L-Citrulline is an amino acid component of the urea cycle in the liver (along with arginine and ornithine). It is a nonessential amino acid which is commonly consumed as an exercise supplement given its purported benefits as an ergogenic aid. Good natural source of L-citrulline is watermelon (from which it was first isolated) especially its rind  and some other citrus fruits. As a performance-enhancing athletic dietary supplement it is usually found in two main forms – L-citrulline and citrulline malate (CM). L-citrulline is the free version of amino acid citrulline, while citrulline malate has a molecule of malic acid attached to it.
It has been shown that 4 to 10 grams of citrulline malate is appropriate dose for improving exercise performance and boosting pre-workout NO levels .
Citrulline vs. Arginine
During high-intensity exercise, the concentration of ammonia (byproduct from muscle metabolism) is widespreading in skeletal muscles . Citrulline supplementation may facilitate the detoxification of ammonia . Citrulline is easily taken up by the gut , and it has been shown that its supplementation is more efficient in increasing plasma L-arginine concentration than oral L-arginine supplementation [3,7], which is rapidly broken down in the liver before it reaches circulation . Upon stimulation, about 80% of L-citrulline is recycled to arginine by endotherial cells to produce nitric oxide . Therefore, it is a very effective precursor to arginine and thus holds great promise as nutritional pharmacotherapeutic treatment as well as bodybuilding supplement.
It is estimated that 3g of citrulline malate is equivalent to a 6g dose of arginine, suggesting that citrulline may have twice the potency of arginine for increasing arginine levels in the blood stream .
Citrulline malate as Performance Enhancer
Citrulline in the form of citrulline malate (CM) was shown to reduce muscle fatigue in animals [2,5,8] as well as humans [4,6]. This reduced sensation of fatigue is reported to be due to increased oxidative ATP production during exercise and the rate of phosphocreatine recovery after exercise . Bendahan et al.  have shown that 6 grams of oral CM per day increased aerobic performance. Pérez-Guisado and colleagues  experimented with 8 g/day of CM and concluded that its use might be useful to increase athletic performance in high-intensity anaerobic exercises. Wax, et al.  reported that advanced weightlifters ingesting 8 grams of CM performed significantly higher number of repetitions during 5 sequential sets (60% 1 repetition maximum) to failure on the leg press, hack squat, and leg extension machines compared to those that received group.
In a double-blind, placebo-controlled, crossover study , 10 well-trained males consumed either 12 g of CM or placebo. Subjects performed 10 (15 seconds) maximal cycle sprints (with 30-second rest intervals) followed by 5 minutes recovery before completing a cycle time-to-exhaustion test at 100% of individual peak power. CM supplementation significantly increased plasma citrulline (8.8-fold), ornithine (3.9-fold), and glutamine (1.3-fold), however no acute ergogenic benefits were observed for high-intensity cycling performance. Also, no significant effects on total number of repetitions, time to exhaustion, VO2max, anaerobic threshold, or flow-mediated vasodilation was reported by Cutrufello and colleagues .
Study conducted on rats demonstrated that CM supplementation increases anaerobic performance , and another study in mice noted that exercise-induced blood ammonia elevation was repressed .
Citrulline malate has also been shown to enhance the use of amino acids, especially branched chain amino acids during exercise . Besides that, CM may also increase growth hormone to a higher level than exercise alone .
So, it seems that weight lifters and bodybuilders will benefit the most from CM supplementation while it appears to be ineffective in improving aerobic exercise performance.
Stacking Citrulline with Glutathione – Increased Pump!
Some previous studies have indicated that glutathione stimulates L-arginine turnover and increases nitric oxide synthase (NOS) which suggested it may be preventing oxidative reaction and sustaining the release of NO. Glutathione is a tripeptide consisting of the amino acids cysteine, glutamic acid, and glycine. According to Danielle Citrolo: “Glutathione is known to work in the body to eliminate toxic chemicals, maintain cell proteins and act as an antioxidant.”
A recent randomized, double-blind, placebo-controlled, human clinical trial  in 66 healthy males found that one week of daily oral supplementation with 200 mg of glutathione and 2 grams of L-citrulline enhanced nitric oxide (NO) levels. This combo did not increase cGMP beyond statistical significance, however citrulline and glutathione increased nitrate and nitrite levels (substrates for NO synthesis) more than citrulline alone. In this study glutathione has been shown to may play an important role in protection against oxidative reaction of NO, thus contributing to the sustained release of NO.
