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).
It has been shown that 4 to 10 grams of citrulline malate is an appropriate dose for improving exercise performance and boosting pre-workout NO levels . For reducing blood pressure doses around 3 to 6 grams daily seem to be effective.
Citrulline vs. Arginine
During high-intensity exercise, the concentration of ammonia (a byproduct of muscle metabolism) is widespread 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 a 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 bloodstream .
Citrulline malate as Performance Enhancer
L-citrulline was once considered mainly as a metabolic intermediate in the urea cycle. It has only recently been shown that it plays an important role in the metabolism and regulation of nitric oxide.
L-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 citrulline malate per day increased aerobic performance. Pérez-Guisado and colleagues  experimented with 8 g/day of citrulline malate and concluded that its use might be useful to increase athletic performance in high-intensity anaerobic exercises. They reported that a single 8 g dose of citrulline malate increased performance by an average of 19%, measured as the number of repetitions performed . Wax, et al.  reported that advanced weightlifters ingesting 8 grams of citrulline malate performed a 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. 8 g of CM has also significantly increased the number of repetitions during upper body resistance exercise in college-age resistance-trained males .
In a double-blind, placebo-controlled, crossover study , 10 well-trained males consumed either 12 g of citrulline malate 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 a total number of repetitions, time to exhaustion, VO2max, anaerobic threshold, or flow-mediated vasodilation was reported by Cutrufello and colleagues .
A 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 .
That is why no modern pre-workout or pump-boosting supplement is complete without citrulline. However, keep in mind that many of these results are preliminary and still need confirmation in larger clinical trials. Nevertheless, the research that exists is encouraging and without any hidden dangers.
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.
Nutrients with Possible Synergetic Effects for Athletic 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 the 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.”
The 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.
Better Glutathione Delivery Options …
A study sponsored by Laboratoires Le Stum  reported that oral administration of glutathione is not considered optimal due to its very poor bioavailability and rapid oxidation. Other indirect means have been developed to circumvent this problem. One of them is the oral delivery of N-acetylcysteine as a source of cysteine. After N-acetylcysteine is absorbed in the intestine, it undergoes the first-pass metabolism in the liver where it is deacetylated to cysteine. Then liver tissue synthesizes new glutathione from this cysteine. This glutathione replenishes the liver stock before being released in the plasma.
Results of this study also suggest that the sublingual glutathione form exhibits a better bioavailability than the oral glutathione. One possible explanation for poor bioavailability of oral glutathione is that it undergoes partial hydrolysis and oxidation during the digestive process. With the sublingual dosage form, the glutathione is directly assimilated through the buccal mucosa and avoid the hepatic first-pass effect.
Branched Chain Amino Acids
Branched-chain amino acids (which are the essential amino acids valine, isoleucine, and leucine) are involved with muscle protein synthesis and degradation. Citrulline malate has been shown to enhance the use of amino acids, especially branched-chain amino acids during exercise  suggesting a synergetic effect.
Sodium bicarbonate or baking soda is a sports supplement that is known for increasing athletic performance. A study by Callis et al.  showed that citrulline malate stimulates synthesis of urea in the liver and improves the renal reabsorption of bicarbonates.
Beetroot juice contains nitrate which is a nitric oxide donor and is beetroots main bioactive constituent. Citrulline malate has been shown to increase nitrite , which is reduced from nitrate.
L-citrulline is the free version of amino acid citrulline, while citrulline malate has a molecule of malic acid attached to it. Malate, or malic acid, is a compound that is usually used as a food preservative it also contributes to the sour flavour of apples and other fruit. As a supplement, malate it is bound to citrulline and other various other supplements to give them stability in the body. Malic acid plays an important role in energy metabolism by helping the body recycle lactic acid and use it for energy. It appears that malate is synergistic when bonded to citrulline and their combination may work better than supplementation of citrulline alone.
