Nitric Oxide, Blood Pressure, and Athletic Performance

How this amino acid found in watermelon boosts nitric oxide production to support blood pressure, exercise performance, and cardiovascular health

L-citrulline is a non-essential amino acid found in high concentrations in watermelon — and increasingly recognized as one of the most effective natural compounds for boosting nitric oxide (NO) production in the body. Nitric oxide relaxes blood vessel walls, improving circulation and lowering blood pressure. Unlike direct arginine supplements, citrulline bypasses the gut and liver, converting to arginine more efficiently in the kidneys [1][3]. The result is better blood flow, lower blood pressure in people with hypertension, and improved exercise capacity — all backed by human clinical trials.

How L-Citrulline Works

The Citrulline-Arginine-Nitric Oxide Pathway

The body produces nitric oxide from the amino acid L-arginine, via the enzyme nitric oxide synthase (NOS). The problem with taking arginine directly as a supplement is that most of it is broken down in the gut and liver before it reaches circulation — a process called first-pass metabolism. This makes oral arginine relatively inefficient at raising blood arginine levels.

L-citrulline sidesteps this bottleneck. After absorption, it travels to the kidneys, where it is converted to arginine by the urea cycle enzymes. This pathway is far more efficient, meaning that citrulline supplementation actually raises blood arginine levels more effectively than arginine supplementation itself [1][3]. Higher arginine availability means more substrate for nitric oxide production, which means more NO in circulation, leading to vasodilation — the widening of blood vessels.

This mechanism has direct downstream effects on:

Blood pressure — relaxed vessel walls lower peripheral resistance
Endothelial function — the inner lining of blood vessels becomes more responsive to blood flow demands
Exercise performance — muscles receive more oxygen and remove metabolic waste faster
Erectile function — penile erection is primarily a nitric oxide-mediated vascular event

Blood Pressure Effects

The blood pressure evidence is among the most consistent in the citrulline literature. A 2019 meta-analysis of clinical trials found that L-citrulline supplementation significantly reduced systolic blood pressure, with greater effects observed at doses of 6 g/day or more [2]. The effect is most pronounced in people who already have elevated blood pressure — those with normal blood pressure see minimal change.

This distinguishes citrulline from many blood pressure supplements: it appears to normalize rather than lower blood pressure uniformly, making it less likely to cause hypotension in people who don't need it.

Exercise Performance

Citrulline's vascular effects translate directly into measurable improvements in physical performance. By increasing blood flow to working muscles, it improves oxygen delivery and speeds the removal of lactic acid and ammonia — the metabolic byproducts that cause fatigue during high-intensity exercise [4].

A 7-day supplementation study using 6 g/day of L-citrulline found significant improvements in oxygen uptake kinetics during severe-intensity cycling exercise, along with better tolerance of high-intensity efforts. Interestingly, arginine at the same dose produced no such benefit — reinforcing that citrulline's route through the kidneys is the key to its efficacy [4].

Metabolic and Diabetes-Related Benefits

Citrulline also shows promise for people with metabolic conditions. In patients with type 2 diabetes, supplementation for one month at 2,000 mg/day produced a 38% increase in plasma nitric oxide levels and a 21% reduction in arginase activity [5]. Arginase is an enzyme that competes with nitric oxide synthase for the arginine substrate — when arginase is overactive (as it often is in diabetes), less arginine is available for NO production, impairing blood vessel function. By reducing arginase activity, citrulline helps restore the balance toward NO production and healthier vascular tone.

Practical Dosing and Sources

Food sources:

Watermelon is the richest natural source — approximately 2–3 g of citrulline per kg of flesh, or about 1 g per two cups. The rind contains even more, though it's rarely eaten.
Cucumbers, squash, and pumpkins contain smaller amounts.

Supplement dosing:

Blood pressure/cardiovascular: 3–6 g/day of L-citrulline, taken consistently
Exercise performance: 6–8 g of citrulline malate (a 2:1 formulation with malic acid) taken 60 minutes before exercise is the most studied protocol
Note on citrulline malate vs. pure citrulline: Citrulline malate is widely used in sports nutrition. The malate component contributes to energy production in the Krebs cycle and may provide additive ergogenic effects. For cardiovascular benefits, pure L-citrulline is typically used.

Safety: L-citrulline is considered safe at doses up to 10 g/day in short-term studies. It has no significant known interactions with common medications, though people taking blood pressure medications or PDE5 inhibitors (e.g., sildenafil) should use caution due to potential additive hypotensive effects.

Cross-reference: For related NO-boosting strategies, see our Beets page, which covers dietary nitrates as an alternative pathway to nitric oxide production.

Evidence Review

Cardiometabolic Overview: Allerton et al. 2018

The narrative review by Allerton et al. (PMID 30029482), published in Nutrients, synthesized evidence across the citrulline literature covering blood pressure, vascular function, muscle metabolism, and metabolic health outcomes. The authors identified a consistent pattern: L-citrulline supplementation reliably raises plasma arginine and citrulline concentrations in a dose-dependent fashion, and this elevated arginine availability translates into measurable increases in NO biomarkers (plasma NOx). The review highlighted that older adults and populations with metabolic dysfunction — who tend to have lower baseline NO production — show the greatest clinical responses to supplementation. This forms the biological rationale for targeting citrulline supplementation toward people with pre-hypertension, diabetes, or age-related vascular decline rather than healthy young adults. The review also identified gaps in long-term supplementation studies and in understanding optimal dose-response relationships.

