IngredientsCitrulline is a non-essential amino acid generated from ornithine and carbamoyl phosphate in the urea cycle, or as a byproduct of arginine through nitric oxide synthase (NOS) catalysis. It exists in two forms: the naturally occurring isomer L-Citrulline and the less common but industrially applicable D-Citrulline. The systematic IUPAC chemical name for L-Citrulline is (S)-2-amino-5-(carbamoylamino)pentanoic acid, and its molecular formula is C6H13N3O3. In mammalian physiology, L-citrulline is a naturally occurring amino acid of the formula H2NC(O)NH(CH2)3CH(NH2)CO2H that functions in the detoxification of catabolic ammonia (urea production) and is a key element in the production of the vasodilator, nitric oxide.
Citrulline is a non-protein amino acid capable of forming peptide bonds but does not participate in protein synthesis. L-citrulline is a naturally occurring nonessential amino acid present in mammals and also in each living organism, but conditionally essential in stress and diseases.
Its name is derived from citrullus, the Latin name for watermelon. It was extracted in 1914 by Koga and Odake from watermelon and identified by Wada in 1930. More specifically, citrulline was first isolated from watermelon by the Japanese researchers Yotaro Koga and Ryo Odake in 1914 and further validated in 1930.
L-citrulline's main natural source is watermelon. The botanical species most associated with high citrulline content is Citrullus lanatus (watermelon) of the family Cucurbitaceae. In plants, citrulline is present at high levels in some Cucurbitaceae, especially the watermelon. Both the rind and flesh of watermelon contain citrulline at concentrations of 1–3 mg citrulline per gram of fresh tissue. Citrulline's role in watermelon is believed to be a protection against oxidative stress, especially during periods of drought.
Citrulline content varies markedly by fruit variety: yellow watermelon has the most, with 3.5 mg per gram for the flesh and 1.5 mg per gram for the rind. After yellow, orange watermelon is the second highest in L-citrulline content, at 1.8 mg/g for the flesh and 1.5 mg/g for the rind. Red watermelon, which is the most common type, has the least, with 1 mg for the flesh and 0.8 mg per gram for the rind. Given its close metabolic relationship with L-arginine, L-citrulline can be found in at least small amounts in almost any living organism.
L-citrulline is produced exclusively by enterocytes from glutamine. During the urea cycle, there is no release of citrulline into the circulation, and hepatocytes are unable to uptake citrulline from the circulation. Thus, citrulline synthesis in the liver is compartmentalized to the urea cycle and is independent of other metabolic pathways of citrulline. Typical circulating levels of citrulline in adults are 16–55 µmol/L. In children under 12 years of age, the levels are 16–32 µmol/L.
Commercial L-Citrulline reaches the supplement market through two main production routes: direct extraction from plant sources (historically watermelon) and — far more commonly today — microbial fermentation. A third route, chemical synthesis, exists but is rarely favored due to purity and other challenges.
In the supplement market, L-citrulline is available in several forms:
L-citrulline itself was not a recognized entity in traditional medicine; it is a modern biochemical isolate. However, its primary botanical vehicle — watermelon (Citrullus lanatus) — has millennia of recorded use. Earliest records of Citrullus lanatus cultivation date back over 4,000 years to the Nile Valley, where hieroglyphs depict watermelons in ancient Egyptian tombs alongside offerings to the gods.
Under Ayurvedic practice, both the sweet pulp and seeds are employed — pulp for its cooling, hydrating effects and seeds (often ground into a fine powder) for nourishment and diuretic support. The rind, less common in Western cuisine, is used in traditional pickles or candied forms, valued for its fibrous texture and mild bitterness.
Watermelon has been used to treat various ailments, such as cardiovascular diseases, aging-related ailments, obesity, diabetes, ulcers, and various types of cancers. The medicinal properties of watermelon are attributed to the presence of important phytochemicals with pharmaceutical values such as lycopene, citrulline, and other polyphenolic compounds.
For decades after the initial description, citrulline remained primarily a subject of academic biochemistry. Its role in the urea cycle was made clear through mid-century research, and preliminary studies in France during the 1970s hinted at potential therapeutic properties, including effects on fatigue and cognitive function, though these early trials lacked the rigor of modern clinical standards. It was not until the late 1990s and early 2000s — as sports nutrition science matured and researchers began exploring nitric oxide as a performance lever — that citrulline emerged from obscurity and into supplement formulations worldwide.
