Citrulline: Benefits, Side Effects, Dosage, and Interactions

Citrulline is a natural supplement that is considered a non-essential amino acid. This means that the body can make its own citrulline; it can also be found in some foods (such as watermelon). Citrulline is synthesized (made) in the liver and intestine; its function is to detoxify ammonia and act as a vasodilator (dilating the blood vessels). Citrulline is also said to have an antioxidant effect.

There are two forms of citrulline, available as a supplement; these include L-citrulline and citrulline malate. The primary difference between the two types of citrulline is that L-citrulline is simply citrulline without any other substance, and citrulline malate is comprised of L-citrulline, plus DL-malate (a compound that may be instrumental in converting food to energy.)

Also Known As

Citrulline (L-citrulline) is found under several other names, including:

2-amino-5-(carbamoylamino) pentanoic acid
Citrulline malate
L-citrulina
L-citrulline malate
Malate de citrulline

Health Benefits

Although there is very little scientific research evidence to back many of the claims of L-citrulline health benefits, the natural supplement is said to have several health promoting properties, and is used for health conditions, including:

Enhancing physical exercise
Improving athletic performance
Helping with erectile dysfunction
Lowering high blood pressure
Treating sickle cell anemia

Studies

Athletic Performance

A 2010 randomized double-blind study (the gold standard of research studies) involving 41 men, discovered that a single dose of citrulline malate (CM) resulted in a significant increase in the number of barbell bench presses (accounting for 52.92% more repetitions) and a 40% decrease in muscle soreness after exercise. “We conclude that the use of CM might be useful to increase athletic performance in high-intensity anaerobic exercises with short rest times and to relieve post exercise muscle soreness,” wrote the study authors.

Another study, published in 2017, looking at older individuals found citrulline modestly increased muscle blood flow during submaximal exercise in men but not women. The same study found that the diastolic blood pressure of the treated group was lowered in men but not women.

Cardiovascular (Heart and Blood Vessel) Health
Studies have shown that short-term L-citrullline supplementation can lower blood pressure in adults with hypertension (high blood pressure) and those with pre-hypertension. These studies suggest that pharmaceutical/nutraceutical grade L-citrulline was instrumental in promoting heart health. “The safety and efficacy of long-term l-citrulline supplementation therefore requires further investigation,” concluded the study authors.

A paper published in 2019 reviewed 8 trials looking at adults. Their analysis of the data suggested citrulline can lower systolic blood pressure (by 4 mmHg). A significant decrease in diastolic blood pressure was seen only at higher doses. The authors felt it was too soon to recommend citulline supplements but that a diet rich in citrulline containing foods might contribute to the prevention of hypertension.

It’s important to note that there are several other (less potent) grades of supplements of which may be less effective (such as medical grade, nutritional grade, and cosmetic grade). Pharmaceutical grade must be more than 99% pure (from natural sources) and must contain no dyes, filler, binder or unknown substances.

Erectile Dysfunction

L-citrulline is said to boost L-arginine, which in turn helps to elevate nitrogen oxide (NO) synthesis. NO promotes the relaxation of blood vessels, resulting in oxygen-rich blood circulating through the arteries. Therefore, L-arginine is said to promote heart health, but it is also important in erectile function (because of its blood flow promotion properties).

In a study of 24 participants from the age of 56 to 66, the use of L-citrulline was found to improve the erection score from 3 (mild erectile dysfunction) to 4 (normal erectile function) in 50% of the men who took it, as compared to improvement in 8.3% of the men who took a placebo.

The study authors concluded, “Although less effective than phosphodiesterase type-5 enzyme inhibitors [such as Viagra], at least in the short term, L-citrulline supplementation has been proved to be safe and psychologically well accepted by patients. Its role as an alternative treatment for mild to moderate ED, particularly in patients with a psychological fear of phosphodiesterase type-5 enzyme inhibitors, deserves further research.”

Sickle Cell Disease

Studies have shown that some symptoms of sickle cell disease may be alleviated by taking a twice daily dose of L-citrulline by mouth. Not only was blood health improved with the administration of citrulline, study subjects also realized an improvement in overall well-being.

