Citrulline Review: Cranking Up The Effectiveness Of Your Favorite Nitric Oxide (NO) Supplements!


Ever looked at the list of ingredients for your favorite NO (nitric oxide) supplement? The chances are good that—in addition to the usual arginine compounds—you’ll see citrulline listed there too. NO supplements have gotten more sophisticated in the last few years, and the addition of citrulline represents an improvement over formulas that rely on arginine alone.

Citrulline is a non-essential, non-protein amino acid that serves as an intermediate in the urea cycle. The urea cycle is used by the body to detoxify and excrete excess ammonia produced when amino acids are broken down. Without the urea cycle, ammonia would rapidly build up to a toxic—and ultimately fatal—level.

Other amino acids participating in the urea cycle are ornithine and arginine.

Citrulline converts to arginine in the urea cycle, so at first glance, it would seem that they’re interchangeable. This isn’t quite true from your body’s perspective, however. Research has shown that chronic supplementation with arginine leads to increased arginase expression, which, in turn, increases the rate at which ingested arginine is broken down.

Citrulline, on the other hand, does not have this effect. On the flip side, nitric oxide synthase (NOS) regenerates citrulline in the course of converting arginine to nitric oxide. This cycling results in a much longer half life for citrulline, and ultimately, arginine in the body.

In other words, citrulline may be a better source of supplemental arginine than arginine itself. When taken together, arginine and citrulline work synergistically to enhance NO production and improve blood flow.

Citrulline may prove to be useful for therapeutic purposes. Citrulline is currently being tested in clinical trials for prevention of of hepatic venoocclusive disease (HVOD) and acute lung injury (ALI) in patients receiving chemotherapy for bone marrow transplants. A second clinical trial is also underway to see if citrulline can improve exercise tolerance in patients with Peripheral Arterial Disease (PAD).

Experimentally, citrulline has been used to prevent post-operative hypertension (high blood pressure) and to retard the progression of atherosclerosis. It appears to be quite safe, and is well-tolerated in doses up to 15 g (at least over the short term).

Does citrulline supplementation have any advantages for healthy, exercising people—beyond being a source of arginine for NO production?

It looks like the answer is yes, at least for the most common supplemental form, citrulline malate. During intense exercise, there are increases in both ammonia (from amino acid catabolism) and lactic acid production.

Citrulline malate can enhance the clearance of both. In addition, it’s been shown to promote aerobic energy production in exercising muscle.

There is also some experimental evidence that it can promote resistance to muscle fatigue, although (of course) more research in humans needs to be done.

It may be that the malate part of the supplement is responsible for some of these effects. A recent study looking at the effects of free form L-citrulline on exercise in healthy people actually found it reduced the time to exhaustion on a treadmill test.

Malic acid is an important metabolite in the Krebs Cycle, which is the primary metabolic pathway used by the body to produce energy. Thus, it’s entirely possible that it makes a significant contribution.

The feedback on citrulline malate I’ve seen is pretty positive…not so much for strength, but for cardio. Most users report that it reduces fatigue and helps provide a boost in energy/stamina. Unfortunately, this is all anecdotal—there is very little research on the use of citrulline malate in healthy people. So it could be an example of the placebo effect in action too. I tend to doubt it, though, as some of the feedback has come from people I know who are fairly skeptical.

What’s an useful dose? When using bulk citrulline malate, most people use 3–6 grams, taken prior to a cardio workout. This is almost certainly a higher dose than is found in NO supplements, where it has a more supportive function.

Overall, citrulline appears to be a promising supplement for enhancing NO production and—in the malate form—increasing endurance/stamina during aerobic exercise. As such, it’s worth experimenting with, although the bulk powder form may be preferable to a branded supplement which includes it as part of a proprietary blend.

Citrulline (pure) or citrulline containing products include:

NOW L-Citrulline, PrimaForce Citrulline Malate, Supplement Direct Citrulline Malate, MAN Body Octane, Next Ultimate Orange, Anabolic Innovations Chaos, BSN NO-Xplode, Designer Supplements Replenish, iSatori H+ Blocker, Ultimate Nutrition Horse Power, VPX NO Shotgun.

Many of these products are available at!

Author: elissa

Elissa is a former research associate with the University of California at Davis, and the author/co-author of over a dozen articles published in scientific journals. Currently a freelance writer and researcher, Elissa brings her multidisciplinary education and training to her writing on nutrition and supplements.

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