L-citrulline is a nonessential, non-coded alpha-amino acid that has a key role during the urea cycle in the liver. In the urea cycle, L-citrulline is synthesized from ornithine and metabolized by argininosuccinate synthetase. Citrulline is an end product of glutamine metabolism and a metabolite of arginine.
The most clinically significant mechanism of L-citrulline relates to its conversion to L-arginine and subsequent augmentation of nitric oxide (NO) synthesis. Orally ingested L-citrulline mainly leads to the biosynthesis of L-arginine. L-citrulline, released from the small intestine into the circulation, bypasses hepatic metabolism and is absorbed by the proximal tubular cells of the kidneys.
Citrulline is absorbed intact in the small intestine, enters systemic circulation, and is converted to L-arginine primarily in the kidneys via the sequential action of argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL). This conversion pathway — known as the citrulline-NO cycle — regenerates L-arginine for sustained nitric oxide production by endothelial nitric oxide synthase (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS).
Nitric oxide is a key signaling molecule that promotes vasodilation by activating soluble guanylyl cyclase and increasing cyclic GMP (cGMP), which relaxes vascular smooth muscle and allows more blood to flow through arteries.
Almost all ingested free arginine is cleared by the liver and does not reach the bloodstream. In contrast, citrulline is not cleared from portal circulation and is converted to L-arginine in the kidney, where it is then circulated to other organs in the body. Citrulline supplementation administered orally increases plasma arginine concentration and augments NO-dependent signaling in a dose-dependent manner.
L-citrulline is not acted on by arginase enzyme or first-pass extraction, but is converted to L-arginine by argininosuccinate lyase in the kidneys. Increased circulating L-arginine serves as a substrate for eNOS to produce nitric oxide and increase smooth muscle vasodilation.
Beyond the arginine–NO axis, research has identified several additional mechanisms:
Citrulline is a popular dietary supplement, primarily thought to exert ergogenic effects on exercise performance through the enhancement of nitric oxide synthesis and ammonia buffering. However, recent findings surrounding citrulline's effect on endurance performance have been inconsistent.
A systematic review and meta-analysis published in Nutrients (2022) assessed the effects of citrulline supplementation on aerobic exercise performance outcomes. The review covered multiple studies and analyzed outcomes including time-to-exhaustion, peak power output, and VO2 measures. L-citrulline or citrulline malate supplementation produced either positive or negative effects. Six out of ten trials found that taking L-citrulline or citrulline malate improved performance, by boosting repetitions, lowering rating of perceived exertion (RPE), or reducing muscular exhaustion.
A separate 2023 systematic review and meta-analysis in Journal of the International Society of Sports Nutrition specifically examined citrulline's effect on endurance performance in young healthy adults, noting the inconsistency of findings across trials.
A systematic review and meta-analysis published in PMC (2020) examined post-exercise outcomes specifically. The analysis included 13 eligible articles including a total of 206 participants. The most frequent dosage used in the studies was 8 g of citrulline malate. Citrulline supplementation significantly reduced RPE (n = 7, p = 0.03) and muscle soreness 24 hours after post-exercise (n = 7, p = 0.04); the effect on soreness at 48 hours did not reach significance (n = 6, p = 0.25).
One often-cited individual RCT (Pérez-Guisado et al., 2010) found that there was a noticeable increase in repetitions between the placebo and citrulline malate treatments. Moreover, at 24 and 48 hours after exercise, the muscle soreness score was significantly reduced in the citrulline malate trial compared to placebo, with an equivalent reduction of approximately 40% at each time point.
On the other hand, Esen et al. (2022) concluded that 8 days of either L-arginine or L-citrulline supplementation had no impact compared to placebo in terms of nitric oxide levels, 200- or 100-meter swimming time trials, or blood lactate levels in athletes.
