L-Citrulline Additional Information
L-citrulline is a non-essential (meaning the body naturally produces some levels) amino acid. The name for L-citrulline comes from the Latin word citrullus, meaning watermelon, as the fruit contains large amounts of the amino acid. Other than watermelon, L-citrulline is found in squash, melons, cucumber, and pumpkins. (1,2,3,4)
L-citrulline acts as a precursor for the conditional amino acid, L-arginine. (1,2,3,4). L-arginine is a conditionally essential amino acid that directly produces nitric oxide. Made from carbamoyl phosphate and L-ornithine, L-citrulline is an intermediate in the urea cycle (UC). The basic function of the urea cycle is to detoxify ammonia and convert it to urea. L-citrulline has been used for over 30 years to aid in the care of urea cycle disorders (UCDs). (4) In both the liver and intestines of humans, L-citrulline is synthesized by the addition of carbon dioxide and ammonia to ornithine. L-citrulline is also produced from L-arginine as a by-product of the production of nitric oxide. (2)
While L-citrulline is an amino acid, it is not one of the amino acids coded for DNA nor is it involved in the protein synthesis. (2) Despite not being involved in protein synthesis, L-citrulline is known to be part of several proteins that are. The family of enzymes that contain L-citrulline are known as peptidylarginine deiminases (PADs). (2)
As a dietary supplement, L-citrulline is popular for its ability to support cardiovascular health by improving nitric oxide metabolism. (2,3) This has led to L-citrulline becoming popular in the athletic community. L-citrulline has also shown promise for reducing fatigue and muscle soreness. (16,18)
L-Citrulline Benefits
By increasing L-arginine levels in the body, L-citrulline is able to increase the amount of NO and the cascade of benefits that are associated. Increasing NO levels plays a role in vascular relaxation and immune response. (14)
Another major benefit of L-citrulline is a reduction in fatigue and muscle soreness as a result of physical activity. (19) This is done via its mechanism of increasing levels of ATP and sequestering ammonia with the added support of NO improving cardiovascular health. (5,16,18)
In addition to the benefits brought on through and increase in ATP and NO, L-citrulline has additional benefits that will be discussed in “L-Citrulline Research” that includes:
- Decreases blood pressure (21)
- Boosts immune health (22)
- Improves erectile hardness (12)
How to Use L-Citrulline
L-citrulline is most commonly found as a powdered capsule for supplementation. Although it is recommended to take L-citrulline with food, this is only to avoid the potential side effect of an upset stomach. L-citrulline is water soluble and therefore does not need to be taken with food, but it is highly recommended. L-citrulline has a sour or tart taste so supplementation with capsules is recommended over the powder to avoid this.
L-citrulline supplementation for improved circulation and cardiovascular health should be taken with breakfast, lunch, and dinner. If using L-citrulline for the purpose of increasing energy levels during a workout, it can be taken shortly before exercise.
L-Citrulline Dosage Instructions
The average dosage recommendation for L-citrulline is 3,600mg per day, split across three dosages. Other dosages for L-citrulline depend on the intended benefit of the supplement.
For athletic benefits, 3,600mg – 5,400mg of L-citrulline can be taken shortly before exercise. When taking L-citrulline for erectile benefits, 1,500mg per day has shown to be effective. (12) For general fatigue, 2,400mg per day has shown to be effective. (13)
Half-life and Duration of Effects
L-citrulline begins to work approximately 30-40 minutes once entering your system. The half-life of L-citrulline has not been determined. L-citrulline that converts to L-arginine has shown to have a half-life of an average of one to two hours. (25)
L-Citrulline Safety and Side Effects
L-citrulline has been reported to be very safe with doses as high as 3g/kg of body weight being well-tolerated in rats. (4,24) Similar trials on puppies and kittens have shown normal growth rate in doses as high as 830mg/kg/day. (4)
Supplementation of L-citrulline should be avoided if taking any medication for erectile dysfunction. Some of these medications work to increase nitrates, similarly to L-citrulline, and there may be interactions if both are used together.
