CITRULLINE MALATE IN MEDICAL AND SPORT APPLICATIONS
Abstract
Background. Nitric oxide has emerged as a key physiological signalling molecule that has a significant impact on vessels, skeletal muscle function and exercise performance. With this in mind, increasing its production is of great interest to clinicians and athletes, making citrulline malate a potential medication and one of the most popular ergogenic supplements.
Aim. This article aims to review current knowledge on citrulline malate supplementation, with emphasis on its pharmacokinetics, proposed medical application and ergogenic benefits.
Material and Methods. Literature search in PubMed and Google Scholar for clinical trials, meta-analyses, and reviews on citrulline malate using keywords: citrulline malate, nitric oxide, muscle endurance, medical applications, supplementation”.
Results. Citrulline malate exhibit its positive impact on many medical conditions. In pulmonary hypertension by improving exercise tolerance and modestly reducing arterial pressure. In metabolic conditions, leading to better glycaemic control, improved lipid profiles, and reduced inflammation in diabetes. Men with mild erectile dysfunction report subjective improvements when using citrulline malate alone or alongside other therapies. In atherosclerosis, it increases the elasticity of the arteries, which becomes weaker in advanced disease. Beyond medical applications, citrulline malate supplementation is primarily known for supporting short-term, high-intensity exercise by delaying fatigue, improving endurance, lowering perceived exertion during resistance training and reducing post-workout muscle soreness.
Conclusion: Citrulline malate could be used as medical application and can enhance exercise performance by delaying fatigue and reducing muscle soreness. Larger, rigorously controlled trials are required to establish optimal dosing, target activities and long-term safety.
References
Aguiar, A. F., & Casonatto, J. (2022). Effects of Citrulline Malate Supplementation on Muscle Strength in Resistance-Trained Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of Dietary Supplements, 19(6), 772–790. https://doi.org/10.1080/19390211.2021.1939473
Allen, M. J., & Sharma, S. (2025). Physiology, Adrenocorticotropic Hormone (ACTH).
Allerton, T., Proctor, D., Stephens, J., Dugas, T., Spielmann, G., & Irving, B. (2018). l-Citrulline Supplementation: Impact on Cardiometabolic Health. Nutrients, 10(7), 921. https://doi.org/10.3390/nu10070921
Azizi, S., Mahdavi, R., Mobasseri, M., Aliasgharzadeh, S., Abbaszadeh, F., & Ebrahimi‐Mameghani, M. (2021). 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. Phytotherapy Research, 35(6), 3157–3166. https://doi.org/10.1002/ptr.6997
Cheung, K., Hume, P. A., & Maxwell, L. (2003). Delayed Onset Muscle Soreness. Sports Medicine, 33(2), 145–164. https://doi.org/10.2165/00007256-200333020-00005
Cormio, L., De Siati, M., Lorusso, F., Selvaggio, O., Mirabella, L., Sanguedolce, F., & Carrieri, G. (2011). Oral L-Citrulline Supplementation Improves Erection Hardness in Men With Mild Erectile Dysfunction. Urology, 77(1), 119–122. https://doi.org/10.1016/j.urology.2010.08.028
Demir, R., & Kucukoglu, M. S. (2015). Six-minute walk test in pulmonary arterial hypertension. Anadolu Kardiyoloji Dergisi/The Anatolian Journal of Cardiology, 15(3), 249–254. https://doi.org/10.5152/akd.2015.5834
Devrim-Lanpir, A., Ihász, F., Demcsik, M., Horváth, A. C., Góczán, P., Czepek, P., Takács, J., Kimble, R., Zare, R., Gunes, F. E., Knechtle, B., Weiss, K., Rosemann, T., & Heinrich, K. M. (2024). Effects of Acute Citrulline Malate Supplementation on CrossFit® Exercise Performance: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Study. Nutrients, 16(19), 3235. https://doi.org/10.3390/nu16193235
El Khoury, D., & Antoine-Jonville, S. (2012). Intake of Nutritional Supplements among People Exercising in Gyms in Beirut City. Journal of Nutrition and Metabolism, 2012, 1–12. https://doi.org/10.1155/2012/703490
Faria, V. S., & Egan, B. (2024). Effects of 3 days of citrulline malate supplementation on short‐duration repeated sprint running performance in male team sport athletes. European Journal of Sport Science, 24(6), 758–765. https://doi.org/10.1002/ejsc.12090