A more recent direct-comparison RCT showed that among 43 healthy, resistance-trained men and women (average age 24), taking citrulline malate (5.3 g citrulline plus 2.7 g malate) 45 minutes before low-to-moderate-volume resistance training did not improve muscle strength or endurance compared to supplementation with the same dose (5.3 g) of pure L-citrulline without malate, and neither form showed improvement compared to placebo (Martin-Olmedo et al., Int J Sport Nutr Exerc Metab, 2024). Additionally, a systematic review concluded that the addition of malate to citrulline has not been demonstrated to enhance exercise performance (Gough et al., Eur J Appl Physiol, 2021).
Overall evidence strength for exercise: Small studies have found that taking L-citrulline supplements improved performance in aerobic exercise, specifically cycling and weightlifting. However, the National Institutes of Health (NIH) states that research in using L-citrulline to boost exercise performance is limited and conflicting. The evidence for reducing RPE and acute muscle soreness is somewhat more consistent, though still based on relatively small sample sizes.
Because citrulline is converted to arginine, which in turn may increase nitric oxide production and promote vasodilation, it has been evaluated for cardiovascular benefits. Evidence has been mixed.
Multiple meta-analyses have examined this question, with different methodologies and inclusion criteria producing different conclusions:
Supplementation with L-citrulline has shown promise as a blood pressure-lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. The included studies' sample sizes ranged between 12 and 34 subjects, with mean ages between 22 and 71 years. Dosage of L-citrulline supplementation varied from 3 to 9 g/day, and duration of the intervention ranged between 1 and 17 weeks.
Overall evidence strength for blood pressure: Results across meta-analyses are inconsistent, likely reflecting heterogeneity in study populations, doses, and durations. Effects appear more pronounced in individuals with elevated baseline blood pressure. Sample sizes across individual trials have generally been small, limiting conclusions.
L-arginine supplementation improves nitric oxide-mediated vasodilation and endothelial function; however, oral administration has been hampered by extensive presystemic metabolism. In contrast, L-citrulline escapes presystemic metabolism and is converted to L-arginine, thus setting the rationale for oral L-citrulline supplementation as a donor for the L-arginine/nitric oxide pathway of penile erection.
The primary human clinical study on this topic is a single-blind crossover trial published in Urology (2011). In this study, men with mild erectile dysfunction (erection hardness score of 3) received a placebo for 1 month and L-citrulline, 1.5 g/d, for another month. The erection hardness score, number of intercourses per month, treatment satisfaction, and adverse events were recorded. A total of 24 patients, mean age 56.5 ± 9.8 years, completed the study without adverse events. The preliminary clinical research showed that taking L-citrulline at 1.5 g per day for one month improved erections, moving from "mild erectile dysfunction" to "normal erectile function" in 50% of patients.
Overall evidence strength for erectile dysfunction: Extremely limited. Evidence rests primarily on a single small, single-blind, crossover study in 24 men with mild ED. Larger, double-blind, placebo-controlled RCTs are lacking.
Treatment recommendations for urea cycle disorders (UCDs) include supplementation with amino acids involved in the urea cycle — arginine and/or citrulline, depending on the enzyme deficiency — to maximize ammonia excretion through the urea cycle. A retrospective study of UCD patients treated with citrulline at a reference center since 1990 found that mean ammonia concentrations during treatment were 35.9 µmol/L with citrulline, compared to 49.8 µmol/L with arginine. Mean plasma arginine concentrations increased significantly from the beginning to the end of citrulline treatment periods (from 67.6 µmol/L to 84.9 µmol/L, P < 0.05).
A survey-based study from Japan of 43 UCD patients reported that L-citrulline effectively reduced ammonia levels, increased protein intake, and improved weight gain in UCD patients, concluding that L-citrulline should be considered a standard therapy in ornithine transcarbamylase deficiency (OTCD) and carbamoyl phosphate synthetase deficiency (CPSD) patients.
Overall evidence strength for UCDs: Moderate. Citrulline has an established clinical role in managing specific urea cycle enzyme deficiencies, with dosing practiced in specialist metabolic settings for decades.
Hemolysis-associated nitric oxide (NO) depletion plays a central role in the pathogenesis of vaso-occlusion in sickle cell disease (SCD). Citrulline is an effective NO booster, even during conditions of inflammation and acute arginase-induced arginine deficiency, characteristic of SCD.
