L-CITRULLINE

OTHER NAME(S):

2-amino-5-(carbamoylamino)pentanoic acid, Citrulline, Citrulline Malate, L-Citrulina, L-Citrulline AKG, L-Citrulline-Alpha Ketoglutaric Acid, L-Citrulline Malate, Malate de Citrulline.

Overview

Overview Information

L-citrulline is an amino acid. But unlike some amino acids, L-citrulline is not used to make protein. It is found in watermelon. The name "citrulline" comes from "citrullus," which is the Latin term for watermelon. The body can also make citrulline.

L-citrulline is used for heart failure and improving athletic performance. It is also used for sickle cell disease, erectile dysfunction, high blood pressure in the lungs, and many other conditions, but there is no good scientific evidence to support these other uses.

How does it work?

L-citrulline is a naturally occurring amino acid found in food, such as watermelon. It is also made naturally in the body. The body changes L-citrulline into another amino acid called L-arginine and also to a chemical called nitric oxide. L-citrulline might help increase the supply of ingredients the body needs to make certain proteins. It might also help open up veins and arteries to improve blood flow and reduce blood pressure.

Uses

Uses & Effectiveness?

Possibly Effective for

  • Athletic performance. Taking L-citrulline by mouth might be effective for improving some types of exercise performance when taken for up to 7 days. L-citrulline may help some athletes work harder, lift weights longer, and go faster on an exercise bike. But it does not seem to help people run for longer distances. Also, taking L-citrulline for up to 8 weeks does not seem to increase muscle size or strength.
  • Heart failure. L-citrulline can help people with heart failure who are already treated with standard medications. Taking L-citrulline by mouth seems to reduce blood pressure in the lungs in these patients. This helps the heart work better, allowing people with heart failure to walk farther.

Insufficient Evidence for

  • Erectile dysfunction (ED). Taking L-citrulline by mouth seems to improve sexual function in some men with erectile dysfunction.
  • An inherited disorder marked by the body's inability to properly break down the amino acids lysine, arginine, and ornithine (lysinuric protein intolerance). Taking L-citrulline with meals may improve symptoms in children with this condition.
  • A group of inherited disorders that cause muscle weakness and muscle loss (muscular dystrophy). Early research shows that taking L-citrulline with or without the drug metformin may improve muscle function and reduce muscle loss in adults or children with less severe muscular dystrophy. But it doesn't seem to help children with more severe muscle weakness.
  • High blood pressure in arteries in the lungs after surgery (postoperative pulmonary hypertension). Higher levels of L-citrulline in the blood might help reduce the high blood pressure that can occur after heart surgery in children. Some people have naturally higher levels. Taking L-citrulline increases blood levels in some people.
  • High blood pressure in arteries in the lungs (pulmonary hypertension). Taking L-citrulline by mouth may lower blood pressure in the lungs and help people with pulmonary hypertension walk farther.
  • Sickle cell disease. Taking L-citrulline by mouth might improve some symptoms in people with sickle cell disease.
  • Alzheimer disease.
  • A disorder that causes brain and liver damage (Reye syndrome).
  • Diabetes.
  • Diseases, such as Alzheimer disease, that interfere with thinking (dementia).
  • Fatigue.
  • Heart disease.
  • High blood pressure.
  • Tissue damage caused when there is limited blood flow and then blood flow is restored (ischemia-reperfusion injury).
  • Other conditions.
More evidence is needed to rate the effectiveness of L-citrulline for these uses.

Side Effects

Side Effects & Safety

When taken by mouth: L-citrulline is POSSIBLY SAFE for most adults when taken by mouth in appropriate amounts. Although side effects are rare, L-citrulline can cause stomach upset, heartburn, cough, changes in urination, and swelling in some people.

Special Precautions & Warnings:

Pregnancy and breastfeeding: There isn't enough reliable information to know if L-citrulline is safe to use when pregnant or breast-feeding. Stay on the safe side and avoid use.

Children: L-citrulline is POSSIBLY SAFE when taken by mouth or when given by IV in appropriate amounts.

Interactions

Interactions?

We currently have no information for L-CITRULLINE Interactions.

Dosing

Dosing

The following doses have been studied in scientific research:

ADULTS

BY MOUTH:

  • For athletic performance: 2.4 grams or 5 grams daily for 7 days. A single dose of 8 grams just before exercise has also been used. L-citrulline maleate 2 grams daily for up to 8 weeks has also been used. 1.2 grams daily plus L-arginine 1.2 grams daily for 7 days has also been used.
  • For heart failure: 3 grams daily for 2-4 months.

