L-citrulline

L-citrulline is a non-essential, non-proteinogenic amino acid — meaning it occurs in the body but is not used to build proteins. It was first isolated from watermelon (Citrullus lanatus), from which it takes its name, and it remains particularly abundant in watermelon rind and flesh, with smaller quantities found in cucumbers, pumpkins, and other gourds.⁴ In human metabolism, L-citrulline functions as a key intermediate in the urea cycle and in the endogenous synthesis of L-arginine: it is taken up efficiently by the kidneys and converted to L-arginine, which in turn serves as the substrate for nitric oxide synthase to produce nitric oxide — a signaling molecule that promotes vasodilation and increased blood flow.¹⁴

This metabolic conversion is the practical reason L-citrulline supplementation is commonly used in place of direct L-arginine supplementation: oral L-arginine is heavily metabolized in the gut and liver before reaching the systemic circulation, while L-citrulline bypasses this first-pass metabolism and produces more sustained increases in plasma L-arginine concentrations.¹

Two forms are commonly sold as supplements:¹

• L-citrulline (free form): Pure citrulline, typically used at lower doses.
• Citrulline malate (CitMal): L-citrulline bonded to malic acid in a 1:1 or 2:1 ratio, marketed primarily for exercise performance. The malate component is an intermediate in the citric acid cycle and is theorized to contribute additional ergogenic effects, although the evidence for malate's independent contribution remains limited.

L-citrulline is studied and used primarily for two purposes: enhancing exercise performance (particularly high-intensity strength training and the subjective experience of muscle "pump") and improving certain cardiovascular and endothelial outcomes via the L-citrulline–arginine–nitric oxide pathway.

A 2021 meta-analysis by Vårvik and colleagues, published in the International Journal of Sport Nutrition and Exercise Metabolism, pooled data from randomized controlled trials of citrulline malate supplementation before strength training. The analysis found that 6 to 8 grams of citrulline malate consumed 40 to 60 minutes before exercise produced a small but statistically significant increase in the total number of repetitions performed before failure (approximately 6.4% on average), with the effect most pronounced for lower-body exercises.¹ A separate 2019 meta-analysis by Trexler and colleagues, focused on high-intensity strength and power performance, similarly reported a small ergogenic effect of acute citrulline supplementation.²

The evidence for aerobic performance is less favorable. A 2022 PRISMA-guided systematic review and meta-analysis by Viribay and colleagues, also published in a peer-reviewed journal, pooled 10 randomized controlled trials of citrulline supplementation and aerobic exercise outcomes and concluded that supplementation did not produce statistically significant improvements in aerobic performance, rate of perceived exertion, oxygen uptake kinetics, or blood lactate.³ This pattern — modest benefit for resistance training and minimal benefit for aerobic exercise — is consistent across the broader literature.

The NIH ODS fact sheet on exercise and athletic performance includes citrulline among the amino acids studied for ergogenic effect and similarly characterizes the evidence as mixed, with modest benefits for some endpoints and equivocal results for others.⁴

Documented dosing approaches from the research literature:¹²

• Citrulline malate (for strength training): 6 to 8 g consumed 40 to 60 minutes before exercise.
• L-citrulline (free form): Studies have used 3 to 6 g daily, also typically taken 30 to 60 minutes before exercise.

L-citrulline supplementation has not been associated with a single uniformly recommended daily dose because the underlying randomized trials have used a range of dose and duration combinations without consistent head-to-head comparison. No Tolerable Upper Intake Level has been established, and the available clinical literature has not identified a specific dose-related toxicity threshold within the studied range.⁴

Oral, as powder, capsules, tablets, or as an ingredient in pre-workout combination products.

Standard storage in a cool, dry place out of direct sunlight. Powdered citrulline malate has a notably sour taste owing to the malic acid component and is commonly flavored or combined with other ingredients in commercial products.

L-citrulline is generally well-tolerated in the studied dose range. Reported side effects across clinical trials have been infrequent and mild, with no consistent pattern of significant adverse events at typical doses.¹⁴ Gastrointestinal symptoms — nausea, bloating, mild abdominal discomfort — have been occasionally reported, particularly at higher doses or with citrulline malate's sour taste.

Several practical considerations apply:¹⁴

• Blood pressure: Because L-citrulline increases nitric oxide via the arginine pathway, it can produce small reductions in blood pressure. This is generally not clinically meaningful in healthy individuals but is a consideration in individuals taking antihypertensive medications.
• PDE5 inhibitors (sildenafil, tadalafil, vardenafil) and nitrate medications: These medications also act on the nitric oxide pathway. Concurrent use with high-dose L-citrulline has not been well studied, and theoretical additive effects on blood pressure are plausible; clinician consultation is reasonable.
• Erectile dysfunction: A small number of clinical studies have explored L-citrulline supplementation in mild erectile dysfunction by the same nitric-oxide-pathway mechanism; results have been preliminary and L-citrulline is not approved for this indication.
• Pregnancy and lactation: Insufficient safety data exist for use during pregnancy or breastfeeding; use during these periods should involve clinician discussion.
• Chronic kidney disease: Because L-citrulline is converted to L-arginine in the kidneys, individuals with significant chronic kidney disease should consult their clinician before supplementing.

Long-term safety data beyond the typical study duration (weeks to a few months of supplementation) are limited, and the long-term consequences of daily L-citrulline supplementation across years are not fully characterized in the published literature.⁴