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Citrulline

L-Citrulline, or simply just citrulline, is a nonessential amino acid. It is efficiently turned into L-arginine in the kidneys after supplementation, which makes it a good choice for increasing nitric oxide synthesis in the body.

Our evidence-based analysis on citrulline features 107 unique references to scientific papers.

Research analysis led by and reviewed by the Examine team.
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Summary of Citrulline

Primary information, health benefits, side effects, usage, and other important details

What is citrulline?

Citrulline is one of the three dietary amino acids in the urea cycle (the other two are L-arginine and L-ornithine). Taking citrulline increases plasma levels of ornithine and arginine and improves the ammonia recycling process and nitric oxide metabolism. Consequently, citrulline may be useful in situations in which nitric oxide is relevant, such as athletic performance, vascular health, and erectile dysfunction. There are very few foods that have useful amounts of citrulline, but watermelon is a notable exception.

What are citrulline’s main benefits?

A considerable amount of research suggests that chronic supplementation with citrulline mildly reduces blood pressure and mildly improves blood flow, particularly in individuals with hypertension or other cardiovascular problems. Limited research suggests that supplementation with citrulline, both short-term and long-term, can reduce fatigue, increase power output, and improve endurance in both aerobic and anaerobic exercise. More research is needed for citrulline’s potential effects on erectile dysfunction, but a small amount of research suggests a beneficial effect.

What are citrulline’s main drawbacks?

Although the safety of long-term supplementation with high doses of citrulline warrants further investigation, research to date suggests that it is well tolerated in most individuals. Unlike arginine and ornithine, high doses of citrulline don't seem to result in gastrointestinal distress.

How is citrulline taken?

Most studies that examined the effect of citrulline on circulatory health have used daily doses of 6 grams. For improving sports performance, the daily dose used in most studies was 6 grams of citrulline or 8–12 grams of citrulline malate, which is a combination of citrulline and malate (an ionized form of malic acid).

How does citrulline work?

Citrulline supplementation increases the body’s arginine levels. Because arginine is the main substrate for the synthesis of nitric oxide, citrulline ingestion can indirectly increase nitric oxide production. In turn, given the role of nitric oxide in vasodilation, mitochondrial respiration, calcium handling, and glucose uptake, greater amounts of nitric oxide can improve circulatory health and muscle function and reduce fatigue.

📝 Want a quick summary of citrulline’s health benefits?

We've analyzed over 100 studies to summarize the research on citrulline’s potential health benefits.

How to Take

Recommended dosage, active amounts, other details

To supplement L-citrulline for circulatory health or to alleviate erectile dysfunction, take 2,000 mg of citrulline, three times a day with meals, for a total daily dose of 6,000 mg. L-citrulline does not need to be taken with meals, however.

To supplement for circulatory health with a citrulline malate supplement, take 1.76 g of citrulline malate for every 1 gram of citrulline you would normally take.

To supplement L-citrulline to enhance sports performance, take 6,000 – 8,000 mg of citrulline malate about an hour before exercise. On days that you don't exercise, it can be broken up into smaller doses.

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Human Effect Matrix

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The Human Effect Matrix summarizes human studies to tell you what effects Citrulline has on your body, how much evidence there is, and how strong these effects are.

