The History of Citrulline Malate: How the Supplement Became Popular

Citrulline malate is today one of the most popular ingredients in pre-workout formulas. Yet this substance's path to the shelves of sports nutrition took almost a century and ran through biochemistry, cardiology and clinical medicine. Our editorial team has traced the key stages of this history.

The Discovery of Citrulline

The name "citrulline" comes from the Latin name for watermelon —Citrullus lanatus. It was from watermelon juice that Japanese researchers isolated a new amino acid in the first half of the 20th century. The definitive identification and naming of the substance is associated with the work of the Japanese scientist Mitiro Wada, published in 1930.

Unlike most of the amino acids known at the time, citrulline is not part of proteins, meaning it is not encoded by the genetic code. Because of this, it long remained a "biochemical curiosity" whose role in the body was little understood.

Watermelon still remains one of the richest natural sources of citrulline, especially its white part near the rind. However, the amount of the substance in an ordinary portion of food is far less than that used in sports studies, so a dietary source is not a practical substitute for a supplement.

Already at this stage, the key feature of citrulline that would later determine its popularity had taken shape: it is an intermediate link between the amino acids ornithine and arginine and can be converted into the latter in the body.

The Urea Cycle and Nitric Oxide

The true significance of citrulline became clear in 1932, when Hans Krebs and Kurt Henseleit described the urea cycle — the first cyclic metabolic pathway ever discovered. In it, citrulline is formed from ornithine and then converted into arginine, allowing the body to excrete excess nitrogen in the form of urea.

The next major step came in the 1980s. Groups of researchers established that vascular endothelial cells synthesize nitric oxide (NO) from L-arginine, and that it is NO that is the "endothelium-derived relaxing factor" which dilates blood vessels (Palmer et al., 1988). In this reaction, citrulline is formed alongside NO. In 1998, Robert Furchgott, Louis Ignarro and Ferid Murad received the Nobel Prize in Physiology or Medicine for discovering the role of NO as a signaling molecule.

These discoveries made arginine a fashionable supplement ingredient for "blood flow." However, it turned out that orally taken arginine is largely broken down in the intestine and liver before it reaches the general bloodstream.

Citrulline, on the other hand, is weakly taken up by the liver and is converted into arginine mainly in the kidneys. A pharmacokinetic study by Schwedhelm and colleagues (2008) showed that oral citrulline raises plasma arginine levels more effectively than arginine itself. This became one of the scientific arguments in favor of citrulline in sports supplements.

Malate and Medical Use for Fatigue

Malate — a salt of malic acid — is an intermediate product of the Krebs cycle, the central pathway of cellular energy metabolism. Combining citrulline with malate was based on the idea that both components could support energy metabolism and the removal of ammonia, which accumulates during physical exertion.

In France, citrulline malate was used for decades as a medicine for the symptomatic treatment of functional asthenia, that is, a feeling of fatigue without an identified organic cause. It was this medical history that gave the substance a certain reputation even before its appearance in sports stores.

The work of Bendahan and colleagues (2002) proved important for sport. Using phosphorus-31 magnetic resonance spectroscopy, the authors showed that in men complaining of fatigue, taking citrulline malate was associated with an increase in the rate of oxidative ATP synthesis in the muscle during exercise and with faster phosphocreatine recovery.

It should be remembered that this study was not conducted on trained athletes and measured biochemical parameters rather than athletic performance. Nevertheless, it became a starting point for subsequent work and is often cited by supplement manufacturers.

Arrival in Sports Nutrition

In the 2000s, the sports nutrition market was dominated by arginine-based products advertised as agents for "pumping." Gradually, manufacturers began adding citrulline malate to them, and then replacing arginine with it entirely, relying on data about better bioavailability.

A turning point was the randomized crossover study by Pérez-Guisado and Jakeman (2010). Participants who took 8 g of citrulline malate an hour before strength training performed more repetitions in sets of the bench press to failure and reported less pronounced delayed-onset muscle soreness than on placebo.

It was this study that cemented the "standard" dose of 8 g of citrulline malate before training in sports culture. It can still be seen on the labels of many products and in trainers' recommendations.

Subjective sensations also contributed to its popularity: some people notice a pronounced "filling" of the muscles during training. Although this sensation is not proof of effectiveness, it made citrulline a recognizable ingredient among gym-goers.

What Science Has Changed in Recent Years

As the number of studies grew, the picture became more restrained. A meta-analysis by Trexler and colleagues (2019) showed a small but statistically significant positive effect of citrulline on strength and power indicators during high-intensity exercise. The authors emphasized the heterogeneity of the studies and the modest effect size.

A review by Gonzalez and Trexler (2020) summarized that results vary depending on the protocol, dose, form (pure L-citrulline or citrulline malate) and the training status of the participants. Some works found no advantage over placebo.

• The effect of citrulline malate exists, but it is moderate and not present in all studies.
• The role played by malate itself has not been definitively established.
• The ratio of citrulline to malate varies across products, so it is important to read the label.
• Long-term studies of the effect on muscle mass are still few.

Thus, the history of citrulline malate is an example of how an ingredient travels the road from enthusiasm to a more measured assessment. This does not make it useless, but it helps to set expectations correctly.

Editorial Conclusions

Citrulline has traveled the road from an amino acid in watermelon to one of the main ingredients of pre-workout formulas. Its popularity rests on real biochemical discoveries: its role in the urea cycle and its connection to nitric oxide synthesis.

The medical use of citrulline malate in France and studies from 2002 and 2010 made it well known in sport, while later meta-analyses clarified that the effect is moderate and heterogeneous.

Today citrulline malate should be regarded as a supplement with a proven but modest effect on strength performance, not as a "magic" agent for the pump.

We also recommend reading our materials on citrulline malate for women, citrulline malate after 40, and its role during the mass-gaining period.

References

1. Krebs HA, Henseleit K. Untersuchungen über die Harnstoffbildung im Tierkörper. Hoppe-Seylers Z Physiol Chem. 1932;210:33–66.
2. Palmer RM, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature. 1988;333(6174):664–666.
3. Bendahan D, Mattei JP, Ghattas B, et al. Citrulline/malate promotes aerobic energy production in human exercising muscle. Br J Sports Med. 2002;36(4):282–289.
4. 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.
5. Pérez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res. 2010;24(5):1215–1222.
6. Trexler ET, Persky AM, Ryan ED, et al. Acute effects of citrulline supplementation on high-intensity strength and power performance: a systematic review and meta-analysis. Sports Med. 2019;49(5):707–718.
7. 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.