Nitrosigine: The Nitric Oxide Booster That Enhances Brain Function

Nitrosigine

Move over L-arginine, Nitrosigine (inositol-stabilized arginine silicate) actually makes it work as originally desired!

Nitrosigine®, a patented blend of arginine and inositol, is one of the more innovative ingredients in the “nitric oxide” corner of the supplement industry. In this article we’ll discuss the major benefits and any potential downsides associated with one of one of the most interesting new ingredients to make its way into pre workout supplements. Will it really increase nitric oxide and give weight lifters massive pumps when training?

What is Nitrosigine?

Nitrosigine® is a patented complex of arginine, inositol, and potassium silicate engineered by Nutrition 21. Many of our long-term readers may scoff when they see “arginine” here, but keep reading. Besides being inferior to citrulline as a pump ingredient,[1] straight L-arginine can cause many bowel-wrecking side effects.[2]

Nutrition 21

Nutrition 21, the creators of Nitrosigine, provided full-text resources cited in this article

However, our really dedicated followers will get excited because they know that if we can get around the drawbacks of L-arginine, we know we have something extraordinarily useful. Nitrosigine was announced sometime around 2013 on PricePlow and other outlets, and the quality of research has expanded so much that we’re due for a research update.

The Three Hit Punch – Arginine, Silica, and Inositol

With this combination of ingredients, the arginine silicate complex is doing the heavy lifting. The inositol acts as a stabilizer. The research refers to the finalized structure as inositol-stabilized arginine silicate. This three-hit-punch is much more bioavailable than other forms of arginine available on the market, as shown in the original patent application and subsequent research.[3,14] Since the major issue with arginine is its inferior bioavailability when compared to ingredients like citrulline, this benefit makes Nitrosigine a serious contender for a label spot in any well-formulated pump product.

Arginine Silicate

It all started with this data from the 2002 Arginine Silicate Patent Application, announced in the supplement industry in 2014. Since then, we’ve collected far more data!

To summarize its inception, Nitrosigine is an inositol-stabilized blend of arginine and silicate that offers superior bioavailability to other forms of arginine supplementation. This enhanced bioavailability has helped circumvent the gastric side-effects associated with other forms of arginine, but note that there is no research proving this – just plenty of anecdotal reports in the first five years of use in roughly 100 products.

Nitrosigine’s Benefits: What can it do for me?

We can talk all-day about “bioavailability this” and “stabilized structure that”, but we take supplements to perform better. The main thing that matters about Nitrosigine is what it can do for us in the weight room. There is now a plethora of research to tackle, so let’s get to it:

  • Better, longer-lasting nitric oxide boost

    Arginine itself is well-known as a pump product. Before we discuss how Nitrosigine works in this manner, it’s prudent to describe how most pump products work.

    Nitrosigine Plasma Arginine

    A six hour boost of plasma L-arginine, with hours 0.5 hours, 1 hour, and 1.5 hours reaching statistical significance on day 1, and by day 14, significant increases at 2 and 3 hours!

    Most ingredients work via nitric oxide, one of the principal oxides of nitrogen. Nitric oxide is a gaseous signaling molecule and is one of the most important biological messengers in vertebrate organisms — including humans. Most relevant to our interests, cells of the inner lining of blood vessels use nitric oxide to relax smooth muscle surrounding the blood vessel.[4] Relaxing the smooth muscle results in dilation, a process we call vasodilation. Inversely, constricting the smooth muscle results in constriction, or vasoconstriction. An increase in vasodilation allows for an increase in blood flow and nutrient delivery… and “pumps”.[5]

    Nitric oxide synthesis from arginine

    Arginine is synthesized by the body from citrulline via a costly metabolic pathway. While arginine is important for cell division, wound healing, performing the urea cycle, and immune function, it is also a reagent in nitric oxide synthesis.[6] Therefore, the logic of arginine supplementation is to provide more building blocks for nitric oxide. Think of it as “building blocks for a massive pump”.

  • Nitrosigine research on performance

    Nitrosigine Benefits

    Image courtesy Nutrition 21

    Nitrosigine is well-documented as a nitric oxide enhancer for exercise. While most ingredients are supported indirectly in research, a particular investigation studied the use of “inositol-stabilized arginine silicate” (ASI) as a workout ingredient… which, of course, is Nitrosigine.

