Citrulline is an intermediate, nonprotein-forming amino acid in the urea cycle serving as a precursor to arginine. It derives its name from the watermelon (Citrullus vulgaris), where it was first isolated and identified.

It is easily absorbed by the gut and bypasses the liver, making it an effective method for repleting arginine.

Other food sources of citrulline include muskmelons, bitter melons, squashes, gourds, cucumbers and pumpkins.

Citrulline can also be synthesized from arginine and glutamine in enterocytes, which can then be metabolized by the kidneys back into arginine.

Because citrulline is produced in enterocytes, it has been proposed as a marker of enterocyte mass in conditions of villous atrophy. Given the importance of arginine in nitric oxide production for vasodilation and muscle protein synthesis, citrulline is sometimes administered therapeutically to deliver arginine to endothelial and immune cells. It is also supplemented in sarcopenia to stimulate protein synthesis in skeletal muscle through the rapamycin (mTOR) pathway. Citrulline supplementation has been studied in conditions like erectile dysfunction, sickle cell anemia, short bowel syndrome, hyperlipidemia, cancer chemotherapy, urea cycle disorders, Alzheimer’s disease, multi-infarct dementia, and as an immunomodulator.