L-Citrulline

1) What is L-citrulline?

L-citrulline (or simply, citrulline) is a non-essential and non-proteinogenic amino acid, which means it is naturally produced in the body and it is not used to build body proteins.  However, this unique amino acid has become a noteworthy pre-workout ingredient because of its role as nitric oxide booster.  Although citrulline is not very abundant in many foods, it can be found naturally in watermelon, cucumbers, and other melons.  The highest concentrations of citrulline are found in watermelon, and it even gets its name from the Latin term for watermelon, Citrullus vulgaris.  However, you would need to eat several pounds of watermelon flesh and rind each day to reach a performance-enhancing dose of citrulline.  Citrulline is among the most popular pre-workout ingredients primarily due to its potential to increase nitric oxide production and improve exercise capacity.  Other than beetroot juice, citrulline supplementation has been the most researched nutritional strategy for supporting nitric oxide synthesis. It is typically included in pre-workout formulas as either isolated L-citrulline or citrulline malate (a combination of citrulline and malate).

L-citrulline is a non-essential amino acid found primarily in watermelon that is included in pre-workout formulas to increase “the pump” due to its potential as a nitric oxide booster.

2) Evidence for effectiveness

Body Composition
Endurance
Energy
Focus
Mood
Pump
Strength

3) Pre-workout benefits of L-citrulline. 

Citrulline serves as an endogenous precursor to the amino acid, arginine.  In other words, after drinking a citrulline supplement, citrulline can be converted to arginine, which promotes nitric oxide synthesis through a pathway known as the arginine-nitric oxide pathway.  Subsequently, the improved nitric oxide bioavailability can induce many favorable physiological effects to enhance exercise performance.  Most notably, nitric oxide induces vascular smooth muscle relaxation leading to vasodilation (i.e., opening of the blood vessels) thereby improving blood flow.  Enhanced vasodilation can, in turn, improve delivery of blood, oxygen, and nutrients to the working muscles and aid in clearance of metabolic byproducts that we want to be eliminated from the muscle.  Nitric oxide may also improve other important functions during exercise including mitochondrial respiration, glucose and calcium homeostasis, and skeletal muscle contractility.      

While nitric oxide boosting properties are predicated on arginine availability, the attention has shifted from arginine supplementation to citrulline supplementation over the past several years for good reason.  Simply, the inclusion of citrulline is preferred over arginine as an effective pre-workout ingredient.  Unlike arginine, citrulline is not broken down in the gut or extracted from systemic circulation via hepatic clearance.  This makes citrulline a more efficient means of elevating plasma arginine concentrations than supplementing directly with arginine.  For these reasons, citrulline has shown to promote nitric oxide synthesis and more reliably improve exercise performance to a greater degree than arginine.  In fact, evidence for arginine’s performance-enhancing effects is weak, and side effects such as gastrointestinal distress are often observed when supplementing with higher doses of arginine.  On the other hand, citrulline is well-tolerated even at high doses and more likely to improve vascular and muscular function.

A secondary mechanism by which citrulline may improve exercise performance is by improving ammonia clearance via the urea cycle.  During high-intensity exercise, ammonia production is ramped up, which has been associated with exercise-induced muscle fatigue.  High ammonia concentrations can have negative consequences such as greater lactate production and blunted oxidative metabolism.  Citrulline may exert anti-fatigue properties by enhancing ammonia-buffering capacity via its role in the urea cycle, a process that eliminates ammonia in the form of urea.  Detoxifying ammonia during high-intensity exercise may enhance aerobic utilization of pyruvate and energy supply to the working muscle. 

Overall, the evidence suggests that citrulline has great potential for favorably affecting both endurance and resistance training performance.  

Citrulline is converted to arginine, which promotes nitric oxide synthesis.  Improved nitric oxide bioavailability can induce many favorable physiological effects to enhance exercise performance, including improved blood flow.

4) The latest science 

The research on exercise performance following citrulline supplementation has grown substantially over the last several years.  Numerous studies have investigated the potential for citrulline to improve cardiovascular endurance and high-intensity training including resistance exercise.  Given some of the mixed findings in the research, several review papers have comprehensively synthesized the evidence to provide an overall understanding of citrulline’s impact on exercise.  A 2019 review sought to investigate the acute effects of citrulline supplementation on high-intensity strength and power performance.  Based upon the twelve studies published, a small, but meaningful, benefit was noted following a single dose of citrulline supplementation compared to placebo treatments during strength and power performance.  A 2020 review investigating the effect of citrulline on recovery parameters concluded that supplementing with citrulline prior to exercise significantly reduced post-exercise ratings of perceived exertion and muscle soreness without affecting blood lactate levels.  These findings indicate that citrulline may make your workout feel less difficult and aid in the recovery process.  

Another comprehensive review article published in 2020 evaluated the effects of citrulline supplementation on vascular function and exercise performance in humans. It was concluded that acute citrulline supplementation has consistently shown to increase plasma citrulline and arginine concentrations, along with total nitrate and nitrite concentrations (blood markers that are indicative of nitric oxide bioavailability). Nevertheless, while the theoretical rationale for citrulline improving vasodilation and blood flow is strong, the actual supportive evidence is rather limited.  Overall, several studies have reported that citrulline supplementation can enhance exercise performance and recovery.  It was also noted that chronic dosing (e.g., more than 7 days) seems to be more effective than an acute single-dose protocol for enhancing exercise performance, but more research is needed in this area.

