Are Nitric Oxide Supplements Beneficial For Strength and Hypertrophy?

Nitric oxide is a bodybuilding supplement staple.

If you’ve ever used a dietary supplement with more than four ingredients, you’ve probably used a nitric oxide (NO) booster. Back in the early 2000s, it seemed like just about every supplement company came out with a formula promising “skin-splitting pumps.” The foundation of such formulas was virtually always an NO precursor of some type. This trend has largely stood the test of time; while the favored NO precursor has shifted over the years, NO precursors remain as one of the most popular classes of supplements on the market.

Nitric Oxide: What Is It, And How Do We Increase It?

Nitric oxide is a gaseous cell signaling molecule with an incredible number of roles and effects in the human body. When it comes to exercise, we tend to focus on a small subset of these effects. Most notably, NO is known as a vasodilator, meaning it causes blood vessels to relax, thereby promoting more blood flow. In fact, this is how NO was actually discovered in the body; scientists knew there was something causing pronounced vasodilation in their experiments, but they hadn’t identified the exact molecule(s) at hand. So, they just called it “endothelium-derived relaxation factor,” until ultimately realizing that NO was the primary molecule causing the effect. That’s the kind of stuff that wins you a Nobel Prize (and they did) and gets NO officially declared as “Molecule of the Year” in 1992. As a result, most pre-workout supplements are sure to include an NO booster, in hopes of enhancing the “pump” we experience as muscle blood flow is increased during exercise.

While skin-splitting pumps dominate the advertisements for NO products, there’s much more going on with regard to strength performance and hypertrophy. Aside from the subjective enjoyment of a great pump, it has been postulated that increased blood flow may allow NO to improve performance and recovery by facilitating the delivery of energy substrates and oxygen, while facilitating the clearance of fatigue-inducing exercise metabolites. However, this is but one of many ways that NO may influence exercise performance. As reviewed previously, NO is thought to influence energy efficiency (the amount of energy we use to perform a fixed amount of exercise), intramuscular calcium handling (which has critical implications for force production and muscle power output), and other facets of energy metabolism and muscle fatigue.

Unfortunately, you can’t just throw NO powder in a container and put it on the shelf. Nitric oxide is a gas, and its half-life is usually estimated to be no longer than a second or two. So, once the body produces it, it will rapidly decide to either do its job or become something else. Figure 1 shows an over-simplified visualization of the many fates this newly formed NO may take.

Figure 1. Once nitric oxide (NO) is formed, it will rapidly be guided toward one of the paths drawn above. It may: 1) Activate guanylyl cyclase (GC), which increases cyclic guanosine monophosphate (cGMP), resulting in vasodilation. 2) Become nitrite (NO2-) or nitrate (NO3-), which can be considered a form of “short term storage” for the NO. 3) Nitrosylate or otherwise modify numerous proteins throughout the body (there are over 3,000 nitrosylation targets in mammals), forming RSNO and exerting a wide range of effects throughout the body. 4) Get converted to peroxynitrite (ONOO-), which is generally terrible. Peroxynitrite is essentially a waste of perfectly good NO and causes unfavorable effects like protein damage, DNA damage, and nitric oxide synthase (NOS) uncoupling. Luckily, antioxidants do their best to increase the half-life of NO and guide it away from this particular fate. For a painfully detailed (and very good) summary of NO metabolism, check out this paper for further reading.

Two Paths, One Destination

Given these logistical hurdles, we are left to supplement with nitric oxide precursors, which enhance our ability to produce NO when we are ready to immediately use it. As it turns out, there are two completely separate pathways by which we can create NO.

