Evidence for Arginine and Citrulline Supplementation in NO Synthesis

// Corey Schuler, MS, DC, LN, CNS


The year was 1998 and I was finally cool. Actually, I was still a huge nerd, but my chosen field, inorganic chemistry was now cool. Why? Because before that, most inorganic chemists were destined to a life of plastics, polymers, paints, and packages. And while that’s still mostly true, 1998 was the year of nitric oxide (NO), an inorganic molecule with major biological significance. Louis Ignarro, PhD, Robert F. Furchgott, PhD and Ferid Murad, MD, PhD won the Nobel Prize in medicine for their work on biological uses of NO. It just so happens that the first phosphodiesterase type-5 (PDE5) inhibitor was released that same year. Forget materials, mom! I’m going to be a hero.

The role of argninine and citrulline in NO synthesis

Healthy sexual function requires several factors, but vascular health may be most important. That is where safe and useful approaches including two amino acids, arginine and citrulline, enter the scene.

There have been many studies of supplementation with arginine, many of which have focused on its ability to support healthy NO function.1 It also increases blood flow to the heart.2Arginine improves efficiency of exercise and allows healthy people to exercise more vigorously.3 Arginine also supports the heart by increasing the efficiency of the heart's pumping action.4 Arginine is great for athletes, because it reduces the oxygen cost of aerobic exercise, supports healthy blood pressure*, and enhances exercise tolerance. Athletes, especially cyclists, often suffer in silence as they seek to support their sexual health.5

Most studies using arginine to support healthy sexual function have studied it in combination with other ingredients, such as French maritime pine bark extract6-9, – yohimbine10,11, or adenosine monophosphate.12 Only a few studies have looked at arginine by itself for supporting sexual health. In a small, uncontrolled trial, men were given 2.8 g arginine per day for two weeks. Forty percent of the men in the treatment group experienced improvement, compared to none in the placebo group.13 In a double-blind trial, men seeking support for healthy sexual function took 5 g arginine per day or a matching placebo for six weeks.14 Nine of 29 (31%) patients taking L-arginine reported a significant subjective improvement in sexual function. All nine patients treated with L-arginine and who had subjectively improved sexual performance had had an initially low urinary nitric oxide, and this level had doubled at the end of the study. Men given just 500 mg three times daily in another trial experienced no better improvement than placebo.15 These results suggest that higher doses may be needed, and that men with lower nitric oxide levels might benefit the most.

In single blind, short-term study in men seeking support for sexual function, L-citrulline was given 1.5 g/day for a month. Researchers concluded it was safe and psychologically well-accepted and very satisfying to test subjects, and supported sexual function score improvements.16

*Already within normal limits

1. Loscalzo J. L-arginine and atherothrombosis. J Nutr. 2004 Oct;134(10 Suppl):2798S–2800S; discussion 2818S-2819S.
2. Blum A, Porat R, Rosenschein U, et al. Am J Cardiol 1999;83:1488–90 Bailey SJ, Winyard PG, Vanhatalo A, et al. J Appl Physiol. 2010 Nov;109(5):1394-40 doi: 10.1152/japplphysiol.00503.2010. Epub 2010 Aug 19.
4. Orozco-Gutiérrez JJ, Castillo-Martínez L, Orea-Tejeda A, et al. Cardiol J. 2010;17(6):612–8.
5. Gulino G, Sasso F, D'Onofrio A, et al. Urologia. 2010 Apr-May;77(2):100–6.
6. Aoki H, Nagao J, Ueda T, et al. Phytother Res. 2012 Feb;26(2):204–7. doi: 10.1002/ptr.3462. Epub 2011 May 27.
7. Ledda A, Belcaro G, Cesarone MR, Dugall M, Schönlau F. BJU Int. 2010 Oct;106(7):1030–3. doi: 10.1111/j.1464-410X.2010.09213.x. Epub 2010 Feb 22.
8. Stanislavov R, Nikolova V. J Sex Marital Ther. 2003 May-Jun;29(3):207–13.
9. Stanislavov R, Nikolova V, Rohdewald P Int J Impot Res. 2008 Mar-Apr;20(2):173–80. Epub 2007 Aug 16.
10. Kernohan AF, McIntyre M, Hughes DM, et al. Br J Clin Pharmacol. 2005 Jan;59(1):85–93.
11. Lebret T, Hervé JM, Gorny P, Worcel M, Botto H. Eur Urol. 2002 Jun;41(6):608–13; discussion 613.
12. Neuzillet Y, Hupertan V, Cour F, Botto H, Lebret T. Andrology. 2013 Mar;1(2):223–8. doi:1111/j.2047-2927.2012.00046.x. Epub 2012 Dec 26.
13. Zorgniotti AW, Lizza EF. Int J Impot Res 1994;6:33–6.
14. Chen J, Wollman Y, Chernichovsky T, et al. BJU Int 1999;83:269–73.
15. Klotz T, Mathers MJ, Braun M, Bloch W, Engelmann U. Urol Int. 1999;63(4):220–3.
16. Cormio L, De Siati M, Lorusso F, et al. Urology 2011;77:119–22.


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