    Enhanced blood flow and energy perception

    16 participants ingested 1500mg/day of ASI in a double-blind placebo-controlled crossover-design study.[7] In the group given, perceived energy increased after 72 hours of supplementation compared to placebo. In addition, the ASI group experienced hyperemia (an excess of blood… more blood flow likely caused by vasodilation) and enhanced blood flow after supplementation.

    The research also revealed enhanced creatine kinase levels (CK) upon supplementation — CK is associated with recovery, so Nitrosigine may assist with sports recovery as well, beyond just improving nutrient delivery.[7]

    Long-lasting, fast impacting

    The nitric oxide boosting effects of Nitrosigine last a long time yet kick in quickly. One study reported that the nitric oxide boosting effects of Nitrosigine take place within about a half hour.[7] The duration of the boost has varied in the research — one investigation found the boost to last 1.5 hours while one investigation showed improvement over six hours.[7,8] Almost enough time to last one of those epic “8-hour arm days”!

  • An underrated nootropic? Keeping your head in the game

    Prolonged exercise, such as fast-paced athletic events, are demanding of an athlete’s cognitive facilities and can cause mental fatigue to build up. This mental fatigue may deteriorate an athlete’s perception and motor skills, resulting in missed plays. It turns out that ASI may help athletes circumvent the mental fatigue associated with athletic endeavours.

    One investigation gave 24 males 1,500mg of inositol-stabilized arginine silicate before a workout. Compared to placebo, a single dose was shown to improve cognitive function across several measured domains including acuity, focus, and processing speed. The study measured cognitive function using a “trail making test”. The take home is that an increase in time to completion was reflective of cognitive decline, while a decrease in completion time implied cognitive enhancement. The placebo group took much longer to complete the task than the group given ASI.[10]

    Enhanced Cognitive Flexibility

    Besides restoring cognitive function by reduction of mental fatigue, Nitrosigine may improve cognitive flexibility. “Cognitive flexibility” refers to our ability to adapt our cognition to new scenarios and challenges. It refers to how we think on our feet when challenged with a new obstacle or stimulus.

    Nitrosigine Nootropic

    Nitrosigine as a nootropic? Research shows vastly improved TMT scores,[13] and the arginine nitric oxide pathway does work in the brain, so…

    This is a huge advantage for athletes competing in fast-paced sports. Imagine having a heightened ability on the field to overcome the opposition — ie. to avoid that tackle.

    A recent investigation showed that Nitrosigine may improve cognitive flexibility as compared to a control group. This study once again used a trail making test as its parameter for measuring cognitive ability.[16] If we ran a supplement company… this is the benefit we’d stress a bit more.

    Trail making test-A, or TMT-A, involves connecting an ascending sequence of 25 numbers, while TMT-B relies on an alternating sequence of 25 numbers and letters. TMT-B is a more complex task as it involves concept switching and task-switching. For their “scoring” the researchers used a parameter called TMT B-A… or the difference in TMT-A and TMT-B scores. To refresh, a lower score infers higher cognitive abilities.

    In this study, the researchers tested sixteen young, healthy males. They found that inositol-stabilized arginine silicate (Nitrosigine) led to a significant decrease in TMT score when compared to placebo.[13] The study was successful and it was repeated — one was done at 15 minutes after dosing and another under fatigue, after roughly an hour.[13]

    Cognitive flexibility is imperative for sports of all varieties — including video games. In our eyes, the most interesting part is that cognitive benefit arises from an acute dose. You can take it before a challenging task and experience the benefits right away — no need to wait for “build-up”. This could make Nitrosigine a new unsung favorite of the nootropic community!

  • Enhanced Bioavailability of Arginine

    While we touched upon this benefit earlier, we’d like to discuss a recent investigation that may explain why Nitrosigine helps the body use arginine more effectively.

    Is arginase inhibition the secret to Nitrosigine’s longer-lasting effects?

    Nitrosigine vs. Arginine HCl

    With Arginine HCl, plasma arginine drops off a cliff. With Nitrosigine, it keeps on ticking. The uptick at hour 4 seems to be due to arginase inhibition![9]

    A lab tested human plasma samples from 10 males after 15 days of supplementation with both ASI and arginine HCl (one of the more popular forms used in supplements). The researchers took painstaking measures to ensure that the findings were as consistent and accurate as possible. The subjects showed up to the study twice in the 2-week period along with a 7 day washout period between the product administration. Samples were collected pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours post-dose.