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Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
grade-b Minor Moderate See all 19 studies
A decrease in blood pressure is noted secondary to increasing plasma arginine (and thus increasing nitric oxide). It applies to both resting and active blood pressure, and to healthy and hypertensive participants in general, though the reduction will naturally be greater for those with hypertension.
grade-b Minor Very High See all 8 studies
There seems to be a distinction between acute and chronic supplementation; whereas acute citrulline supplementation doesn't seem to reliably improve performance, the studies that gave citrulline for a week prior to testing saw improvements. Additionally, a meta-analysis found a small but statistically significant increase for studies overall.
grade-b - Very High See all 6 studies
There do not appear to be any significant influences of supplemental citrulline on blood glucose concentrations in healthy participants. It is possible that there's some benefit of citrulline in diabetic people, but much more research is needed.
grade-b - Moderate See all 8 studies
No significant influence on heart rate seems likely, although some studies suggest a small reduction during and around the time of exercise, but this effect is inconsistent.
grade-b - High See all 4 studies
Most studies note that there is no significant change in insulin concentrations, although a lone study (not replicated) suggested that the exercise-induced increase in insulin was suppressed with citrulline. As this study also noted performance degradation, it may be a flaw
grade-c Notable Moderate See all 3 studies
The decrease in fatigue during exercise is thought to underlie most of the benefit seen with training capacity (work volume), although in men who self-report fatigue issues supplemental citrulline appears to help with that as well (independent of exercise)
grade-c Notable Very High See 2 studies
Nitric oxide derivatives (nitrate and urinary cGMP, since nitric oxide itself is hard to measure these biomarkers are indicative of nitric oxide production) appear to be reliably increased following oral consumption of citrulline supplementation
grade-c Notable Very High See all 4 studies
Citrulline can increase plasma arginine concentrations, and due to acting as a resevoir of arginine it is actually more effective overall at increasing plasma arginine than arginine itself (acute peaks are still observed to a higher level with arginine supplementation).
grade-c Notable - See study
The increase in work capacity seen with citrulline supplementation appears to be time dependent. While there are no inherent and immediate effect, the reduction of fatigue later in a weight lifting workout causes a relative increase that has at least one doubled reps conducted (on set 8 of exhaustive exercise)
grade-c Minor - See all 3 studies
Some improvement in cycling time trial performance has been found in a couple of studies, though the time to exhaustion in another wasn't improved. Much more research is needed to understand when citrulline might be effective.
grade-c Minor High See all 4 studies
Overall, there has been a reduction in arterial stiffness in most studies, particularly when in response to cold stress. More research is still needed to evaluate the effects on arteries of elderly participants with atherosclerosis.
grade-c Minor Very High See all 6 studies
An increase in blood flow is noted with citrulline supplementation in persons with impaired blood flow, and one study found an improvement in healthy participants, though much evidence is needed.
grade-c Minor - See 2 studies
A notable reduction was found in one study that used 2 g daily in NAFLD patients, but another didn't find an effect in middle-aged, healthy men. Much more research is needed.
grade-c Minor Very High See 2 studies
An increase in growth hormone has been noted with exercise, but not at rest. Practical significance of this information is unknown, since Arginine supplementation has unreliable effects itself
grade-c Minor - See study
Neutrophil oxidative burst post-workout appears to be enhanced when the exercise is preloaded with citrulline supplementation
grade-c Minor - See 2 studies
One study found a notable reduction from continuous use in type 2 diabetes whereas another didn't found one from acute supplementation prior to exercise.
grade-c Minor Very High See all 3 studies
Some studies have found a reduction when taking citrulline acutely prior to exercise, though this isn't entirely consistent and much more research is needed to confirm its effects.
grade-c Minor Low See all 8 studies
Even though citrulline doesn't appear to reduce subjective fatigue, participants taking citrulline generally are able to perform more reps in muscle-fatiguing exercises.
grade-c Minor Moderate See 2 studies
Although acute usage does not appear to influence plasma glutamine, a week of high dose supplementation (0.18g/kg) has been noted to reduce glutamine concentrations slightly.
grade-c Minor Very High See 2 studies
An increase in plasma nitrate has been noted with citrulline supplementation, but not to the degree of supplemental nitrate itself
grade-c Minor - See all 4 studies
The effect seems to be fairly inconsistent, and it's not clear why, but reductions during physically demanding exercise have been noted.
grade-c Minor Very High See all 3 studies
An increase in urea is seen with citrulline supplementation (possibly due to increased serum ornithine sequestering ammonia)
grade-c - Very High See all 7 studies
No significant influence on lactate production seen with citrulline supplementation before exercise
grade-c - - See 2 studies
A slight increase in creatinine has been noted with one study but not another, practical relevance or cause unknown.
grade-c - - See study
No significant influence of citrulline on DNA damage
grade-c - - See study
No significant influence on HDL-C concentrations
grade-c - - See study
No demonstrated effects on IGF-1 concentrations following the usage of citrulline supplementation
grade-c - Very High See 2 studies
Studies haven't found a notable effect on AST, ALP, LDH, or ALT, but none have been conducted in participants with liver disease.
grade-c - - See study
No significant influence on LDL-C concentrations in serum following citrulline supplementation
grade-c - - See study
Currently no human evidence to support a practically significant increase in muscle protein synthesis at rest with citrulline supplementation
grade-c - - See study
No significant influence on total cholesterol concentrations
grade-d Notable - See study
One study in patients with systolic heart failure found a notable increase.
grade-d Notable - See study
A decrease was found in NAFLD, whereas the placebo group saw a notable worsening.
grade-d Minor - See study
One low-quality study found a reduction in severity, but it wasn't statistically significant, and much more research is needed.
grade-d Minor - See study
The difference in one study had more to do with the placebo group seeing an increase due to exercise than citrulline seeing a reduction, but it can be interpreted as attenuation of the increase.
grade-d Minor - See study
Hardness of erections in persons with mild erectile dysfunction appears to be increased following supplementation of citrulline supplementation.
grade-d Minor - See study
There was an improvement in 6-minute walking distance for patients with hypertension and Eisenmenger Syndrome ion one study.
grade-d Minor - See study
Citrulline has been noted to increase physical exercise capacity in persons with heart failure.
grade-d Minor Moderate See 2 studies
An increase in muscle ATP production via aerobic means was noted in men given 6g citrulline daily, but this appeared to be attenuated with time. In another study, there didn't seem to be a notable difference.
grade-d
Minor
- See study
Improved for young but not old participants, and men but not women in one study. More research is needed.
grade-d Minor Very High See 2 studies
In persons with heart failure with normal ejection fractions, right ventricular ejection fraction during exercise appears to be increased relative to control.
grade-d Minor - See study
Handgrip strength was improved in female tennis players in one study.
grade-d Minor - See study
Antioxidant capacity increased significantly in one study in type 2 diabetes.
grade-d - - See study
Actually cycling. One instance of a Wingate test didn't find a meaningful effect.
grade-d - - See study
No apparent effect on glutathione peroxidase or superoxide dismutase in one study in type 2 diabetes.
grade-d - Very High See 2 studies
No apparent effect of 6 g for 8 weeks.
grade-d - - See study
No apparent effect in one study.
grade-d - High See all 3 studies
Overall, studies haven't found a notable effect on cycling endurance, though more research in different contexts is needed.
grade-d - Moderate See 2 studies
Mixed evidence, more research is needed.
grade-d - - See study
No apparent effect in one study.
grade-d - - See study
No apparent effect in one study.
grade-d - - See study
grade-d - - See study
No apparent effect in one study.
grade-d - - See study
No apparent effect on fibrosis in one study.
grade-d - - See study
No apparent effect on steatosis in one study.
grade-d - - See study
grade-d - - See study
grade-d - - See study
No apparent effect in one study.
grade-d - - See study
No apparent effect in one study.
grade-d - - See study
No apparent effect in one 8-week study.
grade-d - - See study
No apparent effect in one study.

Studies Excluded from Consideration

  • Confounded with the inclusion of L-arginine[1]

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Frequently Asked Questions and Articles on Citrulline

Combining citrulline with glutathione could increase your pump

Things to Note

Primary Function:

Other Functions:

Also Known As

L-Citrulline, Stimol (Brand Name), Watermelon extract

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