The first generation of pre-workout supplements opted for arginine and understandably so. Arginine is, after all, converted directly to NO by the nitric oxide synthase (NOS) enzymes. Unfortunately, arginine has pretty poor bioavailability, so its use as an orally ingested supplement is quite limited. But, there is good news: Citrulline has very good bioavailability, and if we ingest citrulline, we can increase the levels of arginine in our blood, which therefore enhances our capacity to make NO. Most commonly, citrulline is used in the form of citrulline malate. This is important, because citrulline and malate have potential effects beyond NO production. Citrulline facilitates ammonia clearance via the urea cycle, which may help to attenuate fatigue. In addition, malate is a tricarboxylic acid (TCA) cycle intermediate. As such, it could theoretically contribute to aerobic ATP production and attenuate the accumulation of fatigue-inducing metabolites of anaerobic metabolism.

Aside from arginine and citrulline, there is another pathway for NO formation. This involves ingesting some source of nitrate, which is converted to nitrite, which is converted to NO. Some studies have used sodium nitrate as the nitrate source, but products on the market most commonly use beetroot juice, or some other beetroot- or pomegranate-derived extract. As an added bonus, most plant-based nitrate sources tend to be high in antioxidants, which prolong the half-life and increase the bioactivity of NO. The nitrate pathway has some pretty nice features compared to the NOS-dependent pathway used by arginine and citrulline. Since it doesn’t require the NOS enzymes, it also doesn’t require high oxygen availability in order to produce NO. In fact, this pathway is actually stimulated by hypoxia and acidosis; this could be particularly favorable for high-intensity exercise (like resistance training), which tends to be largely anaerobic in nature.

In line with this logic, previous rodent studies have shown that the effects of nitrate on exercise blood flow and muscle force production are more pronounced in type 2 muscle fibers than type 1. The only downside is that this pathway is heavily reliant on oral bacteria to convert nitrate to nitrite. If you regularly use antibacterial mouthwash, you’ll completely abolish any potential benefits from high nitrate intake. One might argue that you should therefore supplement with nitrite instead of nitrate, but nitrite use is associated with a far greater likelihood of serious side effects. It seems as if this nitrate to nitrite conversion serves as a helpful safeguard that tends to keep nitrite and NO production within a reasonably safe workable range, and prevents blood pressure reduction and methemoglobin formation from going completely off the rails (although you can still get some nasty side effects and acute toxicity with extremely high sodium nitrate doses). A summary of the two NO production pathways is presented in Figure 2, showing how either beetroot juice or citrulline malate can influence NO production and resistance exercise performance.

Figure 2. Pathways of nitric oxide formation, starting with either beetroot juice or citrulline malate, and the purported effects of nitric oxide on various mechanisms related to resistance exercise. Abbreviations: O2 = oxygen, ROS = reactive oxygen species, ATP = adenosine triphosphate, RFD = rate of force development

For a more simplified figure comparing and contrasting the similarities and differences of the two major NO precursors and the two pathways they target, see Figure 3.

Figure 3. A simple Venn diagram comparing and contrasting citrulline malate and beetroot juice, which target two distinct pathways of nitric oxide production. Some studies have shown both precursors to enhance “reps to fatigue,” or the number of repetitions completed prior to failure of a resistance training task. Abbreviations: TCA = tricarboxylic acid, NOS = nitric oxide synthase

To this point, everything we have discussed about NO, its precursors, and its production can be filed under “interesting.” But it’s not actually useful unless this stuff relates to performance in the gym. So let’s take a look at that evidence.

Do Nitric Oxide Precursors Actually Enhance Strength Performance?

Citrulline

The first notable citrulline malate study seemed like it clipped their exercise test straight out of a late-’90s muscle magazine (that’s a statement of nostalgic endearment, not criticism): 4 chest exercises, 16 sets, all to failure. I have to assume it looked like an old Dorian Yates training video on the last few sets, with these exhausted subjects trying to revive their depleted pecs for one last hurrah. In any case, the study made a strong case that participants were able to complete more repetitions prior to failure, or repetitions to fatigue (RTF), when they consumed citrulline malate an hour prior to testing (in comparison to a placebo treatment). More specifically, this benefit was more pronounced in the later sets, as fatigue really started to accumulate.

