How do you make citrulline?

December 12, 2025 •

4 min read

The human body naturally produces the amino acid citrulline, primarily in the intestines and kidneys from other amino acid precursors. While this endogenous synthesis is a primary source of the compound, many wonder how do you make citrulline from other sources, including food and supplements, to optimize levels for performance and health.

Quick Summary

Citrulline is synthesized endogenously in the body via the urea cycle and as a byproduct of nitric oxide synthesis, but it can also be obtained from rich food sources like watermelon and supplements.

Key Points

Natural Synthesis: The body creates citrulline primarily in the small intestine and kidneys from other amino acids as part of the urea cycle and nitric oxide production.
Dietary Sources: Watermelon is the richest food source of citrulline, but other cucurbits like cucumbers and pumpkins also contain it.
Supplemental Forms: Commercial citrulline is made via extraction from watermelon or microbial fermentation and is sold as pure L-citrulline or citrulline malate.
Nitric Oxide Production: Supplemental citrulline is highly bioavailable and efficiently converted into arginine in the kidneys, leading to increased nitric oxide production.
Improving Levels Naturally: To increase citrulline, incorporate more precursor-rich foods like meat, dairy, and legumes, and support nitric oxide production with foods high in nitrates, such as beets and spinach.
Performance Benefits: Enhanced citrulline levels can improve athletic performance, cardiovascular function, and reduce fatigue and muscle soreness.

Endogenous Production: How the Body Makes Citrulline

Within the human body, citrulline is primarily synthesized through two key metabolic pathways. It is considered a non-essential amino acid because the body can produce it, though external intake can still be beneficial.

The Urea Cycle

One of the main roles of citrulline is as a crucial intermediate in the urea cycle, a process that takes place mainly in the liver and kidneys to help the body detoxify and excrete ammonia. The synthesis of citrulline in this cycle involves a reaction between ornithine and carbamoyl phosphate, catalyzed by the enzyme ornithine transcarbamylase. This metabolic route allows the body to efficiently manage nitrogen waste.

Nitric Oxide Synthase Pathway

Citrulline is also produced as a byproduct of the enzymatic production of nitric oxide (NO) from the amino acid arginine, a reaction catalyzed by the nitric oxide synthase (NOS) family of enzymes. This pathway is particularly important because citrulline can be recycled back into arginine, helping to maintain and amplify nitric oxide production, which is crucial for blood vessel dilation and blood flow. The recycling of citrulline to arginine via the kidneys is often a more efficient way to increase plasma arginine levels than supplementing with arginine directly, as citrulline bypasses liver metabolism.

Natural Dietary Sources to Increase Citrulline

While the body produces its own supply, increasing dietary intake of citrulline is a popular method to boost systemic levels. Fortunately, some common foods are excellent sources.

Foods High in Citrulline

Watermelon: The name citrulline is derived from Citrullus lanatus, the scientific name for watermelon, its most abundant natural source. Both the flesh and rind contain citrulline, with varying concentrations depending on the cultivar.
Other Cucurbits: Other members of the gourd family also contain this amino acid, including cucumber, pumpkin, muskmelon, and bitter melon.
Other Food Sources: Smaller amounts can also be found in chickpeas, squash, nuts, and some types of soy products.

Industrial Production and Supplementation

For many athletes and individuals, consuming enough food to achieve therapeutic levels of citrulline is impractical. For this reason, supplements are widely available. Industrially, citrulline is produced through several methods.

Extraction from Watermelon

Patented processes exist for extracting L-citrulline from watermelon juice, often using ion-exchange media to isolate and recover the compound without the use of harsh chemicals or high temperatures.

Microbial Fermentation

Commercial production often relies on microbial fermentation, utilizing engineered bacteria such as Corynebacterium glutamicum to efficiently synthesize L-citrulline. This method allows for large-scale, cost-effective production of the amino acid for dietary supplements and other applications.

Forms of Citrulline Supplements

L-Citrulline: The purest supplemental form, this is the bioactive isomer naturally produced by the body. It is often recommended for its high bioavailability.
Citrulline Malate: This form combines L-citrulline with malic acid. Malic acid, found in fruits like apples, plays a role in the Krebs cycle, which is essential for cellular energy production. For this reason, citrulline malate is popular in athletic supplements, with some research suggesting it may provide additional benefits related to energy and endurance.

