Citrulline: A Multifunctional Compound for Health, Performance, and Therapeutic Applications
DOI:
https://doi.org/10.12775/JEHS.2025.78.57706Keywords
citrulline, NO, hypertension, sport, neuroprotectionAbstract
Introduction:
L-citrulline, a non-proteinogenic amino acid, is predominantly synthesized in the enterocytes of the small intestine, with smaller amounts produced in the kidneys, which plays a critical role in the detoxification of ammonia in the urea cycle, and serves as a precursor for nitric oxide (NO). Recent studies have highlighted citrulline's potential benefits in diverse physiological and pathological contexts, ranging from enhancing physical performance and muscle recovery to supporting cardiovascular health, mitigating endothelial dysfunction, and acting as a therapeutic agent in various health conditions.
Aim of study:
The study aims to provide a comprehensive summary of current knowledge on the biochemical characteristics, physiological functions, and therapeutic potential of citrulline. Materials and methods:
A comprehensive scientific literature review was conducted using the PubMed database, focusing on studies published up to 2024, reporting experimental, clinical, or in vivo data related to citrulline's synthesis, biological functions, and therapeutic applications.
Conclusion:
Emerging evidence highlights citrulline's potential in treating various health conditions, such as erectile dysfunction, neurodegenerative diseases, and intestinal barrier dysfunction, as well as its protective effects in hepatic failure, wound healing, and oxidative stress-related damage. These findings suggest that citrulline may serve as a multifaceted therapeutic agent, meriting further research to optimize its clinical use.
References
Aguayo E, Martínez-Sánchez A, Fernández-Lobato B, Alacid F. L-Citrulline: A Non-Essential Amino Acid with Important Roles in Human Health. Applied Sciences. 2021; 11(7):3293. DOI: https://doi.org/10.3390/app11073293.
Agarwal U, Didelija IC, Yuan Y, Wang X, Marini JC. Supplemental Citrulline Is More Efficient Than Arginine in Increasing Systemic Arginine Availability in Mice. J Nutr. 2017;147(4):596-602. DOI: https://doi.org/10.3945/jn.116.240382
Rachel Botchlett, John M. Lawler, Guoyao Wu, Chapter 55 - l-Arginine and l-Citrulline in Sports Nutrition and Health, Editor(s): Debasis Bagchi, Sreejayan Nair, Chandan K. Sen, Nutrition and Enhanced Sports Performance (Second Edition), Academic Press, 2019, Pages 645-652, ISBN 9780128139226, DOI: https://doi.org/10.1016/B978-0-12-813922-6.00055-2
Bahri S, Zerrouk N, Ausseil F, et al. Citrulline: from metabolism to therapeutic use. Nutrition. 2013;29(3):479-484. DOI: https://doi.org/10.1016/j.nut.2012.07.002.
Sureda A, Pons A. Arginine and citrulline supplementation in sports and exercise: ergogenic nutrients?. Med Sport Sci. 2012;59:18-28. DOI: https://doi.org/10.1159/000341937
Rhim HC, Kim SJ, Park J, Jang KM. Effect of citrulline on post-exercise rating of perceived exertion, muscle soreness, and blood lactate levels: A systematic review and meta-analysis. J Sport Health Sci. 2020;9(6):553-561. DOI: https://doi.org/10.1016/j.jshs.2020.02.003
Perez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res. 2010;24(5):1215-1222. DOI: https://doi.org/10.1519/JSC.0b013e3181cb28e0.
Allerton TD, Proctor DN, Stephens JM, Dugas TR, Spielmann G, Irving BA. l-Citrulline Supplementation: Impact on Cardiometabolic Health. Nutrients. 2018;10(7):921. DOI: https://doi.org/10.3390/nu10070921.
Porto AA, Gonzaga LA, Benjamim CJR, Valenti VE. Absence of Effects of L-Arginine and L-Citrulline on Inflammatory Biomarkers and Oxidative Stress in Response to Physical Exercise: A Systematic Review with Meta-Analysis. Nutrients. 2023;15(8):1995. DOI: https://doi.org/10.3390/nu15081995.
Yabuki Y, Shioda N, Yamamoto Y, et al. Oral L-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection. Brain Res. 2013;1520:157-167. DOI:https://doi.org/10.1016/j.brainres.2013.05.011
Figueroa A, Wong A, Hooshmand S, Sanchez-Gonzalez MA. Effects of watermelon supplementation on arterial stiffness and wave reflection amplitude in postmenopausal women. Menopause. 2013;20(5):573-577. DOI: https://doi.org/10.1097/GME.0b013e3182733794.