L-citrulline has been reported to be very well tolerated with the only reported side effects being an upset stomach. (24)
How L-Citrulline Works
The primary mechanism of action for L-citrulline is its conversion to L-arginine. (2,3,5) This conversion happens by the enzymes argininosuccinate synthetase and argininosuccinate lyase in the presence of L-aspartate and ATP. Once converted to L-arginine, it is released into the bloodstream by the kidneys and becomes available for the entire body. (6)
Many of the therapeutic qualities of L-citrulline come from L-arginine’s production of nitric oxide (NO) via the nitric oxide synthase (NOS) enzymes. (2,5) NO works through the soluble cyclic guanylyl receptors, to activate the enzyme guanylate cyclase, to produce cyclic guanosine monophosphate (cGMP), which leads to a cascade of actions. (7)
NOS has similar sequences to cytochrome P450 reductase, which is integral for the catalysis of all P450 enzymes. These enzymes are responsible for the oxidization of steroids and fatty acids as well as for the clearance of various compounds, and hormone synthesis and breakdown. There are several isoforms of NOS that are either constitutive, or inducible by immunological/inflammatory stimuli. (2)
One of these constitutive isoforms, eNOS, is present in the brain, spinal cord, and nervous system. eNOS is primarily responsible for the generation of NO in the vascular endothelium. (8) The isoform induced by immunological/inflammatory stimuli is iNOS and is involved in immune response and produces NO as an immune defense mechanism. (9)
L-citrulline supplementation is more effective than L-arginine supplementation because L-arginine is not as efficiently absorbed by the body. (5) L-arginine supplements are also quickly removed from the body due to the activity of arginase. L-arginine also has shown to cause more side effects than L-citrulline. (10) The lack of side effects, along with the ability of L-citrulline to be easily absorbed and converted to L-arginine in greater quantities, makes it the better supplement to increase levels of L-arginine. (1,2,3,4,5)
Along with L-arginine and L-ornithine, L-citrulline is one of the three amino acids in the UC. The UC mediates the removal of ammonia as urea, which is then eliminated through urine. (11) At the conclusion of condensation with ornithine, carbamoyl phosphate is converted to L-citrulline. This occurs during the ornithine transcarbamylase reaction. L-citrulline is then released to cytosol. The UC helps to prevent hyperammonemia activity and irreversible brain injury. (11)
L-citrulline has shown to increase levels of ATP. (15) L-citrulline modulates enzymes in the glycogenolysis (glycogen breakdown) and glycolysis (converting glucose into ATP) pathways. By increasing the efficiency of energy production, L-citrulline is able to beneficially interact with ATP production. (16)
Similar to its mechanism of increasing levels of L-arginine, L-citrulline has shown to have a similar impact on ornithine concentrations. (17) By stimulating hepatic ureagenesis, via ornithine sequestering ammonia, there is an increase in ornithine. (17) As ammonia normally signals for muscle fatigue due to its inhibition of Pyruvate to Acetyl-CoA, by sequestering it, L-citrulline is able to increase physical performance. (18)
L-Citrulline Research
Reduces Fatigue and Muscle Soreness (13,19)
A double-blind, randomized, placebo-controlled study was conducted to determine the efficacy of L-citrulline on cycling time trial performance. 22 trained males consumed 2.4g of L-citrulline or a placebo daily for seven days. The subjects would be measured on the time to complete a 4km cycle along with subjective feelings of muscle fatigue.
On the 8th day, the groups were administered their supplement or placebo one hour prior to the cycling time trial. The group administered L-citrulline had reduction in completion time compared to the placebo group by 1.5%. The L-citrulline group also reported greater subjective feelings on fatigue and concentration compared to the placebo group.
A separate study was conducted on a group of 18 males who had reported feelings of fatigue. Prior to citrulline supplementation, during supplementation, and after supplementation, the volunteers performed a rest-exercise (finger flexions)-recovery protocol.
Citrulline supplementation resulted in a significant reduction of fatigue along with a 20% increase in phosphocreatine and 34% increase in the rate of ATP production. These changes indicated that citrulline may promote aerobic energy production.
Improves Vascular Health (20)
Via its mechanism to increase NO, L-citrulline is thought to regulate blood flow. This is thought to occur as endothelial NO synthase (eNOS) is responsible for the regulation. However, more recent reports indicate that neuronal NO synthase (nNOS) may play a role. L-citrulline acts as an inhibitor for nNOS.
This study utilized volunteers who have angiographically normal arteries. Supplementation with L-citrulline reduced radial arty blood flor by ~36% but did not negatively impact flow-mediated dilation. This confirms L-citrullines inhibitory actions on nNOS and aids to regulate blood flow.
