Reviews

Nitro CM: An Evidence-Based Review

Nitro CM is PMD’s non-stimulant pump pre-workout. It contains a variety of ingredients, some which have demonstrated more efficacy than others. Unfortunately, we have some concerns about the dosing of certain ingredients, particularly Citrulline Malate (the CM in Nitro CM)…

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Agmatine Sulfate

Agmatine remains very under-researched, despite possessing a variety of health/performance implications. Recently, Agmatine has become quite pervasive in pre-workout supplements because of its alleged ability to regulate Nitric Oxide Synthase (NOS), an enzyme that catalyzes the production of NO from Arginine, and either elevate or reduce its presence, depending on the type of NOS. NOS is a widely misunderstood enzyme, mostly due to supplement companies not properly explaining its function and how that function relates to physical performance. It is largely thought that NOS is the enzyme that “breaks down” NO, when it is actually the enzyme that catalyzes the production of NO from Arginine in the first place.

Nitric Oxide generally has a positive connotation in the bodybuilding/athletic community because it is associated with vasodilation, which clearly has performance/health benefits. However, this beneficial effect of NO only pertains to NO in the blood vessels. Elsewhere in the body (like the brain) NO can inflict damage and actually be quite harmful. So ideally, what we really are after is a way to reduce NO in the areas of the body where it can cause harm, while increasing it in blood vessels where it can beneficially influence physical performance.

It’s important to understand that there are several types of NOS, all which are required for the production of NO. Inducible NOS (iNOS) and Neuronal NOS (nNOS) are considered harmful because they elevate NO in immune cells (causing inflammation) and the brain (causing neuronal damage), while Endothelial NOS (eNOS) is considered beneficial as this is the kind which increases Nitric Oxide in the blood vessels, resulting in vasodilation. Agmatine has been demonstrated to up-regulate eNOS (the “good” NOS) while inhibiting the other NOS enzymes (the “bad” NOS). However, as mentioned above, Agmatine remains under-researched because it is a relatively new entrant in the supplement industry.

Currently, most of the research has been done in vitro, with absolutely no studies regarding the potential physical performance benefits of Agmatine in humans. Because of the lack of human studies, no optimal dose has been established for Agmatine, though average doses in pre-workout formulas are 500-1000mg. Nitro CM contains 750mg of Agmatine which, according to most anecdotal evidence, is an effective dose (though we’d like to reiterate that there is no “optimal dose”).

L-Arginine AKG

Arginine is a non-essential amino acid that acts as a precursor to Nitric Oxide. Supplement manufactures claim that, because Arginine is a precursor to Nitric Oxide, supplemental Arginine may boost Nitric Oxide levels, resulting in vasodilation. However, recent studies have found that Arginine isn’t all it’s cracked up to be. A 2012 study, published in “Nutrition and Metabolism”, found that acute (one-time) L-Arginine supplementation with 6 grams did not increase plasma (blood) levels of Nitric Oxide in normal, healthy individuals.

Furthermore, recent studies have questioned whether Arginine may in fact be counter-productive during exercise. A 2011, placebo controlled study, found that subjects performed worse after receiving 3700mg of Arginine Alpha-Ketoglutarate prior to resistance training. Due to the size of this study, it cannot be considered conclusive, but it certainly should warrant further studies. While most studies have failed to prove that L-Arginine supplementation increases strength, a 2012 double-blind placebo controlled study, found that supplementation with 6 grams of L-Arginine increased muscle blood volume post-workout, but did not increase intra-workout strength. Overall, the results with Arginine are pretty mixed, but given the availability of research indicating that Citrulline is far superior (in absorption and effect) we question why any supplement company would continue to put Arginine in their formulas.

Citrulline Malate

Citrulline is a precursor to the amino acid Arginine, which is a precursor to Nitric Oxide (NO). As demonstrated in a 2007 study, supplemental Citrulline is significantly more effective at raising plasma Arginine than supplemental Arginine itself.

The problem with supplemental Arginine is that it is metabolized in the intestines and liver into other substances such as Ornithine and Urea. The intestines and liver contain relatively high levels of Arginase, the enzyme that converts Arginine to Ornithine and Urea. As a result, very little goes on to be involved with the synthesis of NO because it is being diverted for other purposes. Citrulline, on the other hand, is able to bypass the liver and is metabolized into Arginine elsewhere, where not as much Arginase is present. Thus, more of the Arginine is able to convert into NO.