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Next: Uses

View References

REFERENCES:

  • Barr FE, Tirona RG, Taylor MB, et al. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg 2007;134:319-26. View abstract.
  • Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr 2001;138:S56-61. View abstract.
  • Carpenter TO, Levy HL, Holtrop ME, et al. Lysinuric protein intolerance presenting as childhood osteoporosis. Clinical and skeletal response to citrulline therapy. New Engl J Med 1985;312:290-4. View abstract.
  • Collins JK, Wu G, Perkins-Veazie P, et al. Watermelon consumption increases plasma arginine concentrations in adults. Nutrition 2007;23:261-6. View abstract.
  • Curis E, Nicolis I, Moinard C, et al. Almost all about citrulline in mammals. Amino Acids 2005;29:177-205. View abstract.
  • Hayashi T, Juliet PAR, Matsui-Hirai H, et al. L-citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci U S A 2005;102:13681-6. View abstract.
  • Hickner RC, Tanner CJ, Evans CA, et al. L-citrulline reduces time to exhaustion and insulin response to a graded exercise test. Med Sci Sports Exerc 2006;38:660-6. View abstract.
  • Mandel H, Levy N, Izkovitch S, Korman SH. Elevated plasma citrulline and arginine due to consumption of Citrullus vulgaris (watermelon). J Inherit Metab Dis 2005;28:467-72. View abstract.
  • Moinard C, Nicolis I, Neveux N, et al. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. Br J Nutr 2008;99:855-62. View abstract.
  • Osowska S, Duchemann T, Walrand S, et al. Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab 2006;291:E582-6. View abstract.
  • Osowska S, Moinard C, Neveux N, et al. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut 2004;53:1781-6. View abstract.
  • Romero MJ, Platt DH, Caldwell RB, Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev 2006;24:275-90. View abstract.
  • Ruiz E, Del Rio M, Somoza B, et al. L-citrulline, the by-product of nitric oxide synthesis, decreases vascular smooth muscle cell proliferation. J Pharmacol Exp Therap 1999;290:310-3. View abstract.
  • Ruiz E, Tejerina T. Relaxant effects of L-citrulline in rabbit vascular smooth muscle. Br J Pharmacol 1998;125:186-92. View abstract.
  • Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9. View abstract.
  • Smith HA, Canter JA, Christian KG, et al. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg 2006;132:58-65. View abstract.
  • Tremblay GC. Ornithine or citrulline therapy in treatment of Reye's syndrome (letter). New Engl J Med 1975;292:160-1. View abstract.
  • Waugh WH, Daeschner CW 3rd, Files BA, et al. Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc 2001;93:363-71. View abstract.
  • Bailey SJ, Blackwell JR, Lord T, et al. l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. J Appl Physiol (1985) 2015;119:385-95. View abstract.
  • Balderas-Munoz K, Castillo-Martínez L, Orea-Tejeda A, et al. Improvement of ventricular function in systolic heart failure patients with oral L-citrulline supplementation. Cardiol J 2012;19:612-7. View abstract.
  • Barr FE, Tirona RG, Taylor MB, et al. Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: potential therapy for postoperative pulmonary hypertension. J Thorac Cardiovasc Surg 2007;134:319-26. View abstract.
  • Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr 2001;138:S56-61. View abstract.
  • Carpenter TO, Levy HL, Holtrop ME, et al. Lysinuric protein intolerance presenting as childhood osteoporosis. Clinical and skeletal response to citrulline therapy. New Engl J Med 1985;312:290-4. View abstract.
  • Collins JK, Wu G, Perkins-Veazie P, et al. Watermelon consumption increases plasma arginine concentrations in adults. Nutrition 2007;23:261-6. View abstract.
  • Cormio L, De Siati M, Lorusso F, et al. Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology 2011;77:119-22. View abstract.
  • Curis E, Nicolis I, Moinard C, et al. Almost all about citrulline in mammals. Amino Acids 2005;29:177-205. View abstract.
  • Cutrufello PT, Gadomski SJ, Zavorsky GS. The effect of l-citrulline and watermelon juice supplementation on anaerobic and aerobic exercise performance. J Sports Sci 2015;33:1459-66. View abstract.
  • Figueroa A, Trivino JA, Sanchez-Gonzalez MA, Vicil F. Oral L-citrulline supplementation attenuates blood pressure response to cold pressor test in young men. Am J Hypertens 2010;23:12-6. View abstract.
  • Hafner P, Bonati U, Klein A, et al. Effect of combination L-citrulline and metformin treatment on motor function in patients with Duchenne muscular dystrophy: a randomized clinical trial. JAMA Netw Open. 2019;2(10):e1914171. View abstract.
  • Hanff E, Hafner P, Bollenbach A, et al. Effects of single and combined metformin and L-citrulline supplementation on L-arginine-related pathways in Becker muscular dystrophy patients: possible biochemical and clinical implications. Amino Acids. 2018;50(10):1391-1406. View abstract.