Decreases Blood Pressure (21)
Similar to its mechanism on vascular health, L-citrulline may have effects on decreasing blood pressure. This study was aimed at examining what those effects would be on cardiac electrical activity and blood flow. For this study, 12 young adult volunteers were administered 3g of L-citrulline per day. Their cardiac electrical activity was measured by an ECG and blood flow was measured by IR-plethysmography.
Citrulline supplementation decreased diastolic and systolic blood pressure. Citrulline also altered sympathovagal balance which is a major determinant in short-term blood pressure.
Boost Immune Health (22)
Boosting levels of NO have shown to have a positive impact on immune response. (14) One study aimed to determine the impact of L-citrulline supplementation increasing immune response via an increase in NO. 17 professional male cyclists were randomly assigned a placebo or 6g of L-citrulline. Blood samples were taken prior to, immediately following, and three hours after cycling.
Polymorphonuclear neutrophils (PMNs), a type of white blood cell, aid in fighting infections. The group that was administered L-citrulline saw significantly higher counts of PMNs in the blood samples taken after cycling than the group that received the placebo. This increase in PMNs demonstrates L-citrulline’s mechanism to boost immune health.
Improves Erectile Hardness (12)
L-citrulline’s mechanism of increasing NO has shown promise for improving penile erection. In this study, men with reported erectile hardness scores below 3 (out of 4), alternated one month of a placebo and one month of 1.5g of L-citrulline. In addition to erectile hardness score, the participants were also tracked on number of intercourse sessions and treatment satisfaction.
Erectile hardness score increased in 50% of the volunteers when supplementing with L-citrulline compared to an 8% increase with the placebo. The number of intercourse sessions increased from 1.37 per month to 2.3 per month with L-citrulline, and 1.53 per month with the placebo. All volunteers reported an increase in satisfaction.
L-Citrulline FAQ
Is L-citrulline supplementation better than L-arginine supplementation?
One of L-citrulline’s primary mechanisms is to convert into L-arginine in the body. However, L-citrulline has shown to be more bioavailable than L-arginine and therefore more effective at boosting levels of L-arginine.
Can you take L-citrulline and L-arginine together?
Stacking both supplements has shown to effectively boost short term NO levels.
Why is L-citrulline popular for athletes?
L-citrulline supplementation has become popular for athletes as it has shown to reduce muscle fatigue and soreness.
Is L-citrulline powder better than the capsules?
L-citrulline powder has a very sour or tart taste which is why the capsules are recommended. Based on your provider, you can also be consistent in your doses.
Can I obtain L-citrulline through my diet?
L-citrulline is found in watermelons, squash, melons, or cucumber. You can increase levels of NO through your diet with foods like beets, garlic, or meat.
Cited Sources
- https://www.webmd.com/vitamins-and-supplements/l-citrulline-uses-and-risks#1
- https://www.ncbi.nlm.nih.gov/pubmed/27934657
- https://www.fda.gov/media/109619/download
- https://www.ncbi.nlm.nih.gov/pubmed/17662090/
- https://www.ncbi.nlm.nih.gov/pubmed/16082501/
- https://examine.com/supplements/arginine/#cardiovascular-health_nitric-oxide-and-nos
- https://www.ncbi.nlm.nih.gov/pubmed/16416260
- https://www.ncbi.nlm.nih.gov/pubmed/21138269
- https://www.ncbi.nlm.nih.gov/pubmed/17513449
- https://www.ncbi.nlm.nih.gov/books/NBK27982/
- https://www.ncbi.nlm.nih.gov/pubmed/21195829
- https://www.ncbi.nlm.nih.gov/pubmed/26900386
- https://examine.com/topics/nitric-oxide/
- https://www.ncbi.nlm.nih.gov/pubmed/23592530
- https://www.ncbi.nlm.nih.gov/pubmed/21664351
- https://www.ncbi.nlm.nih.gov/pubmed/1930358
- https://www.ncbi.nlm.nih.gov/pubmed/4260884
- https://www.ncbi.nlm.nih.gov/pubmed/12145119
- https://www.ncbi.nlm.nih.gov/pubmed/19433760
- https://www.ncbi.nlm.nih.gov/pubmed/27333912
- https://www.ncbi.nlm.nih.gov/pubmed/19585317
- https://www.ncbi.nlm.nih.gov/pubmed/23224924
- https://www.ncbi.nlm.nih.gov/pubmed/21908948
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1873701/
