L-Citrulline
Overview
L-citrulline is a non-essential amino acid that converts to L-arginine in the kidneys, subsequently producing nitric oxide (NO) - a critical signaling molecule that dilates blood vessels and improves circulation.
Interestingly, citrulline supplementation raises blood arginine and NO levels more effectively than direct arginine supplementation. Arginine undergoes significant first-pass metabolism in the liver and intestines, while citrulline bypass es this degradation and converts to arginine systemically.
Primary applications include exercise performance (particularly resistance training), blood pressure reduction, erectile function, and cardiovascular health. Evidence quality varies across these uses.
Citrulline exists in two supplemental forms: L-citrulline and citrulline malate (citrulline bound to malic acid). Both work, though dosing and specific benefits differ slightly.
Safety is excellent with minimal side effects even at high doses used in exercise research.
What it means
L-Citrulline converts to arginine in your body, which then makes nitric oxide (NO) - dilates blood vessels and improves blood flow. Surprisingly, taking citrulline raises arginine and NO better than taking arginine directly (arginine gets destroyed in the gut/liver first). Used for exercise performance, lowering blood pressure, erectile function, and heart health. Comes as L-citrulline or citrulline malate (with malic acid) - both work. Very safe with minimal side effects.
Mechanisms of Action
Nitric oxide production occurs when citrulline converts to arginine via the citrulline-NO cycle. Arginine is then substrate for nitric oxide synthase (NOS) enzymes, producing NO and regenerating citrulline, completing the cycle.
NO's vascular effects include smooth muscle relaxation in blood vessel walls, causing vasodilation (widening). This improves blood flow, reduces blood pressure, and enhances nutrient/oxygen delivery to tissues including working muscles.
Ammonia clearance benefits from citrulline's role in the urea cycle. During intense exercise, ammonia accumulates as a fatigue-inducing metabolite. Citrulline supports ammonia conversion to urea for excretion, potentially delaying fatigue.
ATP production may be supported by malate (in citrulline malate). Malate is an intermediate in the Krebs cycle, potentially enhancing aerobic energy production. This is specific to citrulline malate, not L-citrulline alone.
Exercise-induced muscle damage and soreness reduction might occur through improved blood flow facilitating nutrient delivery and waste removal, plus potential anti-inflammatory effects.
What it means
Citrulline converts to arginine, which makes nitric oxide (NO). NO relaxes blood vessel walls, widening them - improving blood flow, lowering blood pressure, delivering more oxygen/nutrients to muscles. It helps clear ammonia (fatigue-causing waste product from exercise) by supporting the urea cycle. Citrulline malate includes malic acid which helps energy production in the Krebs cycle (citrulline alone doesn't have this). Better blood flow might also reduce muscle damage and soreness.
Effects and Benefits
Exercise Performance
Resistance training performance shows the most consistent benefits. Multiple studies demonstrate increased repetitions to failure, particularly in multi-set protocols where fatigue accumulates.
Research by Pérez-Guisado and Jakeman (2010) found citrulline malate (8 grams) increased bench press repetitions by about 53 percent and reduced muscle soreness by 40 percent at 24 and 48 hours post-exercise.
The effect appears strongest in exercises performed later in a workout when fatigue is highest. First-set performance shows minimal improvement, but subsequent sets benefit more noticeably.
Endurance performance benefits are less consistent. Some studies show improved time to exhaustion or power output; others find no effect. Benefits may be more apparent in submaximal endurance efforts.
Muscle soreness reduction appears reliably across studies, with 20 to 40 percent reductions in perceived soreness 24 to 72 hours post-exercise.
Blood Pressure
Modest blood pressure reductions occur with citrulline supplementation. Meta-analyses show systolic blood pressure reductions of 4 to 8 mmHg and diastolic reductions of 2 to 4 mmHg with 6 to 18 grams daily.
Effects appear strongest in prehypertensive and hypertensive individuals. Normotensive individuals show smaller or absent reductions.
Erectile Function
Small studies suggest citrulline improves erectile function in mild erectile dysfunction. A study by Cormio et al. (2011) found 1.5 grams daily L-citrulline improved erection hardness in men with mild ED.
The mechanism involves NO-mediated vasodilation in penile tissue. Effects are modest compared to prescription medications (PDE5 inhibitors like sildenafil) but citrulline offers a low-side-effect alternative for mild cases.