  • Hayashi T, Juliet PAR, Matsui-Hirai H, et al. L-citrulline and L-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proc Natl Acad Sci U S A 2005;102:13681-6. View abstract.
  • Hickner RC, Tanner CJ, Evans CA, et al. L-citrulline reduces time to exhaustion and insulin response to a graded exercise test. Med Sci Sports Exerc 2006;38:660-6. View abstract.
  • Hwang P, Morales Marroquín FE, Gann J, et al. Eight weeks of resistance training in conjunction with glutathione and L-Citrulline supplementation increases lean mass and has no adverse effects on blood clinical safety markers in resistance-trained males. J Int Soc Sports Nutr 2018;15(1):30. View abstract.
  • Kameda N, Okigawa T, Kimura T, et al. The effect of L-citrulline ingestion on ECG QT interval and autonomic nervous system activity. J Physiol Anthropol 2011;30:41-5. View abstract.
  • Mandel H, Levy N, Izkovitch S, Korman SH. Elevated plasma citrulline and arginine due to consumption of Citrullus vulgaris (watermelon). J Inherit Metab Dis 2005;28:467-72. View abstract.
  • Martínez-Sánchez A, Alacid F, Rubio-Arias JA, Fernández-Lobato B, Ramos-Campo DJ, Aguayo E. Consumption of watermelon juice enriched in l-citrulline and pomegranate ellagitannins enhanced metabolism during physical exercise. J Agric Food Chem 2017;65(22):4395-4404. View abstract.
  • McKinley-Barnard S, Andre T, Morita M, Willoughby DS. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis. J Int Soc Sports Nutr 2015;12:27. View abstract.
  • Mirenayat MS, Moradi S, Mohammadi H, Rouhani MH. Effect of L-citrulline supplementation on blood pressure: a systematic review and meta-analysis of clinical trials. Curr Hypertens Rep. 2018;20(11):98. View abstract.
  • Moinard C, Nicolis I, Neveux N, et al. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. Br J Nutr 2008;99:855-62. View abstract.
  • Nguyen S, Rajfer J, Shaheen M. Safety and efficacy of daily Revactin in men with erectile dysfunction: a 3-month pilot study. Transl Androl Urol. 2018;7(2):266-73. View abstract.
  • Ochiai M, Hayashi T, Morita M, et al. Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men. Int J Cardiol 2012;155:257-61. View abstract.
  • Orozco-Gutiérrez JJ, Castillo-Martínez L, Orea-Tejeda A, 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 2010;17:612-8. View abstract.
  • Osowska S, Duchemann T, Walrand S, et al. Citrulline modulates muscle protein metabolism in old malnourished rats. Am J Physiol Endocrinol Metab 2006;291:E582-6. View abstract.
  • Osowska S, Moinard C, Neveux N, et al. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut 2004;53:1781-6. View abstract.
  • Pérez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res 2010;24:1215-22. View abstract.
  • Romero MJ, Platt DH, Caldwell RB, Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev 2006;24:275-90. View abstract.
  • Ruiz E, Del Rio M, Somoza B, et al. L-citrulline, the by-product of nitric oxide synthesis, decreases vascular smooth muscle cell proliferation. J Pharmacol Exp Therap 1999;290:310-3. View abstract.
  • Ruiz E, Tejerina T. Relaxant effects of L-citrulline in rabbit vascular smooth muscle. Br J Pharmacol 1998;125:186-92. View abstract.
  • Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. Br J Clin Pharmacol 2008;65:51-9. View abstract.
  • Sharif Kashani B, Tahmaseb Pour P, Malekmohammad M, et al. Oral l-citrulline malate in patients with idiopathic pulmonary arterial hypertension and Eisenmenger Syndrome: a clinical trial. J Cardiol 2014;64:231-5. View abstract.
  • Smith HA, Canter JA, Christian KG, et al. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrulline. J Thorac Cardiovasc Surg 2006;132:58-65. View abstract.
  • Sureda A, Córdova A, Ferrer MD, et al. L-citrulline-malate influence over branched chain amino acid utilization during exercise. Eur J Appl Physiol 2010;110:341-51. View abstract.
  • Suzuki I, Sakuraba K, Horiike T, et al. A combination of oral L-citrulline and L-arginine improved 10-min full-power cycling test performance in male collegiate soccer players: a randomized crossover trial. Eur J Appl Physiol 2019;119(5):1075-84. View abstract.
  • Suzuki T, Morita M, Kobayashi Y, Kamimura A. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover study. J Int Soc Sports Nutr 2016;13:6. View abstract.
  • Tremblay GC. Ornithine or citrulline therapy in treatment of Reye's syndrome (letter). New Engl J Med 1975;292:160-1. View abstract.
  • Waugh WH, Daeschner CW 3rd, Files BA, et al. Oral citrulline as arginine precursor may be beneficial in sickle cell disease: early phase two results. J Natl Med Assoc 2001;93:363-71. View abstract.

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