How Can Citrulline Help High Blood Pressure?

Hypertension is the medical term for high blood pressure that stays high over time. Primary hypertension (also called essential hypertension) is the most common type, affecting about 90% of people with high blood pressure. If your blood pressure stays too high, you are much more likely to have serious health problems like strokes, heart attacks, kidney disease, and vision loss [1].

What is citrulline?

Citrulline is an amino acid, a building block of protein. The body can make citrulline itself, but citrulline is also found in foods like watermelon [2]. It was first discovered in 1914 and first produced in a lab in 1930 [3]. Later, researchers discovered that citrulline is important for blood vessel health.

How does citrulline help blood pressure?

People with primary hypertension often have blood vessels that don’t work as they should. Normally, blood vessels widen or narrow to control blood pressure. But in people with hypertension, the blood vessels are stiff and narrow, so blood pressure stays high. This happens because blood vessels need a substance called nitric oxide to work properly, and people with hypertension have low levels of it [4]. The body needs an amino acid called arginine to make nitric oxide. Citrulline is turned into arginine in the body, so it may help increase nitric oxide levels and support blood pressure [2]. Improving arginine levels also helps to lower the levels of substances in the body that block nitric oxide from being made. Citrulline can also help reduce inflammation in the blood vessels, which may help to prevent heart attacks and strokes [2 , 5]. Taking citrulline with arginine has been shown to improve exercise performance, likely by boosting arginine and nitric oxide levels [6 , 7].

What evidence is there that citrulline supplements help blood pressure?

Studies show that citrulline can increase arginine and nitric oxide levels, two things which are key to help blood vessels work properly [2 , 8]. However, two large reviews of multiple trials found that citrulline does not significantly lower blood pressure [9 , 10]. This may be because the participants and designs of each trial were very different, making comparisons difficult [11]. More trials are definitely needed.

What could be the best dose?

There is limited safety data on citrulline, but studies show that doses up to 15 grams do not cause harm [12]. However, this may be more than needed. The suggested effective dose is between 3 and 10 grams per day [2]. Since watermelon is high in citrulline, eating 1–1.5 kg of it daily provides about 3 grams of citrulline.

Verdict: Start with 3 grams daily, and do not to exceed 10 grams daily.

What could be the best regime?

The best regime for citrulline may be 2-3 times per day. This is because after taking citrulline, blood levels increase and then slowly decreases back to normal within 8 hours [13].

Verdict: 2-3 times per day.

What could be the best course length?

Again, safety data on citrulline is limited. However, trials of citrulline taken over 6 weeks have not reported any adverse effects [12].

Verdict: Consult with a healthcare professional.

What could be the best form?

Citrulline supplements come in three forms: L-citrulline, citrulline malate, and watermelon extract. Studies have been done on all three. L-citrulline is the natural form found in the body and in watermelon [14]. Citrulline malate is a combination of citrulline and malate, a natural acid in fruit. It is cheaper to produce, so citrulline malate supplements often cost less.

Verdict: L-citrulline is likely the best choice. However, check that the supplement is third-party tested for purity, as some have been found to be contaminated [12].

When should citrulline be avoided?

As citrulline gets turned into arginine in the body, it should be avoided in the same way as arginine [15 , 16].

·         Cancer: People with cancer may need to avoid citrulline, which turns into arginine, as it could increase tumour growth. More research is needed to confirm this [9].

·         Recent Heart Attack: Taking citrulline, which turns into arginine in the body, soon after a heart attack may increase the risk of serious complications, including death. It should be avoided.

·         Upcoming Surgery: Citrulline should be stopped at least 2 weeks before surgery, as it may make it harder to control blood pressure during the procedure.

When should you be cautious?

·         Pregnancy, breast feeding and children: There isn’t enough research to confirm citrulline is safe during pregnancy, breastfeeding, or in children, so it should be used with caution.

·         Guanidinoacetate methyltransferase deficiency (GAMT): This rare genetic condition causes a buildup of a toxic substance when arginine is taken. Because citrulline turns into arginine in the body, people with GAMT should avoid citrulline.

What medications interact with citrulline?

·         Blood Pressure Medication: Citrulline may lower blood pressure, so taking it with blood pressure medications (like ramipril, lisinopril, candesartan, losartan, amlodipine, and others) could lower it too much. Viagra (sildenafil) may have a similar effect.

·         Certain Water Tablets (Potassium-Sparing Diuretics): Citrulline may interact with water tablets like spironolactone, raising potassium levels and potentially causing an irregular or fast heartbeat.

·         Diabetes Medication: Citrulline may make insulin work better, which could lower blood sugar too much if you’re also taking diabetes medication.

·         Blood Thinners: As citrulline is turned into arginine in the body, it may make blood thinners (like warfarin, apixaban, rivaroxaban, aspirin, clopidogrel) more effective, increasing the risk of bleeding.

Disclaimer and advice going forward

The information above is for education and awareness only and is not a substitute for professional medical advice. The information above does not cover all possible interactions, adverse effects, precautions and uses. Always consult a qualified healthcare professional before taking any supplement, herb or therapy or changing your medications.

For personalised naturopathic advice and assessment of your health situation, you can book a free video call with Dr. Ramiz Ahmed-Man to enquire further. 