Blood Pressure Meta-Analysis: Barkhidarian et al. 2019

Barkhidarian et al. (PMID 30788274) conducted a systematic review and meta-analysis of randomized controlled trials examining L-citrulline supplementation and blood pressure. Eight trials with ten datasets met inclusion criteria. The pooled analysis found a significant reduction in systolic blood pressure (mean difference: −4.10 mmHg; 95% CI: −7.94 to −0.26; p = 0.037). Diastolic blood pressure showed a non-significant trend toward reduction overall, but a significant effect emerged in the subgroup of trials using doses of 6 g/day or higher. The magnitude of systolic reduction — approximately 4 mmHg — is clinically meaningful: population-level reductions of this size correspond to reduced rates of stroke and coronary heart disease. The trials included in the meta-analysis varied in population (healthy adults, older adults with obesity, postmenopausal women, athletes), duration (1–8 weeks), and dose (3–9 g/day), which introduces heterogeneity but also suggests the effect generalizes across different groups.

Vascular Function and Exercise: Figueroa et al. 2017

The 2017 review by Figueroa et al. (PMID 27749691), one of the most cited researchers in the citrulline literature, examined both vascular function and exercise performance outcomes from citrulline and watermelon supplementation studies. The review confirmed that citrulline supplementation reduces aortic blood pressure and arterial stiffness — key markers of cardiovascular aging — through NO-mediated vasodilation and reduced wave reflection. In exercise contexts, citrulline improves blood flow to active muscle, reduces the oxygen cost of submaximal exercise, and decreases post-exercise muscle soreness. The review noted that watermelon-derived citrulline behaves identically to synthetic citrulline at equivalent doses, suggesting the food matrix does not impair bioavailability. This has practical implications for whole-food enthusiasts who prefer to get nutrients from sources rather than supplements — consuming roughly 500 g of watermelon per day would provide approximately 1–1.5 g of citrulline, while clinically effective doses range from 3–8 g, making supplementation more practical for therapeutic goals.

Exercise Performance Mechanisms: Bailey et al. 2015

The randomized crossover study by Bailey et al. (PMID 26023227), published in the Journal of Applied Physiology, is one of the most mechanistically rigorous citrulline exercise trials. Ten healthy men completed moderate- and severe-intensity cycling on days 6 and 7 of separate 7-day supplementation periods with placebo, L-arginine (6 g/day), and L-citrulline (6 g/day). Key findings: citrulline lowered the VO2 mean response time during severe-intensity exercise from 59 ± 8 seconds (placebo) to 53 ± 5 seconds — indicating faster oxygen uptake kinetics and more efficient aerobic metabolism. Time to exhaustion and total work completed also improved significantly with citrulline. Notably, arginine at the same dose produced no significant benefit on any exercise measure, directly demonstrating that the efficacy advantage of citrulline is rooted in its superior bioavailability. Blood pressure was also lower after the citrulline period. This study provided strong mechanistic evidence linking citrulline's renal arginine conversion pathway to real-world performance outcomes.

Diabetes and Nitric Oxide: Shatanawi et al. 2020

The clinical study by Shatanawi et al. (PMID 33414716), published in Frontiers in Pharmacology, enrolled 25 patients with established type 2 diabetes who received 2,000 mg/day of L-citrulline for one month. Plasma NO levels increased by 38% from baseline, while arginase activity decreased by 21%. This is a mechanistically important finding: in diabetes, chronic low-grade inflammation and oxidative stress upregulate arginase, which degrades arginine before it can be used for NO synthesis — a process called "arginine uncoupling" or "NOS uncoupling." By reducing arginase activity, citrulline shifts the competitive balance back toward NO production. The study did not assess cardiovascular outcomes directly, but the changes in NO biomarkers are consistent with improved endothelial function, which in turn is associated with reduced risk of the macrovascular complications (heart disease, stroke) that are leading causes of morbidity in type 2 diabetes.

Overall Evidence Assessment

The citrulline evidence base is solid for blood pressure reduction in hypertensive/pre-hypertensive populations and for acute exercise performance enhancement. The mechanistic picture — citrulline → renal arginine conversion → NO synthesis → vasodilation — is well-established and explains both sets of outcomes within a single coherent framework. Evidence is more preliminary for long-term cardiovascular outcomes, erectile function, and metabolic health, though the mechanistic rationale is sound. Key limitations across the literature include relatively short study durations (most trials are 1–8 weeks), small sample sizes, and heterogeneous populations. Citrulline has an excellent safety profile, and the availability of watermelon as a natural food source adds a real-food option for those who prefer dietary over supplemental approaches — though therapeutic doses are more practically achieved through supplements.

References

l-Citrulline Supplementation: Impact on Cardiometabolic HealthAllerton TD, Proctor DN, Stephens JM, Dugas TR, Spielmann G, Irving BA. Nutrients, 2018. PubMed 30029482 →
Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysisBarkhidarian B, Khorshidi M, Shab-Bidar S, Hashemi B. Avicenna Journal of Phytomedicine, 2019. PubMed 30788274 →
Influence of L-citrulline and watermelon supplementation on vascular function and exercise performanceFigueroa A, Wong A, Jaime SJ, Gonzales JU. Current Opinion in Clinical Nutrition and Metabolic Care, 2017. PubMed 27749691 →
l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humansBailey SJ, Blackwell JR, Lord T, Vanhatalo A, Winyard PG, Jones AM. Journal of Applied Physiology, 2015. PubMed 26023227 →
L-Citrulline Supplementation Increases Plasma Nitric Oxide Levels and Reduces Arginase Activity in Patients With Type 2 DiabetesShatanawi A, Momani MS, Al-Aqtash R, Hamdan MH, Gharaibeh MN. Frontiers in Pharmacology, 2020. PubMed 33414716 →