Effect of L-Citrulline Supplementation on Blood Pressure: a Systematic Review and Meta-Analysis of Clinical Trials

  • Mohammad Sadegh Mirenayat
  • Sajjad Moradi
  • Hamed Mohammadi
  • Mohammad Hossein RouhaniEmail author
Guidelines/Clinical Trials/Meta-Analysis (JB Kostis, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Guidelines/Clinical Trials/Meta-Analysis


Purpose of Review

Several interventional studies assessed the impact of dietary supplements on blood pressure. The aim of the present systematic review and meta-analysis was to determine the efficacy of L-citrulline supplementation on blood pressure.

Recent Finding

Pubmed, Scopus, Google Scholar, and ISI Web of Science were comprehensively searched until May 2018 to assess whether L-citrulline reduces blood pressure. Human clinical trials which reported the effect of L-citrulline supplementation on aortic and brachial blood pressure were included. Characteristics of studies and potential sources of heterogeneity were tabulated. A subgroup analysis was performed to attenuate observed inter-study heterogeneity. A total of five interventions were found for meta-analysis. The impact of L-citrulline on brachial systolic (change 0.28 mmHg; 95% CI − 2.87, 2.31 mmHg) and diastolic (change − 1.56 mmHg; 95% CI − 4.32, 1.20 mmHg) blood pressure was not significant. Also, there was no changes in aortic systolic (change 0.22 mmHg; 95% CI − 4.81, 4.38 mmHg) and diastolic (change 0.26 mmHg; 95% CI − 2.27, 2.80 mmHg) blood pressure after L-citrulline supplementation. Participants’ body weight status was a source of observed heterogeneity.


The present systematic review and meta-analysis suggests that L-citrulline supplementation had no beneficial effect on blood pressure.


