Nutritional supplementation is extremely common among bodybuilders and physique athletes. Whether ingested alone or in a multi-ingredient blend, supplements containing nitric oxide (NO) boosters are among the most commonly used supplements. But why bother with NO boosters?
Nitric oxide is a vasodilator, which increases blood flow. Because NO is gaseous and has a very short half-life, people rely on various NO precursors to help promote NO production. Nitric oxide boosters may benefit exercise performance, soreness, and training adaptations by influencing oxygen and substrate delivery, muscle contractile function, metabolite clearance, and transient cellular swelling. Plus, let’s be honest: In the vain world of bodybuilding, a supplement that causes a temporary “pump” that increases muscle circumference and vascularity is bound to be a crowd favorite.
There are two pathways of NO production; one is reliant on the nitric oxide synthase (NOS) enzymes, and the other is not. In the NOS-dependent pathway, L-arginine is oxidized to L-citrulline and NO (1). This process not only requires the presence of NOS enzymes, but also a number of other substrates and cofactors, including oxygen.
In the NOS-independent pathway, nitrate (NO3) is reduced to nitrite (NO2), which is reduced to NO. This pathway does not require the NOS enzymes, nor does it require oxygen— in fact, this pathway is stimulated by hypoxia (low oxygen availability) and the accumulation of hydrogen ions (H+), which are observed during intense exercise (1).
The first generation of NO boosters used one or more forms of arginine as the ingredient of choice. This makes sense, considering arginine’s role in the NOS-dependent pathway. However, arginine has two primary shortcomings. First, it doesn’t appear to improve performance in trained subjects, despite some positive findings in untrained subjects (2). Second, oral arginine supplementation is a poor method of increasing plasma levels of arginine. This is because much of the arginine ingested is metabolized in the gut and liver before it ever has a chance to reach systemic circulation (3). Together, these factors suggest that arginine is not the ideal nitric oxide booster for your pre-workout cocktail. A number of formulations have moved away from an emphasis on arginine, with increased interest in other potential NO boosters.
I call this section “the present” because ingredients in this section are currently found in many NO supplement blends, and performance-oriented human research on them is at least starting to surface. Compared to arginine, citrulline supplementation presents a better method of increasing plasma arginine levels, which may therefore increase NO production. The most popular form of citrulline, citrulline malate, may also affect exercise performance by influencing ammonia clearance and ATP production (4). Despite citrulline’s excellent reputation, there’s a surprisingly scarce amount of human performance research available. Citrulline malate improves muscular endurance for both upper-body (4) and lower-body (5) resistance exercise, and improves recovery from resistance training (4). What we don’t know, at the moment, is exactly which mechanism(s) deserve the credit. If viewing citrulline specifically as a “nitric oxide booster,” more research is needed to demonstrate that citrulline supplementation increases blood flow during exercise via an NO-mediated mechanism, and that this is actually dictating some of the performance and recovery benefits that have been observed.
Dietary nitrate is another NO booster that falls into the “present” category. The most common nitrate supplements are beetroot-based, but there are others on the market, such as pomegranate extract. Dietary nitrate does improve exercise performance (2, 6, 7), but previous literature has mostly looked at low-intensity, aerobic forms of exercise. In 2014, our lab published a paper demonstrating that pomegranate extract increased blood flow and blood vessel diameter in humans, while improving moderate-intensity running performance (7). We, and other researchers, have since found evidence to suggest that nitrate also helps out with sprint performance (8, 9), and a recent study showed an improvement in resistance exercise performance from beetroot supplementation (10). By targeting a pathway that is stimulated during hypoxic, acidic conditions, dietary nitrate could potentially be an ideal NO-booster for physique athletes doing high-intensity exercise, but this research is only beginning to emerge.
Future research will certainly tell us more about if (and how) citrulline and dietary nitrate may improve resistance training outcomes. But future research may also inform us of a few “other” ingredients that have snuck their way into some formulations. While these ingredients have already surfaced in a number of products, sufficient human performance research on them is not yet available. Agmatine, commonly seen in the form of agmatine sulfate, is one such ingredient. While agmatine may influence the NOS-dependent pathway of NO production, agmatine itself is not directly converted to NO (11). Agmatine is widely regarded as a vasodilator, but there is conflicting evidence regarding its effects on NO production (11-12), and the only human research on agmatine was evaluating effects on pain and depression symptoms (12, 13). Another one of these “other” ingredients is L-norvaline, which inhibits the arginase enzyme (14). By inhibiting arginase, it may help to preserve serum levels of arginine, thereby supporting NO production. Similarly to agmatine, there is no research directly investigating the effects of norvaline on human exercise performance. Agmatine and norvaline could feasibly make for effective NO-boosters, but we currently lack relevant research to verify this speculation
So, what should a pump-seeking lifter look for in an NO booster?
