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). NO 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 NO may improve sports performance through its effects on blood flow, muscles and metabolic actions.
The U.S. Food and Drug Administration (FDA) does not regulate L-citrulline as a drug.
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).
UCDs are rare, affecting only 2,000 to 2,500 people in the U.S., but as many as 75 percent of those people may require L-citrulline supplements to survive.
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.
|Urea Cycle Disorder||Description|
|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 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 drug Buphenyl (sodium phenylbutyrate) or 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.
|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 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|
|Lysinuric protein intolerance – rare disorder in which the body is unable to digest and use some amino acids||Along with prescription drugs, may help restore urea function|
|Reye syndrome – sudden, acute brain damage and liver function problems that have occurred in children given aspirin when sick with chickenpox or flu||May help reduce ammonia levels in blood|
Possible Side Effects and Interactions
Since L-citrulline occurs naturally in the body, it is believed there are no significant side effects or interactions. 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.
There has been little research on how L-Citrulline might affect pregnant or nursing women – medical professionals recommend they not ingest it.
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.
Patients with sickle cell disease found twice daily doses of L-citrulline found improvements in symptoms of well-being as well as blood health.
In a 2010 study, patients who had suffered heart failure were given 8 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 (vardenafil) 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. The reasoning is, as one study summed up, L-citrulline’s ability to generate nitric oxide, which “is a potential modulator of blood flow, muscle energy metabolism, and mitochondrial respiration 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% 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 1999 study gave L-citrulline to marathon runners and the result was that they performed more poorly than those given a placebo. And a 2006 study suggested runners on a treadmill actually became exhausted much sooner if given L-citrulline.
Terry Turner is an Emmy-winning former television journalist turned senior writer at Drugwatch. In more than 25 years of reporting, he has seen countless examples of how people armed with comprehensive, quality information have the power to make better decisions for their lives and holding those who harm them accountable.
- NIH. (n.d.) PubChem Compound Database; CID=9750; L-citrulline. Retrieved from: https://pubchem.ncbi.nlm.nih.gov/compound/L-citrulline#section=Top
- FDA. (2014, February 17). FDA Lab Testing Finds N-acetyl-leucine in Samples of Recalled Medisca Product Labeled as L-citrulline. Retrieved from: https://www.fda.gov/Drugs/DrugSafety/ucm385964.htm
- DrugBank. (n.d.). L-Citrulline. Retrieved from: https://www.drugbank.ca/drugs/DB00155
- Meriam-Webster. (n.d.). Nonessential Amino Acid. Retrieved from: https://www.merriam-webster.com/dictionary/nonessential%20amino%20acid
- Suzuki, T. (2016, February 19). Oral L-citrulline Supplementation Enhances Cycling Time Trial Performance in Healthy Trained Men: Double-Blind Randomized Placebo-Controlled 2-Way Crossover Study. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4759860/
- FDA. (2016, March 8 & 9). FDA Briefing Document; Pharmacy Compounding Advisory Committee (PCAC) Meeting. Retrieved from: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/pharmacycompoundingadvisorycommittee/ucm486146.pdf
- U.S. Pharmacopeial Convention. (2016, Winter). Public Health Impact; A Suitable Test for L-citrulline – How Validated Test Methods May Impact Public Health. Retrieved from: http://www.usp.org/sites/default/files/usp_pdf/EN/dietarySupp/newsletter/dsc_dec2016.pdf
- National Urea Cycle Disorders Foundation. (n.d.). What Is a Urea Cycle Disorder? Retrieved from: http://www.nucdf.org/ucd.htm
- Paul, V and Ekambaram, P. (2011, May). Involvement of Nitric Oxide in Learning & Memory Processes. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3121276/
- NIH. (2017, May 2). Sickle Cell Disease. Retrieved from: https://ghr.nlm.nih.gov/condition/sickle-cell-disease
- FDA. (2016, May). Frequently Asked Questions About Medical Foods; Second Edition; Guidance for Industry. Retrieved from: https://www.fda.gov/downloads/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/UCM500094.pdf
- Kato, G.J. (2009, November). Novel Small Molecule Therapeutics for Sickle Cell Disease: Nitric Oxide, Carbon Monoxide, Nitrite, and Apolipoprotein A-I. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778246/
- NIH. (2017, May 2). Lysinuric Protein Intolerance. Retrieved from: https://ghr.nlm.nih.gov/condition/lysinuric-protein-intolerance
- Lukkarinen, M., et al. (1999, June). B and T Cell Immunity in Patients with Lysinuric Protein Intolerance. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1905322/
- NIH. (2017, April 4). Reye Syndrome. Retrieved from: https://medlineplus.gov/ency/article/001565.htm
- Waugh, W.H. (2001, October). Oral Citrulline as Arginine Precursor May Be Beneficial in Sickle Cell Disease: Early Phase Two Results. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2594068/?page=1
- Orozco-Gutierrez, J.J., et al. (2010). Effect of L-arginine or L-citrulline Oral Supplementation on Blood Pressure and Right Ventricular Function in Heart Failure Patients with Preserved Ejection Fraction. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/21154265
- Ochiai, M., et al. (2010, November 9). Short-Term Effects of L-citrulline Supplementation on Arterial Stiffness in Middle-Aged Men. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/21067832
- Cormio, L. (2011, January). Oral L-citrulline Supplementation Improves Erection Hardness in Men with Mild Erectile Dysfunction. Retrieved from: http://www.goldjournal.net/article/S0090-4295(10)01661-4/fulltext
- Bruno, G. (n.d.). Nitric Oxide Boosters. Retrieved from: http://www.hchs.edu/literature/Nitric%20Oxide%20Boosters.pdf
- Suzuki, T., et al. (2015, September 11). Oral L-citrulline Supplementation Enhances Cycling Time Trial Performance in Healthy Trained Men: Double-blind Randomized Placebo-Controlled 2-Way Crossover Study. Retrieved from: https://jissn.biomedcentral.com/articles/10.1186/s12970-016-0117-z
- Chen, I-F., et al. (2016, February 18). Branched-Chain Amino Acids, Arginine, Citrulline Alleviate Central Fatigue after 3 Simulated Matches in Taekwondo Athletes: A Randomized Controlled Trial. Retrieved from: https://jissn.biomedcentral.com/articles/10.1186/s12970-016-0140-0
- Hickner, R.C., et al. (2006, April). L-Citrulline Reduces Time to Exhaustion and Insulin Response to a Graded Exercise Test. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/16679980
- Buchman, A.L., et al. (1999, July). The Effect of Arginine or Glycine Supplementation on Gastrointestinal Function, Muscle Injury, Serum Amino Acid Concentrations and Performance during a Marathon Run. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/10452229
- Mew, N.A., (2015, April 29). Urea Cycle Disorders Overview. Retrieved from: https://www.ncbi.nlm.nih.gov/books/NBK1217/
- By Sandstein (Own work) [CC BY 3.0 (http://creativecommons.org/licenses/by/3.0)], via Wikimedia Commons