An early Phase I dose-escalation study of IV citrulline in SCD patients found that the intravenous bolus infusion of 20 mg/kg of citrulline yielded a mean peak citrulline level of 259 µmol/L. All subjects had a significant rise in their arginine level within one hour of receiving the bolus, with a mean increment of 182%. Bolus intravenous citrulline was safe and well tolerated in patients with SCD but has a rapid clearance.
Overall evidence strength for sickle cell disease: Preliminary. Evidence from early-phase clinical studies is promising, but this research is at an early stage and has not yet been confirmed by large controlled trials.
Preliminary evidence is available for L-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible or older populations.
Preliminary data indicate that citrulline could be of value in sarcopenia in the elderly. It appears that citrulline is an anabolic pharmaconutrient that can be safely administered even in critically ill patients. Promising results in cardiovascular diseases and in disease-related malnutrition can now be considered sufficient to justify formal clinical exploration in these areas and in sarcopenia in general.
Additional studies are necessary to confirm the effect of citrulline supplementation in sarcopenia delay.
Overall evidence strength for sarcopenia: Preliminary; mostly small exploratory trials. Evidence is insufficient to support definitive recommendations at this time.
A 2025 systematic review and dose-response meta-analysis of 21 RCTs (published in PMC) assessed the impact of citrulline on anthropometric parameters. Twenty-one RCTs were included. Overall, citrulline supplementation had no substantial effects on body mass index (BMI), body weight, fat mass, waist circumference, body fat percentage, and fat-free mass.
Overall evidence strength for body composition: Available evidence does not support a significant effect of L-citrulline supplementation on body composition outcomes.
Plasma levels of L-citrulline are decreased on average by 60% in critically ill ICU patients; such decreases in non-ICU patients with short bowel syndrome reflect severe loss of enterocyte mass. Plasma citrulline concentration has therefore been studied as a biomarker of functional enterocyte mass. Potential therapeutic applications of L-citrulline include short bowel syndrome and protein-energy malnutrition in aging.
Overall evidence strength for intestinal failure: Plasma citrulline as a biomarker has been validated in several studies. Its use as a therapeutic supplement for intestinal failure remains under investigation.
The following dosages are drawn directly from published clinical studies and reviews. They are not recommendations.
Citrulline is generally recognized as safe (GRAS) for oral use. In contrast to arginine, citrulline at high doses (i.e., greater than 10 g in a single bolus) may induce gastrointestinal side effects, but citrulline is generally well tolerated. Generally safe, with some (but not all) studies reporting gastrointestinal symptoms as the main side effect. Theoretically, citrulline may interact with other agents that lower blood pressure.
Interactions exist — notably potential additive blood-pressure lowering when combined with antihypertensive drugs and nitrates, which could cause dangerously low blood pressure.
L-citrulline may interact with some prescription medications, such as medications for hypertension, cardiovascular disease, and erectile dysfunction. Medications for male sexual dysfunction (PDE5 inhibitors): this combination is rated as a major concern. L-citrulline might decrease blood pressure, and some medications for male sexual dysfunction can also decrease blood pressure.
The interaction of L-citrulline with other pharmaceutical drugs for the treatment of hypertension, atherosclerosis, insulin resistance, type 2 diabetes, and cardiovascular disease should be investigated, as some of these drugs have been shown to affect citrulline metabolism.
In one sickle cell disease pharmacokinetic study, one subject transiently dropped the diastolic blood pressure by >20% within 30 minutes of study drug administration, with no intervention needed. There were no other reported side effects.
There is not enough reliable scientific information to know if L-citrulline is safe to take during pregnancy or while breast-feeding.
The FDA has not reviewed L-citrulline for safety and effectiveness. Citrulline is generally recognized as safe (GRAS) for oral use.
The safety and efficacy of long-term L-citrulline supplementation requires further investigation. Most L-citrulline supplementation studies fail to report the plasma/serum concentrations that were achieved. The direct role of L-citrulline, outside of its function as a precursor of L-arginine, is still not well characterized.
Health conditions that L-citrulline may help support.
