N.O. Supplements? No Way!

This article is published here with the permission of the author, Ellen Coleman, RD, MA, MPH

Supplements that allegedly increase nitric oxide (NO) levels within the body are being heavily marketed to build muscles. “Nitric oxide” supplements supposedly: 1) promote an extended “muscle pump;” 2) signal muscle growth and speed recovery; and 3) increase muscle strength and improve muscle stamina. Nitric oxide (a gas manufactured by the body) is a key signaling molecule in the cardiovascular system. It is different from other known signal molecules and so unstable that it is converted to nitrate and nitrite within seconds.

Nitric oxide regulates blood pressure and acts as a gatekeeper of blood flow to different organs. In addition to vascular regulation, nitric oxide plays an important role in immune responses and neuronal signal transmission. The 1998 Nobel Prize in Physiology or Medicine was awarded for discoveries concerning nitric oxide as a signal molecule (see Nobel webpage) – a fact which some websites capitalize on to promote their “nitric oxide” supplements. The non-essential amino acid arginine is the substrate for the nitric oxide synthase enzyme, which catalyzes the oxidation of arginine to produce nitric oxide and citrulline.

Nitric oxide supplements usually contain arginine alpha-ketoglutarate, which purportedly increases and maintains a high level of nitric oxide in muscles. In theory, the production of nitric oxide from the supplemental arginine promotes vasodilation, which increases blood flow, oxygen transport, and delivery of nutrients to skeletal muscle during resistance training. This purportedly results in dramatic increases in muscle size and strength. The directions for one product recommend taking 3 tablets (3 grams) twice a day, once in the morning on an empty stomach and 30 minutes prior to lunch for a total of 6 grams per day. But wait, where’s the scientific support for “nitric oxide” supplements?

Campbell and colleagues at the Exercise and Sport Nutrition Lab of Baylor University in Waco, Texas examined the effects of arginine alpha-ketoglutarate (AAKG) supplementation during training on body composition and training adaptations in experienced resistance-trained men (see Campbell et al, 2004). The study was presented as a poster presentation at a sports nutrition conference in Las Vegas, Nevada in June. The 35 resistance-trained male subjects were matched according to fat free mass and randomly assigned to ingest in a double blind manner supplements containing either a placebo or AAKG. The subjects took 4 grams of the supplements three times daily (12 grams/day) for 8-weeks during standardized training. At 0, 4, and 8-weeks, subjects had DEXA body composition determined and performed bench press one repetition max (1RM), a 50 repetition MVC isokinetic leg extension endurance test, a Wingate 30-s anaerobic capacity test, and a VO2max test on a treadmill using the Bruce protocol. The researchers found no significant differences between the groups in changes in body mass, fat free mass, fat mass, or percent body fat. Changes in bench press 1RM, sprint peak power, time to peak power, and rate to fatigue were significantly greater in the AAKG group while no significant differences were observed in average power or total work between the two groups. No significant differences were observed in VO2max or isokinetic leg extension peak torque, max repetition total work, time to peak torque, total work, work fatigue, or average power during the muscular endurance test. The researchers concluded that AAKG supplementation may augment 1RM strength and sprint power in response to training but does not appear to significantly effect body composition. It should be noted that this investigation was sponsored by the manufacturers of the “nitric oxide” supplement used in the study – Medical Research Institute (MRI) in San Francisco, CA.

At present, there is no research published in peer-reviewed journals to support the assertion that an increase in nitric oxide levels promotes greater muscle protein synthesis or improves muscle strength. There is also no evidence that the arginine alpha-ketoglutarate in “nitric oxide” supplements have any effect on nitric oxide levels in muscles. Measuring nitric oxide is no small achievement, as the gas is highly reactive and has a very short life. Rather than measuring nitric oxide levels, clinical studies usually measure flow-mediated vasodilation to evaluate the effect of arginine supplementation on the vascular system (see Boger 1998; Hambrecht, 2000; Maxwell, 2002). There is evidence that supplemental arginine may be beneficial in the clinical setting, particularly for patients with cardiovascular disorders.

