L-Citrulline: Benefits, Side Effects, Best Time to Take It & More

L-Citrulline

(Citrulline)

Evidence: High
Possible Benefits: Very High
Safety: High

What is L-citrulline?

Citrulline is a conditionally essential amino acid that naturally comes from watermelons and other foods or gets synthesized in the body from L-arginine. As a supplement, most people use it for burning fat, increasing blood flow, and improving exercise performance. Citrulline can be very effective in these areas and also has many additional benefits. This article is about the main benefits of L-citrulline, its potential side effects, the best time to take it, and more.

What does L-citrulline do for the body?

Citrulline is a conditionally essential amino acid, which means it can be necessary for survival under certain conditions but typically isn’t. Even when you do not need to consume it to survive, this amino acid still plays a significant role in human health.

The body can turn L-citrulline into L-arginine. Most citrulline from supplements goes towards producing arginine. In fact, supplemental L-citrulline is more effective for raising the levels of arginine in the body than arginine itself.

Along with L-arginine and L-ornithine, L-citrulline is an intermediate in the urea cycle, a cycle of biochemical reactions that produces urea from ammonia.

The body makes nitric oxide from arginine, which can widen blood vessels and improve blood flow. However, oral supplementation is ineffective in this regard.

Arginine also makes agmatine, a signaling molecule that shows promise for alleviating pain, reducing compulsiveness, protecting against strokes, and benefitting cognitive health.

Arginine interacts with lysine in many ways and they should be kept in balance unless you have a strong reason to off-balance them (such as herpes simplex). Taking too much of one can override the functions of the other. For example, high doses of lysine could hinder the ability of arginine (and thus citrulline) to produce nitric oxide.

Since citrulline can also increase the amount of arginine in the body, it has to be kept in balance with lysine as well.

L-citrulline vs. L-arginine

In the body, arginine can be converted into citrulline and vice versa. Consuming enough of either of them should prevent a deficiency in the other.

Counter-intuitively, supplemental L-citrulline raises arginine levels in the body more than supplemental L-arginine.

Supplemental L-citrulline also has unique benefits that do not seem to apply to supplemental L-arginine, such as reducing fatigue and muscle soreness. Citrulline is much more bioavailable and overall a better supplement to take for most people.

Possible benefits

All of the potential benefits mentioned below are dose-dependent. Generally, the higher the dose, the more pronounced the effects are. However, they do reach a plateau at a certain point. We will discuss the best dosing protocol later in this article.

Major benefits

Increased plasma levels of arginine – L-citrulline is more effective in this regard than L-arginine itself.
Reduced fatigue – Citrulline is very effective at reducing both exercise-induced fatigue and fatigue independent of exercise, especially in men who self-report fatigue issues. The supplement increases muscle ATP production and muscle oxygenation.
Reduced erectile dysfunction – L-citrulline seems to increase sexual function and intensity of erections in people with ED.
Reduced muscle soreness – One study in which citrulline was taken right before a workout shows a 40% reduction in muscle soreness the following two days after the workout.

Minor benefits

Improved immune function – This benefit mainly happens when you combine citrulline with exercise. Taking citrulline before a workout can enhance the neutrophil oxidative burst.
Increased exercise capacity in people with heart problems – People with heart conditions such as heart failure see an improvement in their exercise capacity (volume, power output, and more) following L-citrulline supplementation.
Increased training volume – An increase in work capacity applies mainly to those who do longer workout sessions. This benefit is secondary to the reduction of fatigue.
Increased blood flow – L-citrulline can increase blood flow by increasing nitric oxide production but this effect is rather small and only seems to apply to those with impaired blood flow.
Reduced blood pressure – This benefit mainly applies to people with hypertension or prehypertension and may apply to diabetics and people with insulin resistance as well.
Fat loss – This benefit only applies to people with impaired glucose tolerance. Citrulline doesn’t help healthy individuals burn fat.
Antioxidant properties – Reduced oxidation has been observed in people with impaired glucose tolerance and is associated with an increase in superoxide dismutase activity.
Reduced symptoms of angina – The supplement seems to reduce chest pain and improve exercise tolerance and quality of life in people with angina. However, it doesn’t seem to help widen blood vessels that are narrowed in angina.
Improved insulin sensitivity – An increase in insulin sensitivity has been noted in persons
with impaired glucose tolerance using arginine for long periods. This effect likely applies to citrulline supplements as well.
Reduced anxiety – This benefit only applies if you combine the supplement (or L-arginine) with L-lysine. The combination is effective at reducing state and trait anxiety. It may also reduce generalized anxiety disorder (GAD) but science is not yet clear on that. For best results, take 2.5 grams of each amino acid daily spread into 2 or more doses.

