L-Citrulline, watermelon extract, Citrulline

Citrulline is a non-essential amino acid that participates in the urea cycle and increases the plasma levels of ornithine and arginine in the body, improving the ammonia recycling process and nitric oxide metabolism. Consequently, citrulline acts where nitric oxide is used, such as cardiovascular health, athletic performance and erectile dysfunction.

  • Origin: Plant Based, Animal Product, Nonessential
  • Source: Milk, Eggs, Meat, Fish, Nonessential, Watermelon, Melon, Pumpkin, Cucumber
  • Type: Amino Acids
  • Age Range: Adults, Seniors
  • Toxicity: May be toxic in high doses
  • Outcomes: Muscle Health, Fatigue Prevention

What are Citrulline benefits?

Citrulline, also known as L-citrulline, is one of three dietary amino acids in the urea cycle, alongside L-arginine and L-ornithine. Intake of L-citrulline increases plasma levels of ornithine and arginine, improving the process of ammonia recycling and nitric oxide metabolism. It is worth noting that citrulline can be found in watermelon. In addition, according to scientific evidence, several benefits of citrulline supplementation have been found in research, suggesting that it can: reduce blood pressure and improve blood flow, especially for people with hypertension and other cardiovascular problems; improve strength production; reduce fatigue; and provide greater endurance for aerobic and anaerobic exercise.

Table of relations

Consistent effects
Strength of effects
Scientific articles

Muscle Health Citrulline and Muscle Health

The muscles are responsible for body movement, stabilization, regulation of organs, substance transportation and production of heat in addition to being strongly associated with the circulatory and nervous systems. Muscle quality is essential for well being. Supplements that help keep muscles healthy are related to different factors, such as glucose and insulin regulation, protein synthesis, energy metabolism, and others.
  • Fatigue Prevention

    Fatigue is characterized by a reduction in mental energy. It can also appear as acute and/or chronic fatigue. Acute fatigue is due to excessive mentally demanding work. Chronic fatigue is multifactorial, influenced by insomnia, stress, anxiety, depression, causing tiredness and constant lack of motivation. The substances indicated for fatigue help to improve sleep and mood problems as they are neuroprotective, affecting neurological function.