Ochiai M, Hayashi T, Takanami Y, et al. Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men. Int J Cardiol. 2012;155(2):257-261. DOI: https://doi.org/10.1016/j.ijcard.2010.10.004.
Romero MJ, Platt DH, Caldwell RB, Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev. 2006;24(3-4):275-290. DOI: https://doi.org/10.1111/j.1527-3466.2006.00275.x.
Agostoni A, Marasini B, Biondi ML, et al. L-arginine therapy in Raynaud's phenomenon?. Int J Clin Lab Res. 1991;21(2):202-203. DOI: https://doi.org/10.1007/BF02591645.
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(4):660-666. DOI: https://doi.org/10.1249/01.mss.0000210197.02576.da
Smeets ETHC, Mensink RP, Joris PJ. Effects of L-citrulline supplementation and watermelon consumption on longer-term and postprandial vascular function and cardiometabolic risk markers: A meta-analysis of randomized controlled trials in adults. Br J Nutr. Published online December 6, 2021. DOI: https://doi.org/10.1017/S0007114521004803.
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(1):51-59. DOI: https://doi.org/10.1111/j.1365-2125.2007.02990.x.
Fike CD, Summar M, Aschner JL. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 2014;103(10):1019-1026. DOI: https://doi.org/10.1111/apa.12707
Le Roux-Mallouf T, Pelen F, Vallejo A, Halimaoui I, Doutreleau S, Verges S. Effect of chronic nitrate and citrulline supplementation on vascular function and exercise performance in older individuals. Aging (Albany NY). 2019;11(10):3315-3332. DOI: https://doi.org/10.18632/aging.101984.
Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertens (Greenwich). 2006;8(12 Suppl 4):53-62. DOI: https://doi.org/10.1111/j.1524-6175.2006.06026.x
El Taieb M, Hegazy E, Ibrahim A. Daily Oral l-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction: A Double-Blinded, Randomized, Controlled Clinical Trial. J Sex Med. 2019;16(9):1390-1397. DOI: https://doi.org/10.1016/j.jsxm.2019.06.009.
Mykoniatis I, Pyrgidis N, Sokolakis I, et al. Assessment of Combination Therapies vs Monotherapy for Erectile Dysfunction: A Systematic Review and Meta-analysis. JAMA Netw Open. 2021;4(2):e2036337. DOI: https://doi.org/10.1001/jamanetworkopen.2020.36337.
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(1):119-122. DOI: https://doi.org/10.1016/j.urology.2010.08.028.
Esposito K, Giugliano F, De Sio M, et al. Dietary factors in erectile dysfunction. Int J Impot Res. 2006;18(4):370-374. DOI: https://doi.org/10.1038/sj.ijir.3901438.
Azizi S, Mahdavi R, Mobasseri M, Aliasgharzadeh S, Abbaszadeh F, Ebrahimi-Mameghani M. The impact of L-citrulline supplementation on glucose homeostasis, lipid profile, and some inflammatory factors in overweight and obese patients with type 2 diabetes: A double-blind randomized placebo-controlled trial. Phytother Res. 2021;35(6):3157-3166. DOI: https://doi.org/10.1002/ptr.6997.
Tovar-Villegas VI, Kang Y, Ibarra-Reynoso LdR, et al. Oral L-Citrulline Supplementation Improves Fatty Liver and Dyslipidemia in Adolescents with Abdominal Obesity: A Parallel, Double-Blind, Randomized Clinical Trial. Gastroenterology Insights. 2024;15(2):354-365. DOI: https://doi.org/10.3390/gastroent15020024.
Imbard A, Bouchereau J, Arnoux JB, et al. Citrulline in the management of patients with urea cycle disorders. Orphanet J Rare Dis. 2023;18:207. DOI: https://doi.org/10.1186/s13023-023-02800-8.
Jegatheesan P, De Bandt JP. Hepatic steatosis: a role for citrulline. Curr Opin Clin Nutr Metab Care. 2016;19(5):360-365. DOI: https://doi.org/10.1097/MCO.0000000000000301.
Curis E, Crenn P, Messager A, et al. Citrulline and the gut. Curr Opin Clin Nutr Metab Care. 2007;10(5):620-626 DOI:https://doi.org/10.1097/MCO.0b013e32829fb38d.