Possible side effects

These side effects are dose-dependent. The risk for them increases (often linearly but sometimes exponentially) as you increase the dose. Some of the side effects only apply to very high doses.

Nausea
Diarrhea – This effect usually happens when a person takes 10+ grams at once.
Reduced glutamine levels – Long-term supplementation with L-citrulline seems to slightly reduce plasma glutamine levels
Faster growth of herpes simplex – Arginine (which can be synthesized in the body from citrulline) is considered a nutrient for HSV and promotes its replication while lysine prevents replication. If you suffer from herpes, supplementing with 2 or more grams of L-lysine can help. Lysine supplements can override and block the absorption of arginine.
Amino acid imbalance – Essential and non-essential amino acids should be kept in balance as they act synergistically in many ways. Too much of one amino acid can sometimes cause side effects if there isn’t enough of another amino acid. For example, this principle applies to glycine and methionine, lysine and arginine, and the BCAA trio. There are many other proven and unproven examples. Food or a protein powder is usually a better choice for getting enough amino acids unless you have a specific goal in mind targeted by a particular amino acid/s.
Lysine deficiency – Citrulline interacts with lysine in many ways and they should be kept in balance unless you have a strong reason to off-balance them (such as herpes simplex). Taking too much of one can override the functions of the other. For example, high doses of lysine could hinder the ability of citrulline to produce nitric oxide.
Toxicity – While acute toxicity is extremely rare, taking high amounts of L-citrulline could lead to chronic toxicity and cause some health problems. To prevent chronic toxicity, it is best to stay below 10 grams a day unless you have a great reason to take more.
Contamination – Contaminated supplements are uncommon in the USA and other well-regulated countries. However, if you wish to buy products from China, India, or other countries without strict regulations, beware that the supplements may be contaminated. Either way, you need to choose the brand you order from wisely. It is highly recommended to check the certificates or read through some reviews for the specific product before you buy it. The FDA (Food and Drug Administration) has the power to regulate dietary supplements but can only do so after they have been on the market for a while. That’s because supplement companies are not obligated to announce to the FDA when releasing a new product on the market. The FDA has to discover the product and test it for potential impurities, which can take a lot of time. During that time, the supplement can be sold on the market even if it’s impure. Also, supplement companies can change their manufacturers without announcing it to the FDA.

Who should not take L-citrulline?

You should probably avoid taking the supplement if you:

suffer from herpes simplex
are deficient in lysine
get enough citrulline or arginine from food
are a healthy, insulin-sensitive individual (in which case, most potential benefits of arginine do not apply to you)
take high doses of ornithine
experience a severe adverse reaction after taking the amino acid
are on a tight supplement budget (since there are more cost-effective supplements on the market for most people)

Who will benefit the most?

You should consider taking the supplement if you:

consume very little protein (less than 0.3 grams/pound of body weight)
suffer from hypertension or prehypertension (citrulline can improve blood flow in this regard)
take high doses of L-lysine (citrulline can prevent or offset some of the side effects associated with L-lysine supplementation)
have impaired glucose tolerance (such as during diabetes)
suffer from renal failure (people with renal failure may become subclinically deficient, otherwise, a deficiency is rare

How much L-citrulline should you take?

Since this amino acid can be found in food or synthesized in the body, you may already get sufficient amounts without taking it as a supplement. About 0.36 grams of protein/pound of body weight should generally be enough to prevent any symptom deficiency.

If you plan to take L-citrulline as a supplement, 2-6 grams appears to be the best daily target for most people. This amount should provide most of the benefits without meaningful side effects.

Some people may benefit from doses higher than 6 grams. These include diabetics and people with renal failure.

If you take this amino acid to reduce anxiety, pair 2.5 grams of L-citrulline with 2.5 grams of L-lysine.

The upper safety limit for arginine is not well-established. To stay on the safe side, don’t take more than 10 grams daily unless you have a great reason to do so. Higher amounts may cause problems if you take the supplement for a prolonged period.

If you take a dose higher than 5 grams, always pair L-citrulline with a similar amount of L-lysine.

Food sources of citrulline

The richest food source of citrulline is watermelon (2.1 mg/gram of wet weight).

For raising L-arginine levels in the body, 330 grams of watermelon is equivalent to 1 gram of supplemental L-arginine.

Muskmelons, bitter melons, squashes, gourds, cucumbers, and pumpkins also contain high amounts of citrulline.

Since the body can produce citrulline from arginine (and vice versa), you can also get enough citrulline by consuming arginine-rich foods.

L-arginine is found in all whole foods that contain dietary protein.

The amount of L-arginine per gram of protein varies from food to food but a general rule of thumb is that the more protein you eat, the more arginine you are getting from food.