Replication is a critical aspect of science, and replication attempts were carried out and published a few years later. Wax and colleagues published studies showing enhanced repetitions to fatigue in both upper-body and lower-body exercise tests. Both studies utilized male participants only and completed similar testing protocols in which multiple sets of multiple exercises were taken to failure. The results were also replicated in resistance-trained female participants, completing both upper-body and lower-body exercise tests. As of 2016ish, the citrulline malate literature looked pretty straightforward and promising. Then the literature came back down to earth a little bit.

Gonzalez, Cutrufello, Farney, Chappell: Four studies, four null findings, suggesting that citrulline malate did not significantly enhance a variety of strength and power outcomes. As a few null findings came out in rapid succession, feelings about citrulline malate’s potential turned a bit sour, and it seemed like the literature was “all over the place.” But it really isn’t, from a more mathematically oriented perspective.

When we look at a big group of studies on a topic, we expect there to be an average effect of the treatment, but we don’t expect every study ever to fall exactly on that average. It’s really a distribution of effects, and a variety of factors may pull a single study’s outcome in one direction or another (sex, training status, exercise test, sampling error, measurement reliability, etc.). We also expect that a large study will typically have a more precise estimate of the “true” effect of the treatment, whereas smaller studies are a little less reliable, and therefore more likely to fluctuate from the mean in one direction or the other. If you ever hear the terms “publication bias” or “small-study effects,” those concepts are often associated with an asymmetrical trend in this fluctuation. Basically, the results of published small studies tend to fluctuate in the same direction, usually favoring the treatment having a large effect. In such a case, you have to be nervous about the possibility that people actually did other small studies showing less positive results, and simply neglected (or failed) to publish them

If you take stock of the citrulline literature as of late 2018, specifically looking at studies pertaining to strength and/or power outcomes, it will indeed look chaotic if you view each individual study as a binary outcome (i.e., it either worked or it didn’t work). However, a more nuanced look tells a different story. Overall, the studies generally show an average effect size that I would consider somewhere between trivial and small. Sure, some of the smaller studies show effect sizes (standardized mean differences, interpreted similarly to a cohen’s D value) around or even a little below 0, and some show effect sizes up above 0.5, but the typical effect size falls in the middle, right around the trivial-to-small range. Whether that is praise or criticism of the supplement is really in the eye of the beholder; from my perspective, that’s par for the course in the supplement world. It’s simply not an area of research in which large effect sizes are expected. So, if you thought citrulline was the next creatine, you’re probably incorrect. In terms of resistance training outcomes, it’s more like the next caffeine or the next beta-alanine. For now, creatine still stands in a league of its own when it comes to resistance training supplements.

Nitrate

Unfortunately, the nitrate section is a lot simpler to write. Beetroot juice and other sources of nitrate have been extensively studied in the realm of endurance performance, but comparatively little has been done with regards to resistance exercise. As reviewed elsewhere, nitrate has been shown to enhance endurance training in a number of studies, with key mechanisms including vasodilation, reduced energy cost, enhanced glucose uptake, and improved intramuscular calcium handling. For aerobic outcomes, they have studied a variety of modalities at a variety of intensities, including walking, running, cycling, and rowing.

When it comes to what we consider typical or traditional resistance exercise (load a bar, crank out some reps), there’s really only one study to go with so far. It was set up a lot like the early citrulline malate studies, where an exercise was performed with multiple sets taken to failure. In this case, the researchers used bench press performed at a load corresponding to 60% of the participant’s one-repetition maximum. Preceding the test, participants consumed a beetroot shot or placebo for six days. Similarly to the old citrulline malate literature, the beetroot treatment appeared to enhance repetitions to fatigue.