The future of NO boosters remains to be determined. We still need to determine what (if any) roles agmatine and norvaline can play in these formulations, and what mechanisms are really calling the shots for citrulline malate’s effects. But for now, I’d generally hope that your NO supplement of choice isn’t putting all of its eggs in the arginine basket. Similarly, I’d be a bit cautious about formulations that are entirely focused on agmatine or norvaline, simply due to the lack of human performance research on them. For a consumer interested in boosting NO production, blood flow, and performance, the safest bet would be to seek out a nitrate- or citrulline malate-based product that is effectively dosed. If those criteria are met, you’re likely to experience some of the performance and recovery benefits that have been documented in previous research. And you’ll probably enjoy the transient pump that comes with them.
- Bailey SJ, Vanhatalo A, Winyard PG, Jones AM. The nitrate-nitrite-nitric oxide pathway: Its role in human exercise physiology. European Journal of Sport Science. 2011 2012/07/01;12(4):309-20.
- Bescos R, Sureda A, Tur JA, Pons A. The effect of nitric-oxide-related supplements on human performance. Sports medicine. 2012 Feb 1;42(2):99-117. Epub 2012/01/21.
- Schwedhelm E, Maas R, Freese R, Jung D, Lukacs Z, Jambrecina A, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. British journal of clinical pharmacology. 2008 Jan;65(1):51-9.
- Perez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. Journal of strength and conditioning research / National Strength & Conditioning Association. 2010 May;24(5):1215-22.
- Wax B, Kavazis AN, Weldon K, Sperlak J. Effects of supplemental citrulline malate ingestion during repeated bouts of lower-body exercise in advanced weightlifters. Journal of strength and conditioning research / National Strength & Conditioning Association. 2015 Mar;29(3):786-92.
- Lansley KE, Winyard PG, Bailey SJ, Vanhatalo A, Wilkerson DP, Blackwell JR, et al. Acute dietary nitrate supplementation improves cycling time trial performance. Med Sci Sports Exerc. 2011 Jun;43(6):1125-31. Epub 2011/04/08.
- Trexler ET, Smith-Ryan AE, Melvin MN, Roelofs EJ, Wingfield HL. Effects of pomegranate extract on blood flow and running time to exhaustion. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2014 Sep;39(9):1038-42.
- Roelofs EJ, Smith-Ryan AE, Trexler ET, Hirsch KR, Mock MG. Effects of pomegranate extract on blood flow and vessel diameter after high-intensity exercise in young, healthy adults. Eur J Sport Sci. 2017 Apr;17(3):317-25.
- Wylie LJ, Bailey SJ, Kelly J, Blackwell JR, Vanhatalo A, Jones AM. Influence of beetroot juice supplementation on intermittent exercise performance. European journal of applied physiology. 2016 Feb;116(2):415-25.
- Mosher S, Sparks SA, Williams E, Bentley DJ, Mc Naughton LR. Ingestion of a nitric oxide enhancing supplement improves resistance exercise performance. Journal of strength and conditioning research / National Strength & Conditioning Association. 2016 Apr 2.
- Galea E, Regunathan S, Eliopoulos V, Feinstein DL, Reis DJ. Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. The Biochemical journal. 1996 May 15;316 ( Pt 1):247-9.
- Keynan O, Mirovsky Y, Dekel S, Gilad VH, Gilad GM. Safety and Efficacy of Dietary Agmatine Sulfate in Lumbar Disc-associated Radiculopathy. An Open-label, Dose-escalating Study Followed by a Randomized, Double-blind, Placebo-controlled Trial. Pain medicine. 2010 Mar;11(3):356-68.
- Shopsin B. The clinical antidepressant effect of exogenous agmatine is not reversed by parachlorophenylalanine: a pilot study. Acta neuropsychiatrica. 2013 Apr;25(2):113-8.
- Chang CI, Liao JC, Kuo L. Arginase modulates nitric oxide production in activated macrophages. Am J Physiol. 1998 Jan;274(1 Pt 2):H342-8.