Table of negative interactions


Related videos about Citrulline


  1. a b Figueroa A, et al. Effects of watermelon supplementation on aortic blood pressure and wave reflection in individuals with prehypertension: a pilot studyAm J Hypertens. (2011)
  2. a b Kaore SN, Amane HS, Kaore NM. Citrulline: pharmacological perspectives and its role as an emerging biomarker in futureFundam Clin Pharmacol. (2013)
  3. ^ Rimando AM, Perkins-Veazie PM. Determination of citrulline in watermelon rindJ Chromatogr A. (2005)
  4. ^ Mandel H, et al. Elevated plasma citrulline and arginine due to consumption of Citrullus vulgaris (watermelon)J Inherit Metab Dis. (2005)
  5. ^ Tangphao O, et al. Pharmacokinetics of intravenous and oral L-arginine in normal volunteersBr J Clin Pharmacol. (1999)
  6. ^ Collins JK, et al. Watermelon consumption increases plasma arginine concentrations in adultsNutrition. (2007)
  7. a b Curis E, et al. Almost all about citrulline in mammalsAmino Acids. (2005)
  8. ^ Metabolism of citrulline in man.
  9. ^ Tomlinson C, et al. Arginine synthesis from enteral glutamine in healthy adults in the fed stateAm J Physiol Endocrinol Metab. (2011)
  10. ^ van de Poll MC, et al. Intestinal and hepatic metabolism of glutamine and citrulline in humansJ Physiol. (2007)
  11. ^ van de Poll MC, et al. Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolismAm J Clin Nutr. (2007)
  12. a b c d e f g h Rougé C, et al. Manipulation of citrulline availability in humansAm J Physiol Gastrointest Liver Physiol. (2007)
  13. ^ Bommarius AS, Makryaleas K, Drauz K. An enzymatic route to L-ornithine from L-arginine–activation and stabilization studies on L-arginaseBiomed Biochim Acta. (1991)
  14. ^ Bommarius AS, Drauz K. An enzymatic route to L-ornithine from arginine–activation, selectivity and stabilization of L-arginaseBioorg Med Chem. (1994)
  15. a b Häberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disordersOrphanet J Rare Dis. (2012)
  16. a b Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes.
  17. ^ Enzymes of Arginine Metabolism.
  18. ^ Lameu C, de Camargo AC, Faria M. L-arginine signalling potential in the brain: the peripheral gets centralRecent Pat CNS Drug Discov. (2009)
  19. ^ Flam BR, Eichler DC, Solomonson LP. Endothelial nitric oxide production is tightly coupled to the citrulline-NO cycleNitric Oxide. (2007)
  20. a b Dhanakoti SN, et al. Renal arginine synthesis: studies in vitro and in vivoAm J Physiol. (1990)
  21. a b c d e f g h i j Sureda A, et al. L-citrulline-malate influence over branched chain amino acid utilization during exerciseEur J Appl Physiol. (2010)
  22. a b c d e f g h i j k l Thibault R, et al. Oral citrulline does not affect whole body protein metabolism in healthy human volunteers: results of a prospective, randomized, double-blind, cross-over studyClin Nutr. (2011)
  23. a b c d e Moinard C, et al. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic studyBr J Nutr. (2008)
  24. ^ Curis E, Crenn P, Cynober L. Citrulline and the gutCurr Opin Clin Nutr Metab Care. (2007)
  25. ^ Bahri S, et al. Mechanisms and kinetics of citrulline uptake in a model of human intestinal epithelial cellsClin Nutr. (2008)
  26. a b Sureda A, et al. Effects of L-citrulline oral supplementation on polymorphonuclear neutrophils oxidative burst and nitric oxide production after exerciseFree Radic Res. (2009)
  27. ^ Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism.
  28. ^ Intestinal and hepatic metabolism of glutamine and citrulline in humans.
  29. ^ Source and fate of circulating citrulline.
  30. ^ Levillain O, Parvy P, Hassler C. Amino acid handling in uremic rats: citrulline, a reliable marker of renal insufficiency and proximal tubular dysfunctionMetabolism. (1997)
  31. ^ Whole body nitric oxide synthesis in healthy men determined from {15N} arginine-to-{15N}citrulline labeling.
  32. ^ Sase A, et al. Changes of hippocampal beta-alanine and citrulline levels are paralleling early and late phase of retrieval in the Morris Water MazeBehav Brain Res. (2013)
  33. ^ Orozco-Gutiérrez JJ, 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 fractionCardiol J. (2010)
  34. ^ Orea-Tejeda A, et al. The effect of L-arginine and citrulline on endothelial function in patients in heart failure with preserved ejection fractionCardiol J. (2010)
  35. ^ Kameda N, et al. The effect of L-citrulline ingestion on ECG QT interval and autonomic nervous system activityJ Physiol Anthropol. (2011)
  36. ^ Ochiai M, et al. Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged menInt J Cardiol. (2012)
  37. ^ Changes in central artery blood pressure and wave reflection during a cold pressor test in young adults.
  38. ^ Ahlund C, Pettersson K, Lind L. Pulse wave analysis on fingertip arterial pressure: effects of age, gender and stressors on reflected waves and their relation to brachial and femoral artery blood flowClin Physiol Funct Imaging. (2008)
  39. ^ West SG, et al. Oral L-arginine improves hemodynamic responses to stress and reduces plasma homocysteine in hypercholesterolemic menJ Nutr. (2005)
  40. ^ Figueroa A, et al. Oral L-citrulline supplementation attenuates blood pressure response to cold pressor test in young menAm J Hypertens. (2010)