Citrulline has been shown to have a potential to affect protein metabolism via various mechanisms . Animal , as well as human studies , are showing increased muscle protein synthesis with a citrulline-enriched diet as compared to a supplement of non-essential amino acids with the same nitrogen content. In a previously mentioned study by McKinley-Barnard et al.  sixty-six healthy volunteers who supplemented with citrulline and reduced glutathione exhibited an improvement in cGMP activity, suggesting direct effects on
muscle protein synthesis and muscle performance. On the other hand, a study by Thibault et al.  in well-nourished volunteers and Bouillanne’s study  in 29 moderately malnourished elderly subjects both reported no changes in whole-body protein synthesis. However, Bouillanne et al.  reported higher muscle mass and fat-free mass, and lower fat mass with 3-week citrulline supplementation (10 g/day) than controls supplemented with non-essential amino acids.
Data also suggest an involvement of the mTOR pathway in the effect of citrulline on protein synthesis . Additionally, NOS activity is necessary for calcium-induced activation of the Akt pathway through a cGMP/PI3K-dependent pathway. Serum nitrite (reduced form of nitrate) increases during exercise following consumption of 6g citrulline malate  which has been shown to enhance mTOR activity and cell proliferation of myoblasts .
Supplementing with 6g citrulline malate prior to a prolonged (137km) cycling test has been shown to increase growth hormone to a higher level than exercise alone ; the citrulline group had 66.8% higher growth hormone concentration compared to placebo group. Moinard, C., et al.  on the other hand reported that plasma growth hormone was unaffected with doses of 2-15g when at rest.
Citrulline supplementation does not affect plasma insulin concentrations [11, 36, 40].
Decreases in brachial systolic blood pressure (SBP) and diastolic blood pressure (DBP) have been reported in patients with heart failure after 8 weeks of L-citrulline supplementation (3g/daily) . Same was noted in prehypertensive and hypertensive obese postmenopausal women after 8 weeks with a higher dose (6g/daily) . However, in seemingly healthy population, l-citrulline in either watermelon  or in synthetic  form does not seem to reduce blood pressure.
Production of NO by vascular endothelial cell NOS is essential for normal cardiovascular regulation which depends on the availability of L-arginine. Short L-arginine supply has been linked to cardiovascular diseases, including hypertension, atherosclerosis, diabetic vascular disease, hyperhomocysteinemia, heart failure and ischemia-reperfusion injury . However, it has been reported, in rabbits, that with chronic therapy the benefits of supplemental L-arginine are not maintained or may convert to a negative outcome . While clinical trial in humans showed that patients receiving supplemental L-arginine (9 g/day for 6 months) following myocardial infarction were associated with higher mortality . A large portion of orally administered L-arginine is catabolized by arginase to ornithine and urea in the liver . Furthermore, high levels of dietary or circulating L-arginine can increase arginase activity which increases the rate of L-arginine catabolism . Therefore, in most of the work in the cardiovascular area, citrulline is given with the intention of boosting levels of arginine and as a NO precursor. L-citrulline being a natural precursor for L-arginine plays an important role in supplying L-arginine to NOS as it bypasses metabolism in the liver and it is not an inducer of arginase .
It is therefore not surprising that a study from 2010 that involved subjects with heart failure found that consumption of 3g citrulline for two months helped improve performance on a treadmill and also resulted in lower blood pressure and better heart function (arginine was equally effective but required a higher dose of 8g) . Another study found that healthy male subjects who consumed 5.6 g/day of L-citrulline a day for seven days had improved arterial function because arterial walls were less stiff, compared to a placebo group .
Citrulline is believed to be a pro-erectile supplement as it is a precursor for arginine and has also been reported to ease symptoms of mild-to-moderate erectile dysfunction .
Side Effects of Citrulline
Citrulline malate appears to be well tolerated even at doses high doses [2,5] and because it is a natural amino acid, it’s generally considered safe. It has been administered in doses as high as 15g 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 .
