What is citrulline? How does it work and what are its effects?

Japanese researchers isolated citrulline from watermelon juice as early as 1914. It was not until 1930 that the compound was characterised in greater detail and named, in reference to the Latin name for watermelon – Citrullus. Citrulline is found not only in plants but also in the human body, which is capable of producing it naturally. It is now also an ingredient in popular dietary supplements, particularly those intended for people who engage in physical activity.

citrulline

What is citrulline and where does it occur naturally?
How does citrulline work in the body, and in which processes does it play a part?
L-citrulline versus citrulline malate – how do these forms differ?
Citrulline in supplements – dosage and safety
FAQ – frequently asked questions about citrulline

What is citrulline and where does it occur naturally?

Citrulline is an amino acid and an endogenous compound, meaning it is produced by the body. No recommended daily intake has been established for it. The best-known dietary source of citrulline is watermelon (Citrullus lanatus). Analyses of the red flesh have found, amongst other things, approximately 40–160 mg of this amino acid per 100 g of fresh fruit. This means that a 200 g portion may contain approximately 80–320 mg of citrulline within this range.

Citrulline has also been detected in the white part of the watermelon rind. Some analyses have shown higher concentrations there than in the flesh, although the results also depend on whether fresh or dried plant material is being compared. This compound is also found in other plants of the Cucurbitaceae family, including cucumbers, melons, pumpkins and bitter melon.

Estimated L-citrulline content in selected plant products other than watermelon

Product	L-citrulline content (mg/100 g)
Cantaloupe melon	34,0-41,0
Fresh cucumber	21,1-29,1
Honeydew melon	16,3-17,7
Courgette	4,2-8,5

How does citrulline work in the body, and in which processes does it play a part?

Citrulline is primarily produced in the epithelial cells of the small intestine, known as enterocytes. Its synthesis involves the conversion of other amino acids, including ornithine, glutamine and proline. Citrulline then enters the bloodstream, and some of it is taken up by the kidneys, where it can be converted into arginine.

Arginine acts as a substrate for enzymes known as nitric oxide synthases, which produce nitric oxide (NO) and citrulline. Nitric oxide is a short-lived signalling molecule involved, amongst other things, in regulating the tone of the smooth muscle in blood vessels. The citrulline produced in this process can once again participate in the metabolic processes leading to the regeneration of arginine.

Another function of citrulline is its role in the urea cycle, which takes place primarily in the liver. In this multi-stage process, toxic ammonia – produced during the metabolism of nitrogenous compounds – is converted into urea, which is then excreted by the kidneys.

L-citrulline versus citrulline malate – how do these forms differ?

citrulline

In dietary supplements, L-citrulline and citrulline malate are primarily used. The former refers to the free form of the amino acid, without the addition of the latter component. L-citrulline is usually available in powder, capsule and tablet form. Citrulline malate is a combination of citrulline and malate, a compound derived from malic acid. Malate also plays a role in the body’s natural energy metabolism, including the citric acid cycle.

In the case of citrulline malate, the ratio of its components is important. The designation 2:1 usually refers to two parts citrulline to one part malate. With this stated ratio, 6 g of the mixture contains 4 g of citrulline and 2 g of malate, whilst a 1:1 mixture contains 3 g of each. Multi-ingredient preparations may also contain creatine, arginine, caffeine, beta-alanine, sweeteners or flavourings, which should be taken into account when assessing the overall composition.

Citrulline in supplements – dosage and safety

No single official recommended dose for citrulline has been established for all adults. In human studies, various amounts of L-citrulline have been used, often ranging from 3 to 6 g per day, whilst studies on citrulline malate have involved single doses of 8 g. These are regimens used in experiments and do not constitute recommendations from the European Food Safety Authority (EFSA).

Caution is advised for people taking medication that affects blood pressure, as well as those with kidney or liver disease. During pregnancy, whilst breastfeeding, and in children, the use of supplements containing citrulline requires individual medical consultation.

"Citrulline is an amino acid that the body produces itself and uses, amongst other things, for the production of arginine and the regulation of processes related to nitric oxide. For this reason, it has attracted the interest of scientists studying physical performance and blood vessel function." Łukasz Domeracki – Dietitian

FAQ – frequently asked questions about citrulline

What is citrulline used for and how does it work?

Citrulline is involved in the urea cycle, which helps the body remove excess nitrogen, and in the metabolic processes leading to the formation of arginine. Arginine is required for the production of nitric oxide (NO), a substance involved in regulating blood vessel tone.

Does citrulline increase strength and endurance?

Citrulline is being studied for its effects on physical exercise, but the mechanism of action alone is not sufficient to confirm an improvement in strength or endurance. The effects may depend on the type of exercise, the supplement used and the individual’s response.

Which is better: L-citrulline or citrulline malate?

L-citrulline contains the amino acid on its own, whilst citrulline malate is a combination of citrulline and malate. The most important difference when comparing product labels relates to the actual amount of citrulline. One form cannot be considered more effective than the other based on the name alone.

What does ‘2:1 citrulline malate’ mean?

The 2:1 ratio usually indicates a proportion of two parts citrulline to one part malate. For example, 6 g of such a mixture corresponds to the declared 4 g of citrulline and 2 g of malate. Therefore, 6 g of citrulline malate is not the same as 6 g of pure L-citrulline.

What does citrulline malate 2:1 mean?

How much citrulline is there in watermelon?

According to data cited in the article, 100 g of red watermelon flesh may contain approximately 40–160 mg of citrulline. A 200 g portion therefore provides approximately 80–320 mg. The content depends, amongst other things, on the variety of the fruit and the part of the plant analysed.

How much citrulline was used in the studies?

In human studies, doses of 3 to 6 g of L-citrulline per day were often used, whilst in some experiments involving citrulline malate, a single dose of 8 g of the preparation was administered. These are research doses, not official recommendations for all users. No single universal supplementation dose has been established for citrulline.

Can citrulline lower blood pressure?

Citrulline is involved in the metabolic processes associated with the production of nitric oxide, which affects blood vessel tone. However, it should not be regarded as a substitute for medication for high blood pressure. People taking blood pressure-lowering medication should consult their doctor before taking this supplement, as it may enhance the blood pressure-lowering effect.

Is citrulline safe?

Safety depends on the dose, the type of supplement, age and general health. Particular caution is advised for people with kidney or liver disease and those taking medication that affects blood pressure. In the case of children and adolescents, as well as during pregnancy and breastfeeding, there is insufficient data to recommend self-administered supplementation.

Sources:

Corleto, K. A., Singh, J., Jayaprakasha, G. K., & Patil, B. S. (2019). A sensitive HPLC-FLD method combined with multivariate analysis for the determination of amino acids in l-citrulline rich vegetables. Journal of food and drug analysis, 27(3), 717–728. https://doi.org/10.1016/j.jfda.2019.04.001
Bahri, S., Zerrouk, N., Aussel, C., Moinard, C., Crenn, P., Curis, E., Chaumeil, J. C., Cynober, L., & Sfar, S. (2013). Citrulline: from metabolism to therapeutic use. Nutrition (Burbank, Los Angeles County, Calif.), 29(3), 479–484. https://doi.org/10.1016/j.nut.2012.07.002
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