  41. ^ Smith HA, et al. Nitric oxide precursors and congenital heart surgery: a randomized controlled trial of oral citrullineJ Thorac Cardiovasc Surg. (2006)
  42. ^ Nakata M, Yada T. Endocrinology: nitric oxide-mediated insulin secretion in response to citrulline in islet beta-cellsPancreas. (2003)
  43. a b Nakata M, et al. Citrulline-argininosuccinate-arginine cycle coupled to Ca2+-signaling in rat pancreatic beta-cellsBiochem Biophys Res Commun. (1997)
  44. a b c Hickner RC, et al. L-citrulline reduces time to exhaustion and insulin response to a graded exercise testMed Sci Sports Exerc. (2006)
  45. ^ Faure C, et al. Citrulline enhances myofibrillar constituants expression of skeletal muscle and induces a switch in muscle energy metabolism in malnourished aged ratsProteomics. (2013)
  46. a b c d e f g Giannesini B, et al. Citrulline malate supplementation increases muscle efficiency in rat skeletal muscleEur J Pharmacol. (2011)
  47. a b Bendahan D, et al. Citrulline/malate promotes aerobic energy production in human exercising muscleBr J Sports Med. (2002)
  48. ^ Bescós R, et al. Acute administration of inorganic nitrate reduces VO(2peak) in endurance athletesMed Sci Sports Exerc. (2011)
  49. ^ Bailey SJ, et al. Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise toleranceJ Appl Physiol. (2010)
  50. ^ Brown GC. Nitric oxide and mitochondrial respirationBiochim Biophys Acta. (1999)
  51. ^ Briand J, et al. Use of a microbial model for the determination of drug effects on cell metabolism and energetics: study of citrulline-malateBiopharm Drug Dispos. (1992)
  52. a b c d 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 manArzneimittelforschung. (1991)
  53. ^ Demura S, et al. The effect of L-ornithine hydrochloride ingestion on performance during incremental exhaustive ergometer bicycle exercise and ammonia metabolism during and after exerciseEur J Clin Nutr. (2010)
  54. ^ Sugino T, et al. L-ornithine supplementation attenuates physical fatigue in healthy volunteers by modulating lipid and amino acid metabolismNutr Res. (2008)
  55. ^ Ammonia Production in Muscle and other Tissues: the Purine Nucleotide Cycle.
  56. ^ Regulation of the urea cycle and TCA cycle by ammonia.
  57. ^ Fitts RH, Balog EM. Effect of intracellular and extracellular ion changes on E-C coupling and skeletal muscle fatigueActa Physiol Scand. (1996)
  58. a b c Takeda K, et al. Effects of citrulline supplementation on fatigue and exercise performance in miceJ Nutr Sci Vitaminol (Tokyo). (2011)
  59. a b c d e Le Plénier S, et al. Effects of leucine and citrulline versus non-essential amino acids on muscle protein synthesis in fasted rat: a common activation pathwayAmino Acids. (2012)
  60. a b Osowska S, et al. Citrulline modulates muscle protein metabolism in old malnourished ratsAm J Physiol Endocrinol Metab. (2006)
  61. a b Faure C, et al. Leucine and citrulline modulate muscle function in malnourished aged ratsAmino Acids. (2012)
  62. a b Direct action of citrulline on muscle protein synthesis: role of the mTORC1 pathway.
  63. a b Cynober L, de Bandt JP, Moinard C. Leucine and citrulline: two major regulators of protein turnoverWorld Rev Nutr Diet. (2013)
  64. a b c Pérez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle sorenessJ Strength Cond Res. (2010)
  65. ^ Komori K, et al. Nitric oxide synthesis leads to vascular endothelial growth factor synthesis via the NO/cyclic guanosine 3′,5′-monophosphate (cGMP) pathway in human corpus cavernosal smooth muscle cellsJ Sex Med. (2008)
  66. ^ Xin ZC, et al. Effects of icariin on cGMP-specific PDE5 and cAMP-specific PDE4 activitiesAsian J Androl. (2003)
  67. ^ Mulhall JP, et al. Validation of the erection hardness scoreJ Sex Med. (2007)
  68. ^ Oral L-Citrulline Supplementation Improves Erection Hardness in Men With Mild Erectile Dysfunction.
  69. a b McKinley-Barnard S, et al. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesisJ Int Soc Sports Nutr. (2015)
  70. a b Berthe MC, et al. Arginine or citrulline associated with a statin stimulates nitric oxide production in bovine aortic endothelial cellsEur J Pharmacol. (2011)
  71. a b c Ye Y, et al. The role of eNOS, iNOS, and NF-kappaB in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatinAm J Physiol Heart Circ Physiol. (2008)
  72. a b Nakata S, et al. Statin treatment upregulates vascular neuronal nitric oxide synthase through Akt/NF-kappaB pathwayArterioscler Thromb Vasc Biol. (2007)
  73. a b Kolyada AY, Fedtsov A, Madias NE. 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors upregulate inducible NO synthase expression and activity in vascular smooth muscle cellsHypertension. (2001)
  74. a b Grimble GK. Adverse gastrointestinal effects of arginine and related amino acidsJ Nutr. (2007)
  75. ^ Collier SR, Casey DP, Kanaley JA. Growth hormone responses to varying doses of oral arginineGrowth Horm IGF Res. (2005)
  76. Cormio L, et al. Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunctionUrology. (2011)
  77. Babak Sharif Kashani, et al. Oral l-citrulline malate in patients with idiopathic pulmonary arterial hypertension and Eisenmenger Syndrome: a clinical trialJ Cardiol. (2014)