A double-blind clinical research study involving study participants with sickle cell anemia (SCA) discovered a link between an increased level of NO and a decrease in the frequency that the study subjects experienced pain. L-citrulline is thought to promote an increase in the level of NO in the body, as well as promoting L-arginine levels. This study found that L-arginine supplementation may serve to potentiate the treatment of sickle cell anemia, but the study authors explained that more research is needed to evaluate the long-term safety and efficacy of these natural supplements.

How it Works

In the body, L-citrulline is transformed into a different amino acid, called L-arginine, which is converted into a chemical called nitric oxide. It is thought that L-citrulline may help to supply the body with the raw material it requires to make specific proteins. L-citrulline may also act as a vasodilator (a substance that widens the veins and arteries to help improve blood flow while lowering blood pressure).

Possible Side Effects

Citrulline has been used as an oral (by mouth) supplement) for many years, without reports of serious safety concerns. Although side effects of citrulline are uncommon, there have been some reports of mild symptoms such as nausea, indigestion, and diarrhea.

Contraindications

A contraindication is a treatment, medication, or procedure (such as surgery) that is not recommended because of a high potential of causing harm to the patient. This means that in specific conditions (such as pregnancy) a medication, supplement, or procedure should not be given/performed. It may also indicate that two specific medications (including prescription drugs, over the counter medications and natural supplements) should not be given together. Contraindications for L-citrulline include:

Pregnancy (there is not enough clinical research data to prove the safety of citrulline during pregnancy).
Breastfeeding (there is not enough clinical research data to prove the safety of citrulline during breastfeeding).

Those who are taking certain prescription drugs should not take citrulline, these include:

Phosphodieterase-5 inhibitors (medication for erectile dysfunction such as Viagra and Levitra) because both L-citrulline and phosphodieterase-5 inhibitors can lower blood pressure and the combination of these two medications together can cause hypotension (low blood pressure)
Nitrates (drugs that increase the blood flow to the heart): Taking nitrate medications (often used to treat angina) along with citrulline may result in an increase in blood flow to the heart that could cause side effects such as headaches, flushing, dizziness, fainting, low blood pressure (hypotension), or irregular heart rhythms (arrhythmia). Nitrate drugs include Dilatrate-SR and Isordil (isosorbide dinitrate), ISMO (isosorbide mononitrate), and Nitro-Dur, Nitrolingual or Nitrostat (nitrogylcerin).
Antihypertensive drugs (high blood pressure medications) such as Norvasc or Lotrel (amlodipine), Cardizem CD, Cardizem SR, Dilacor XR, or Tiazac (diltiazem), Calan SR ( verapamil), HydroDIURIL (hydrochlorothiazide), Lasix (furosemide), and more.

Other prescription medications could interact with citrulline and it could have a negative impact on certain clinical states (such as those with associated hypotension), hence its possible use should be discussed with a physician.

The FDA notes that limited safety data is available so safety issues cannot be ruled out.

Preparation and Dosage

Preparation

L-citrulline is commonly available in a powder form that can be mixed with liquid or added to nutritional shakes.

For exercise performance enhancement, 2 to 5 grams of L-citrulline per day is an average dose. Studies have shown that doses of 3 to 6 grams per day of L-citrulline and 8 grams of citrulline malate can be taken with no side effects. In fact, one study, conducted in France, discovered that taking up to 15 grams of citrulline was safe and well-tolerated by the study participants. No side effects were reported, even when supplement doses of up to 20 grams of citrulline malate were taken.

What to Look For

Natural supplements (such as citrulline) are not regulated by the Food and Drug Administration (FDA) or any other governmental agency, like prescription and over-the-counter drugs. What this indicates is that the burden to ensure a person is buying a safe, pure and effective product, is on the consumer. Simply reading the label may not provide enough information to make a well-informed buying decision on products such as citrulline.

It’s important to purchase a product that is organic, and one that has been certified by a third-party agency, such as the U.S. Pharmacopeia, NSF International, or ConsumerLab.com. These organizations evaluate and report on a product’s level of safety, purity, and potency.

The Health Benefits of Citrulline

For the Treatment of Sickle Cell Disease, Heart Health and More