References

1.    Feather A, Randall D, Waterhouse M, editors. Hypertension. In: Kumar and Clark’s Clinical Medicine. 10th ed. Elsevier; 2020. p. 1133-1145.

2.    Allerton TD, Proctor DN, Stephens JM, Dugas TR, Spielmann G, Irving BA. l-Citrulline Supplementation: Impact on Cardiometabolic Health. Nutrients. 2018 Jul 19;10(7):921. doi: 10.3390/nu10070921. PMID: 30029482; PMCID: PMC6073798 https://pubmed.ncbi.nlm.nih.gov/30029482/

3.    Fragkos KC, Forbes A. Was citrulline first a laxative substance? The truth about modern citrulline and its isolation. Nihon Ishigaku Zasshi. 2011 Sep;57(3):275-92. PMID: 22397107 https://pubmed.ncbi.nlm.nih.gov/22397107/

4.    Gambardella J, Khondkar W, Morelli MB, Wang X, Santulli G, Trimarco V. Arginine and Endothelial Function. Biomedicines. 2020 Aug 6;8(8):277. Doi: 10.3390/biomedicines8080277. PMID: 32781796; PMCID: PMC7460461. https://pubmed.ncbi.nlm.nih.gov/12481979/

5.    Hayashi T, Juliet PA, Matsui-Hirai H, Miyazaki A, Fukatsu A, Funami J, Iguchi A, Ignarro LJ. 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 Sep 20;102(38):13681-6. doi: 10.1073/pnas.0506595102. Epub 2005 Sep 12. PMID: 16157883; PMCID: PMC1224660. https://pubmed.ncbi.nlm.nih.gov/16157883/

6.    Gonzalez AM, Trexler ET. Effects of Citrulline Supplementation on Exercise Performance in Humans: A Review of the Current Literature. J Strength Cond Res. 2020 May;34(5):1480-1495. doi: 10.1519/JSC.0000000000003426. PMID: 31977835. https://pubmed.ncbi.nlm.nih.gov/31977835/

7.    Suzuki I, Sakuraba K, Horiike T, Kishi T, Yabe J, Suzuki T, Morita M, Nishimura A, Suzuki Y. 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 May;119(5):1075-1084. doi: 10.1007/s00421-019-04097-7. Epub 2019 Feb 16. PMID: 30847640; PMCID: PMC6469824. https://pubmed.ncbi.nlm.nih.gov/30847640/

8.    Theodorou AA, Zinelis PT, Malliou VJ, Chatzinikolaou PN, Margaritelis NV, Mandalidis D, Geladas ND, Paschalis V. Acute L-Citrulline Supplementation Increases Nitric Oxide Bioavailability but Not Inspiratory Muscle Oxygenation and Respiratory Performance. Nutrients. 2021 Sep 22;13(10):3311. doi: 10.3390/nu13103311. PMID: 34684312; PMCID: PMC8537281. https://pmc.ncbi.nlm.nih.gov/articles/PMC8537281/

9.    Barkhidarian B, Khorshidi M, Shab-Bidar S, Hashemi B. Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysis. Avicenna J Phytomed. 2019 Jan-Feb;9(1):10-20. PMID: 30788274; PMCID: PMC6369322. https://pmc.ncbi.nlm.nih.gov/articles/PMC6369322/

10. 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 Oct 3;20(11):98. doi: 10.1007/s11906-018-0898-3. PMID: 30284051. https://pubmed.ncbi.nlm.nih.gov/30284051/

11. Hillsley AB, McLachlan CS. Assessment of Registered Clinical Trial Designs: Comparison of L-Arginine and/or L-Citrulline Interventions for Hypertension. Pharmaceuticals (Basel). 2024 Apr 8;17(4):477. doi: 10.3390/ph17040477. PMID: 38675437; PMCID: PMC11053694. https://pubmed.ncbi.nlm.nih.gov/38675437/

12. Oketch-Rabah HA, Roe AL, Gurley BJ, Griffiths JC, Giancaspro GI. The Importance of Quality Specifications in Safety Assessments of Amino Acids: The Cases of l-Tryptophan and l-Citrulline. J Nutr. 2016 Dec;146(12):2643S-2651S. doi: 10.3945/jn.115.227280. Epub 2016 Nov 9. PMID: 27934657. https://www.sciencedirect.com/science/article/pii/S0022316623008192?via%3Dihub

13. Bahri S, Zerrouk N, Aussel C, Moinard C, Crenn P, Curis E, Chaumeil JC, Cynober L, Sfar S. Citrulline: from metabolism to therapeutic use. Nutrition. 2013 Mar;29(3):479-84. doi: 10.1016/j.nut.2012.07.002. Epub 2012 Sep 28. PMID: 23022123. https://pubmed.ncbi.nlm.nih.gov/23022123/

14. Gu I, Balogun O, Brownmiller C, Kang HW, Lee S-O. Bioavailability of Citrulline in Watermelon Flesh, Rind, and Skin Using a Human Intestinal Epithelial Caco-2 Cell Model. Applied Sciences. 2023; 13(8):4882. https://doi.org/10.3390/app13084882

15. WebMD. L-Arginine: Uses, side effects, and more. WebMD.com. [cited 2025 Mar 29]. Available from: https://www.webmd.com/vitamins/ai/ingredientmono-875/l-arginine

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