L-Citrulline
L-Citrulline is a naturally occurring amino acid that supports nitric oxide production, helping to improve blood flow, enhance exercise performance, and reduce muscle fatigue. It is found in small amounts in foods such as watermelon (its richest natural source), cucumbers, and squash. In supplements, L-citrulline is typically produced through fermentation processes to ensure purity and potency. It is often included in pre-workout formulas or taken on its own to support cardiovascular health and athletic performance.
Benefits
Improved Exercise Performance
L-Citrulline increases nitric oxide production, which enhances blood flow, oxygen delivery, and nutrient uptake in muscles. This may boost endurance, reduce fatigue, and improve performance during high-intensity exercise, particularly in resistance training and aerobic activities.
Enhanced Muscle Recovery
By reducing ammonia buildup and muscle soreness, L-Citrulline may speed up recovery post-exercise, allowing for more consistent training.
Cardiovascular Health
L-Citrulline may lower blood pressure and improve arterial function by promoting vasodilation. Studies suggest it benefits individuals with hypertension or stiff arteries, supporting heart health.
Erectile Dysfunction (ED)
By boosting nitric oxide and blood flow, L-Citrulline may improve mild-to-moderate ED. Some studies show it’s as effective than a placebo, though more research is needed.
Immune System Support
Preliminary evidence suggests L-Citrulline may enhance immune function and reduce inflammation, potentially aiding overall health, but more studies are needed.
Potential Muscle Growth
L-Citrulline may indirectly support muscle protein synthesis by improving nutrient delivery and reducing fatigue, though evidence is less direct compared to other benefits.
Mechanism of Action
Nitric Oxide (NO) Production
L-Citrulline is converted to L-arginine in the kidneys, which is then used by endothelial nitric oxide synthase (eNOS) to produce NO. This promotes vasodilation, improving blood flow to muscles, heart, and other tissues.
Ammonia Detoxification
L-Citrulline participates in the urea cycle, clearing ammonia (a fatigue-inducing byproduct) from the body, which enhances exercise endurance and recovery.
Antioxidant Effects
By increasing NO and improving blood flow, L-Citrulline reduces oxidative stress and supports nutrient delivery to tissues, aiding muscle repair and cardiovascular health.
Clinical Trials
Oral L-Citrulline Supplementation Enhances Cycling Time Trial Performance in Healthy Trained Men: Double-Blind Randomized Placebo-Controlled Study
Study: This RCT (Suzuki et al., 2016, NCT02221843) involved 22 trained male cyclists in a double-blind, placebo-controlled, two-way crossover design. Participants received 2.4 g/day L-citrulline or placebo for 7 days, with an additional 2.4 g dose 1 hour before a 4-km cycling time trial on day 8. Primary outcomes were time to complete the trial and power output/VO2 ratio (PO/VO2). Secondary outcomes included plasma L-arginine, nitrite/nitrate (NOx), and visual analog scale (VAS) scores for fatigue and concentration.
Findings: L-citrulline significantly reduced completion time by 1.5% (p<0.05) and improved PO/VO2 compared to placebo. Plasma L-arginine levels increased significantly (p<0.05), but NOx levels did not, possibly due to insensitive measurement timing or assay (colorimetric vs. chemiluminescence). VAS scores showed reduced muscle fatigue and improved concentration post-exercise (p<0.05). No adverse events were reported. The study supports L-citrulline’s ergogenic effects at low doses (2.4 g/day) in trained athletes, likely via NO-mediated blood flow improvements.
Link: Journal of the International Society of Sports Nutrition
Effect of L-Citrulline Supplementation on Blood Pressure: A Systematic Review and Meta-Analysis of Clinical Trials
Study: This meta-analysis (Mirenayat et al., 2018) included 8 RCTs (n=12–34 per study) through November 2017, evaluating L-citrulline (3–10 g/day, via L-citrulline or watermelon extract) on blood pressure (BP) in normotensive, pre-hypertensive, and hypertensive adults. Outcomes were systolic BP (SBP) and diastolic BP (DBP), pooled using random-effects models. Subgroup analyses assessed dose (<6 g/day vs. ≥6 g/day) and duration (<4 weeks vs. ≥4 weeks).