Hambrecht and associates found that supplemental arginine (8 grams/day) improved endothelium-dependent vasodilation to the same extent as regular physical exercise in patients with chronic heart failure (see Hambrecht et al, 2000). Boger and colleagues found that supplemental arginine (8 grams/twice a day) restored nitric oxide formation and endothelium-dependent vasodilation and improved the clinical symptoms of intermittent claudication in patients with peripheral arterial occlusive disease (Boger et al, 1998). Maxwell and coworkers found that 6.6 grams of supplemental arginine per day (along with antioxidant vitamins and minerals) improved vascular function, exercise capacity and aspects of quality of life in patients with chronic, stable angina.


Boger RH, Bode-Boger SM, Thiele W et al. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. Journal of the American College of Cardiology. 1998; 32:1336-44.

Campbell B, Baer J, Roberts M et al. Effects of arginine alpha-ketoglutarate supplementation on body composition and training adaptations. http://www.sportsnutritionsociety.org/site/admin/pdf/ISSN%20Abstracts%20SNRJ%201-1-S1-14-2004b.pdf

Hambrecht R, Hilbrich L, Erbs S. Et al. Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation. Journal of the American College of Cardiology. 2000;35:706-13.

Maxwell AJ, Zapien MP, Pearce GL et al. Randomized trial of a medical food for the dietary management of chronic, stable angina. Journal of the American College of Cardiology. 2002;39:37-45.

Nobel webpage: http://www.nobel.se/medicine/laureates/1998/press.html

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20 Responses to N.O. Supplements? No Way!

  1. Andy February 7, 2009 at 2:22 pm #

    Hmmm…I’ve used a products such as N02 Platinum, NO2 Black, NaNO3. And although it did not increase my strength just from taking it, it did significantly increase my stamina in the gym which then helped increase my strength quicker. I do feel as if it did give me somewhat of edge, however I don’t think it was worth the high cost (at least for the MRI NO2 Black/Platinum). Also, NO2 Black (the more expensive one) is touted as being stronger than the NO2 Platinum. I did not see any difference, it is likely a marketing gimmick.

    • Drew Baye February 7, 2009 at 5:36 pm #

      What you experienced was either a placebo effect or the result of other ingredients, most likely some kind of stimulant. It was not the NO.

    • Elliott March 15, 2016 at 5:58 pm #

      That’d be the caffeine

  2. Chris Chapleau February 23, 2009 at 6:28 pm #

    I’m a competitive cyclist, is there any supplement that you would recommend for increasing stamina?

  3. Christian Bland August 23, 2009 at 5:44 am #

    I compete in Taekwon-do are there any supplements that you recommend to aid energy and recovery?

    • Drew Baye August 23, 2009 at 10:36 am #


      Assuming you are already eating correctly, most supplements will provide little additional benefit. However, one supplement I highly recommend to any athlete in contact sports is creatine. In addition to improving anaerobic performance and increasing muscle size, recent research has shown creatine has a protective effect against brain damage.

      Dietary supplement creatine protects against traumatic brain injury. Patrick G. Sullivan, Jonathan D. Geiger, Mark P. Mattson, Stephen W. Scheff. Annals of Neurology, Volume 48, Issue 5 , Pages723 – 729


      Creatine, one of the most common food supplements used by individuals at almost every level of athleticism, promote gains in performance, strength, and fat-free mass. Recent experimental findings have demonstrated that creatine affords significant neuroprotection against ischemic and oxidative insults. The present experiments investigated the possible effect of creatine dietary supplementation on brain tissue damage after experimental traumatic brain injury. Results demonstrate that chronic administration of creatine ameliorated the extent of cortical damage by as much as 36% in mice and 50% in rats. Protection seems to be related to creatine-induced maintenance of mitochondrial bioenergetics. Mitochondrial membrane potential was significantly increased, intramitochondrial levels of reactive oxygen species and calcium were significantly decreased, and adenosine triphosphate levels were maintained. Induction of mitochondrial permeability transition was significantly inhibited in animals fed creatine. This food supplement may provide clues to the mechanisms responsible for neuronal loss after traumatic brain injury and may find use as a neuroprotective agent against acute and delayed neurodegenerative processes.