About 0.36 grams of protein per pound of body weight should be enough for most people to avoid any sign of deficiency.

The easiest way to find out exactly how much protein and specific amino acids you are getting from food is with Cronometer.com. This app is free and allows you to track all vitamins, minerals, and more.

Best time to take L-citrulline

Like most other amino acids, citrulline is water-soluble, so you don’t have to take it with food to absorb it well. To maximize absorption, take the supplement at least an hour before or after a meal so it doesn’t compete for absorption with other amino acids.

To maximize the benefits, take L-citrulline right before a workout.

Whether you take the supplement in the morning or the evening doesn’t matter much. It should not interrupt your sleep in any way.

If you practice time-restricted eating, take this amino acid during your eating window to guarantee it won’t break your fast.

L-Citrulline supplementation is more effective at maintaining elevated arginine levels for long periods but it still has a relatively short half-life. Unless it feels too impractical, spread the daily dose into 2+ smaller doses throughout the day.

Interactions

L-lysine
This combination is highly effective for reducing many types of anxiety, state and trait anxiety in particular. Combining these two amino acids may and may not be effective for generalized anxiety disorder (GAD). To maximize this benefit, it is best to take L-citrulline and L-lysine together and take 2.5 grams of each daily. Beware that taking these two together may negate the benefits of L-lysine related to the treatment of herpes simplex.
Other amino acids
Essential and non-essential amino acids should be kept in balance as they act synergistically in many ways. Too much of one amino acid can sometimes cause side effects if there isn’t enough of another amino acid. For example, this principle applies to glycine and methionine, lysine and arginine, and the BCAA trio. There are many other proven and unproven examples. Food or a protein powder is usually a better choice for getting enough amino acids unless you have a specific goal in mind targeted by a particular amino acid/s.

Where to buy L-citrulline

Amazon is the best option for ordering L-citrulline supplements in most countries. They offer some very affordable products backed by many positive reviews. Also, you can choose from a wide range of brands without having to search through other markets on the internet.

Beware some brands display the dosage per serving instead of per pill or capsule. Therefore, you may accidentally buy something less potent than you intended. Do not fall for this marketing trick.

FAQ

You can take the amino acid daily and do not need to cycle it. However, it is certainly not a problem if you don’t take it daily. Not taking the supplement every once in a while could lead to better absorption. That is yet to be proven or disproven.

All of these options are fine. The two most important things to consider are the price and dosing. Powders are almost always the cheapest form. However, you may need a highly accurate scale to dose them correctly (preferably 0.001g). You can get one for as little as $20 from Amazon. Dosing the powders also takes some time that can add up over months or years. The disadvantage of capsules is that they often contain bovine gelatin, which rarely comes from an ethical source.

Yes. Most amino acids, including citrulline, absorb and digest well if you take them before falling asleep. The supplement should not impact sleep quality in any significant way.

This amino acid should not become harmful once it exceeds the expiration date but can lose potency over time.

Keep the supplement in a cold, dark, and dry place, and it should remain just as potent for many months or even years.

While toxicity is rare, too much citrulline in the system can cause some health problems, often related to depleting lysine levels. It is best to stay below 10 grams a day to prevent these side effects.

You may need more of this amino acid if you:
– eat very little protein (less than 0.3 grams/pound of body weight)
– suffer from hypertension or prehypertension (citrulline can improve blood flow in this regard)
– are a type 2 diabetic or have impaired glucose tolerance
– suffer from renal failure
– take high doses of L-lysine (citrulline can prevent or offset some of the side effects associated with L-lysine supplementation)

The half-life of L-citrulline in the body is approximately 1 hour. The citrulline that gets converted into arginine has to then go through the half-life of arginine to get utilized, which takes about 1-2 hours. L-Citrulline supplementation is more effective at maintaining elevated arginine levels for long periods.

You can notice the exercise-related benefits of citrulline during or right after an exercise session. In the long term, you need to take the supplement for about 2-4 weeks to begin noticing the benefits.

You can easily find vegan-friendly citrulline pills and powders but always check the label to be sure. If you buy the amino acid in a capsulated form, beware that the capsules often contain animal-based gelatin. Instead, find a brand that puts its products into cellulose capsules.

Like most other amino acids, citrulline is water-soluble, so you don’t have to take it with food to absorb it well.

L-citrulline should not break a fast unless you take a very high dose at once. If you practice time-restricted eating, take this amino acid during your eating window so it doesn’t break your fast.

References

Most of the information provided in this guide is supported by scientific research that can be found and verified in the PubMed medical library. We highly encourage you to use the library to verify anything said in this article. We excluded from consideration studies that are either confounded or have a high conflict of interest.

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