Citrulline Malate and the Liver and Kidneys: Is It Safe
Citrulline malate is a popular component of pre-workout complexes, used for the «pump» and for increasing endurance. Unlike many supplements, citrulline is closely connected specifically with the work of the kidneys and liver: the kidneys convert it into arginine, and in the liver it is a participant in the urea cycle. The editorial team explains what this means for safety and who should be careful.
What citrulline malate is
L-citrulline is an amino acid that is not part of proteins but plays an important role in nitrogen metabolism. It got its name from the watermelon (Citrullus lanatus), in which it was first discovered. In the body, citrulline is synthesized predominantly in the cells of the small intestine from glutamine and other precursors.
Malate is a salt of malic acid, an intermediate compound of the Krebs cycle. In supplements, citrulline is combined with malate in ratios of 1:1 or 2:1. Theoretically, malate may contribute to energy metabolism, but the independent contribution of malate to the effects of the supplement has been little studied.
The interest in citrulline in sport is connected with the fact that it effectively raises the level of arginine in the blood — even better than taking arginine itself. Arginine is a substrate for the synthesis of nitric oxide (NO), which dilates blood vessels. Schwedhelm and co-authors (2008) showed that oral citrulline raises the plasma concentration of arginine in a dose-dependent manner.
The results regarding athletic performance are mixed. The review by González and Trexler (2020) notes that some studies showed an improvement in performance in repeated sets of strength exercises and a reduction in muscle soreness, as in the well-known work by Pérez-Guisado and Jakeman (2010), whereas other studies found no effect.
The gut-kidney axis: where citrulline is metabolized
A unique feature of citrulline is its path in the body. Citrulline formed in the intestine or coming from a supplement is almost not retained by the liver, unlike most amino acids. It enters the general bloodstream and reaches the kidneys.
In the cells of the proximal tubules of the kidneys, citrulline is converted into arginine with the participation of the enzymes argininosuccinate synthetase and argininosuccinate lyase. The resulting arginine returns to the blood and is distributed to the tissues. In physiology this pathway is called the gut-kidney axis, and it is described in detail in the review by Curis and co-authors (2005).
So it is precisely the kidneys that are the main «converter» of citrulline into arginine. This does not mean that citrulline harms the kidneys: the conversion takes place within the bounds of normal physiological function, and the load from the supplement is comparable to natural metabolism.
However, in people with chronic kidney disease this pathway is disrupted. Their blood citrulline level is often elevated because the kidneys process it worse. How additional citrulline behaves with reduced kidney function has not been sufficiently studied.
The liver and the urea cycle
In the liver, citrulline is known as an intermediate link of the urea cycle — the process by which the body neutralizes ammonia. However, this intrahepatic citrulline is formed and used in the mitochondria of hepatocytes and is almost not exchanged with the blood.
This is precisely why citrulline taken as a supplement does not «overload» the urea cycle of the liver. On the contrary, in some rare hereditary disorders of the urea cycle, citrulline or arginine is prescribed as part of the treatment, which is described in the European guidelines by Häberle and co-authors (2019). This treatment is carried out exclusively under the supervision of specialists.
There is no evidence of hepatotoxicity of citrulline in humans. In pharmacokinetic studies, no changes in liver parameters were reported with short-term intake of even high doses.
As for malate, malic acid is a normal metabolite that participates in the energy metabolism of the liver and other tissues. The amounts that come with the supplement do not constitute a known risk to the liver.
| Organ | Role in citrulline metabolism | Known risk from the supplement in healthy people |
|---|---|---|
| Intestine | The main site of natural synthesis | Good tolerability, less discomfort than from arginine |
| Liver | Urea cycle (intracellular citrulline) | No evidence of harm |
| Kidneys | Conversion of citrulline into arginine | No evidence of harm |
| Blood vessels | Arginine → nitric oxide | A possible slight decrease in blood pressure |
What safety studies say
One of the key studies is the work of Moinard and co-authors (2008), in which healthy volunteers received various single doses of citrulline, up to 15 g. The supplement was well tolerated, and the gastrointestinal disorders characteristic of high doses of arginine were not observed.
In sports studies, 6–8 g of citrulline malate were usually used an hour before training. In these works, no serious side effects were recorded; most often mild stomach discomfort was reported in individual participants.
At the same time, most studies were short — from a single intake to a few weeks. There is little long-term data on regular intake over years in healthy athletes, so it is premature to speak of proven long-term safety for the kidneys and liver, although there are no signals of harm either.
A practical question of quality: analyses of commercial products from different years have shown that the actual ratio of citrulline to malate does not always correspond to what is declared. This affects effectiveness, but not the safety for the organs.
- Good tolerability of single doses up to 15 g in a pharmacokinetic study.
- Fewer gastrointestinal disorders than from arginine.
- The absence of data on hepato- or nephrotoxicity in healthy people.
- A lack of long-term studies of regular intake.
Kidney and liver diseases: when caution is needed
People with chronic kidney disease should discuss taking citrulline with a nephrologist. Since the kidneys are the main site of the conversion of citrulline into arginine, when they are damaged the metabolism of the substance changes, and there is insufficient safety data for the supplement in this group.
In severe liver diseases, in particular cirrhosis, the metabolism of nitrogen and ammonia is disrupted. Any amino acid supplements in such a situation should be used only by the decision of a hepatologist.
Citrulline, through arginine and nitric oxide, can moderately lower blood pressure. People who take nitrates, phosphodiesterase type 5 inhibitors (sildenafil, tadalafil), or several antihypertensive drugs should take into account the possible summation of effects.
Finally, citrulline is often part of pre-workout complexes together with caffeine and other stimulants. For people with diseases of the kidneys, liver, or heart, the risks of such complexes are determined primarily by their full composition.
Editorial conclusions
Citrulline is physiologically closely connected with the kidneys and liver, but in healthy people studies have not shown harm to these organs.
The supplement is well tolerated even in high single doses, and in this respect it compares favorably with arginine.
People with chronic kidney disease, severe liver diseases, and those who take nitrates or blood pressure medications should coordinate the intake with a doctor.
We also recommend our articles «L-arginine and the Liver and Kidneys: Is It Safe», «Creatine Monohydrate and the Liver and Kidneys: Is It Safe», and «Beta-alanine and the Liver and Kidneys: Is It Safe».
References
- Curis E, Nicolis I, Moinard C, et al. Almost all about citrulline in mammals. Amino Acids. 2005;29(3):177–205.
- Moinard C, Nicolis I, Neveux N, Darquy S, Bénazeth S, Cynober L. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. Br J Nutr. 2008;99(4):855–862.
- 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.
- Gonzalez AM, Trexler ET. Effects of citrulline supplementation on exercise performance in humans: a review of the current literature. J Strength Cond Res. 2020;34(5):1480–1495.
- Pérez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res. 2010;24(5):1215–1222.
- Häberle J, Burlina A, Chakrapani A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: first revision. J Inherit Metab Dis. 2019;42(6):1192–1230.
Andriy Melnyk
A strength-sports coach and author of programs for beginner and intermediate levels. Writes about training planning.