Part of the mechanism responsible for the synergetic effect observed between citrulline and glutathione is that glutathione probably further increases the release of NO from arginine. However, it is not clear how L-citrulline and glutathione reinforce each other’s effect.
“In this study, we were able to determine that combining Setria® Glutathione with L-citrulline not only increased blood levels of nitrite and NOx, but sustained the increases for a longer period of time, compared to placebo,” said Dr. Willoughby, Baylor University, associate professor, Health, Human Performance, and Recreation, director, Exercise and Biochemical Nutritional Lab. “The results of this first-of-its kind study indicate that Setria® Glutathione and L-citrulline may play a role in muscle protein synthesis and muscle performance when combined with resistance exercise.”
Study was funded by Kyowa Hakko Bio Co., Ltd which is patent holder of Setria® Glutathione and manufacturer of L-citrulline and many other amino acids. Also, a participating researchers Masahiko Morita is an employee of this company.
Side Effects of Citrulline
Citrulline malate appears to be well tolerated even at doses high doses [2,5]. It has been administered in doses as high as 15 g to healthy, male adults without any nausea, diarrhoea, or any other side effect . However, Pérez-Guisado et al.  reported stomach discomfort in 14.63% of the subjects at 8 grams per day. Other than that CM was reported to have excellent acceptability among asthenia patients .
- Watermelon May Have Viagra-Effect Retrieved from http://www.sciencedaily.com/ at 10. Feb 2013
Takeda, Kohei, et al. “Effects of citrulline supplementation on fatigue and exercise performance in mice.” Journal of nutritional science and vitaminology 57.3 (2011): 246-250.
Curis, Emmanuel, Pascal Crenn, and Luc Cynober. “Citrulline and the gut.” Current Opinion in Clinical Nutrition & Metabolic Care 10.5 (2007): 620-626.
Bendahan, David, et al. “CM promotes aerobic energy production in human exercising muscle.” British journal of sports medicine 36.4 (2002): 282-289.
Giannesini, Benoît, et al. “CM supplementation increases muscle efficiency in rat skeletal muscle.” European journal of pharmacology 667.1 (2011): 100-104.
Pérez-Guisado, Joaquín, and Philip M. Jakeman. “Citruline malate enhances athletic anaerobic performance and relieves muscle soreness.” The Journal of Strength & Conditioning Research 24.5 (2010): 1215.
Hickner, Robert C., et al. “L-citrulline reduces time to exhaustion and insulin response to a graded exercise test.” Medicine and science in sports and exercise 38.4 (2006): 660-666.
Goubel, Francis, et al. “CM limits increase in muscle fatigue induced by bacterial endotoxins.” Canadian journal of physiology and pharmacology 75.3 (1997): 205-207.
Callis, A., et al. “Activity of CM on acid-base balance and blood ammonia and amino acid levels. Study in the animal and in man.” Arzneimittel-Forschung 41.6 (1991): 660-663.
Solomonson, Larry P., et al. “The caveolar nitric oxide synthase/arginine regeneration system for NO production in endothelial cells.” Journal of Experimental Biology 206.12 (2003): 2083-2087.
Sureda, Antoni, et al. “L-CM influence over branched chain amino acid utilization during exercise.” European journal of applied physiology 110.2 (2010): 341-351.
- Wax, Benjamin, et al. “Effects of supplemental citrulline malate ingestion during repeated bouts of lower-body exercise in advanced weightlifters.” The Journal of Strength & Conditioning Research 29.3 (2015): 786-792.
- Cunniffe, Brian, et al. “Acute CM supplementation and high-intensity cycling performance.” Journal of strength and conditioning research/National Strength & Conditioning Association (2016).
- Cutrufello, Paul T., Stephen J. Gadomski, and Gerald S. Zavorsky. “The effect of l-citrulline and watermelon juice supplementation on anaerobic and aerobic exercise performance.” Journal of sports sciences 33.14 (2015): 1459-1466.
- Moinard, C., et al. “Dose-ranging effects of C administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study.” British journal of nutrition 99.04 (2008): 855-862.
- Castillo, L. E. T. I. C. I. A., et al. “Dietary arginine uptake by the splanchnic region in adult humans.” American Journal of Physiology-Endocrinology And Metabolism 265.4 (1993): E532-E539.
- McKinley-Barnard, Sarah, et al. “Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis.” Journal of the International Society of Sports Nutrition 12.1 (2015): 1.
- Orozco-Gutiérrez, Juan José, et al. “Effect of L-arginine or L-citrulline oral supplementation on blood pressure and right ventricular function in heart failure patients with preserved ejection fraction.” Cardiol J 17.6 (2010): 612-618.