It’s unfair to say that this is the only resistance exercise study in the literature; it’s just that the others utilize strength tests that are more “sciencey” and less “weight-roomy.” A study in heart failure patients showed that a single dose of beetroot juice enhanced knee extension power, but interestingly, this was only observed at pretty high movement velocities. Differences were observed at velocities of 270 and 360 degrees per second, but not at velocities under 270. However, this study has to be taken with a grain of salt. There are all sorts of cardiovascular complexities to consider when dealing with heart failure patients, which is inherently critical when it comes to a nitric oxide intervention. Luckily, the same lab group showed extremely similar findings in healthy subjects, with beneficial effects on torque and power observed at an angular velocity of 360 degrees per second, but not at 90, 180, or 270 degrees per second. This velocity-dependent effect leads us to a very important question: How exactly are these supplements affecting strength and power?

Performance-Enhancing Mechanisms For Resistance Exercise

In the last decade or so, study after study has evaluated the effects of beetroot and other nitrate sources on aerobic exercise. When it comes to aerobic performance, oxygen delivery is the name of the game. I recently had the pleasure of hearing beetroot (and cardiovascular physiology) legend Andrew Jones give a talk about Nike’s Breaking 2 Project, in which they attempted to break the two-hour marathon barrier. He detailed their rigorous calculations on how oxygen could be transported, utilized, and conserved, and the variety of methods aimed at managing this valuable commodity over the course of the marathon.

In this scenario, the effects of beetroot juice on blood flow and mitochondrial efficiency would be of utmost importance; indeed, there is some evidence suggesting that nitrate supplementation increases blood flow to active musculature and enhances exercise energy efficiency. There’s a bit of controversy regarding exactly how this energy efficiency is being enhanced. One study suggested that nitrate reduced the expression of a couple proteins, adenine nucleotide translocase and uncoupling protein 3, which allow protons to travel from the intermembrane space of mitochondria to the inner mitochondrial matrix without passing through ATP synthase (note: the uncoupling protein 3 result was not statistically significant, but it looks like one outlier really threw off the trend). By reducing the expression of these proteins, the mitochondria produce more ATP for a given amount of energy expenditure, thereby yielding enhanced efficiency and energy conservation. However, a different study saw a similar enhancement of exercise energy efficiency from beetroot juice supplementation, but did not observe significant changes in adenine nucleotide translocase or uncoupling protein 3 expression. These authors suggested that there was some explanation for enhanced energy efficiency that operated independently of these key proteins.

When it comes to some of the secondary or tertiary mechanistic explanations for enhanced exercise performance, such as ammonia clearance and lactate clearance, the data are not very convincing at this time. While there are some supporting studies out there, there are also notably underwhelming results in which both citrulline and beetroot supplements have failed to significantly alter indices of ammonia clearance/urea production. The story for lactate clearance is pretty similar; while there are some studies demonstrating modestly favorable effects on lactate levels, the evidence for reduced lactate production or enhanced lactate clearance as primary mechanisms driving ergogenic effects is collectively pretty weak. Most notably, two studies by Wax and colleagues documented significant improvements in repetitions to fatigue despite nonsignificant effects on lactate responses, and the sole beetroot juice study investigating repetitions to fatigue reported the same. For this particular question, it would’ve been really informative if those studies reported the correlation between lactate changes and performance changes, but we aren’t quite lucky enough to have that information. You could argue the possibility that lactate kinetics were improved in these studies, as reflected by more work performed with similar blood lactate responses, but this explanation is challenged by the results of other studies. A recent study showed citrulline malate to result in slightly less work performed and slightly higher absolute post-exercise lactate values following 10 sets of leg extension to failure (neither effect was statistically significant). In addition, beetroot juice was previously shown to have no significant effect on the rise in lactate during work-matched bouts of cycling, and another study reported that citrulline malate did not alter the lactate threshold during a graded cycling test. Taken together, these studies cast doubt on the idea that an altered lactate response is a primary mechanism driving the performance-enhancing effects observed with nitric oxide precursor supplements.

