 randomized controlled trials (30 effect sizes) examining L-arginine supplementation in adults. The pooled analysis demonstrated significant reductions in systolic blood pressure (WMD = −6.40 mmHg; 95% CI: −8.74 to −4.05; P < 0.001) and diastolic blood pressure (WMD = −2.64 mmHg; 95% CI: −3.94 to −1.40; P < 0.001). Subgroup analysis found significant blood pressure reductions across baseline blood pressure status (normotensive and hypertensive populations), trial duration (both ≤24 and >24 days), sex, health status, and BMI category. The dose-response analysis identified ≥4 g/day as the threshold for significant systolic blood pressure reduction. Published in Advances in Nutrition, this is the most current and comprehensive analysis available, drawing on a large and diverse pool of trials.
Blood Pressure — Earlier Systematic Review
Dong et al. (2011, PMID 22137067) analyzed 11 randomized, double-blind, placebo-controlled trials in a meta-analysis published in the American Heart Journal. Compared to placebo, oral L-arginine supplementation was associated with significant reductions in systolic blood pressure (WMD −5.39 mmHg; 95% CI −8.54 to −2.25) and diastolic blood pressure (WMD −2.66 mmHg; 95% CI −3.77 to −1.54). Included trials used oral doses ranging from 4 to 24 g/day with durations from 2 to 24 weeks. The consistency of findings across trials with differing populations, durations, and doses strengthens confidence in the blood-pressure-lowering effect. The authors noted that the mechanism — increased nitric oxide–mediated vasodilation — is well established and mechanistically coherent.
Umbrella Review of L-Arginine Meta-Analyses
McRae (2016, PMID 27660594) conducted an umbrella review aggregating findings from multiple published meta-analyses examining L-arginine's therapeutic benefits across different conditions and outcomes, published in the Journal of Chiropractic Medicine. The review synthesized meta-analyses covering blood pressure, endothelial function, peripheral artery disease, heart failure, preeclampsia, and sexual function. The consistent theme across domains was that L-arginine supplementation improved markers of NO bioavailability and endothelial function most robustly in populations with documented endothelial dysfunction or established cardiovascular risk — while benefit was less consistently seen in healthy individuals with normal baseline endothelial function. The review also noted that co-supplementation strategies (for example, antioxidants alongside arginine) may help sustain NO availability by preventing its oxidative degradation to peroxynitrite.
Erectile Dysfunction — Multicenter Randomized Controlled Trial
Menafra et al. (2022, PMID 34973154) conducted a multicenter, double-blind, randomized, placebo-controlled clinical trial examining 6 g/day L-arginine supplementation for 3 months in 98 men with vasculogenic erectile dysfunction (51 treatment, 47 placebo), with etiology confirmed by penile Doppler ultrasonography. L-arginine supplementation significantly increased IIEF-6 scores (International Index of Erectile Function) in the overall cohort (P < 0.0001), as well as in subgroups with mild-moderate (P < 0.0001) and severe (P = 0.007) vasculogenic ED. This study is notable for its multicenter design, objective etiological classification, and a relatively long treatment duration of 3 months. Erectile dysfunction caused by impaired penile blood flow is considered a vascular condition closely overlapping with systemic endothelial dysfunction, so these results reinforce L-arginine's mechanism of action in NO-dependent vascular beds beyond the coronary circulation.
Wound Healing and Immune Function
Kirk et al. (1993, PMID 7602735) examined the effects of L-arginine supplementation in elderly adults, who typically experience impaired wound healing and immune responses due to age-related changes in arginine metabolism. Supplementation significantly enhanced collagen deposition in standardized subcutaneous wounds compared to placebo, and at both studied doses, increased lymphocyte proliferation in response to mitogenic stimulation — a measure of T-cell immune competence. These findings are mechanistically consistent with arginine's dual role as a substrate for collagen synthesis (via the proline pathway) and for macrophage NO production during immune activation. While this study is older and used surrogate rather than clinical healing endpoints, its findings align with the broader surgical and critical care literature, where arginine-enriched nutritional formulas are now a recognized approach for perioperative wound management in malnourished patients.
Overall Evidence Assessment
L-arginine has one of the stronger evidence bases among amino acid supplements for cardiovascular applications. Two independent meta-analyses, together covering more than 33 randomized controlled trials, consistently demonstrate clinically meaningful blood pressure reductions averaging 5–6 mmHg systolic. The mechanistic rationale — arginine as the rate-limiting substrate for endothelial nitric oxide production — is well established in vascular biology. The evidence for healthy individuals with normal endothelial function is less consistent, possibly because dietary arginine is already sufficient for NO synthesis in healthy tissue, or because endogenous arginine recycling (via the citrulline-arginine pathway) compensates adequately. For individuals with documented endothelial dysfunction, hypertension, or cardiovascular risk factors, the evidence supports genuine therapeutic benefit at 4–6 g/day. Safety at these doses is good; gastrointestinal discomfort is the primary adverse effect at higher doses. The interaction with herpes viruses and the potential for additive hypotension with antihypertensive medications warrant clinical consideration.