Natural Ways to Support Endogenous Citrulline Production

Beyond eating citrulline-rich foods, you can optimize your body's natural synthesis by supporting the metabolic processes involved.

Consume Precursor Nutrients: Ensure a diet rich in glutamine, arginine, and ornithine. Since citrulline is made from these compounds, a balanced protein intake is key. Glutamine is found in protein-rich foods, while arginine is in meat, dairy, nuts, and legumes.
Boost Nitric Oxide Production: Foods high in nitrates, such as beets, leafy greens, radishes, and spinach, can help boost nitric oxide levels. Since citrulline is a byproduct of NO production, supporting this pathway is beneficial.
Exercise Regularly: Engaging in physical activity, particularly intense exercise, can increase the need for NO and subsequently increase the body's synthesis of citrulline and its conversion to arginine.
Increase Antioxidant Intake: Antioxidants can protect nitric oxide from oxidative damage, ensuring that more citrulline can be produced and utilized effectively. Fruits and vegetables high in antioxidants, such as pomegranate and dark chocolate, are good choices.

L-Citrulline vs. Citrulline Malate: A Comparison


Feature	L-Citrulline (Pure)	Citrulline Malate (CM)
Composition	Pure L-citrulline amino acid.	A compound of L-citrulline and DL-malate (malic acid).
Bioavailability	Highly bioavailable and efficiently converted to L-arginine.	May offer enhanced bioavailability in combination with malate.
Energy Production	Indirectly supports energy by improving blood flow and nutrient delivery.	Directly aids cellular energy production via malic acid's role in the Krebs cycle.
Primary Use	General health support, blood flow enhancement, and improving arginine levels.	Often preferred in sports nutrition for muscular endurance and performance benefits.
Dosage Considerations	Typical dosages range from 3 to 6 grams.	Recommended dosages can be higher due to the malate component, such as 8 grams.

Conclusion

In summary, the process of making citrulline is a complex interplay of natural bodily synthesis, dietary intake, and industrial manufacturing. While your body is equipped to produce its own citrulline through the urea cycle and nitric oxide pathways, optimizing levels can be achieved by a balanced diet rich in citrulline-containing foods like watermelon. For those seeking higher concentrations, whether for athletic performance or specific health goals, supplements offer a reliable alternative, particularly since they are well-tolerated and effectively boost plasma arginine levels. Natural production can be further supported by eating nitrate-rich vegetables and maintaining regular exercise. Understanding these diverse pathways provides a comprehensive answer to how one can acquire and increase their citrulline levels. For more in-depth research on citrulline and its effects, you can consult sources like the Examine.com research breakdown.

Frequently Asked Questions

No, you cannot synthesize a pure citrulline supplement at home. While you can create juice or food-based concoctions from sources like watermelon, the industrial process for creating pure L-citrulline powder or capsules involves complex laboratory extraction or microbial fermentation methods.

The most well-known and abundant natural food source of citrulline is watermelon. Its name, in fact, is derived from the Latin word for the fruit. Other good sources include cucumber, pumpkin, and various gourds.

Your body produces citrulline in the small intestine from precursors like glutamine and in the kidneys as part of the urea cycle and the nitric oxide synthase pathway. The amount produced can vary depending on health status and diet.

Supplemental citrulline is not broken down by enzymes in the liver in the same way as supplemental arginine. Instead, it bypasses liver metabolism and is efficiently converted to arginine in the kidneys, leading to higher and more sustained plasma arginine levels.

Neither is universally 'better,' as they serve slightly different purposes. Pure L-citrulline is a straightforward, highly bioavailable amino acid. Citrulline malate is a combination of L-citrulline and malic acid, with some athletes preferring it for potential enhanced energy benefits due to the added malic acid.

A plant-based diet can increase citrulline naturally by emphasizing foods rich in the amino acid, such as watermelon, cucumbers, and other gourds. Additionally, consuming nitrate-rich leafy greens like spinach and beets can boost nitric oxide production, a process that also creates citrulline as a byproduct.

Citrulline is generally well-tolerated, even at higher doses, and does not cause the gastrointestinal distress sometimes associated with high-dose arginine supplementation. However, as with any supplement, a doctor should be consulted regarding appropriate dosage.