It’s entirely possible that these previously mentioned mechanisms contribute to the documented improvements in repetitions to fatigue following NO precursor supplementation. However, with this particular type of exercise, direct effects of NO on muscle function warrant closer attention. In a recent review, Coggan and Peterson synthesize the findings of several recent studies in this area, including some that they themselves conducted. They propose that NO nitrosylates ryanodine receptors and increases protein kinase G activity via guanylyl cyclase activation (if you refer to Figure 1, these paths are represented by “RSNO” [nitrosylation] and “GC,” respectively). They propose that these effects lead to increased intracellular calcium release and increased calcium sensitivity of myofibrils. In order for muscles to create force, we need the sarcoplasmic reticulum to release calcium, and we need that calcium to bind to troponin (a key protein of myofibrils); this allows actin-myosin cross-bridges to attach and create force. So, the authors suggest that NO is benefiting muscle function by enhancing calcium release and the efficiency by which calcium initiates force production, resulting in improved twitch force, rate of force development, shortening velocity, and muscle power. It’s possible that these effects may help to explain the results of a study from about a decade ago, in which beetroot juice was shown to lower the energy cost of muscle contraction using some pretty sophisticated magnetic resonance spectroscopy.

Another recent study helped to partially reinforce the ideas of Coggan and Peterson, while drawing closer connections to the wave of NO precursor studies reporting increased repetitions to fatigue. In this particular study, the researchers found beetroot juice to specifically enhance explosive force production, as noted by a couple previous studies by Coggan and colleagues. Furthermore, the differences in explosive force production were only observed in fatigued conditions, which likely applies to multiple-set repetitions to fatigue protocols, as commonly seen in the NO precursor literature. This may potentially explain, at least in part, why a recent study found no benefit of citrulline malate when using an isokinetic leg extension protocol, which constrains movement velocity at a fixed value that is typically less than 360 degrees per second. Finally, there is reason to believe that chronic NO precursor supplementation may confer some additional benefits with regard to force production, beyond the short-term effects of acute supplementation. In rodents, seven days of nitrate supplementation led to increased contractile force of fast-twitch muscle fibers, along with changes in calsequestrin 1 and dihydropyridine receptor expression. These are both proteins that affect the way calcium is released and transported within muscle fibers, thereby altering force production. Much more research is needed to replicate this finding and translate it to humans. For example, a small human study from last year found force production changes that were consistent with alterations in muscle calcium handling, but analyses of several related proteins (including calsequestrin and dihydropyridine receptor, among others) suggested that significant alterations in protein expression were not observed following beetroot juice supplementation.

Before we get too carried away with mechanisms, it’s important to understand that this body of research is young and largely undeveloped. The case is far from closed when it comes to exactly what types of exercise can be reliably improved by NO precursor supplements, and how the supplements actually increase performance. It’s also important to remember that mechanisms are not mutually exclusive; it’s possible that resistance exercise is affected by a combination of changes in muscle contractile function, mitochondrial efficiency, and oxygen delivery following NO precursor supplementation. While the last few paragraphs summarize the current state of the evidence, additional research will undoubtedly enhance and refine our understanding of NO precursors within the next decade or so.

But What About Hypertrophy?

In terms of hypertrophy, a previous review has detailed some plausible mechanisms by which nitric oxide may be beneficial. In short, an increased accumulation of blood in the working muscle could contribute to acute swelling of the muscle cell, which is thought to play a role in promoting growth of the muscle fiber. While acute muscle swelling is rarely directly measured in NO precursor studies, it’s worth noting that one recently did measure it at the whole-muscle (not single-fiber) level, and the results did not suggest that citrulline malate increased this response to exercise. There is also evidence to suggest that NO directly promotes satellite cell differentiation, which is an important step in the process of initiating muscle growth. As such, rodent studies have shown that administering a potent NO blocker blunts muscle hypertrophy, and that providing an NO donor (isosorbide dinitrate) significantly enhanced the hypertrophic response to voluntary exercise. There’s also the idea that NO precursors will acutely increase your performance in the gym, allowing you to complete a greater volume of training in a given workout, thereby affecting hypertrophy in the long run. This premise of acute training boosts benefiting long-term training adaptations recently failed to pan out for a sodium bicarbonate study, but that doesn’t mean the entire concept is unjustifiable. The theoretical links between NO precursors and hypertrophy are outlined in Figure 4.

