Suzuki T, Morita M, Hayashi T, Kamimura A. The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males. Biosci Biotechnol Biochem. 2017;81(2):372-375.
Double-blind, randomized, placebo-controlled trial
Forty-two healthy non-obese Japanese men aged 20-49; smokers and men who were taking medications or dietary supplements were excluded. The men were randomized to 1 of 4 groups:
- Placebo (cornstarch) (n = 11)
- L-citrulline alone 2.0 g/day (n = 11)
- L-arginine alone 2.0 g/day (n = 10)
- L-citrulline with L-arginine, 1.0 g/day of each (n = 10)
Primary Outcome Measure
Plasma levels of L-arginine after supplementation
One hour after supplementation, all groups had increases in plasma L-arginine levels compared to placebo; however, levels were significantly higher in the combination L-citrulline, L-arginine group (placebo 5.4±16.3; combo 121.9±46.7; citrulline alone 66.3±33.6; arginine alone 72.3±31.5). Levels in the combination group were approximately 40% higher than the L-arginine alone group. None of the participants experienced side effects of any of the treatments during the study.
While previous animal studies have shown that the combination of L-arginine with L-citrulline increases L-arginine plasma levels, to my knowledge this is the first human clinical trial to demonstrate this effect.1,2 This is clinically significant given the research demonstrating the diverse and important health benefits of L-arginine supplementation in men. Human clinical trials have shown that L-arginine supplementation can help improve erectile dysfunction (ED),3 insulin resistance,4 and sports performance.5
Specific to ED, research demonstrates that men with ED have low serum levels of L-citrulline and L-arginine.6 Reduced nitric oxide concentration is linked to increased risk of erectile dysfunction. Arginine is a nitric oxide precursor so it makes sense that low levels of nitric oxide synthase substrates such as L-arginine and L-citrulline could positively influence ED.
This is clinically significant given the research demonstrating the diverse and important health benefits of L-arginine supplementation in men.
There is also evidence that supplemental L-arginine can help prevent and treat cardiovascular disease, which is likely due to its influence on endothelial-derived nitric oxide production.7,8 A 2016 review by Alyavi et al demonstrated clinical benefits of L-arginine supplementation specifically for ischemic heart disease and once again cited synthesis of nitric oxide production as a key mechanism of action.9
Because of past in vitro and in vivo research showing that L-citrulline suppresses arginase activity,10 the researchers of this present study speculate that this could be a potential mechanism that explains the significant increase with the combination of the 2 amino acids. Previous research has demonstrated that oral L-arginine has reduced bioavailability because it is degraded by arginase in the gastrointestinal tract (40%) and liver (15%) on the first pass.11,12 Historically, fairly large doses of L-arginine alone were needed to produce a therapeutic effect in humans. By inhibiting arginase activity via the addition of the L-citrulline, it’s likely that more of the L-arginine can pass through the intestines and liver and into the bloodstream. As demonstrated in this study and previous studies, L-citrulline is a precursor of L-arginine and it alone can increase L-arginine levels.13
From a clinical perspective, because we know that L-arginine can positively influence a man’s health, it makes sense to explore this combination because it appears to enhance bioavailability of oral L-arginine supplementation. Because this was a small study, more research is needed to further confirm this effect.
- Hayashi T, Juliet PA, Matsui-Hirai H, et al. L-citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci USA. 2005;102(38):13681-13686.
- 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.
- Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int. 1999;83(3):269-273.
- Bogdanski P, Suliburska J, Grabanska K, Jablecka A. Effect of 3-month L-arginine supplementation on insulin resistance and tumor necrosis factor activity in patients with visceral obesity. Eur Rev Med Pharmacol Sci. 2012;16:816-823.
- Koppo K, Taes YE, Pottier A, Boone J, Bouckaert T, Derave W. Dietary arginine supplementation speeds pulmonary VO2 kinetics during cycle exercise. Med Sci Sports Exerc. 2009;41(8):1626-1632.
- Barassi A, Corsi Romanelli MM, Pezzilli R, et al. Levels of L-arginine and L-citrulline in patients with erectile dysfunction of different etiology. Andrology. 2017;5(2):256-261.
- Tousoulis D, Antoniades C, Tentolouris C, et al. L-arginine in cardiovascular disease: dream or reality. Vasc Med. 2002;7(3):203-211.
- Bahadoran Z, Mirmiran P, Tahmasebinejad Z, Azizi F. Dietary L-arginine intake and the incidence of coronary heart disease: Tehran lipid and glucose study. Nutr Metabol. 2016;13:23.
- Alyavi AL, Alyavi BA, Sayfiyev NY, et al. Clinical benefits of metabolic therapy of ischemic heart disease with L-arginine supplementation. Saudi J Med Pharm Sci. 2016;2(9):247-249.
- Romero MJ, Platt DH, Tawfik HE, et al. Diabetes-induced coronary vascular dysfunction involved arginase activity. Circ Res. 2008;102(1):95-102.
- Wu G. Intestinal mucosal amino acid catabolism. J Nutr. 1998;128(8):1249-1252.
- O’Sullivan D, Brosnan JT, Brosnan ME. Hepatic zonation of the catabolism of arginine and ornithine in the perfused rat liver. Biochem J. 1998;330(Pt 2):627-632.
- Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamics properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol. 2008;65(1):51-59.