Citrulline

Citrulline is an amino acid that the body makes and uses but does not incorporate into proteins. Its name comes from Citrullus, the Latin for watermelon, the fruit from which it was first isolated in the early twentieth century, and watermelon remains one of the richest dietary sources.

Metabolically, citrulline sits at the heart of two connected pathways. It is an intermediate of the urea cycle, the route by which the body disposes of ammonia by turning it into urea, and it is readily converted to arginine, the direct precursor of nitric oxide. A notable quirk is that oral citrulline is converted to arginine mainly in the kidney and largely bypasses the breakdown that supplemental arginine undergoes in the gut and liver, so citrulline can raise blood arginine levels more effectively than arginine itself.

Most consumer interest concerns exercise and circulation. A review of citrulline supplementation found that it reliably raises plasma citrulline, arginine, and nitrate and nitrite levels, and that several studies report improved performance and recovery, but that direct evidence for enhanced blood flow and vasodilation is scarce and inconsistent ^[1]. A review of nitric-oxide-boosting supplements for strength reached broadly similar conclusions, positioning citrulline as an effective arginine precursor whose downstream performance effects are still being defined ^[2]. A large meta-analysis of foods rich in nitrate, polyphenols, and amino acids found no significant endurance benefit specifically from citrulline-rich foods ^[3]. Beyond sport, blood citrulline is used clinically as a marker of the amount of functioning small-intestine tissue.

Citrulline is regulated as a dietary supplement and is sold both as L-citrulline and as citrulline malate. It has no approval as a prescription drug and is generally regarded as well tolerated.

Very well tolerated, with far less GI upset than arginine even at higher doses. It can modestly lower blood pressure, so combine cautiously with blood-pressure meds or PDE5 inhibitors. There aren't major safety concerns for healthy people. There is a smaller version of the nitrosation cancer concern that applies to the nitric-oxide amino acids: because citrulline raises arginine and nitric oxide, it can modestly contribute to forming carcinogenic nitrosamines, especially alongside sarcosine, PDE5 inhibitors, or high vitamin C, so pairing with an antioxidant like carnosic acid or idebenone is a reasonable precaution. The effect appears weaker than with arginine or sarcosine.