Arginine vs Citrulline

As the supplement industry continues to grow, so too do the products that make that industry. With pre-workout formulations continuing to dominate the market behind protein and creatine, many companies are pouring immense amounts of energy into formulating more effective pre-workout supplements. Within pre-workout supplements, the subset category of nitric oxide supplements has always been a popular choice among supplement users. Recently, many companies have begun to focus their attention on citrulline over the traditional arginine as being a lead ingredient in their nitric oxide type pre-workout blends. What has caused this change and is it warranted?

Nitric Oxide

Nitric oxide, nitric monoxide or just NO is a relatively simple molecule, but one which has huge ramifications in the human body and is featured heavily in the study of neuroscience, physiology and immunology. In fact, it’s such an important molecule that it was once named molecule of the year by the famous journal ‘Science’. Aside from all of nitric oxides other functions in the human body including acting as a neurotransmitter and its role in immunity, it is perhaps most commonly known for its ability to relax the smooth muscle around blood vessels in order to dilate them. This helps to increase blood flow including peripheral blood flow to working skeletal muscles, which has been proposed to help with increased muscle growth and prolonged endurance.

Arginine & NO

In order to produce the majority of nitric oxide in the body arginine is needed in a reaction involving oxygen, a molecule called NADPH and the enzyme nitric oxide synthase to produce citrulline and nitric oxide. For the scientifically minded, the above reaction is shown below:

L-arginine + 3/2 NADPH + H+ + 2 O2 <=> citrulline + nitric oxide + 3/2 NADP+

Arginine is Essential

Arginine is an amino acid that is considered conditionally essential. That is, depending on your health and development status, arginine may or may not need to be supplemented through outside sources. For example, pre-term infants lack the ability to produce arginine internally and so require an exogenous source of arginine. In terms of food sources, arginine is found in abundance in most meats, seafood as well as in high quantities in nuts and seeds. It can also be produced in the body from reactions involving other amino acids such as glutamine and citrulline, however endogenous synthesis of arginine only accounts for 5-15% of total plasma arginine1. From the reaction shown above for the production of nitric oxide, it appears that supplying exogenous supplies of arginine should be capable of increasing nitric oxide levels and thus the amount of vasodilation. However…

The Problem with Arginine

The issue with arginine is that oral supplementation of arginine is often subject to quite extensive ‘pre-systemic’ and ‘systemic’ elimination from bacteria in the stomach and the enzyme arginase in the gut and liver. In fact, some studies have even placed this absorption at around 38-70% 2,3. In fact, one study was even able to show that in people with high cholesterol, only 1% of orally administered arginine was utilised by the enzyme, nitric oxide synthase to produce nitric oxide. As such, several studies in the past few years have looked at oral administration of citrulline as a way to provide arginine as it is an amino acid which bypasses metabolism in the gut and liver.

More on Citrulline

Citrulline is known as a non-protein amino acid. That is, it is not a necessary amino acid to act as a building block for protein. First found in the rinds of watermelons, citrulline can be derived internally via two reactions; as part of the urea cycle or via the nitric oxide synthase reaction shown above. As stated before, new research has begun looking at citrulline as a way of providing endogenous arginine due to its ability to escape being metabolised by our digestive system.

Citrulline can be converted to arginine with the help of two enzymes; argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL), however the reaction can be quite energetic. In other word, it requires ATP, our body’s fuel in order to complete this reaction. Now the story gets complicated. If we require energy to convert citrulline to arginine, why then would we bother switching to oral supplementation of citrulline as a way of providing nitric oxide and with prolonged energy and endurance? The answer to this question may lie in the fact that while both amino acids have its drawbacks in their capability to produce nitric oxide, perhaps citrulline fares slightly better.

Studies on Citrulline & Arginine

In order to make conclusions about the use of either supplement for their production of nitric oxide, lets take a look at some recent studies:

  • Oswoska et al (2004)4 showed that oral citrulline administration was more potent at raising plasma arginine levels in rats with a massive intestinal resection and was able to restore nitrogen balance over that of arginine supplementation. This result also raises questions on whether or not citrulline supplementation can prove beneficial in protein synthesis.
  • As a side note, it is important to keep in mind that often to keep arginine at stable levels in the blood, citrulline produced in the intestines is often necessary. In cases where the intestines don’t work as well such as in resection or even in celiac disease, arginine levels in the body can be compromised.
  • Schwedhelm et al (2008)5 was able to show that oral supplementation of citrulline in humans was able to raise plasma levels of l-arginine at a dose-dependent manner and more effectively than l-arginine. What was interesting in this study was that neither citrulline or arginine were able to significantly lead to increases in flow mediated vasodilation. However, having said that, there was a non significant correlation between plasma arginine levels and vasodilation.
  • Moinard et al (2008)6 however demonstrated that plasma citrulline is cleared quite rapidly when given in one large dose. However, levels still remain relatively high within 2 hours after administration. What Moinard was able to show however was that a high dose of citrulline did not lead to any adverse symptoms, which is surprising considering a large dose of other amino acids (namely arginine and ornithine led to cases of diarrhoea).