Findings: L-citrulline reduced SBP by 4.1–7.5 mmHg (p<0.05) across studies, with significant DBP reductions (2.08–3.77 mmHg, p<0.05) only at doses ≥6 g/day. No significant heterogeneity was found, and results were robust in sensitivity analyses. No serious adverse events were reported. The study suggests L-citrulline may lower BP, particularly in pre-hypertensive/hypertensive individuals, but larger trials are needed to confirm optimal dosing and long-term effects.
Link: Current Hypertension Reports
Enteral Citrulline Supplementation Versus Placebo on SOFA Score on Day 7 in Mechanically Ventilated Critically Ill Patients: The IMMUNOCITRE Trial
Study: This multicenter RCT (Wibault et al., 2023, NCT02864017) enrolled 120 mechanically ventilated ICU patients without sepsis or septic shock, randomized to receive enteral L-citrulline (10 g/day) or placebo for 5 days. The primary outcome was the Sequential Organ Failure Assessment (SOFA) score on day 7. Secondary outcomes included ventilator-free days, lipid profile, hs-CRP, fasting blood sugar (FBS), and lactate dehydrogenase (LDH) levels.
Findings: L-citrulline did not significantly reduce SOFA score on day 7 compared to placebo (p>0.05), despite increasing plasma L-arginine levels (p<0.05). It reduced FBS, LDL-C, TC, and hs-CRP (p<0.05), increased LDH levels (p<0.05), and improved ventilator-free days and SOFA score in secondary analyses. No adverse events were reported. The study suggests potential benefits for metabolic and inflammatory outcomes in ICU patients but no primary effect on organ dysfunction, warranting larger trials.
Link: Critical Care
Effect of Combination L-Citrulline and Metformin Treatment on Motor Function in Patients with Duchenne Muscular Dystrophy: A Randomized Clinical Trial
Study: This RCT (Hafner et al., 2019) involved 47 boys with Duchenne muscular dystrophy (DMD), randomized to receive L-citrulline (2.5 g/day) + metformin (250 mg/day), metformin alone, or standard care for 26 weeks. Outcomes included motor function (Motor Function Measure [MFM] scale), timed function tests, and safety parameters.
Findings: The L-citrulline + metformin group showed stable MFM scores, while the standard care group declined significantly (p=0.03). Timed function tests (e.g., 10-m walk) improved in the combination group (p<0.05). No serious adverse events were reported, though mild gastrointestinal upset occurred in 10% of the combination group. The study suggests L-citrulline + metformin may stabilize motor function in DMD, potentially via NO-mediated vascular effects, but larger trials are needed.
Link: JAMA Network Open
Oral L-Citrulline Supplementation Improves Erection Hardness in Men with Mild Erectile Dysfunction
Study: This RCT (Cormio et al., 2011) enrolled 24 men with mild ED (Erection Hardness Score [EHS] 3), randomized to receive L-citrulline (1.5 g/day) or placebo for 1 month. Outcomes included EHS, International Index of Erectile Function (IIEF) scores, and plasma L-arginine levels.
Findings: The L-citrulline group showed an 8.3% improvement in EHS (50% achieving EHS 4 vs. 8.3% in placebo, p<0.05) and improved IIEF scores (p<0.05). Plasma L-arginine levels increased significantly (p<0.01). No adverse events were reported. The study supports L-citrulline for mild ED, likely via NO-mediated vasodilation, but notes it’s less effective than PDE5 inhibitors (e.g., Viagra).
Link: Urology
Potential Side Effects
Gastrointestinal Issues
Mild side effects include nausea, stomach discomfort, bloating, or diarrhea, particularly at higher doses (e.g., above 10–12 grams/day) or when taken on an empty stomach.
Low Blood Pressure
L-Citrulline increases nitric oxide production, which promotes vasodilation and may lower blood pressure. This can cause dizziness, lightheadedness, or fainting in individuals with already low blood pressure or those taking antihypertensive medications.
Headaches
Some users report mild headaches, possibly due to changes in blood flow or blood pressure, though this is uncommon.
Allergic Reactions
Rare allergic reactions, such as rash, itching, or swelling, may occur, particularly in individuals sensitive to L-Citrulline or its sources (e.g., watermelon-derived supplements). Severe allergic reactions (e.g., anaphylaxis) are extremely rare but possible.