A 2002 study, published in the “British Journal of Sports Medicine” found that Citrulline Mallate supplementation (6g/day for 15 days) significantly increased ATP production during exercise in healthy adult males. A 2009 study, published in the “Journal of Free Radical Research”, found that 6 grams of Citrulline Malate given to male cyclists before a race increased “plasma Arginine availability for NO synthesis and PMNs priming for oxidative burst without oxidative damage”. A 2011 study, the subjects of which were rats, found that supplemental Citrulline increased muscular contraction efficiency (less ATP was required for the same amount of power), in-line with the findings of the above-mentioned human study.

Overall, Citrulline (at doses of around 6g) has multiple mechanisms of action by which it may effectively enhance exercise performance. However, the amount of Citrulline present in the Nitro CM blend is far less than what has demonstrated efficacy in the above mentioned studies.

Norvaline

Norvaline is a close chemical relative of the popular amino acid Valine, though its effects are different. Norvaline has been shown to inhibit Arginase, the enzyme responsible for the breakdown of Arginine both in vitro and in vivo (rats). The result would theoretically be an increase in Arginine, which would result in more Nitric Oxide. However, Norvaline has never been studied in humans as it relates to performance enhancement, so for now we are left with only a theoretical mechanism of action. Given a lack of human studies, an optimal dose has not been established for Norvaline. Common doses of Norvaline range from 100-200mg, though it remains unclear how much is present in the Nitro CM formula.

Vanadyl Sulfate

Vanadium is a chemical element which has been referred to as the “iron of the sea”, because it plays a similar role in sea creatures as iron plays in humans. For decades, bodybuilders have taken vanadium (in forms such as vanadyl sulfate) for its alleged glucose regulating effects. Preliminary research has shown that vanadium may very well act as an insulin mimetic (really it prolongs the signaling of insulin), by suppressing the action protein tyrosine phosphatase (PTP), which signals the degredation of insulin. Though much of the studies conducted were done with rats, the evidence certainly suggests that vanadium may be useful for those looking to control blood glucose. As far as a direct effect on blood-flow, there is no reliable evidence.

Glycine Propionyl-L-Carnitine

Glycine Propionyl-L-Carnitine is a formed when L-Carnitine is bound to the amino acid Glycine. A 2007 study, published in the “Journal of the International Society of Sports Nutrition” found that 3 grams of GPLC was able to increase Nitric Oxide in resistance trained men. A 2009 study published in the “International Journal for Vitamin and Nutrition Research” replicated these findings though the researchers also found that 1 gram did not have the same effect. Ultimately, GPLC does appear to increase Nitric Oxide in most people at a dose of 3 grams, though the dose present in Nitro CM is far less than that (and likely ineffective).

Creatinol-O-Phosphate

Creatinol-O-Phosphate is actually not another form of Creatine, though commonly dismissed as one. In terms of effects, it is actually more like Beta-Alanine in that it may ultimately reduce muscular fatigue during exercise (though through a different mechanism). Creatinol-O-Phosphate is alleged to counter fatigue by increasing cellular glycolysis in the presence of lactic acid. Unfortunately, there are no human studies upon which to draw conclusions. We are left with a few German studies involving rats and the word of various supplement companies who swear this is a revolutionary new ergogenic aid. To be clear, we are not disputing the claims made about Creatinol-O-Phosphate. We’re simply stating that there really isn’t enough evidence to draw conclusions either way. Nitro CM contains 500mg Creatinol-O-Phosphate, but given that there is no optimal dose, this dose is difficult to interpret.

Taurine

Contrary to popular belief, Taurine is not a stimulant but rather an an amino acid with anti-oxidant properties. In a 2011 study, Taurine was shown to significantly decrease oxidative stress in skeletal muscle following exercise. Prior to that, a 2004 study showed that Taurine may decrease exercise induced DNA damage, as well as “enhance the capacity of exercise due to its cellular protective properties”. A recent 2013 study noted a 1.7% improvement in 3k-time trial of runners after supplementing with Taurine, but noted that more research would be required to determine the exact mechanism of action. It’s unfortunate that Taurine has developed a sort of stigma because of its inclusion in energy drinks. While Taurine does not provide “energy” in the way that caffeine does, several studies have shown its effectiveness as an antioxidant with workout-enhancing properties, and while the exact mechanism of action remains unknown, it appears likely that Taurine may improve exercise performance by reducing some of the cellular oxidative damage that generally leads to fatigue. Common doses range from 1000-2000mg, but Nitro CM contains nowhere near that range.

