L-Citrulline
An amino acid that converts to arginine in the kidney more efficiently than arginine itself, increasing nitric oxide production. Studied for cardiovascular health and exercise performance.
What is L-Citrulline?
L-Citrulline is a non-essential alpha-amino acid named after citrullus (watermelon), from which it was first isolated in 1930. Unlike most amino acids, citrulline is not incorporated into proteins. Its primary metabolic role is as an intermediate in the urea cycle and as a highly efficient precursor to L-arginine, which is subsequently converted to nitric oxide (NO) by nitric oxide synthase (NOS). Oral citrulline raises plasma arginine levels more effectively than oral arginine itself due to differences in first-pass metabolism.
Known Health Benefits
How It Works
L-Citrulline's mechanisms center on the nitric oxide pathway and the urea cycle. After oral ingestion, citrulline bypasses hepatic first-pass metabolism (unlike arginine, which is heavily catabolized by hepatic arginase) and is transported to the kidneys, where the enzyme argininosuccinate synthase converts it to argininosuccinate, which is then cleaved by argininosuccinate lyase to yield L-arginine. This renal conversion makes citrulline the most effective oral method of raising systemic arginine levels. The resulting arginine serves as the substrate for endothelial nitric oxide synthase (eNOS), producing nitric oxide — a potent vasodilator that relaxes vascular smooth muscle, reduces peripheral resistance, and lowers blood pressure. Enhanced NO production improves blood flow to skeletal muscles during exercise, supporting oxygen delivery, nutrient transport, and waste removal. In the urea cycle, citrulline participates in ammonia detoxification, converting toxic ammonia to urea for renal excretion, which may contribute to delayed exercise fatigue. Citrulline malate (citrulline bonded with malic acid) provides the additional benefit of malate's role in the Krebs cycle, potentially enhancing aerobic ATP production. Citrulline also stimulates muscle protein synthesis through mTORC1 signaling and may reduce muscle protein catabolism during catabolic states.
What Research Says
L-Citrulline has a growing evidence base in cardiovascular and exercise physiology. Allerton et al. (2018) published a comprehensive review in Nutrients examining citrulline's cardiometabolic effects, concluding that citrulline supplementation consistently lowers blood pressure (systolic by 4–8 mmHg in hypertensive individuals), improves endothelial function, and may benefit heart failure patients through enhanced cardiac output. Figueroa et al. (2010) demonstrated in a randomized controlled trial that oral L-citrulline (6 g/day for 4 weeks) significantly attenuated blood pressure and aortic hemodynamic responses to the cold pressor test in young men. For exercise performance, Rhim et al. (2020) conducted a systematic review and meta-analysis showing that citrulline supplementation reduced perceived exertion, decreased muscle soreness, and lowered blood lactate levels during high-intensity exercise, though effects on time-to-exhaustion were variable. Bailey et al. (2015) demonstrated that L-citrulline supplementation improved oxygen uptake kinetics during severe-intensity exercise, suggesting enhanced mitochondrial efficiency. Citrulline malate has been studied specifically for resistance exercise: Pérez-Guisado and Jakeman (2010) found that 8 g of citrulline malate before resistance exercise increased the number of repetitions performed and reduced muscle soreness by 40% at 24 and 48 hours post-exercise.
Active Compounds
L-citrulline, citrulline malate
Forms & Bioavailability
L-Citrulline has excellent oral bioavailability, with approximately 80% of ingested citrulline reaching systemic circulation. Unlike arginine, citrulline largely bypasses hepatic first-pass metabolism, resulting in sustained elevated plasma arginine levels. Peak plasma arginine levels from citrulline supplementation occur 1–2 hours after ingestion and remain elevated for 6–8 hours, providing a sustained NO-boosting effect superior to direct arginine supplementation.
Dosage Guidance
| Use Case | Dosage |
|---|---|
| Blood pressure support | 3–6 g L-citrulline daily |
| Endurance exercise performance | 3–6 g L-citrulline |
| Resistance training performance | 6–8 g citrulline malate |
| Erectile function support | 1.5–3 g L-citrulline daily |
Always consult a healthcare provider for personalized dosing.