    You may ask what they were looking for in the plasma, and it’s more than just “arginine levels.” More importantly, the scientists were also studying arginase levels.[11]

    Arginase is an enzyme that plays a role in the urea cycle. It mashes arginine and water together into ornithine and urea.[12] The take home for this article is that arginase breaks down arginine into a new product.

    It turns out that those that used ASI (Nitrosigine) had lower levels of arginase in the plasma. The group using Arginine HCl had no difference in their arginase levels.[11]

    The results support the notion that Nitrosigine improves bioavailability by stopping the metabolic breakdown of arginine.[11] By improving the amount of arginine in the plasma, nitric oxide expression should increase. For those taking general chemistry at the college level, more reagent than product shifts a reaction towards the product side. By having more arginine than nitric oxide, the body will (hopefully) create more nitric oxide until an equilibrium is reached.

  • Reduced Inflammation Markers

    Athletes, especially those in contact sports, get physically punished on the playing field, and need as much help as possible to get back to practice after a game. Nitrosigine can help here too.

    A recent preclinical study showed that inositol-stabilized arginine silicate may possess potent anti-inflammatory effects. While this study was conducted in rats, the results are promising (better yet, the doses in the rat model were equilibrated with what a human would take based on weight). The study used four different groups — a control group, an arthritic control group, a group given a simple mixture of arginine HCL + silicon + inositol (but NOT bound), and a final group given the real deal inositol-stabilized arginine silicate as a complex.

    The group given Nitrosigine (ie the complex form) had significantly lower markers of inflammation at the end of the investigation.

    Inositol-stabilized arginine silicate helped the subjects experience less inflammation and less joint pain.[15] If you’re an athlete suffering from joint pain after long training cycles or competitions, Nitrosigine may help you get back in the game with a vengeance.

A statement on research funding

While Nitrosigine always had us excited since we first wrote about it in 2013, the research has come such a long way that now we can easily put our stamp on it.

The one thing to note, however, is that Nutrition 21, the company that developed and sells Nitrosigine, funded much of the research discussed above. However, Nutrition 21 always uses CROs (Contract Research Organizations) to perform their research — it’s not just done in-house. On top of that, we’re excited that it’s been peer-reviewed, placebo-controlled, and published in trusted journals.

In the fall of 2018, PricePlow’s founder Mike Roberto had an interview with Todd Spear of Nutrition 21 where they were talking about their newest ingredient, Velositol (which is used to enhance protein supplements). Todd explained that Nutrition 21 is more of a research company than an “ingredient company” in many ways:

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Fact is, funding for this research has to come from somewhere, and for an ingredient initially marketed to the bodybuilding segment, it’s definitely not going to come from the government or university grants. It needs to come from the patent-holder. So the research must be done at a trusted CRO, and should thus be repeatable and reproducible lest the CRO wants to lose credibility and loads of future business.

This may be subject of a separate blog post and video, since few seem to understand how it works and the most ethical way of publishing research.

Long story short, we trust this research and see major benefits to adding Nitrosigine to various pre workout and nootropic supplements. And it doesn’t need to be an “either or” situation — stacking with L-Citrulline sounds like a best of both worlds situation.

Conclusion: Arginine is back, and this time, it’s for real

As it stands now, there’s little reason to use other forms of arginine besides Nitrosigine. It’s well-researched compared to most other new supplement ingredients and digests well too. If you’re looking for an additional ingredient to make your DIY pre-workout pop, as far as pumps are concerned, consider this as a new candidate.

Nitrosigine

PricePlow Approved!

Arginine always needed help, and in 2013, it finally got it. We jumped on board once we noticed it felt great wasn’t sending us to the bathroom, but it took time for the research to follow. After re-evaluating it for this article, we’re confident that this is the “protection” that arginine needed. If you want to improve your pumps without improving your bathroom-stall time, Nitrosigine is the way to go. However, always keep skeptical about exciting research, but at this point five years in, we’re ready to officially PricePlow Approve it.

