Citulline

Citrulline, specifically the L-enantiomer, is a non-proteinogenic amino acid that participates in the urea cycle. It is not incorporated into proteins. In humans, citrulline is produced in the small intestine and liver as an intermediate and can be released into the bloodstream, where it serves as a precursor for arginine synthesis and, indirectly, nitric oxide production.

In the urea cycle, ornithine combines with carbamoyl phosphate to form citrulline, which is transported to the cytosol and condenses with aspartate to form argininosuccinate. Argininosuccinate is then split into arginine and fumarate. Arginine can be used for protein synthesis or degraded to urea. Circulating arginine is largely replenished by conversion of citrulline to arginine in the kidney.

Natural dietary sources of citrulline include watermelon and other melons, cucurbits, and some cereals, though concentrations are modest compared with supplements. L-citrulline is available as a dietary supplement, alone or as citrulline malate (a compound of citrulline and malate). Common dosages range from 3 to 6 grams of L-citrulline per day, with higher amounts sometimes used in athletic formulations; citrulline malate is frequently used in a 2:1 ratio.

Potential effects studied include increased nitric oxide production, improved blood flow, and modest improvements in exercise performance or recovery, though results are mixed across trials. Citrulline is generally well tolerated; high doses may cause gastrointestinal distress or hypotension in susceptible individuals. People with kidney disease or those taking nitrates or antihypertensive medications should consult a clinician before use, and supplementation is not a substitute for medical treatment in urea cycle disorders or cardiovascular disease.