Gonzalez, A. M., Townsend, J. R., Pinzone, A. G., & Hoffman, J. R. (2023). Supplementation with Nitric Oxide Precursors for Strength Performance: A Review of the Current Literature. Nutrients, 15(3), 660. https://doi.org/10.3390/nu15030660
Gough, L. A., Sparks, S. A., McNaughton, L. R., Higgins, M. F., Newbury, J. W., Trexler, E., Faghy, M. A., & Bridge, C. A. (2021). A critical review of citrulline malate supplementation and exercise performance. European Journal of Applied Physiology, 121(12), 3283–3295. https://doi.org/10.1007/s00421-021-04774-6
Grgic, J., Schoenfeld, B. J., Orazem, J., & Sabol, F. (2022). Effects of resistance training performed to repetition failure or non-failure on muscular strength and hypertrophy: A systematic review and meta-analysis. Journal of Sport and Health Science, 11(2), 202–211. https://doi.org/10.1016/j.jshs.2021.01.007
Grimble, G. K. (2007). Adverse Gastrointestinal Effects of Arginine and Related Amino Acids. The Journal of Nutrition, 137(6), 1693S-1701S. https://doi.org/10.1093/jn/137.6.1693S
Hayashi, T., Juliet, P. A. R., Matsui-Hirai, H., Miyazaki, A., Fukatsu, A., Funami, J., Iguchi, A., & Ignarro, L. J. (2005). l -citrulline and l -arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits. Proceedings of the National Academy of Sciences, 102(38), 13681–13686. https://doi.org/10.1073/pnas.0506595102
Humbert, M., Kovacs, G., Hoeper, M. M., Badagliacca, R., Berger, R. M. F., Brida, M., Carlsen, J., Coats, A. J. S., Escribano-Subias, P., Ferrari, P., Ferreira, D. S., Ghofrani, H. A., Giannakoulas, G., Kiely, D. G., Mayer, E., Meszaros, G., Nagavci, B., Olsson, K. M., Pepke-Zaba, J., … Wort, S. J. (2022). 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal, 43(38), 3618–3731. https://doi.org/10.1093/eurheartj/ehac237
Hwang, P., Morales Marroquín, F. E., Gann, J., Andre, T., McKinley-Barnard, S., Kim, C., Morita, M., & Willoughby, D. S. (2018). 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. Journal of the International Society of Sports Nutrition, 15(1). https://doi.org/10.1186/s12970-018-0235-x
Kiyici, F., Eroğlu, H., Kishali, N. F., & Burmaoglu, G. (2017). The Effect of Citrulline/Malate on Blood Lactate Levels in Intensive Exercise. Biochemical Genetics, 55(5–6), 387–394. https://doi.org/10.1007/s10528-017-9807-8
Macuh, M., & Knap, B. (2021). Effects of Nitrate Supplementation on Exercise Performance in Humans: A Narrative Review. Nutrients, 13(9), 3183. https://doi.org/10.3390/nu13093183
Matsumoto, S., Häberle, J., Kido, J., Mitsubuchi, H., Endo, F., & Nakamura, K. (2019). Urea cycle disorders—update. Journal of Human Genetics, 64(9), 833–847. https://doi.org/10.1038/s10038-019-0614-4
Morishita, S., Tsubaki, A., Takabayashi, T., & Fu, J. B. (2018). Relationship Between the Rating of Perceived Exertion Scale and the Load Intensity of Resistance Training. Strength & Conditioning Journal, 40(2), 94–109. https://doi.org/10.1519/SSC.0000000000000373
Munakata, M. (2014). Brachial-Ankle Pulse Wave Velocity in the Measurement of Arterial Stiffness: Recent Evidence and Clinical Applications. Current Hypertension Reviews, 10(1), 49–57. https://doi.org/10.2174/157340211001141111160957
Murphy, M. P., & O’Neill, L. A. J. (2018). Krebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Transducers. Cell, 174(4), 780–784. https://doi.org/10.1016/j.cell.2018.07.030
Nauli, S. M. (2022). Endothelial Nitric Oxide Synthase (eNOS) and the Cardiovascular System: in Physiology and in Disease States. American Journal of Biomedical Science & Research, 15(2), 155–179. https://doi.org/10.34297/AJBSR.2022.15.002087
Orozco-Gutiérrez, J. J., Castillo-Martínez, L., Orea-Tejeda, A., Vázquez-Díaz, O., Valdespino-Trejo, A., Narváez-David, R., Keirns-Davis, C., Carrasco-Ortiz, O., Navarro-Navarro, A., & Sánchez-Santillán, R. (2010). Effect of L-arginine or L-citrulline oral supplementation on blood pressure and right ventricular function in heart failure patients with preserved ejection fraction. Cardiology Journal, 17(6), 612–618.
