Two Paths for Optimizing Nitric Oxide Production

There’s an old aphorism attributed to baseball great Yogi Berra: “When you come to a fork in the road, take it.”

The New York Yankees legend said it while giving directions to his old friend, Joe Garagiola. He certainly was not talking about nutrition to improve nitric oxide production.

But thanks to the development of two innovative supplement formulations, Berra’s statement could easily apply there too.

Stylized model of Nitric Oxide structure. Image: Molekuul/

Since 1998, when Robert Furchgott, Louis Ignarro, and Ferid Murad won the Nobel Prize in Physiology or Medicine for their discovery of nitric oxide’s role as a cardiovascular signaling molecule, researchers and clinicians alike have recognized the importance of nitric oxide (NO) in maintaining human health.

Though most people associate it with the vasculature, NO is also made by the gut epithelium, and by cells within the immune system.

There are two main biochemical pathways by which the body produces NO:

  1. Conversion of arginine into NO by an enzyme called nitric oxide synthase (NOS). This is the main mode of NO production in the endothelium.
  2. Transformation of nitrate compounds from foods into nitrites, and then into NO. This takes place in the mouth and the gut.

In general, NO production declines with age. It peaks during the early 20s, and by age 40, most people only produce half as much as they did when they were 20. Over 50, it drops further. Smoking, heart disease, diabetes, and many different drugs all blunt NO production.

Boosting NO

Since the earliest days of NO research, many within the clinical community have sought ways to bolster NO production as a way to reduce cardiovascular risk.

Most of the early research focused on the arginine pathway. Louis Ignarro, one of the Nobel-winners, was among the first to advocate L-arginine supplementation to promote NO production.

The arginine-citrulline pathway for production of nitric oxide via the enzyme, nitric oxide synthase.. This is the main mode of NO production in the endothelium

It is only recently that the nitrate-based pathway gained attention. 

“There are basically two ways to supplement to improve NO production. You can use an arginine-citrulline combination, or you can use a high-nitrate supplement. Or you can do both,” said Jay Wilkins, a natural medicine practitioner and dietary supplement formulator. “It’s a good idea to support both pathways.”

Jay Wilkins, Founder, Bionox

Wilkins has spent years gathering and assessing the data on NO— “the most researched molecule in history”—and formulating nutritional products to increase the body’s NO output. He recently launched Bionox, his own company, focused specifically on NO-promoting products.

Bionox’s cornerstones are: M3 Ultimate Nitric Oxide Nutrition which contains L-arginine, L-citrulline, vitamin C, vitamin D, vitamin K and several herbs all of which combine to promote NO production via the arginine pathway; and Nox3 Daily Greens, containing a host of nitrate-rich vegetable and fruit powders, which increase NO output via the nitrate-nitrite pathways.

Both products are powders that users mix with water and drink twice daily.

The Everything Molecule

Most medical people avoid the word “panacea.” But if there’s any compound that deserves this title, it is NO.

“You can ask, what does NO do? But the simpler question is, What doesn’t NO do?” Wilkins says. Here are just a few of its documented effect:

  • Reduces intimal thickness and monocyte accumulation in atherosclerotic plaques
  • Induces vasodilation
  • Decreases cholesterol and triglyceride
  • Improves walking distance in patients with peripheral vascular disease
  • Reduces pain in interstitial cystitis
  • Reduces blood pressure
  • Decreases post-op length of stay
  • Increases HGH
  • Increases exercise tolerance
  • Improves insulin sensitivity and glucose uptake in muscle cells
  • Improves cell-mediated immunity
  • Improves pituitary responsiveness
  • Reduces blood clots and therefore reduces stroke risk
  • Prevents restenosis after angioplasty
  • Attenuates osteoporosis
  • Improves irritable bowel syndrome and peptic ulcers
  • Improves memory and cognitive function

According to Jonathan Stamler, MD, an NO researcher at Duke University, “You cannot name a major cellular response or physiological effect in which NO is not implicated….It is involved in complex behavioral changes in airway relaxation, the beating of the heart, dilation of blood vessels, regulation of intestinal movement, function of blood cells, the immune system, even the way fingers and arms move.”

In a webinar hosted by Holistic Primary Care, and sponsored by Bionox, Wilkins says that it makes good sense to consider NO support for any patient with heart disease.  (Visit

Nitric Oxide was named “Molecule of the Year” by the journal, Science, in 1992

Citing cardiologist John P. Cooke, MD, PhD, head of the Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Wilkins said healthy endothelium “is like Teflon—a smooth, non-stick surface that enhances blood flow. An unhealthy endothelium is like Velcro, causing white blood cells and platelets to stick to it.”

Increasing NO production helps to shift diseased endothelium back toward this healthier non-stick state.