An 8-week uncontrolled human study in 22 patients with vasospastic angina given 800 mg/day L-citrulline found significant improvements in brachial artery flow-mediated dilation (FMD) at 4 and 8 weeks, along with reductions in plasma ADMA levels and oxidized LDL. A separate RCT showed that L-citrulline restores endothelial function via arginase inhibition and increased NO levels, a mechanism directly relevant to the vasospastic pathophysiology of angina.
L-Citrulline enhances antioxidant defense indirectly by restoring NO production, which competes with reactive oxygen species and reduces peroxynitrite formation. Both human and animal studies show citrulline reduces oxidative stress markers including ADMA, oxidized LDL, and MDA while supporting antioxidant enzymes. The Nrf2/HO-1 signaling pathway is identified as a direct mechanistic target in preclinical renal oxidative stress models.
L-Citrulline is a more bioavailable precursor to L-arginine and NO production in endothelial cells. A 2025 comprehensive review of 43 studies found L-citrulline superior to L-arginine in bioavailability and more effective at increasing plasma arginine, with improved endothelial-dependent vasodilation and moderate blood pressure reductions at doses ≥6 g/day.
L-Citrulline enhances arginine bioavailability and nitric oxide synthesis more effectively than L-arginine alone, improving blood flow and exercise performance. Multiple RCTs show it reduces muscle soreness and fatigue, and improves endurance and power output. NIH ODS includes it in its exercise/athletic performance fact sheet.
L-Citrulline is converted to L-arginine in the kidneys, increasing NO production more efficiently than direct L-arginine supplementation. A 2019 meta-analysis of RCTs confirmed significant brachial SBP reduction of −4.49 mmHg and DBP of −3.63 mmHg. It is studied as a nutraceutical for hypertension.
L-Citrulline supplementation has been tested in human trials for its effect on low-grade (meta-) inflammation, particularly in metabolic disease populations. A randomized double-blind trial in type 2 diabetic patients found that 3 g/day for 8 weeks significantly reduced fasting blood glucose, HbA1c, IL-6, and TLR-4 levels, though no significant inter-group difference in inflammatory markers was observed after adjustment for confounders. Animal and in vitro evidence consistently shows anti-inflammatory effects via NO-mediated suppression of oxidative stress and reactive oxygen species, but human clinical evidence remains limited and mixed.
L-citrulline is converted by the kidneys to L-arginine, bypassing first-pass hepatic metabolism and more effectively raising plasma arginine levels than L-arginine supplementation alone. A comprehensive review of 43 studies confirmed L-citrulline and L-arginine supplementation improves endothelial-dependent vasodilation and blood pressure at doses ≥6 g/day. L-citrulline demonstrates superior bioavailability to L-arginine for NO-mediated vascular effects.
L-Citrulline is a non-essential amino acid that is efficiently converted to L-arginine in the kidneys, raising plasma arginine levels more sustainably than direct L-arginine supplementation. A randomized, double-blind, placebo-controlled crossover pilot study (Sexual Medicine, 2018) showed L-citrulline combined with resveratrol improved erectile function in PDE5 inhibitor-using men. It is recognized as a nutraceutical for ED in multiple 2023 reviews.
L-Citrulline improves erectile function by boosting NO-mediated penile vasodilation, with small randomized trials demonstrating improvements in erection hardness and IIEF scores at doses of 1.5–3 g/day. The citrulline–arginine–NO pathway is also physiologically important in testicular and seminal plasma function, with animal studies showing improved sperm motility and density, though dedicated large human sperm-parameter trials are lacking.
NO production declines significantly with age, and L-Citrulline is the most bioavailable oral strategy to restore NO synthesis. Human studies show that citrulline ingestion stimulates de novo arginine synthesis in older adults—whose baseline NO synthesis is approximately 50% lower than in young adults—and clinical trials demonstrate improvements in endothelial function, arterial stiffness, and blood pressure in middle-aged and older populations. Exercise capacity benefits in older adults are also supported by review-level evidence.
L-Citrulline has substantial clinical evidence supporting its role in cardiovascular health, primarily through enhancing nitric oxide (NO) bioavailability. Meta-analyses of randomized controlled trials demonstrate statistically significant reductions in both systolic and diastolic blood pressure. Clinical studies also show improvements in endothelial function (flow-mediated dilation) and benefits in heart failure patients, including improved left ventricular ejection fraction.