(Other names: 2-amino-5-(carbamoylamino)pentanoic acid, L-Citrulina, L-Citrulline-Alpha Ketoglutaric Acid, Citrulline DL-Malate, Watermelon extract, Stimol)
- 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.
- Wax, Benjamin, Andreas N. Kavazis, and William Luckett. “Effects of supplemental citruline-malate ingestion on blood lactate, cardiovascular dynamics, and resistance exercise performance in trained males.” Journal of dietary supplements13.3 (2016): 269-282.
- Orozco-Gutiérrez, Juan José, et al. “Effect of L-arginine or L-citruline oral supplementation on blood pressure and right ventricular function in heart failure patients with preserved ejection fraction.” Cardiology journal 17.6 (2010): 612-618.
- Morita, Masahiko, et al. “Effects of oral L-citrulline supplementation on lipoprotein oxidation and endothelial dysfunction in humans with vasospastic angina.” Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Immunology, Endocrine and Metabolic Agents) 13.3 (2013): 214-220.
- Bailey, Stephen J., et al. “Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans.” Nitric Oxide 59 (2016): 10-20.
- Ochiai, Masayuki, et al. “Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men.” International journal of cardiology 155.2 (2012): 257-261.
- Cormio, Luigi, et al. “Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction.” Urology 77.1 (2011): 119-122.
- Schmitt, Bernard, et al. “Effects of N-acetylcysteine, oral glutathione (GSH) and a novel sublingual form of GSH on oxidative stress markers: A comparative crossover study.” Redox biology 6 (2015): 198-205.
- Romero, Maritza J., et al. “Therapeutic use of citrulline in cardiovascular disease.” Cardiovascular Therapeutics 24.3‐4 (2006): 275-290.
- Jeremy, Richmond W., Hugh McCarron, and David Sullivan. “Effects of Dietary L-Arginine on Atherosclerosis and Endothelium-Dependent Vasodilatationin the Hypercholesterolemic Rabbit: Response According to Treatment Duration, Anatomic Site, and Sex.” Circulation 94.3 (1996): 498-506.
- Schulman, Steven P., et al. “L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.” Jama 295.1 (2006): 58-64.
- Morris Jr, Sidney M. “Regulation of enzymes of urea and arginine synthesis.” Annual review of nutrition 12.1 (1992): 81-101.
- Shearer, JEFFRY D., et al. “Differential regulation of macrophage arginine metabolism: a proposed role in wound healing.” American Journal of Physiology-Endocrinology And Metabolism 272.2 (1997): E181-E190.
- Orea-Tejeda, Arturo, et al. “The effect of L-arginine and citrulline on endothelial function in patients in heart failure with preserved ejection fraction.” Cardiology journal 17.5 (2010): 464-470.
- Ochiai, Masayuki, et al. “Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men.” International journal of cardiology 155.2 (2012): 257-261.
- Breuillard, C., L. Cynober, and C. Moinard. “Citrulline and nitrogen homeostasis: an overview.” Amino Acids 47.4 (2015): 685-691.
- Osowska, Sylwia, et al. “Citruline modulates muscle protein metabolism in old malnourished rats.” American Journal of Physiology-Endocrinology and Metabolism 291.3 (2006): E582-E586.
- Jourdan, Marion, et al. “Citrulin stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet–A pilot study.” Clinical Nutrition 34.3 (2015): 449-456.
- Thibault, Ronan, et al. “Oral citruline does not affect whole body protein metabolism in healthy human volunteers: results of a prospective, randomized, double-blind, cross-over study.” Clinical nutrition 30.6 (2011): 807-811.
- Bouillanne, O., et al. “Effects of CIT Oral Supplementation During 21 Days on Body Composition in Malnourished Elderly Patients.” Clinical Nutrition 34 (2015): S17-S18.
- Papadia, Cinzia, et al. “Citrulline in health and disease. Review on human studies.” Clinical Nutrition (2017).
- Callis, A., et al. “Activity of citrulline malate 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.
- Moinard, C., et al. “Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study.” British journal of nutrition 99.4 (2008): 855-862.