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References

  1. Agarwal, U., Didelija, I. C., Yuan, Y., Wang, X., & Marini, J. C; “Supplemental Citrulline Is More Efficient Than Arginine in Increasing Systemic Arginine Availability in Mice”; The Journal of Nutrition, 147(4), 596–602; 2017; https://academic.oup.com/jn/article/147/4/596/4584706
  2. Grimble, G. K; “Adverse Gastrointestinal Effects of Arginine and Related Amino Acids”; The Journal of Nutrition; 137(6); 2007; https://academic.oup.com/jn/article/137/6/1693S/4664959
  3. Vijaya Juturu, James R. Komorowski; US7576132B2 – “Arginine silicate inositol complex and use thereof”; United States Patent and Trademark Office; 2002; https://patents.google.com/patent/US7576132
  4. Helms, C. C., Gladwin, M. T., & Kim-Shapiro, D. B; “Erythrocytes and Vascular Function: Oxygen and Nitric Oxide”; Frontiers in Physiology, 9; 2018; https://www.frontiersin.org/articles/10.3389/fphys.2018.00125/full
  5. Stryer, Lubert (1995). Biochemistry, 4th Edition. W.H. Freeman and Company. p. 732
  6. Mauro, Claudio; Frezza, Christian (2015-07-13). The Metabolic Challenges of Immune Cells in Health and Disease. Frontiers Media SA. p. 17. ISBN 9782889196227.
  7. Rood-Ojalvo, S., Sandler, D., Veledar, E., & Komorowski, J; “The benefits of inositol-stabilized arginine silicate as a workout ingredient”; Journal of the International Society of Sports Nutrition, 12(S1); 2015; https://jissn.biomedcentral.com/articles/10.1186/1550-2783-12-S1-P14
  8. Kalman, D., Krieger, D., Feldman, S., & Samson, A; “A clinical evaluation to determine the safety, pharmacokinetics, and pharmacodynamics of an inositol-stabilized arginine silicate dietary supplement in healthy adult males”; Clinical Pharmacology: Advances and Applications, 103; 2015; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603712/
  9. Komorowski, J., & Ojalvo, S; “A pharmacokinetic evaluation of the duration of effect of inositol- stabilized arginine silicate and arginine hydrochloride in healthy adult males”; The Journal of the Federation of American Societies for Experimental Biology; 2016; https://www.fasebj.org/doi/abs/10.1096/fasebj.30.1_supplement.690.17
  10. Evans, M., Zakaria, N., & Marzuk, M; “An Evaluation of the Effects of Inositol-Stabilized Arginine Silicate (ASI; Nitrosigine) in Preventing the Decline of Cognitive Function Caused by Strenuous Exercise”; International Society of Sports Nutrition 2018 Conference; 2018; https://blog.priceplow.com/wp-content/uploads/nitrosigine-preventing-cognitive-decline-caused-by-strenuous-exercise.pdf
  11. Komorowski, J., Perez, S., & Sylla, S; “Arginase Inhibition by Inositol-stabilized Arginine Silicate (ASI; Nitrosigine®); A Novel Mechanism by which ASI Enhances Arginine Bioavailability”; Poster Presentation. Retrieved from https://www.eventscribe.com/2018/Nutrition2018/ajaxcalls/PosterInfo.asp?efp=UlhTRFpZVVI0ODYw&PosterID=146640&rnd=0.1401379
  12. Ash, D. E; “Structure and Function of Arginases”; The Journal of Nutrition; 134(10); 2004; https://academic.oup.com/jn/article/134/10/2760S/4688479
  13. Kalman, D., Hewlings, S., Sylla, S., Ojalvo, S., & Komorrowski, J; “An evaluation of the effects of inositol-stabilized arginine silicate (ASI; Nitrosigine®) on cognitive flexibility”; Nutrients; 2016; https://blog.priceplow.com/wp-content/uploads/nitrosigine-cognitive-flexibility-issn-2018.pdf
  14. Sandler, D., Ojalvo, S., & Komorowski, J; “Absorption of bonded arginine silicate compared to individual arginine and silicon components”; Journal of the International Society of Sports Nutrition; 2016; https://jissn.biomedcentral.com/articles/10.1186/s12970-016-0144-9
  15. Ojalvo, P., & Komorrowski, S; “Effect of Bonded Arginine Silicate on Inflammatory Markers and Arthritis; FASEB Journal; 2017; https://www.fasebj.org/doi/abs/10.1096/fasebj.31.1_supplement.166.5
  16. Kalman, Douglas et al; “Randomized Prospective Double-Blind Studies to Evaluate the Cognitive Effects of Inositol-Stabilized Arginine Silicate in Healthy Physically Active Adults”; Nutrients; vol. 8,11 736. 18 Nov. 2016; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133120/
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