Agarwal U, Didelija IC, Yuan Y, Wang X, Marini JC. Supplemental citrulline is more efficient than arginine in increasing systemic arginine availability in mice. 2017;147(4):596-602. doi:10.3945/jn.116.240382.

Randomized control trial

After recovery to presurgery body weight, 6-week-old mice were assigned to one of seven dietary treatment groups

• Arginine
• Citrulline

Citrulline supplementation is more efficient at increasing arginine availability than is arginine supplementation itself in mice.

Khalaf D, Krüger M, Wehland M, Infanger M, Grimm D. The effects of oral L-arginine and L-citrulline supplementation on blood pressure. Nutrients. 2019;11(7):1679. doi:10.3390/nu11071679.

Review

Heterogenic study populations (small trials)

• L-arginine
• L-citrulline

Blood pressure-lowering effect was found in meta-analyses for both L-arginine and L-citrulline; more research with larger study populations is needed to confirm these results.

Morita M, Hayashi T, Ochiai M, et al. Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability. Biochem Biophys Res Commun. 2014;454(1):53-57. doi:10.1016/j.bbrc.2014.10.029.

Randomized trial

15 male rats (9 weeks old) and 9 male rabbits (8 weeks old) after 16-hour fast were given either L-citrulline, L-arginine, or a combination of each at half dosing.

• L-arginine
• L-citrulline

Combination of L-citrulline and L-arginine effectively and rapidly augments. NO-dependent responses at the acute phase. May have clinical utility for the regulation of cardiovascular function in humans.

Shatanawi A, Momani MS, Al-Aqtash R, Hamdan MH, Gharaibeh MN. L-citrulline supplementation increases plasma nitric oxide levels and reduces arginase activity in patients with type 2 diabetes. Front Pharmacol. 2020;11:584669. doi:10.3389/fphar.2020.584669.

Clinical study

25 patients with type 2 diabetes on oral hypoglycemic drugs

• L-citrulline for 1 month

L-citrulline can have therapeutic benefits in patients with diabetes through increasing NO levels and maintaining vascular function, possibly through an arginase inhibition-related pathway.

Wijnands KAP, Vink H, Briedé JJ, et al. Citrulline a more suitable substrate than arginine to restore NO production and the microcirculation during endotoxemia. PLoS One. 2012;7(5):e37439. doi:10.1371/journal.pone.0037439.

Randomized trial

65 male mice received an 18-hour IV infusion of endotoxin combined with either L-citrulline, L-arginine, or
L-alanine (isonitrogenous control) during the last 6 hours; control group received sterile saline combined with L-alanine or L-citrulline during the last 6 hours

• L-alanine (control)
• L-arginine
• L-citrulline

L-citrulline supplementation during endotoxemia positively influenced the intestinal microvascular perfusion compared to L-arginine supplemented and control endotoxemic mice. L-citrulline supplementation (and not L-arginine supplementation) during murine endotoxemia improves the microcirculation and results in increased plasma and tissue availability of citrulline, arginine, and NO during endotoxemia.