Figure 4. Theoretical model linking nitric oxide precursor supplementation to hypertrophy and long-term training adaptations. At this point, the model is highly speculative in nature, and requires validation from long-term (or at least “moderate-term”) training studies. Abbreviations: SC = satellite cells

In any case, whether or not these nitric oxide precursors really lead to enhanced hypertrophy over time is simply a matter of speculation at this point. We have a long-term study on arginine alpha-ketoglutarate showing no benefit for lean body mass gains over eight weeks of resistance training. However, hindsight has shown us that citrulline and nitrate are far more promising supplementation targets than arginine, so I prefer not to borrow from the arginine literature in this regard. There’s also a recent study investigating three treatment groups: 1) 2g citrulline + 200mg glutathione, 2) 2g citrulline malate, and 3) placebo. These supplements were consumed daily in conjunction with eight weeks of resistance training. The citrulline malate and placebo groups gained no lean mass whatsoever. The citrulline + glutathione group had a significant increase from week 0 to week 4, but this was not significant at week 8. This was by no means a bad study, but for the purposes of our question, we have some hurdles to get over: The training program didn’t seem to induce much hypertrophy in general, the citrulline malate was dosed at about 25% of the typical study dose (which made sense for their research question, but not for ours), and the antioxidant effect of glutathione is likely to have a big impact on how effective that 2g dose of citrulline is. These researchers designed a very good study to answer their question, but their question differs from ours in this case, which makes interpretation a bit difficult.

When it comes to studies looking at just citrulline or just nitrate in the absence of a bloated pre-workout formula packed with hugely confounding ingredients (such as caffeine, creatine, and beta-alanine), we simply don’t have anything to go off of. For the present time, we can only conclude that: 1) sufficiently dosed NO precursors increase NO production, 2) NO precursors can (but do not always) acutely improve repetitions completed prior to fatigue, and 3) rodent research has convincingly shown NO to play some role in hypertrophy, but this does not necessarily imply that this effect is the same in humans, or that adequately dosed NO precursor supplementation alters NO production enough to substantially influence hypertrophy outcomes. My interpretation of the current body of literature is that NO precursors have the potential to exert a trivial-to-small positive influence on hypertrophy, but are highly unlikely to have an ergolytic effect (e.g., suppress hypertrophy).

How To Use Each

If you feel inclined to use a nitrate or citrulline supplement after reviewing the evidence, there are a couple of considerations for ensuring you get the most bang for your buck. The most notable decisions include product choice and timing of ingestion.

Citrulline is often available as either L-citrulline or citrulline malate. Based on the current evidence, citrulline malate would be the safer bet for resistance training enthusiasts, as this is the form that has been shown to enhance repetitions to fatigue in multiple studies. I’m pretty skeptical that malate itself is bringing much to the table, but citrulline malate is very affordable, widely available, and tastes fantastic. In fact, I know some people that use it primarily as a beverage flavor-enhancer, capitalizing on its natural citrus-like sourness, and view the potential performance benefit as a nice bonus. Citrulline malate combines citrulline and malate in a ratio of 1:1 or 2:1. Unfortunately (and pretty shockingly), most studies do not report the labeled ratio of the product they purchased. Even more unfortunately (but less shockingly), it kind of doesn’t matter anyway. This is one area where products appear to routinely fall short of the number they slap on the label; even if studies reported the number on the label, it’d probably be wrong in the absence of independent verification. A recent study checked a handful of products; all five claimed to contain a 2:1 ratio, but ratios ranged from 1.11:1 to 1.92:1.

