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L-Citrulline’s Multiple Health Benefits

L-citrulline is a non-essential amino acid that previously was thought of as just an intermediate metabolite. However, over the past decade research on L-citrulline has dramatically increased due to the understanding and importance of L-citrulline’s metabolism. L-citrulline is converted to L-arginine in the body, leading to increases in both L-arginine and nitric oxide. Increased production of nitric oxide (NO) promotes vascular dilation, which helps support normal oxygen and blood circulation throughout the body.1 Since L-citrulline is not a component of proteins unlike most other amino acids, dietary proteins cannot be a direct source of L-citrulline to the body. As a result, interest in this nutrient is emerging in various applications for improving health and wellness. In this paper, we will specifically discuss L-citrulline’s role in NO production, vascular health, muscle protein synthesis, ammonia elimination and immune function.

Nitric Oxide Effects 

L-citrulline is a better precursor of arginine and NO than arginine itself. This is shown by acute oral administration of L-citrulline, raising plasma arginine levels to about 227 percent with 3.8 grams of L-citrulline (within four hours) compared to only 90 percent with the equivalent dose of arginine. Unlike arginine, oral L-citrulline is readily absorbed without any gastrointestinal side effects.2 

Ammonia Detoxification 

L-citrulline is involved in ammonia detoxification as an L-ornithine cycle amino acid. L-citrulline, along with Larginine and L-ornithine, has various functions as an amino acid in the Lornithine cycle. The effect of supplemental L-citrulline on young animals fed arginine-deficient diets is similar to that of supplemental L-arginine. In rat experiments, L-citrulline was shown not only to promote the metabolism of ammonia accumulated in muscle during exercise, but also to elevate the survival rate of rats intraperitoneally injected with a lethal dose of ammonia.3 

Effects on Muscle Protein Metabolism 

A series of studies have proven that Lcitrulline can increase muscle protein content and protein synthesis in animal models. Osowska et. Al., found in malnourished aged rats that were fed a Lcitrulline- supplemented diet, there was an increase in protein synthesis and protein content in the muscle as compared to the standard diet fed rats.4 It was also found that L-citrulline improved nitrogen balance in rats with short bowel syndrome. In addition, Lcitrulline stimulates muscle protein synthesis in fasted adult rats.5 Most recently, Faure et. Al., found that L-citrulline supplementation increases expression of the main myofibrillar proteins and seems to induce a switch in muscle energy metabolism, from aerobia toward anaerobia.6

Vascular Health 

Because L-citrulline is an effective precursor of L-arginine for NO synthesis, it has been implicated to help support vascular health. More recently, many studies have been published exploring its use in various vascular disorders.7,8 

Immune Function 

L-citrulline may be a safe means of immunomodulation that preserves the anti-inflammatory mediator response.9 

Safety Information 

Because it occurs naturally in the living bodies of animals and humans where it plays an important role, L-citrulline is regarded as a highly safe ingredient. Studies in humans have demonstrated that L-citrulline is substantially innocuous.

Kyowa’s L-ctirulline 

Kyowa’s L-citrulline is manufactured in the U.S. using a proprietary fermentation process. It is also the only GRAS (generally recognized as safe) citrulline ingredient on the market.


1 Bahri S. Zerrouk N. Aussel C. Citrulline: from metabolism to therapeutic use. Nutrition. 29(3):479-84, 2012.

2 Kuhn KP, Harris PA, Cunningham GR, Robbins IM, Summar ML, Christman BW. Oral citrulline effectively elevates plasma arginine levels for 24 h in normal volunteers. Circulation AHA Scientific Sessions 2006; abstract 1692, p. II-1339.

3 Ortolani EL. Marcondes MC. Treatment of ammonia intoxication in rats through the use of amino acids from the urea cycle. Veterinary & Human Toxicology. 37(3):217- 20, 1995.

4 Osowska S. Duchemann T. Walrand S. Paillard A. Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab. 291: E582-E586, 2006.

5 Le Plenier S. Walrand S. Noirt R. Effects of Leucine and Citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: a common activation pathway? Amino Acids. 43(3): 1171-8, 2012.

6 Faure C. Morio B. Hartman WJ. Torre PM. Prior RL. Dietary citrulline but not ornithine counteracts dietary arginine deficiency in rats by increasing splanchnic release of citrulline. Journal of Nutrition. 124(10):1950- 60, 1994.

7 Morita M. Sakurada M. Watanabe F. Effects of Oral Lcitrulline Supplementation on Lipoprotein Oxidation and Endothelial Dysfunction in Humans with Vasospastic Angina. Immun., Endoc. & Metab. Agents in Med. Chem., 13: 1-7, 2013.

8 Ochiai M. Hayashi T. Morita M. Short-term effects of L-Citrulline supplementation on arterial stiffness in middle- aged men. International Journal of Cardiology. 155:257-61, 2012.

9 Asgeirsson T., Zhang S., Nunoo R., Mascarenas C. Citrulline: A potential immunomodulator in sepsis. Surgery. 150: 744-51, 2011. 

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