Natural Food Sources
- Watermelon (richest natural food source — rind contains the most)
- Watermelon rind
- Bitter melon
- Cucumbers (small amounts)
- Squash and pumpkin
- Chickpeas (small amounts)
Potential Side Effects
Generally well tolerated; mild GI effects at high doses
Who Should Avoid It
- Concurrent use with PDE5 inhibitors (sildenafil, tadalafil) — additive vasodilation and hypotension risk; requires physician guidance
- Concurrent use with nitrate medications (nitroglycerin) — dangerous blood pressure drops
- Hypotension or orthostatic hypotension
- Citrullinemia (rare urea cycle disorder — citrulline cannot be properly metabolized)
- Caution with antihypertensive medications (additive blood pressure lowering)
Pregnancy & Lactation
L-Citrulline is a natural amino acid present in watermelon and other foods. Some research has explored citrulline's potential to improve uterine blood flow during pregnancy, but safety data for supplemental doses in pregnant or lactating women is insufficient for routine recommendation. Consult a healthcare provider before supplementation.
Known Drug Interactions
May interact with blood pressure medications and nitrate drugs (e.g., sildenafil)
Evidence Classification
Supported by cohort studies, case-control studies, or multiple observational studies with consistent findings.
Frequently Asked Questions
Why is citrulline better than arginine for raising nitric oxide?
Oral arginine is extensively metabolized by the enzyme arginase in the liver and gut during first-pass metabolism, with only about 40% reaching systemic circulation. Citrulline bypasses hepatic metabolism and is converted to arginine in the kidneys, resulting in higher and more sustained plasma arginine levels. Studies show that 3 g of citrulline raises plasma arginine as effectively as 6–9 g of direct arginine supplementation.
What is the difference between L-citrulline and citrulline malate?
L-citrulline is the pure amino acid. Citrulline malate combines L-citrulline with malic acid (typically in a 2:1 ratio). Malic acid is a Krebs cycle intermediate that may enhance aerobic energy production. Citrulline malate is more commonly used in exercise/pre-workout contexts, while pure L-citrulline is often preferred for cardiovascular support.
Can I get enough citrulline from eating watermelon?
Watermelon contains approximately 1–2 g of citrulline per kilogram of flesh (and more in the rind). To reach a therapeutic dose of 3–6 g, you would need to consume 2–4 kg of watermelon flesh daily. Supplementation is far more practical for achieving clinically effective doses.
Does citrulline help with erectile dysfunction?
Preliminary research suggests L-citrulline (1.5 g/day) improved erection hardness in men with mild erectile dysfunction in a small pilot study. The mechanism involves increased nitric oxide-mediated penile blood flow. Effects are milder than PDE5 inhibitors but may complement them. Always consult a physician, especially if using ED medications.
How long does it take for citrulline to work?
For acute exercise performance, citrulline begins raising plasma arginine levels within 1 hour, with peak effects at 1–2 hours. For blood pressure benefits, consistent daily supplementation for 4–7 days produces measurable reductions, with optimal effects at 4+ weeks. Single-dose pre-exercise use provides same-day benefits.
Is citrulline safe with blood pressure medications?
Citrulline has blood pressure-lowering effects through enhanced nitric oxide production, which may be additive with antihypertensive medications. While this can be beneficial, it requires monitoring to avoid excessive blood pressure reduction. Always inform your physician about citrulline supplementation if you take blood pressure medications.
References
- L-Citrulline Supplementation: Impact on Cardiometabolic Health. Allerton TD, Proctor DN, Stephens JM, Dugas TR, Spielmann G, Irving BA. Nutrients (2018)View study
- Effect of citrulline on post-exercise rating of perceived exertion, muscle soreness, and blood lactate levels: A systematic review and meta-analysis. Rhim HC, Kim SJ, Park J, Jang KM. Journal of Sport and Health Science (2020)View study
- L-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. Bailey SJ, Blackwell JR, Lord T, Vanhatalo A, Winyard PG, Jones AM. Journal of Applied Physiology (2015)View study
- Oral L-citrulline supplementation attenuates blood pressure response to cold pressor test in young men. Figueroa A, Trivino JA, Sanchez-Gonzalez MA, Vicil F. American Journal of Hypertension (2010)View study
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This entry is for educational purposes only. It is not medical advice. Always consult a qualified healthcare provider before starting, stopping, or changing any supplement regimen, especially if you take medications or have health conditions.