In research to date, an 8g dose is most commonly used, and a 2:1 ratio can reasonably be expected to be more favorable than 1:1. This dose is typically ingested between 40 minutes and two hours before exercise, with the vast majority of studies settling on one hour. When it comes to timing, you want to remember that we are using citrulline as a precursor to arginine, which is the true precursor to NO. So, it’s important to give your body some time to absorb the citrulline and carry out the conversion to arginine. Pharmacokinetic data suggest that peak arginine levels are reached about 1.4-2.3 hours after citrulline ingestion, so the typical 1-2 hour time frame observed in the literature lines up pretty well. Only one study has directly compared the effects of citrulline supplementation when ingested one versus two hours before exercise. This study reported no significant effect of timing, but also reported no significant performance improvement for either timing protocol, which limits the utility of this observation. Nonetheless, the available performance data and our understanding of citrulline and arginine pharmacokinetics suggest that consuming the dose one or two hours before exercise should be sufficient.

The search for a reliable and cost-effective nitrate product is a lot less clear-cut. Concentrated 70-milliliter beetroot juice shots are most commonly used in studies, which provide anywhere from one to four of these shots as the dose. Each shot of the leading brand contains about 400mg of nitrate, which is equivalent to about 6.4mmol. Some studies report doses in mg units, whereas others use mmol; you can easily convert them to make sense of the literature (62mg nitrate = 1mmol). The majority of studies use doses ranging from 400-800mg, or roughly 6-13 mmol. A study found 8.4mmol (~520mg) to be more effective at enhancing cycling time to exhaustion than 4.2 mmol (~260mg), but increasing the dose to 16.8 mmol (~1040mg) did not confer any significant improvement beyond 8.4mmol. Similarly, a study in rowers found 8.4mmol to be more advantageous for performance than 4.2mmol. As such, an ergogenic dose of nitrate is typically considered to be at least 400-500mg, with no additional benefits expected at doses as high as about 1000mg. It’s critically important to understand that the milligram value pertains specifically to nitrate, not “total material.” So, 100mg of beet powder, spinach powder, pomegranate powder, or whatever other source you choose, does not mean 100mg of nitrate. The actual mass of nitrate will make up only a small percentage of the total material, so carefully read labels to determine which mass is being listed.

One of the great challenges in product selection is a high degree of variability; a recent study revealed dramatic variation in the nitrate concentration of various beet juice products. While variation between products is to be expected, the more surprising statistic was that the mean coefficient of variation among samples of the same exact product was 30%. This is one of those supplements where it actually makes sense to pay a premium for product quality, which generally makes it less cost-effective (price per ergogenic dose) than citrulline malate. It’d be easy to pile on the supplement industry and bash them for inadequate quality control, but the reality is that nitrate is tough to work with. One study grabbed samples of conventional vegetables from the shelves of grocery stores in five different US cities (Chicago, Dallas, Los Angeles, New York, and Raleigh). The average nitrate content of spinach from New York was 564 parts per million (ppm), while the value in Dallas was 4923ppm. The lowest spinach content from New York was 65ppm, whereas the highest in Los Angeles was 8000ppm. Imagine purchasing a cookie, asking how many calories are in it, and being informed that it contained somewhere between 65 and 8000 calories, but probably between 564 and 4923, give or take a few hundred.

Some would argue that, due to this uncertainty with plant nitrate content, sodium nitrate might be a more simple solution for supplementation. That is certainly possible, but comes with some barriers and downsides. Sodium nitrate is generally less accessible to consumers, can be more easily overdosed in an accidental manner that yields unpleasant (and potentially dangerous) side effects, and beetroot juice has been shown to slightly outperform nitrate-matched doses of sodium nitrate in direct head-to-head comparisons of energy efficiency and pain perception following strenuous exercise. While acute nitrate toxicity is possible but fairly unlikely, it is also possible that other components of plant-based nitrate sources may alter the risks associated with nitrate ingestion. As a result, two of the laboratories that conducted some of the seminal studies on dietary nitrate have raised concerns regarding direct supplementation with nitrate or nitrite salts and have advised consumers against doing so.