Crenn P, Coudray-Lucas C, Thuillier F, et al. Post-absorptive plasma citrulline concentration is a marker of absorptive enterocyte mass and intestinal failure in humans. Gastroenterology. 2000;119(6):1496-1505. DOI: https://doi.org/10.1053/gast.2000.20227.
Osowska S, Moinard C, Neveux N, et al. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection in rats. J Nutr. 2004;134(10 Suppl):2913S-2917S. DOI: https://doi.org/10.1136/gut.2004.042317.
van Wijck K, Wijnands KA, Meesters DM, et al. L-citrulline improves splanchnic perfusion and reduces gut injury during exercise. Med Sci Sports Exerc. 2014;46(11):2039-2046. DOI: https://doi.org/10.1249/MSS.0000000000000332.
Moinard C, Cynober L. Citrulline: a new player in the control of nitrogen homeostasis. J Nutr. 2007;137(6 Suppl 2):1621S-1625S. DOI: https://doi.org/10.1093/jn/137.6.1621S.
Sze Wing Ho, Hani El-Nezami, Nagendra P. Shah. Effects of supplementation of citrulline and Lactobacillus helveticus ASCC 511 on intestinal epithelial cell integrity. Journal of Functional Foods. 2020;64:103571. DOI: https://doi.org/10.1016/j.jff.2019.103571.
Ginguay A, Regazzetti A, Laprevote O, et al. Citrulline prevents age-related LTP decline in old rats. Sci Rep. 2019;9(1):20138. DOI: https://doi.org/10.1038/s41598-019-56598-2.
Huang WJ, Zhang X, Chen WW. Role of oxidative stress in Alzheimer's disease. Biomed Rep. 2016;4(5):519-522. DOI: https://doi.org/10.3892/br.2016.630
Martínez-González K, Serrano-Cuevas L, Almeida-Gutiérrez E, Flores-Chavez S, Mejía-Aranguré JM, Garcia-delaTorre P. Citrulline supplementation improves spatial memory in a murine model for Alzheimer's disease. Nutrition. 2021;90:111248. DOI: https://doi.org/10.1016/j.nut.2021.111248
Wijnands KA, Castermans TM, Hommen MP, et al. Arginine and citrulline and the immune response in sepsis. Nutrients. 2015;7(3):1426-1463. DOI: https://doi.org/10.3390/nu7031426.
Mariáurea Matias Sarandy, Silvânia Mól Pelinsari, Lorena Miranda de Souza, et al. l-arginine and l-citrulline supplementation accelerates second intention wound healing in iNOS knockout mice. Journal of Functional Foods. 2023;100:105395. DOI: https://doi.org/10.1016/j.jff.2022.105395.
Christophe Moinard, Servane Le Plenier, Philippe Noirez, Béatrice Morio, Dominique Bonnefont-Rousselot, Caroline Kharchi, Arnaud Ferry, Nathalie Neveux, Luc Cynober, Agathe Raynaud-Simon, Citrulline Supplementation Induces Changes in Body Composition and Limits Age-Related Metabolic Changes in Healthy Male Rats1, 2, 3, The Journal of Nutrition, Volume 145, Issue 7, 2015, Pages 1429-1437, ISSN 0022-3166, DOI: https://doi.org/10.3945/jn.114.200626.
Jiang J, Gan Z, Li Y, et al. REM sleep deprivation induces endothelial dysfunction and hypertension in middle-aged rats: Roles of the eNOS/NO/cGMP pathway and supplementation with L-arginine. PLOS ONE. 2017;12(8):e0182746. DOI: https://doi.org/10.1371/journal.pone.0182746.
Meesters DM, Hannemann PF, van Eijk HM, et al. Enhancement of fracture healing after citrulline supplementation in mice. Eur Cell Mater. 2020;39:183-192. DOI: https://doi.org/10.22203/eCM.v039a12.
Mamdouh Eldesoqui, Lashin Saad Ali, Aya Megahed, et al. Effect of L-Citrulline Supplementation on Cadmium-Induced Testicular Dysfunction in Male Albino Rats: Inhibition of Oxidative Stress and Apoptosis. International Journal of Pharmacology. 2024;20:1339-1349. DOI: https://doi.org/10.3923/ijp.2024.1339.1349.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Marcin Mycyk, Michał Jakub Cioch, Urszula Kaczmarska, Aleksandra Woźniak, Julia Nowak, Kamil Hermanowicz, Katarzyna Doman, Agnieszka Najdek, Daria Oleksy, Dawid Komada

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The periodical offers access to content in the Open Access system under the Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Stats
Number of views and downloads: 44
Number of citations: 0