Since citrulline has been marketed to enhance “the pump” during weight training, many researchers have focused on investigating its impact on muscle endurance during high-intensity strength training.  Although these studies have offered mixed findings, several have shown that taking citrulline pre-workout increases performance during high-intensity strength and power tasks.  Most of the research pertaining to strength training has investigated the effect of citrulline (typically in the form of citrulline malate) on repetitions to failure during single-joint and/or multi-joint resistance exercise. These also have yielded some mixed results.  Fortunately, a 2021 review sought to systematically evaluate the scientific evidence on citrulline’s effect on repetition performance during strength training and reported that a single dose of citrulline supplementation allowed individuals to complete a few more repetitions during weight training when sets were carried out to muscular failure.  Therefore, the evidence suggests that citrulline improves resistance to fatigue during weight training.  Although the long-term effects of citrulline in combination with a training regimen on muscular adaptations have not been extensively investigated, the findings of this review show that citrulline can allow an athlete to increase the amount of work performed during each workout which may spark more gains in strength and hypertrophy over time.  

Several studies have reported that citrulline supplementation can enhance exercise performance and recovery.  The research supports that including citrulline in your pre-workout can improve resistance to fatigue.  This may allow you to perform a few extra reps during your workout. 

5) Other health benefits of L-citrulline (500 words)

Impaired bioavailability of nitric oxide has been suggested to contribute to the development and progression of multiple diseases including hypertension, atherosclerosis, insulin resistance, type 2 diabetes, and cardiovascular disease.  Therefore, citrulline supplementation may offer therapeutic benefits on cardiometabolic health serving as a precursor to nitric oxide synthesis.  Specifically, supplementation with citrulline has shown promise for lowering blood pressure in adults with hypertension. While more long-term human studies are needed, it is possible that citrulline could benefit vascular and metabolic health. 

Citrulline supplementation may offer therapeutic benefits on cardiovascular and metabolic health, along with promise for lowering blood pressure in adults with hypertension. 

6) What to look for on the label – Recommended dosage and other ingredients.

Citrulline has typically been studied in doses ranging from 3 to 6 grams.  The most common dosing strategy prior to strength training is 6 to 8 grams of citrulline malate (offering 3 to 5.3 grams L-citrulline).  Studies have most often provided citrulline approximately 60 minutes prior to exercise, but the optimal timing has not yet been defined.  While loading protocols or regular usage of citrulline are not common in research, chronic dosing would likely exert more favorable effects on endurance and high-intensity exercise performance.  Therefore, consistent use of a pre-workout containing citrulline would likely offer more benefit over time. It is also unclear whether a greater dose of citrulline would offer more pronounced benefits on exercise performance.  Leading experts have speculated that supplementing with a greater dose may more reliably offer a boost in exercise performance.  It is possible that the research, to date, has been underdosing citrulline.  Interestingly, a 2008 study showed that doses up to 10 grams were well tolerated and increased plasma arginine concentrations in a dose–response fashion.  In other words, based on the mechanism of increasing arginine for nitric oxide synthesis – the higher the dose of citrulline, the higher the arginine bioavailability.  

Overall, the minimum effective pre-workout dose seems to be 3 grams, while the maximum effective dose may be as high as 10 to 15 grams.  Be aware that 6 grams of citrulline malate is not the equivalent of 6 grams of citrulline.  Products with citrulline malate in their pre-workout blend provide either a 1:1 or 2:1 ratio of citrulline to malate (which is not always specified).  Therefore, 6 grams of citrulline malate offers, at most, 4 grams of citrulline.  However, reports have found that supplement companies notoriously have a lower concentration of citrulline than displayed on the label when using citrulline malate.  Nevertheless, a 2:1 ratio would be preferred as it should offer more citrulline per gram.  Currently, it appears best to use a product using isolated L-citrulline rather than citrulline malate.  This is based on the premise that malate has never been proven to offer performance enhancing benefits or a synergistic effect when combined with citrulline (see citrulline malate page).  Surprisingly, no study has ever even investigated the effects of malate, in isolation, on exercise performance in humans.  

The minimum effective pre-workout dose of citrulline is 3 grams, while the maximum effective dose is unknown but may be up to 10 grams.  There is currently no reason to believe that citrulline malate would be superior to L-citrulline in a pre-workout formula. 

7) Synergistic Effect with Other Pre-workout Ingredients?

It is possible that citrulline could work synergistically with other pre-workout ingredients.  First, the improved blood flow may aid in the delivery of other ingredients including stimulants and other amino acids.  Next, ingredients that are rich in nitrates may amplify the nitric oxide boosting effects of a pre-workout.  These ingredients, such as nitrates, beet root extract, or red spinach leaf extract, also serve as nitric oxide precursors via an alternative pathway known as the nitrate-nitrite-nitric oxide pathway.  The combination of nitric oxide precursors may work better in combination.  Also, antioxidants have shown to improve the production and bioavailability of nitric oxide.  Therefore, the inclusion of ingredients rich in antioxidants (such as fruit extracts, vitamins, and Co-enzyme Q10) may enhance the effectiveness of citrulline. 

The combination of citrulline with nitrate-rich ingredients and/or antioxidants may enhance the effectiveness of the pre-workout.