Once you get over the general uncertainty of plant-based nitrate dosing, or find a product you have great confidence in, timing is the next factor. It takes time for the nitrate to get absorbed, and then converted to nitrite by oral bacteria (remember: if you are using antibacterial mouthwash, you will not benefit from nitrate supplementation). Based on past research, consuming nitrate 2-3 hours prior to exercise seems to allow enough time for nitrate to be sufficiently absorbed and converted. In addition, results from chronic supplementation studies (in this case, supplementation for three or more days in a row) are generally more consistent and pronounced than acute (single-dose) studies. It’s possible that many of the effects related to mitochondrial function and muscle function are influenced by changes in the expression of key proteins in each structure; prolonged exposure afforded by repeated nitrate dosing may facilitate these effects. Some types of cell regulation are quite fast; when you drink coffee, the caffeine begins blocking adenosine receptors within a matter of minutes. In contrast, marked changes in protein expression typically take place over days, not minutes.

Along these lines, it’s important to acknowledge that regular elevation of nitrate, even to ergogenic levels, is achievable through the diet. One study evaluated the effects of a short-term (six-day) diet intervention, based entirely on increased consumption of high-nitrate fruits and vegetables, on a variety of exercise-related outcomes. The intervention was effective in improving plasma nitrate and nitrite levels, exercise efficiency, and exercise performance. Given the chronic nature of nitrate elevation, the cost disparity between citrulline malate and high-quality beet juice supplements, and the fact that citrulline and nitrate exploit two distinct NO production pathways, you could make a strong case for generally consuming a diet high in nitrate-rich plants and supplementing with citrulline malate prior to exercise. The obvious downside to this approach is the uncertainty of nitrate in any given vegetable, from any given region, at any particular time of year. While growing and storage conditions have huge impacts on the nitrate content of any single vegetable you eat, the idea is that sometimes you’ll miss high, sometimes you’ll miss low, but on average, the inclusion of more nitrate-rich plants in the diet can reasonably be expected to substantially elevate plasma nitrate and nitrite levels.

Conclusions on Nitric Oxide

The literature pertaining to nitric oxide precursor supplements is young and growing, so it’s hard to consider the conclusions it yields as anything but preliminary. While study outcomes are not unanimous, it appears that nitric oxide precursor supplements have potential to enhance muscular endurance, as measured by repetitions completed prior to fatigue. This effect could be mediated by the effects of nitric oxide on calcium release and calcium sensitivity within muscle fibers, thereby enhancing the contractile function of muscle. It’s also possible that the muscle endurance benefits may relate to some of the “classic” mechanisms referenced in the aerobic exercise literature, including increased mitochondrial efficiency and oxygen delivery. Citrulline malate and beetroot juice are the most well-studied, commercially available supplements to target the two separate nitric oxide production pathways, with each having slightly unique pros and cons. Citrulline malate is typically dosed at 8g (2:1 citrulline to malate ratio), consumed 1-2 hours before exercise. Beetroot juice is often dosed to yield at least 400-500mg nitrate, at minimum, and is consumed 2-3 hours before exercise. In addition, it is possible to achieve ergogenic nitrate doses by incorporating nitrate-rich fruits and vegetables into one’s daily diet. Whether or not nitric oxide precursor supplements yield long-term hypertrophy benefits remains to be seen; they could potentially promote hypertrophy via cell swelling, satellite cell activation, or enhanced capacity for training volume, but there is currently insufficient evidence to determine if these theoretical mechanisms pan out in the long run.

Disclaimer: Eric Trexler is not a medical doctor or a dietitian. Speak to a qualified healthcare professional before making any changes to your diet or exercise habits. 

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