L-citrulline is a non-essential amino acid that helps the body produce nitric oxide and improve blood flow. Sold as a dietary supplement and a separate pharmaceutical version, L-citrulline is used to treat a rare genetic disorder and may help with certain vascular problems and other medical conditions.
Amino acids are sometimes called “the building blocks of life.” The ones you acquire in your diet are called “essential amino acids” — you need to ingest them from other sources to live. Others, called “nonessential amino acids” because they are not essential to the human diet to survive, are created by your body.
One of these nonessential amino acids is L-citrulline. Its name comes from “citrullus,” the Latin word for watermelon, from which it was first isolated.
The kidneys break L-citrulline apart into another amino acid called L-arginine and the chemical compound nitric oxide (NO). Nitric oxide improves blood flow by relaxing arteries.
Dietary Supplement and ‘Medical Food’
L-citrulline is produced in both over-the-counter (OTC) versions and as a pharmaceutical-grade medical ingredient.
OTC versions are popular with athletes attempting to gain an edge in endurance and strength. Studies have found that nitric oxide may improve sports performance, possibly through its effects on blood flow, muscles and metabolic actions.
Pharmaceutical grade versions of this amino acid also play critical medical roles.
The U.S. Food and Drug Administration (FDA) does not regulate L-citrulline as a drug, but it is considered a “medical food,” which the FDA defines as “a food which is formulated to be consumed or administered enterally [through the digestive tract] under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”
While the FDA does not consider L-citrulline a drug in itself, the agency lists pharmaceutical grade versions of it as a “bulk drug substance” or “active pharmaceutical ingredient” (API). Pharmaceutical grade L-citrulline can be manufactured as a powder; pharmacies may compound L-citrulline into tablets, capsules or liquids.
Used to Treat Rare Genetic Disorders
L-citrulline is used to treat a group of genetic disorders called inborn errors of metabolism (IEM). Left untreated, IEMs can result in developmental disabilities, brain damage and death.
One of these conditions affects the urea cycle – the body’s process of removing excess ammonia from the bloodstream. The National Urea Cycle Disorders Foundation estimates that up to 20 percent of sudden infant-death syndrome (SIDS) cases may be due to an undiagnosed IEM such as a urea cycle disorder (UCD).
UCD is rare. One 2013 study by Summar and colleagues predicted one disorder for every 35,000 births, or about 113 new patients each year.
People with a UCD have a genetic mutation. It prevents their bodies from making enough key enzymes for the cycle to work properly. These enzymes in a healthy person create chemical reactions that extract nitrogen from the blood and convert it into urea, a chemical compound that is then expelled from the body through urine.
In people with a UCD, nitrogen accumulates as ammonia in the blood stream. If it reaches the brain, it can lead to brain damage, coma and death.
There are six enzymes required for the urea cycle to function properly. A deficiency of any one of these can result in a specific disorder.
- Carbamoyl phosphate synthetase I (CPS1) deficiency
- Most severe UCD. Complete CPS1 in a newborn can rapidly advance to dangerously high levels of ammonia in the blood. Lifetime chronic risk of repeat high levels of ammonia if the newborn recovers
- N-acetyl glutamate synthetase (NAGS) deficiency
- Mimics CPS1 deficiency
- Ornithine transcarbamylase (OTC) deficiency
- In males, OTC can be as severe as CPS1. While not as severe in females, about 15 percent of females with OTC deficiency develop dangerously high ammonia levels in blood during their lifetimes, often requiring chronic medical management
- Citrullinemia type I (ASS1) deficiency
- Slightly easier to treat than other UCDs, but can still be severe
- Argininosuccinic aciduria (ASL) deficiency
- Can result in rapid onset of dangerously high ammonia levels in the blood of newborns. May result in coma or death. Even in those who do not experience coma, may suffer significant developmental disabilities
- Arginase (ARG) deficiency (also called hyperargininemia)
- Rapid onset of elevated ammonia levels in the blood are not typical but people with ARG deficiency may experience other severe symptoms including progressive spasticity, tremor, ataxia (the loss of full control of bodily movements), and choreoathetosis (involuntary movements including migrating contractions, twisting, and writhing)
While the disorders are most notable in children, they can also occur in adults who were born with a mild version of a mutation. Their condition may go unnoticed until their metabolic system comes under heavy stress from things like viruses, excessive exercise or high protein intake.
UCDs are treated through diet, drug treatment, and in some cases, liver transplant. A transplant is the only cure for the disorder.
Short of a transplant, the condition is usually managed through diet and drug treatment. The prescription drugs sodium phenylbutyrate, sodium phenylacetate, and sodium benzoate – sometimes called “ammonia scavengers” – may be used to help remove excess ammonia. But any drug treatment regimen also requires patients to take an amino acid – either L-citrulline or L-arginine depending on the particular condition – for the drug to work properly.