Cardiovascular Health
Endothelial function (blood vessel health) improves with citrulline supplementation in some studies. Flow-mediated dilation, a marker of endothelial function, increases with chronic citrulline use.
Arterial stiffness may be reduced, particularly in individuals with compromised vascular health.
What it means
For resistance training, citrulline increases reps to failure (by ~50% in some studies), especially in later sets when fatigued. Muscle soreness reduces by 20-40% in days after training. Endurance benefits are inconsistent - sometimes helps, sometimes doesn't. Blood pressure drops modestly (4-8 mmHg systolic, 2-4 mmHg diastolic) at 6-18 grams daily, strongest effect if you have high or high-normal BP. Erectile function improves in mild ED at 1.5 grams daily - works through better blood flow. Effects are modest compared to Viagra but way fewer side effects. Blood vessel health (endothelial function) improves with chronic use.
Dosing and Timing
Effective doses range from 3 to 10 grams for acute exercise benefits, typically taken 60 to 90 minutes before training to allow for conversion to arginine and NO production.
For chronic blood pressure and cardiovascular benefits, 6 to 18 grams daily split into two doses (morning and evening) is common in research.
For erectile function, 1.5 to 3 grams daily shows benefits in studies, though response may require several weeks.
L-Citrulline vs Citrulline Malate
**L-citrulline** is pure citrulline. Typical doses are 3 to 6 grams for exercise or 6 to 9 grams for cardiovascular benefits.
**Citrulline malate** is citrulline bound to malic acid in a ratio typically 2:1 or 1:1 (citrulline:malate). An 8-gram dose of 2:1 citrulline malate provides roughly 5.3 grams citrulline.
Citrulline malate may offer additional benefits through malate's role in energy production. Most exercise research uses citrulline malate specifically.
For blood pressure and cardiovascular health, both forms work. L-citrulline allows more precise citrulline dosing since you're not calculating the malate content.
Effects develop gradually for cardiovascular benefits over weeks. Acute exercise effects occur within hours of dosing.
What it means
For exercise, use 6-8 grams citrulline malate (or 3-6 grams L-citrulline) 60-90 minutes before training. For blood pressure/heart health, use 6-18 grams daily split into 2 doses. For erectile function, 1.5-3 grams daily over weeks. L-citrulline vs citrulline malate: Citrulline malate includes malic acid (helps energy production) - most exercise studies use this. An 8-gram dose of 2:1 citrulline malate gives ~5.3 grams actual citrulline. L-citrulline is pure, easier to dose precisely. Both work; citrulline malate might be better for exercise. Cardiovascular benefits take weeks; exercise effects happen within hours.
Safety and Interactions
General Safety
Citrulline is very safe at typical doses (up to 18 grams daily in research). Side effects are rare and mild.
Gastrointestinal upset (stomach discomfort, mild diarrhea) can occur at high doses, particularly above 10 grams taken at once. Splitting doses reduces this.
No serious adverse effects are documented in research even with chronic high-dose use over months.
Medication Interactions
Nitrates and PDE5 inhibitors: Citrulline enhances NO production. Combining with nitrate medications (nitroglycerin for angina) or PDE5 inhibitors (sildenafil, tadalafil for erectile dysfunction) could theoretically cause excessive vasodilation and dangerous blood pressure drops. Use citrulline cautiously or avoid if taking these medications.
Antihypertensive medications: Citrulline's blood pressure-lowering effects might add to blood pressure medications. Monitor blood pressure when starting citrulline if on antihypertensives.
No other significant drug interactions are well-documented.
Population Considerations
Pregnancy and breastfeeding: Safety data is limited. While citrulline is a normal metabolite, supplemental doses during pregnancy or lactation lack adequate study.
Children: Safety and efficacy in children are unstudied. Use should be limited to medical supervision.
What it means
Citrulline is very safe - even 18 grams daily shows minimal problems. Occasional stomach upset at high single doses (above 10 grams) - split doses if this happens. Be careful combining with nitrate medications (nitroglycerin) or erectile dysfunction drugs (Viagra, Cialis) - could cause dangerous blood pressure drops. Blood pressure meds might have additive BP-lowering - monitor when starting. Limited safety data in pregnancy/breastfeeding and children - use under medical guidance only.
Stacking and Combinations
With Beta-Alanine
This is an extremely common pre-workout combination. Beta-alanine buffers muscle acidity while citrulline improves blood flow and reduces ammonia. Different mechanisms create complementary performance benefits.