L-citrulline Blood pressure Systematic review Meta-analysis 



Food Security Research Center, Isfahan University of Medical Sciences, Isfahan, Iran, supported the present study.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Balakumar P, Maung UK, Jagadeesh G. Prevalence and prevention of cardiovascular disease and diabetes mellitus. Pharmacol Res. 2016;113:600–9.CrossRefGoogle Scholar
  2. 2.
    Pourmasoumi M, Hadi A, Rafie N, Najafgholizadeh A, Mohammadi H, Rouhani MH. The effect of ginger supplementation on lipid profile: a systematic review and meta-analysis of clinical trials. Phytomedicine. 2018;43:28–36.CrossRefGoogle Scholar
  3. 3.
    Wenger NK, Arnold A, Bairey Merz CN, Cooper-DeHoff RM, Ferdinand KC, Fleg JL, et al. Hypertension across a woman’s life cycle. J Am Coll Cardiol. 2018;71:1797–813.CrossRefGoogle Scholar
  4. 4.
    Sanchez-Gonzalez MA, Koutnik AP, Ramirez K, Wong A, Figueroa A. The effects of short term L-citrulline supplementation on wave reflection responses to cold exposure with concurrent isometric exercise. Am J Hypertens. 2013;26:518–26.CrossRefGoogle Scholar
  5. 5.
    Adler AJ, Prabhakaran D, Bovet P, Kazi DS, Mancia G, Mungal-Singh V, et al. Reducing cardiovascular mortality through prevention and management of raised blood pressure: a world heart federation roadmap. Glob Heart. 2015;10:111–22.CrossRefGoogle Scholar
  6. 6.
    Dojki FK, Bakris GL. Blood pressure control and cardiovascular/renal outcomes. Endocrinol Metab Clin N Am. 2018;47(1):175–84.CrossRefGoogle Scholar
  7. 7.
    Figueroa A, Alvarez-Alvarado S, Ormsbee MJ, Madzima TA. Impact of L-citrulline supplementation and whole-body vibration training on arterial stiffness and leg muscle function in obese postmenopausal women with high blood pressure. Exp Gerontol. 2015;63:35–40.CrossRefGoogle Scholar
  8. 8.
    Jourdan M, Nair KS, Carter RE, Schimke J, Ford GC, Marc J, et al. Citrulline stimulates muscle protein synthesis in the post-absorptive state in healthy people fed a low-protein diet–a pilot study. Clin Nutr. 2015;34:449–56.CrossRefGoogle Scholar
  9. 9.
    Morita M, Hayashi T, Ochiai M, Maeda M, Yamaguchi T, Ina K, et al. Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability. Biochem Biophys Res Commun. 2014;454:53–7.CrossRefGoogle Scholar
  10. 10.
    Fike CD, Summar M, Aschner JL. L-citrulline provides a novel strategy for treating chronic pulmonary hypertension in newborn infants. Acta Paediatr. 2014;103:1019–26.CrossRefGoogle Scholar
  11. 11.
    •• Kashani BS, Pour PT, Malekmohammad M, Behzadnia N, Sheybani-Afshar F, Fakhri 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 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure. CrossRefGoogle Scholar
  12. 12.
    •• Wong A, Alvarez-Alvarado S, Jaime SJ, Kinsey AW, Spicer MT, Madzima TA, et al. Combined whole-body vibration training and L-citrulline supplementation improves pressure wave reflection in obese postmenopausal women. Appl Physiol Nutr Metab. 2015;41:292–7 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure. CrossRefGoogle Scholar
  13. 13.
    Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1–12.CrossRefGoogle Scholar
  14. 14.
    • Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions: Wiley; 2011. This is one the most important textbooks in the field of systematic review and meta-analysis. In this book, systematic review and meta-analysis have been explored step by step. Google Scholar
  15. 15.
    • Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88 This article can help researchers to calculate effect size for clinical trials included in meta-analysis. CrossRefGoogle Scholar
  16. 16.
    • Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34 This article provided evidence regarding detecting publication bias by statisticl graphs. Detecting publication bias has an important role in validity of the results of a meta-analysis. CrossRefGoogle Scholar
  17. 17.
    • Sterne J, Bradburn M. Meta-analysis in Stata. In: Egger M, Smith G, Altman D, editors. Systematic reviews in health care. London: BMJ Publishing Group; 2001. p. 347–72. This book explore the procedure of detecting publication bias by Stata. As Stata is considered as one of the mpst important statistical software in meta-analysis, detecting publication bias by this software is necessary. CrossRefGoogle Scholar
  18. 18.
    •• Figueroa A, Alvarez-Alvarado S, Jaime SJ, Kalfon R. L-Citrulline supplementation attenuates blood pressure, wave reflection and arterial stiffness responses to metaboreflex and cold stress in overweight men. Br J Nutr. 2016;116:279–85 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure. CrossRefGoogle Scholar
  19. 19.
    •• 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 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure. CrossRefGoogle Scholar
  20. 20.
    •• Gonzales JU, Raymond A, Ashley J, Kim Y. Does l-citrulline supplementation improve exercise blood flow in older adults? Exp Physiol. 2017;102:1661–71 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure. CrossRefGoogle Scholar
  21. 21.
    •• Ochiai M, Hayashi T, Morita M, Ina K, Maeda M, Watanabe F, et al. Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men. Int J Cardiol. 2012;155:257–61 This study provided evidence regarding the effect of L-citrulline supplementation on blood pressure. CrossRefGoogle Scholar
  22. 22.
    Wang KL, Cheng HM, Sung SH, Chuang SY, Li CH, Spurgeon HA, et al. Wave reflection and arterial stiffness in the prediction of 15-year all-cause and cardiovascular mortalities: a community-based study. Hypertension. 2010;55:799–805.CrossRefGoogle Scholar
  23. 23.
    Safar ME, Jankowski P. Central blood pressure and hypertension: role in cardiovascular risk assessment. Clin Sci (Lond). 2009;116:273–82.CrossRefGoogle Scholar
  24. 24.
    Pini R, Cavallini MC, Palmieri V, Marchionni N, Di Bari M, Devereux RB, et al. Central but not brachial blood pressure predicts cardiovascular events in an unselected geriatric population: the ICARe dicomano study. J Am Coll Cardiol. 2008;51:2432–9.CrossRefGoogle Scholar
  25. 25.
    Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure–lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113:1213–25.CrossRefGoogle Scholar
  26. 26.
    Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, 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.CrossRefGoogle Scholar
  27. 27.
    Wu G, Collins JK, Perkins-Veazie P, Siddiq M, Dolan KD, Kelly KA, et al. Dietary supplementation with watermelon pomace juice enhances arginine availability and ameliorates the metabolic syndrome in Zucker diabetic fatty rats. J Nutr. 2007;137:2680–5.CrossRefGoogle Scholar
  28. 28.
    Windmueller HG, Spaeth AE. Source and fate of circulating citrulline. Am J Phys. 1981;241:E473–80.Google Scholar
  29. 29.
    Merino J, Ferre R, Girona J, Aguas D, Cabre A, Plana N, et al. Physical activity below the minimum international recommendations improves oxidative stress, ADMA levels, resting heart rate and small artery endothelial function. Clin Investig Arterioscler. 2015;27:9–16.PubMedGoogle Scholar
  30. 30.
    Huang T, Larsen KT, Ried-Larsen M, Moller NC, Andersen LB. The effects of physical activity and exercise on brain-derived neurotrophic factor in healthy humans: a review. Scand J Med Sci Sports. 2014;24:1–10.CrossRefGoogle Scholar
  31. 31.
    Erdos B, Backes I, McCowan ML, Hayward LF, Scheuer DA. Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats. Am J Physiol Heart Circ Physiol. 2015;308:H612–22.CrossRefGoogle Scholar
  32. 32.
    e Silva Ade S, da Mota MP. Effects of physical activity and training programs on plasma homocysteine levels: a systematic review. Amino Acids. 2014;46:1795–804.CrossRefGoogle Scholar
  33. 33.
    van Guldener C, Nanayakkara PW, Stehouwer CD. Homocysteine and blood pressure. Curr Hypertens Rep. 2003;5:26–31.CrossRefGoogle Scholar
  34. 34.
    Riccioni G, Scotti L, Guagnano MT, Bosco G, Bucciarelli V, Di Ilio E, et al. Physical exercise reduces synthesis of ADMA, SDMA, and L-Arg. Front Biosci (Elite Ed). 2015;7:417–22.CrossRefGoogle Scholar
  35. 35.
    Jira M, Zavodna E, Honzikova N, Novakova Z, Vasku A, Izakovicova Holla L, et al. Association of eNOS gene polymorphisms T-786C and G894T with blood pressure variability in man. Physiol Res. 2011;60:193–7.Google Scholar
  36. 36.
    Li J, Cun Y, Tang WR, Wang Y, Li SN, Ouyang HR, et al. Association of eNOS gene polymorphisms with essential hypertension in the Han population in southwestern China. Genet Mol Res. 2011;10:2202–12.CrossRefGoogle Scholar
  37. 37.
    Zago AS, Park JY, Fenty-Stewart N, Kokubun E, Brown MD. Effects of aerobic exercise on the blood pressure, oxidative stress and eNOS gene polymorphism in pre-hypertensive older people. Eur J Appl Physiol. 2010;110:825–32.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Students’ Research Committee, Department of Community Nutrition, School of Nutrition and Food ScienceIsfahan University of Medical SciencesIsfahanIran
  2. 2.Halal Research Center of IRIFDATehranIran
  3. 3.Department of Community Nutrition, School of Nutrition and Food Science, Food Security Research CenterIsfahan University of Medical SciencesIsfahanIran

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