A randomized double-blind placebo-controlled trial in 54 type 2 diabetic patients showed that 3 g/day L-citrulline for 8 weeks significantly reduced fasting blood glucose and HbA1c, though it did not improve QUICKI or HOMA-β measures of insulin sensitivity. A separate RCT in middle-aged/older adults with type 2 diabetes found 4 weeks of L-citrulline improved FMD, pulse wave velocity, and blood glucose. Animal studies confirm the mechanism involves inhibition of serine phosphorylation of insulin receptor substrate-1 (IRS-1), improving hepatic insulin signaling.
L-citrulline is an amino acid converted endogenously to L-arginine with greater bioavailability, thereby raising plasma arginine and NO levels more effectively than direct L-arginine supplementation. A small 2011 RCT found L-citrulline supplementation (1.5 g/day) significantly improved erectile hardness scores in men with mild ED compared to placebo.
Altered L-arginine/NO homeostasis is implicated in the pathogenesis of pulmonary hypertension (PH), bronchopulmonary dysplasia, asthma, and COPD. A human clinical trial in patients with idiopathic pulmonary arterial hypertension (IPAH) and Eisenmenger Syndrome found that L-citrulline malate reduced mean pulmonary artery pressure and improved 6-minute walk distance. Preclinical data in neonatal animal models further establish citrulline's structural and functional benefits in pulmonary vascular remodeling.
L-Citrulline's precursor role in NO synthesis addresses multiple pillars of metabolic syndrome: endothelial dysfunction, hypertension, insulin resistance, and dyslipidemia. A comprehensive 2018 PMC review documented that watermelon-derived L-citrulline supplementation reduced blood pressure in human trials, with emerging evidence for lipid/lipoprotein benefits. Meta-analyses of RCTs confirm significant blood pressure reduction, and animal models show amelioration of the full metabolic syndrome phenotype.
Multiple RCTs and a systematic review/meta-analysis have evaluated L-citrulline or citrulline malate for post-exercise recovery, demonstrating reductions in perceived exertion and muscle soreness markers. A 2020 systematic review and meta-analysis (Rhim et al., J Sport Health Sci) found citrulline supplementation reduced post-exercise RPE and muscle soreness based on pooled data from multiple RCTs. Benefits appear most consistent for muscular endurance-type exercise, with typical dosing of 6–8 g citrulline malate or 3–6 g L-citrulline taken pre-exercise.
Human RCTs consistently show pre-exercise L-citrulline or citrulline malate supplementation reduces post-exercise muscle soreness scores. A 2020 systematic review and meta-analysis confirmed significant reductions in delayed-onset muscle soreness (DOMS) and RPE across multiple RCTs, with single acute doses taken 1–2 hours before exercise. The mechanism involves improved muscle perfusion, reduced lactate accumulation, and attenuation of exercise-induced oxidative stress.
L-citrulline is converted to L-arginine in the kidneys via the citrulline-NO cycle, making it a more bioavailable oral NO precursor than L-arginine itself. Clinical trials show it raises plasma arginine and NO metabolites more effectively than equivalent oral arginine doses. It is well-studied for endothelial function, blood pressure, and exercise performance.
L-Citrulline is a non-essential amino acid that serves as a more effective precursor to arginine and nitric oxide than L-arginine itself, promoting vasodilation and improved oxygen/nutrient delivery during exercise. While a 2023 meta-analysis found no significant overall benefit for endurance performance, multiple individual RCTs show benefits for muscular endurance and reduced fatigue at doses of 6–8 g/day.
L-Citrulline is a precursor to arginine and nitric oxide that enhances blood flow, nutrient delivery to healing tissues, and collagen synthesis in post-surgical recovery. It is included alongside arginine in evidence-based post-surgical supplement formulations for increasing nitric oxide production and supporting circulatory delivery to surgical wounds.
L-Citrulline is an endogenous nitric oxide precursor that more efficiently raises plasma arginine than L-arginine itself by avoiding first-pass liver metabolism. Integrative medicine reviews (Liebertpub, 2025) list citrulline alongside arginine as important supplements for managing post-acute COVID-19 sequelae, particularly endothelial dysfunction and exercise intolerance.
Body systems that L-citrulline may help support.
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