With Nitrate Sources (Beetroot)
Both citrulline and dietary nitrates (from beetroot, arugula, spinach) increase NO through different pathways. Combining might offer additive vasodilation benefits, though research on this specific combination is limited.
With Creatine
Creatine supports ATP-PC energy system while citrulline improves blood flow and reduces ammonia. Both are well-established for performance, and combining addresses different limiting factors.
With Arginine
This combination is redundant since citrulline converts to arginine more effectively than direct arginine supplementation. Use citrulline alone rather than combining them.
What it means
Citrulline pairs excellently with beta-alanine - extremely common pre-workout combo addressing different performance limiters (blood flow/ammonia vs acid buffering). Combining with nitrate sources like beetroot might boost NO further through different pathways - makes sense but limited research. Stacking with creatine addresses different energy systems and performance factors - very common and logical. Don't combine with arginine - redundant since citrulline converts to arginine better than taking arginine directly.
Research Strength and Limitations
Citrulline exercise research is moderate quality with consistent findings for resistance training performance and muscle soreness. Most positive studies use citrulline malate specifically.
Endurance performance research is more mixed with variable results across studies. Benefits may depend on exercise intensity, duration, and population studied.
Blood pressure research shows consistent modest reductions across multiple studies and meta-analyses. Effects are well-replicated though not dramatic.
Erectile function research is limited to small studies but findings are consistent. Larger trials would strengthen conclusions.
Mechanisms (NO production, ammonia clearance) are well-understood from basic physiology. Citrulline's superiority over arginine for raising blood arginine is well-established.
Long-term safety is supported by chronic supplementation trials lasting months with good tolerability.
What it means
Resistance training research is solid - consistent benefits across studies, though most use citrulline malate specifically. Endurance research is mixed - sometimes works, sometimes doesn't. Blood pressure reduction is well-replicated across studies though effects are modest. Erectile function studies are small but consistent. Mechanisms are well-understood from physiology - we know why citrulline works and why it's better than arginine. Long-term safety looks good - months-long studies show good tolerability.
Practical Considerations
Citrulline makes most sense for resistance training performance, particularly for those doing high-volume training where fatigue accumulates across sets. Benefits for first-set performance are minimal but subsequent sets improve.
For blood pressure management, citrulline offers a safe adjunct to lifestyle modifications and medications, though effects are modest. Don't rely on it as sole blood pressure treatment.
For erectile function, citrulline provides a low-side-effect option for mild ED. For moderate to severe ED, prescription medications are more effective.
Product choice matters. Citrulline malate is backed by most exercise research. Calculate actual citrulline content when dosing citrulline malate (typically 56 to 67 percent citrulline by weight depending on ratio).
Cost is moderate. Citrulline is more expensive than creatine but still reasonable for daily use.
Watermelon is a natural citrulline source containing about 1.5 grams per kilogram. However, consuming enough watermelon to match supplemental doses (6 to 8 grams) is impractical and provides excessive sugar.
Timing for exercise is important - take 60 to 90 minutes before training to allow conversion to arginine and NO production. For cardiovascular benefits, split daily doses to maintain more stable levels.
What it means
Use citrulline mainly for resistance training (high-volume workouts benefit most - later sets improve more than first). For blood pressure, it's a modest adjunct to other treatments, not a replacement. For erectile dysfunction, it's good for mild cases (prescription drugs better for moderate/severe). Citrulline malate is what most studies use - calculate actual citrulline content (56-67% depending on ratio). It's moderately priced. Watermelon has citrulline but you'd need to eat tons (too much sugar). Dose 60-90 minutes before training; split daily doses for cardiovascular use.
References
Cormio L, De Siati M, Lorusso F, et al. Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology. 2011;77(1):119-122.
Figueroa A, Sanchez-Gonzalez MA, Perkins-Veazie PM, Arjmandi BH. Effects of watermelon supplementation on aortic blood pressure and wave reflection in individuals with prehypertension: a pilot study. Am J Hypertens. 2011;24(1):40-44.
Pérez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res. 2010;24(5):1215-1222.
Sureda A, Córdova A, Ferrer MD, Pérez G, Tur JA, Pons A. L-citrulline-malate influence over branched chain amino acid utilization during exercise. Eur J Appl Physiol. 2010;110(2):341-351.