Osowska, S. (2004). Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut, 53(12), 1781–1786. https://doi.org/10.1136/gut.2004.042317
Papadia, C., Osowska, S., Cynober, L., & Forbes, A. (2018). Citrulline in health and disease. Review on human studies. Clinical Nutrition, 37(6), 1823–1828. https://doi.org/10.1016/j.clnu.2017.10.009
Rhim, H. C., Kim, S. J., Park, J., & Jang, K.-M. (2020). Effect of citrulline on post-exercise rating of perceived exertion, muscle soreness, and blood lactate levels: A systematic review and meta-analysis. Journal of Sport and Health Science, 9(6), 553–561. https://doi.org/10.1016/j.jshs.2020.02.003
Rogers, J. M., Gills, J., & Gray, M. (2020). Acute effects of Nitrosigine® and citrulline malate on vasodilation in young adults. Journal of the International Society of Sports Nutrition, 17(1). https://doi.org/10.1186/s12970-020-00343-y
Sharif Kashani, B., Tahmaseb Pour, P., Malekmohammad, M., Behzadnia, N., Sheybani-Afshar, F., Fakhri, M., Chaibakhsh, S., Naghashzadeh, F., & Aidenlou, S. (2014). Oral l-citrulline malate in patients with idiopathic pulmonary arterial hypertension and Eisenmenger Syndrome: A clinical trial. Journal of Cardiology, 64(3), 231–235. https://doi.org/10.1016/j.jjcc.2014.01.003
Shirai, M., Hiramatsu, I., Aoki, Y., Shimoyama, H., Mizuno, T., Nozaki, T., Fukuhara, S., Iwasa, A., Kageyama, S., & Tsujimura, A. (2018). Oral L-citrulline and Transresveratrol Supplementation Improves Erectile Function in Men With Phosphodiesterase 5 Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Crossover Pilot Study. Sexual Medicine, 6(4), 291–296. https://doi.org/10.1016/j.esxm.2018.07.001
Stuehr, D. J. (2004). Enzymes of the L-Arginine to Nitric Oxide Pathway. The Journal of Nutrition, 134(10), 2748S-2751S. https://doi.org/10.1093/jn/134.10.2748S
Theofilidis, G., Bogdanis, G., Koutedakis, Y., & Karatzaferi, C. (2018). Monitoring Exercise-Induced Muscle Fatigue and Adaptations: Making Sense of Popular or Emerging Indices and Biomarkers. Sports, 6(4), 153. https://doi.org/10.3390/sports6040153
Tizar, E., Erdoğan, R., & Tizar, G. R. (2024). The Effect of Citrulline Malate Supplement Applied in Addition to Fitness Trainings on Hormone Metabolism of Athletes. Journal of Pioneering Medical Science, 13(5), 79–82. https://doi.org/10.61091/jpms202413514
Trexler, E. T., Keith, D. S., Schwartz, T. A., Ryan, E. D., Stoner, L., Persky, A. M., & Smith-Ryan, A. E. (2019). Effects of Citrulline Malate and Beetroot Juice Supplementation on Blood Flow, Energy Metabolism, and Performance During Maximum Effort Leg Extension Exercise. Journal of Strength and Conditioning Research, 33(9), 2321–2329. https://doi.org/10.1519/JSC.0000000000003286
Trexler, E. T., Persky, A. M., Ryan, E. D., Schwartz, T. A., Stoner, L., & Smith-Ryan, A. E. (2019). Acute Effects of Citrulline Supplementation on High-Intensity Strength and Power Performance: A Systematic Review and Meta-Analysis. Sports Medicine, 49(5), 707–718. https://doi.org/10.1007/s40279-019-01091-z
Vårvik, F. T., Bjørnsen, T., & Gonzalez, A. M. (2021). Acute Effect of Citrulline Malate on Repetition Performance During Strength Training: A Systematic Review and Meta-Analysis. International Journal of Sport Nutrition and Exercise Metabolism, 31(4), 350–358. https://doi.org/10.1123/ijsnem.2020-0295
Wang, R.-S., Huang, S., Waldo, S. W., Hess, E., Gokhale, M., Johnson, S. W., Zeder, K., Choudhary, G., Leopold, J. A., Oldham, W. M., Kovacs, G., Freiberg, M. S., Tedford, R. J., Maron, B. A., & Brittain, E. L. (2023). Elevated Pulmonary Arterial Compliance Is Associated with Survival in Pulmonary Hypertension: Results from a Novel Network Medicine Analysis. American Journal of Respiratory and Critical Care Medicine, 208(3), 312–321. https://doi.org/10.1164/rccm.202211-2097OC
Copyright (c) 2025 Paweł Radkowski, Urszula Justyna Wojciechowska, Adam Rafałowicz, Magdalena Rafałowicz, Paweł Jakub Wojciechowski, Łukasz Grabarczyk

This work is licensed under a Creative Commons Attribution 4.0 International License.
All articles are published in open-access and licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Hence, authors retain copyright to the content of the articles.
CC BY 4.0 License allows content to be copied, adapted, displayed, distributed, re-published or otherwise re-used for any purpose including for adaptation and commercial use provided the content is attributed.