Both L-citrulline and L-arginine accelerate urea cycle enzymes, promoting proper ammonia removal.
Other Common Medical Uses for L-citrulline
Because the body converts L-citrulline into nitric oxide (NO), it may benefit blood flow or other bodily functions in patients with certain medical conditions. Medical professionals may sometimes recommend it to help treat some diseases and disorders. However, there is limited information on the use of L-citrulline as an over-the-counter agent for many disorders.
|L-citrulline May Be Assigned For||Potential Benefit|
|Erectile dysfunction||Beneficial effect on blood vessels|
|Alzheimer’s disease||Improved effects of NO on the brain|
|Dementia||Improved effects of NO on the brain|
|High blood pressure||Beneficial effect on blood vessels|
|Cardiovascular disease||Beneficial effect on blood vessels|
|Sickle cell disease – a group of disorders that affects red blood cells’ ability to deliver oxygen to cells in the body||Added NO may have a beneficial effect on patients|
Possible Side Effects and Interactions
Since L-citrulline occurs naturally in the body, it is believed to be a safe supplement. There is not enough information available to determine for sure whether over-the-counter L-citrulline is safe to take. However, since there has been little research on how it might affect pregnant or nursing women, medical professionals recommend they not ingest L-citrulline supplements.
Because it affects some of the same bodily functions as drugs for high blood pressure, cardiovascular disease, and erectile dysfunction, patients should talk to their doctor if they are on any of those drugs before taking any prescription or over-the-counter L-citrulline product.
Medical Studies Explore L-citrulline’s Potential for Medical Conditions
Studies of L-citrulline’s medicinal benefits beyond UCDs have been limited and inconclusive, but health care professionals may sometimes assign it for certain medical conditions.
A 2001 study of five patients with sickle cell disease found twice daily doses of L-citrulline, with amounts determined by patient weight, “resulted in dramatic improvements in symptoms of well-being” as well as blood health.
In a 2010 study, patients who had suffered heart failure were given 3 grams of L-citrulline per day for two months. They were then placed on a treadmill for a stress test. Researchers found their blood pressure had “decreased significantly” while improving the function of the right ventricle in their hearts.
Another 2010 study found short-term L-citrulline supplementation may improve stiffness of arteries. Researchers found stiffness was “significantly reduced” compared to the placebo group, but noted no difference in blood pressure changes between the two groups.
A 2011 study compared L-citrulline to phosphodiesterase type 5 (PDE5) inhibitors for treating erectile dysfunction (ED). PDE5 inhibitors include Viagra (sildenafil), Cialis (tadalafil) and Levitra (vardenafil). While L-citrulline did not perform as well, researchers concluded that L-citrulline supplementation “proved to be safe and psychologically well accepted” by patients with erectile dysfunction.
“Its role as an alternative treatment for mild to moderate ED, particularly in patients with a psychological fear of [PDE5] inhibitors, deserves further research,” the researchers wrote.
Studies Inconclusive on L-citrulline Exercise Benefits
Over the counter (OTC) versions of L-citrulline have been marketed as enhancing aerobic exercise as well as building, feeding and repairing muscle fibers. L-citrulline may help with blood flow, help muscles work better, and increase the body’s ability to use oxygen during exercise. But most studies of L-citrulline in this area have been made up of small groups and have been inconclusive.
A 2015 study gave 22 trained male cyclists 2.4 grams of either oral L-citrulline or a placebo once a day for eight days. On the eighth day, the men took their dose one hour before taking part in a 4 km (2.48 miles) time trial. Those taking L-citrulline had a finish time roughly 1.5 percent faster than those taking the placebo.
A 2016 study looked at using L-citrulline and L-arginine in alleviating exercise-induced fatigue. Researchers put 12 male taekwondo athletes through the equivalent of three martial arts matches. Each match consisted of three, two-minute rounds. At the end of the second match, some athletes were given a mixture of the two amino acids while others were given a placebo before continuing into the third match.
Researchers reported those given the L-citrulline and L-arginine performed “significantly better” than those given a placebo.
But other studies have shown L-citrulline may have a negative effect on performance or no effect at all. A 2006 study suggested runners on a treadmill actually became exhausted much sooner if given L-citrulline.
A November 2022 study tested L-citrulline to reduce high blood pressure induced by obstructive sleep apnea. Researcher found that the supplement significantly reduced blood pressure by 9.92 percent and decreases aortic and myocardial stress.
“Citrulline may be used as the primary therapy after CPAP refusal or in combination with CPAP and/or lifestyle interventions,” authors wrote, though more study is needed.
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