  4. Jacob February 26, 2010 at 12:21 am #

    @Chris Chapleau
    Take quercetin and/or moderate amounts of caffeine. Both have peer reviewed published studies showing increased cycling performance when taken. Also, Lance Armstrong takes and publicly supports quercetin and FRS drinks which contain quercetin. Quercetin is a natural plant based flavanoid found in Capers and apples among others and is one of the top anti-oxidants rated in the ORAC score.

  5. Tim March 9, 2010 at 6:46 pm #

    So is your recommendation of creatine for athletes who participate in contact sports, for them only? or can people just trying to build muscle benefit from it as well?

    • Drew Baye March 15, 2010 at 11:47 am #


      I recommend creatine supplementation for both muscle building and athletes in contact sports.

  6. Tim March 15, 2010 at 9:17 pm #

    Thanks for the response Drew! Any idea of when your book will be done? I’m dying to read it!

    • Drew Baye March 17, 2010 at 12:29 pm #

      Most of the writing is done and it is currently being edited. It should be completed within the next few weeks.

  7. Tim March 17, 2010 at 3:02 pm #

    Awesome! I’m sure reading your book will be a highlight in 2010 for me.: )

  8. tim duty April 9, 2010 at 7:00 pm #

    Hey Drew, what are your thoughts on the book “nutrient timing”? Years ago you recommended some things to me out of that book, just wondering if you still supported some or all of the info in the book.

    • Drew Baye April 10, 2010 at 3:50 pm #


      It’s been a while since I’ve read the book, but I recall agreeing with most of it. I do not believe the timing is nearly as essential as the overall quality and quantity of food eaten, however, and that one can get good results with a variety of eating schedules as long as they are eating high quality food in appropriate amounts for their goals.

  9. Chris June 2, 2011 at 8:57 pm #

    This makes sense. NO is simply a signaling molecule.

    “What you experienced was either a placebo effect or the result of other ingredients, most likely some kind of stimulant. It was not the NO.”

    I took Yok3d several times before cardio training and also before resistance training, and did not notice any “mental” edge. However, after taking any other NO supplement (NO-Explode, C4, Black Powder, GNC’s brand, SuperPump, M5), there was a psychological effect. This probably has to do with the caffeine (copious amounts in GNC’s) or other methylxanthines. I’d say this supports your research.

    Anyway, I did notice that some products contain L-DOPA, did some research, and found that it’s a dopamine precursor and consequently a treatment for Parkinson’s. Any idea what this compound is doing in an NO supplement?

  10. R.Sessoms September 4, 2011 at 11:14 pm #

    So I noticed that on a lot of these pre-workout supplements that the serving on the individual supplements are fairly low when u look at the blended intake. Just wondering if I were to buy these supplements separate and combine them with the recommended dosage how would that go?

    • Drew Baye September 5, 2011 at 12:21 pm #


      You’d be better off focusing on eating optimally than wasting money on pre or post workout supplements. Other than a few things like creatine, fish oil, and vitamin D (if you don’t get enough sun) most are a waste of money.

  11. Katie October 25, 2015 at 6:22 pm #

    Just curious; is this the most current research available regarding NO? Noticed some of it’s over 10 yrs old. Curious about any newer findings?

    • Drew Baye October 25, 2015 at 7:24 pm #

      Hey Katie,

      There has been more research since then, but nothing that would change anything in the article.

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