  • This study was also able to show that at high levels of citrulline administration, conversion to arginine appears to get saturated. So somewhere between 6g and 15g of citrulline, conversion to arginine becomes saturated. Another finding from this study was that citrulline was unable to affect plasma insulin or growth hormone levels, a different story to that of increased arginine or ornithine.
  • Berthe et al (2011)7 was able to show that while citrulline is quickly metabolised, a sustained release exogenous supply of citrulline in animals may be the ideal method of increasing arginine and citrulline levels over a sustained period of time. Whether this is necessary for everyday performance in the gym is debatable.

The Benefits of Citrulline Over Arginine

So having examined the studies in question, citrulline does provide a couple of benefits over arginine supplementation. Namely, several studies have been able to show that it can actually result in higher plasma arginine levels than arginine supplementation itself. Furthermore, high intakes of citrulline are well tolerated, unlike that of arginine.

Anabolic Citrulline

Citrulline supplementation may also have additional ergogenic effects. In Cynober et al’s (2010)8 excellent review of citrulline, there have been studies showing citrulline may have an anabolic potential. With regards to aging related muscle wasting, citrulline has been found to increase muscle protein synthesis rate and prevent declines in strength and muscle force. In fact, citrulline has been found to exert similar muscle protein synthesis abilities as that of leucine. However, the main drawback is that many of these studies have not only been animal studies, but studies in which the animals were protein deficient. However it does offer a new direction for ergogenic supplement research.

On a side note, it seems that in animal studies, leucine works best in an environment of high amino acid availability while citrulline is synthesized best in the body when in a fasted state. This prompts the author to suggest that perhaps supplementation of citrulline would work best in a fasted state. In terms of human studies, Thibault et al (2011)9 argues that while citrulline supplementation over 7 days increases both plasma citrulline and arginine levels, that in fasted, well nourished individuals, there was no effect on whole body protein synthesis. This is in contrast to another study by Rouge et al (2007)10 where fed patients who were given a single citrulline supplementation dose had a 24% rise in nitrogen balance.

More Benefits of Citrulline

Citrulline supplementation in the form of citrulline malate has also been implicated with improving strength, aerobic performance and muscle soreness.11,12,13,14 With regards to fatigue, the jury is still out as there have been at least one study showing a reduced time to fatigue with citrulline supplementation15, moreso for those who supplemented throughout the day than those who supplemented 3 hrs prior to treadmill running. The problem with many exercise and sports based citrulline studies have been that it has either been a poorly designed study, an animal study or the supplement was in malate form, which is a potential ergogenic compound in itself. Still other benefits of citrulline supplementation include the capacity to act as a buffering agent against fatigue inducing ammonia as well as a possible treatment for erectile dysfunction16.

Arginine's Properties

Of course arginine is still the key chemical in the production of nitric oxide as well as being incredibly useful in a wide variety of medical conditions ranging from acute wound healing to long term chronic diseases such as obesity17. Whether or not arginine is an ergogenic aid is still under investigation as a recent review from Alvares et al (2011)18 has stated that the results are split between benefits and non significant effects from both acute or chronic supplementation with arginine.

Arginine or Citrulline?

There is no doubt that both arginine and citrulline are great amino acids in their own right with several positives. While there is quite a lot of evidence in favour of oral supplementation of citrulline over that of arginine, research is still in its early days and better conclusions are still a long way off. However, with all the benefits mentioned above as well as its rising potential as an anabolic agent capable of promoting muscle protein synthesis, citrulline is gathering more and more interest in the exercise, bodybuilding, athletic and sports science community. In terms of dosing instructions, evidence is limited, but having at least 6g of arginine and/or 6-15g of citrulline per day just before exercise seems to be the best estimate so far for maximising ergogenic effects. Arginine can also be taken prior to sleep in order to potentially increase growth hormone release.

1. Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Böger RH. ‘Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.’ Br J Clin Pharmacol. 2008 Jan;65(1):51-9. Epub 2007 Jul 27.
2. Bode-Böger SM, Böger RH, Galland A, Tsikas D, Frölich JC. ‘L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship.’ Br J Clin Pharmacol. 1998 Nov;46(5):489-97.
3. Castillo L, Chapman TE, Yu YM, Ajami A, Burke JF, Young VR. ‘Dietary arginine uptake by the splanchnic region in adult humans.’ Am J Physiol 1993; 265: E532–E539
4. Osowska S, Moinard C, Neveux N, Loï C, Cynober L. ‘Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection.’ Gut. 2004 Dec;53(12):1781-6.
5. Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, Spickler W, Schulze F, Böger RH. ‘Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism.’ Br J Clin Pharmacol. 2008 Jan;65(1):51-9. Epub 2007 Jul 27.
6. Moinard C, Nicolis I, Neveux N, Darquy S, Bénazeth S, Cynober L. ‘Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study.’ Br J Nutr. 2008 Apr;99(4):855-62. Epub 2007 Oct 22.
7. Berthe MC, Darquy S, Breuillard C, Lamoudi L, Marc J, Cynober L, Chaumeil JC, Couderc R. ‘High plasma citrulline and arginine levels ensured by sustained-release citrulline supplementation in rats.’ Nutrition. 2011 Nov-Dec;27(11-12):1168-71. Epub 2011 Apr 9.
8. Cynober L, Moinard C, De Bandt JP. ‘The 2009 ESPEN Sir David Cuthbertson. Citrulline: a new major signaling molecule or just another player in the pharmaconutrition game?’ Clin Nutr. 2010 Oct;29(5):545-51. Epub 2010 Aug 16.
9. Thibault R, Flet L, Vavasseur F, Lemerle M, Ferchaud-Roucher V, Picot D, Darmaun D. ‘Oral citrulline does not affect whole body protein metabolism in healthy human volunteers: Results of a prospective, randomized, double-blind, cross-over study.’ Clin Nutr. 2011 Dec;30(6):807-11. Epub 2011 Jul 5.
10. Rougé C, Des Robert C, Robins A, Le Bacquer O, Volteau C, De La Cochetière MF, Darmaun D. ‘Manipulation of citrulline availability in humans.’ Am J Physiol Gastrointest Liver Physiol. 2007 Nov;293(5):G1061-7. Epub 2007 Sep 27.
11. Bendahan D, Mattei JP, Ghattas B, Confort-Gouny S, Le Guern ME, Cozzone PJ. ‘Citrulline/malate promotes aerobic energy production in human exercising muscle.’ Br J Sports Med. 2002 Aug;36(4):282-9.
12. Pérez-Guisado J, Jakeman PM. ‘Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness.’ J Strength Cond Res. 2010 May;24(5):1215-22.
13. Giannesini B, Le Fur Y, Cozzone PJ, Verleye M, Le Guern ME, Bendahan D. ‘Citrulline malate supplementation increases muscle efficiency in rat skeletal muscle.’ Eur J Pharmacol. 2011 Sep 30;667(1-3):100-4. Epub 2011 Jun 6.
14. Takeda K, Machida M, Kohara A, Omi N, Takemasa T. ‘Effects of citrulline supplementation on fatigue and exercise performance in mice.’ J Nutr Sci Vitaminol (Tokyo). 2011;57(3):246-50.
15. Hickner RC, Tanner CJ, Evans CA, Clark PD, Haddock A, Fortune C, Geddis H, Waugh W, McCammon M. ‘L-citrulline reduces time to exhaustion and insulin response to a graded exercise test.’ Med Sci Sports Exerc. 2006 Apr;38(4):660-6.
16. Cormio L, De Siati M, Lorusso F, Selvaggio O, Mirabella L, Sanguedolce F, Carrieri G. ‘Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction.’ Urology. 2011 Jan;77(1):119-22.
17. McKnight JR, Satterfield MC, Jobgen WS, Smith SB, Spencer TE, Meininger CJ, McNeal CJ, Wu G. ‘Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health.’ Amino Acids. 2010 Jul;39(2):349-57. Epub 2010 May 1.
18. Álvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS. ‘L-Arginine as a potential ergogenic aid in healthy subjects.’ Sports Med. 2011 Mar 1;41(3):233-48. doi: 10.2165/11538590-000000000-00000.

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