Alpha Linoleic Acid

Alpha Lipoic Acid is a versatile anti-oxidant with variety of potential benefits, though within the context of Blue Cycle, BioRhythm appears primarily concerned with the cardio-vascular benefits. A 2005 study, the subjects of which were rats, found that Alpha Lipoic Acid treatment effectively reversed impairment of vasorelaxation in obese rats. A later (2010) study, published in “Experimental and Clinical Endocrinology & Diabetes”, replicated these findings in human subjects with Hypothyroidism. This has also been replicated in subjects with type 2 Diabetes, and impaired fasting glucose. Unfortunately, while these studies certainly lend credibility to the notion that Alpha Lipoic Acid can enhance blood flow in individuals with impaired blood flow, it can’t be definitively stated that it can enhance blood flow in normal, healthy subjects.

Coenzyme Q10

Coenzyme Q10 is an antioxidant compound that has been under investigation for several potential benefits. CoQ10 possesses general antioxidant properties which may decrease overall oxidative stress resulting from exercise. There is preliminary evidence to suggest that Coenzyme Q10 may increase time to fatigue (resulting from oxidation), but these effects would most likely be negligible in the average athlete. Overall, CoQ10 is definitely not a bad addition to an antioxidant exercise blend, but to say that it is highly effective for reducing fatigue/increasing exercise capacity would be an exaggeration.

Grape Seed Extract

A 2012 study, published in the “British Journal of Nutrition”, found that Grape Seed Extract was able to reduce exercise induced oxidative stress while simultaneously increasing Nitric Oxide levels in rats. These findings were replicated in a 2013 study from “Phytotherapy Research”, also using rats. Despite these promising preliminary findings, there are no human studies to test whether these benefits extend to humans, let alone exercising humans. However, given the popularity of Grape Seed Extract in recent years, such studies are likely underway.

Phosphatidylserine

There is a vast amount of scientific evidence in favor of Phosphatidylserine as an effective cortisol blocker, especially in regards to post-exercise. Cortisol, for those who are unfamiliar, is a hormone that the body produces when exposed to both physical and mental stress. Among the many unfriendly side effects of cortisol are: decreased water excretion, decreased amino acid uptake (by muscle cells), inhibition of protein synthesis, and reduced bone formation. The evolutionary function of cortisol is basically to help us survive tough spots. All of these negative effects actually become the lesser of two evils, when compared to death. However, as humans have evolved, cortisol has gone from something that saved our lives at one point, to something that is quite troublesome for those trying to build and maintain muscle mass. Physical stress (i.e. intense physical activity) releases cortisol which immediately starts to eat away at muscle protein, making it the number one enemy of body builders or athletes looking to gain muscle through training. However, PS has been shown to exert this anti-cortisol effect only in doses of at least 600 mg, far exceeding the dose that could possibly be present in the Nitro CM formula. So, in the context of Nitro CM, PS is likely a pretty useless ingredient.

Pine Bark

Most of the research regarding Pine Bark Extract’s effect on blood flow has been directed at certain conditions such as hyper-tension and Coronary Artery Disease (CAD). However, a 2007 study found that 180mg daily for 2 weeks effectively increased acetylcholine-induced vaso-relaxation in healthy men, indicating that Pine Bark (as Pycnogenol) can increase blood flow regardless of health state. This is good news for bodybuilders and athletes, and while the performance enhancement capabilities of Pine Bark remain under-researched, it may certainly be effective as a “pump” ingredient. Pine Bark can positively influence blood flow with relatively low doses, but given that its listed last in an 800mg proprietary blend, Nitro CM most likely does not contain a particularly effective dose.

The Bottom Line

Nitro CM contains the usual pump-based ingredients (Agmatine, Arginine, GPLC, etc.), as well as a few anti-oxidant compounds which may or may (at the right doses) positively influence blood flow. However, aside from Agmatine, just about every ingredient in the Nitro CM formula is under-dosed, some quite significantly. The Nitro CM formula appears to be based on the assumption that combining effective ingredients at low doses can somehow create a powerful result, but this isn’t science.  It’s just speculation.

If you’re looking for a supplement that will actually give you some massive pumps, check out our Top 10 Pre-Workout Supplements List.

