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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