Given the age-associated NO decline, anybody over age 40 will likely benefit from NO support. This is especially true if their health is already compromised. This includes people with:

  • Metabolic syndrome or type 2 diabetes: NO is a precursor to insulin and it also increases insulin sensitivity
  • Poor immune system function: NO boosts T cell and B cell function
  • Low energy & fatigue: NO increases tissue oxygenation, which tends to improve energy levels
  • Arthritis and other chronic inflammatory conditions: NO quells inflammation
  • Erectile Dysfunction: This “ED” is usually a manifestation of the deeper “ED”: endothelial dysfunction, which can be greatly improved by increasing NO
  • Glaucoma: Bausch & Lomb markets an NO-promoting glaucoma treatment called Vyzulta
  • “Brain Fog” and other Neurocognitive Issues: In addition to improving oxygenation, NO is also a precursor for serotonin, dopamine, and acetylcholine.
  • Insomnia & other sleep problems: NO is a precursor for human growth hormone (HGH), which promotes sleep

A Role in COVID-19?

In many emergency departments worldwide, nitric oxide gas is a first line intervention for incoming patients with COVID-19 or other forms of acute respiratory distress. NO quells inflammation—a hallmark of the acute COVID syndrome—and promotes vasodilation, thus improving oxygenation.

A recent literature review by Nagasai Adusumilli and colleagues at George Washington University, concluded that “NO has demonstrated promise in similar respiratory disease models in modulating the prominent inflammation, and the early reported proofs of concept urgently call for randomized control trials in treating COVID-19. Exogenous NO therapy geared toward the right population at the optimal stage of infection may be an accessible, compelling option.”

There’s also a flicker of evidence that NO may have direct antiviral effects against SARS-CoV-2, at least in vitro. In infected cells treated with an NO donor compound called S-nitroso-N-acetylpenicillamine (SNAP), the resulting increase in NO “delayed or completely prevented the development of viral cytopathic effect in treated cells, and the observed protective effect correlated with the level of inhibition of the viral replication.”

A small 14-patient clinical study in 2005 showed that inhaled NO mitigated viral spread through the lungs of people infected with the SARS virus that swept Asia nearly 20 years ago. Earlier studies have shown that NO has direct antiviral effects against herpes virus, coxsackievirus, and hantavirus.

Wilkins added that there is currently a trial underway looking at the potential of sildenafil (Viagra)—the world’s first NO-promoting pharmaceutical—in the treatment of COVID.

There’s no evidence that NO-focused nutritional support could prevent or treat COVID-19, but it raises a question worthy of serious research attention.

Production of NO in the gut via the Nitrate-Nitrite pathway. This mode is highly dependent on commensal bacteria in the mouth, and low pH in the stomach. (Image: Carlstrom M, Montenegro MF. Journal of Internal Medicine 2018)

Choosing the Path

From a clinical perspective, each of the NO pathways has virtues and drawbacks.

NO synthesis from arginine is independent of the presence of particular oral or intestinal flora, and is less affected by the overall condition of the patient’s gut.  

However, supplementation with arginine can sometimes activate herpes virus in people who carry it. It may also trigger shingles, though the latter occurrence is very rare. Patients who have herpes may not be able to tolerate arginine-based NO products. However, Wilkins has found that some people, if they continue supplementing past the initial herpes surge, experience a marked decrease in subsequent outbreaks.

Another way to mitigate the herpes activation is to take 1,000 mg of lysine 1-2 hours following the L-arginine dose. But it is important to avoid taking lysine and arginine together; the two amino acids are competitive and cancel each other. In general, Wilkins advises people not to take arginine with protein-rich meals. 

A big drawback to nitrate-based products is the fact that many nitrate-rich vegetables—especially dark leafy greens—are also high in oxalates, which can be problematic for many people. Wilkins says his company is working on developing an oxalate-free formula but this is not available yet.

The other downside is that the nitrate-to-nitrite conversion is highly dependent on the microbiome, which is easily disrupted.

Having the option of an arginine-based or a nitrate-based product enables clinicians to tailor NO support to the specific needs and sensitivities of each patient.

Aside from supplementation, there are other steps patients can take to increase their NO production.

Shifting to a vegetable-rich diet will help. Wilkins notes that by weight, arugula—not beetroot–is the vegetable with the highest nitrate concentration. “An arugula-beet salad with goat cheese is a great way to boost dietary intake.” He added that people who follow the DASH diet are getting between 1,200 and 1,800 mg of nitrates per day.

Be aware that antibacterial mouthwashes can kill off the bacteria that convert nitrate to nitrite, thus diminishing downstream NO production. Likewise, proton pump inhibitors and other acid-suppressing drugs can squelch conversion of nitrites to NO, which requires an acidic environment.

Monitor Carefully

As people get healthier on NO support, their medication needs may change. It is important to stay on top of this.

When considering NO support for people with hypertension or other blood pressure issues, it is important to monitor them carefully, especially if they are already on medications. “You don’t want the pressure to drop too low,” Wilkins cautions.

The same is true for patients on anticoagulant drugs. While NO is not a direct anticoagulant it may have indirect effects that might warrant dose adjustments.

For a patient with pre-existing heart disease, it is wise to consult with his or her cardiologist before beginning NO support. The good news, Wilkins says, is that many cardiologists now recognize the importance of NO in vascular health, and they are generally supportive of helping people increase their NO production.


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