  78. Jeffrey M Rogers, Joshua Gills, Michelle Gray. Acute effects of Nitrosigine® and citrulline malate on vasodilation in young adultsJ Int Soc Sports Nutr. (2020)
  79. Joaquin U Gonzales, et al. Does l-citrulline supplementation improve exercise blood flow in older adults?Exp Physiol. (2017)
  80. Alexei Wong, Oksana Chernykh, Arturo Figueroa. Chronic l-citrulline supplementation improves cardiac sympathovagal balance in obese postmenopausal women: A preliminary reportAuton Neurosci. (2016)
  81. Arturo Figueroa, et al. Impact of L-citrulline supplementation and whole-body vibration training on arterial stiffness and leg muscle function in obese postmenopausal women with high blood pressureExp Gerontol. (2015)
  82. Arturo Figueroa, et al. l-Citrulline supplementation attenuates blood pressure, wave reflection and arterial stiffness responses to metaboreflex and cold stress in overweight menBr J Nutr. (2016)
  83. Huan-Huan Yang, et al. Effect of oral L-citrulline on brachial and aortic blood pressure defined by resting status: evidence from randomized controlled trialsNutr Metab (Lond). (2019)
  84. S Azizi, et al. Oxidative stress and nitrate/nitrite (NOx) status following citrulline supplementation in type 2 diabetes: a randomised, double-blind, placebo-controlled trialJ Hum Nutr Diet. (2020)
  85. Zahra Darabi, et al. Inflammatory markers response to citrulline supplementation in patients with non-alcoholic fatty liver disease: a randomized, double blind, placebo-controlled, clinical trialBMC Res Notes. (2019)
  86. Fernando Holguin, et al. L-Citrulline increases nitric oxide and improves control in obese asthmaticsJCI Insight. (2019)
  87. John Ashley, Youngdeok Kim, Joaquin U Gonzales. Impact of l-citrulline supplementation on oxygen uptake kinetics during walkingAppl Physiol Nutr Metab. (2018)
  88. Fatih Kiyici, et al. The Effect of Citrulline/Malate on Blood Lactate Levels in Intensive ExerciseBiochem Genet. (2017)
  89. da Silva DK, et al. Citrulline Malate Does Not Improve Muscle Recovery after Resistance Exercise in Untrained Young Adult MenNutrients. (2017)
  90. Sean T Stanelle, Kelsey L McLaughlin, Stephen F Crouse. One Week of L-Citrulline Supplementation Improves Performance in Trained CyclistsJ Strength Cond Res. (2020)
  91. Andrew J Chappell, Daniel M Allwood, Trevor N Simper. Citrulline Malate Fails to Improve German Volume Training Performance in Healthy Young Men and WomenJ Diet Suppl. (2020)
  92. Eric T Trexler, et al. Effects of Citrulline Malate and Beetroot Juice Supplementation on Blood Flow, Energy Metabolism, and Performance During Maximum Effort Leg Extension ExerciseJ Strength Cond Res. (2019)
  93. Juliano Casonatto, Daniel Massaharu Enokida, Kamila Grandolfi. Inter-Individual Responses to Citrulline Malate Oral Supplementation on Post-Exercise Hypotension in Hypertensives: A 24-Hour AnalysisArq Bras Cardiol. (2019)
  94. Joshua L Gills, et al. Acute citrulline-malate supplementation is ineffective during aerobic cycling and subsequent anaerobic performance in recreationally active malesEur J Sport Sci. (2020)
  95. Hwang P, 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 malesJ Int Soc Sports Nutr. (2018)
  96. Glenn JM, et al. Acute citrulline-malate supplementation improves maximal strength and anaerobic power in female, masters athletes tennis playersEur J Sport Sci. (2016)
  97. Suzuki T, et al. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover studyJ Int Soc Sports Nutr. (2016)
  98. Brian Cunniffe, et al. Acute Citrulline-Malate Supplementation and High-Intensity Cycling PerformanceJ Strength Cond Res. (2016)
  99. Glenn JM, et al. Acute citrulline malate supplementation improves upper- and lower-body submaximal weightlifting exercise performance in resistance-trained femalesEur J Nutr. (2017)
  100. Bailey SJ, et al. l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humansJ Appl Physiol (1985). (2015)
  101. Wax B, Kavazis AN, Luckett W. Effects of Supplemental Citrulline-Malate Ingestion on Blood Lactate, Cardiovascular Dynamics, and Resistance Exercise Performance in Trained MalesJ Diet Suppl. (2016)
  102. Wax B, et al. Effects of supplemental citrulline malate ingestion during repeated bouts of lower-body exercise in advanced weightliftersJ Strength Cond Res. (2015)
  103. Kim van Wijck, et al. L-citrulline improves splanchnic perfusion and reduces gut injury during exerciseMed Sci Sports Exerc. (2014)
  104. Marcos Angel Sanchez-Gonzalez, et al. The effects of short term L-citrulline supplementation on wave reflection responses to cold exposure with concurrent isometric exerciseAm J Hypertens. (2013)
  105. Karla Balderas-Munoz, et al. Improvement of ventricular function in systolic heart failure patients with oral L-citrulline supplementationCardiol J. (2012)
  106. Adam M Gonzalez, et al. Acute Effect of Citrulline Malate Supplementation on Upper-Body Resistance Exercise Performance in Recreationally Resistance-Trained MenJ Strength Cond Res. (2018)
  107. Eric T Trexler, et al. Acute Effects of Citrulline Supplementation on High-Intensity Strength and Power Performance: A Systematic Review and Meta-AnalysisSports Med. (2019)