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Supplement Facts

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  3. Bloomer, Richard J., Lesley C. Tschume, and Webb A. Smith. “Glycine propionyl-L-carnitine modulates lipid peroxidation and nitric oxide in human subjects.” International journal for vitamin and nutrition research 79.3 (2009): 131-141.
  4. Bloomer, Richard J., Webb A. Smith, and Kelsey H. Fisher-Wellman. “Glycine propionyl-L-carnitine increases plasma nitrate/nitrite in resistance trained men.”Journal of the International Society of Sports Nutrition 4.1 (2007): 1-6.
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  11. Sureda, Antoni, et al. “Effects of L-citrulline oral supplementation on polymorphonuclear neutrophils oxidative burst and nitric oxide production after exercise.” Free radical research 43.9 (2009): 828-835.
  12. Saheki, Takeyori, Shigeo TAKADA, and Tsunehiko KATSUNUMA. “Regulation of Urea Synthesis in Rat Liver Inhibition of Urea Synthesis by L-Norvaline.”Journal of biochemistry 86.3 (1979): 745-750.
  13. Godfraind, Theophile, and M. M. Saleh. “Action of creatinol-O-phosphate on the contractility changes evoked by hypoxia and ischemia in rat isolated heart.”Arzneimittel-Forschung 34.9 (1983): 968-972.
  14. Godfraind, T., and X. Sturbois. “An analysis of the reduction by creatinol O-phosphate of the myocardial lesions evoked by isoprenaline in the rat.”Arzneimittel-Forschung 29.9a (1978): 1457-1464.
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  16. Matsuzaki, Yasushi, Teruo Miyazaki, Syunpei Miyakawa, Bernard Bouscarel, Tadashi Ikegami, and Naomi Tanaka. “Decreased Taurine Concentration in Skeletal Muscles after Exercise for Various Durations.” Medicine & Science in Sports & Exercise34.5 (2002): 793-97.
  17. Matsuzaki, Yasushi., et al. “Decreased taurine concentration in skeletal muscles after exercise for various durations.” Medicine and science in sports and exercise 34.5 (2002): 793-797.
  18. Balshaw, Thomas G., et al. “The effect of acute taurine ingestion on 3-km running performance in trained middle-distance runners.” Amino acids 44.2 (2013): 555-561.
  19. Yatabe, Yoshihisa, et al. “Effects of taurine administration on exercise.” Taurine 7. Springer New York, 2009. 245-252
  20. Heinisch, B. B., et al. “Alpha‐lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo‐controlled randomized trial.”European journal of clinical investigation 40.2 (2010): 148-154.
  21. Heitzer, Thomas, et al. “Beneficial effects of α-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress.” Free Radical Biology and Medicine31.1 (2001): 53-61.
  22. Lee, Woo Je, et al. “α-Lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase.” Arteriosclerosis, thrombosis, and vascular biology 25.12 (2005): 2488-2494.
  23. Xiang, G. D., et al. “Alpha-lipoic acid improves endothelial dysfunction in patients with subclinical hypothyroidism.” Experimental and clinical endocrinology & diabetes 118.09 (2010): 625-629.
  24. Yang, L., NY Calingasan, EG Wille, K. Cormier, K. Smith, RJ Ferrante, and MF Beal. “Combination Therapy with Coenzyme Q10 and Creatine Produces Additive Neuroprotective Effects in Models of Parkinson’s and Huntington’s Diseases.” Journal of Neurochemistry (2009)
  25. Sarter, Barbara. “Coenzyme Q10 and Cardiovascular Disease: A Review.” Journal of Cardiovascular Nursing 16.4 (2002): 9-20.
  26. Monteleone, Palmiero, et al. “Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans.” Neuroendocrinology52.3 (2008): 243-248.
  27. Benton, D., et al. “The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor.” Nutritional neuroscience 4.3 (2001): 169.
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  29. Mizuno, Kei, et al. “Antifatigue effects of coenzyme Q10 during physical fatigue.” Nutrition 24.4 (2008): 293-299.
  30. Belviranlı, Muaz, et al. “Effects of grape seed polyphenols on oxidative damage in liver tissue of acutely and chronically exercised rats.” Phytotherapy Research27.5 (2013): 672-677.
  31. Belviranlı, Muaz, et al. “Effects of grape seed extract supplementation on exercise-induced oxidative stress in rats.” British Journal of Nutrition 108.02 (2012): 249-256.
  32. Enseleit, Frank, et al. “Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study.” European heart journal 33.13 (2012): 1589-1597.
  33. Liu, Ximing, et al. “Pycnogenol®, French maritime pine bark extract, improves endothelial function of hypertensive patients.” Life sciences 74.7 (2004): 855-862.
  34. Nishioka, Kenji, et al. “Pycnogenol®, French maritime pine bark extract, augments endothelium-dependent vasodilation in humans.” Hypertension Research 30.9 (2007): 775.

 

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