Overview
Nitric oxide is the same toxic free radical found in smog, and it does the same thing inside the body that it does in polluted air: it blocks the respiratory enzyme cytochrome c oxidase and shuts down oxidative energy production. It is analogous to carbon monoxide and cyanide in its ability to compete with oxygen at the mitochondria. From 1990 to 1996, the research clearly showed nitric oxide killing the insulin-producing beta cells of the pancreas and damaging every tissue it was studied in. Then Viagra came on the market in the late 1990s, the patent and the publicity reversed the literature almost overnight, and suddenly nitric oxide was being promoted as a wonder substance that prevents hypertension and protects every function. The actual situation is that excess nitric oxide is one of the central mediators of inflammation, aging, cancer, diabetes, and degenerative disease, and the popular promotion of arginine supplements, beet products, and erectile dysfunction drugs designed to raise it is one of the more dangerous trends in nutritional and pharmaceutical advertising.
Key Points
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Nitric oxide blocks mitochondrial respiration the same way carbon monoxide and cyanide do. It poisons cytochrome oxidase, the final respiratory enzyme, and also damages the earlier electron-transport components of the mitochondrion. When oxidative metabolism is interrupted, electrons leak out and the cell shifts into a reduced chemical state, producing lactic acid (even in the presence of oxygen). This is the Warburg cancer metabolism, and nitric oxide is one of the things that creates it.
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Excess nitric oxide kills insulin-producing beta cells in the pancreas and is a major cause of diabetes. In the early 90s, there was a sustained run of papers documenting this very clearly. Inflammation or stress increases nitric oxide locally in the pancreas and damages the cells that make insulin. Reports of new diabetes cases in men who started Viagra were one of the early signals that the drug's mechanism was systemically toxic.
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Carbon dioxide, not nitric oxide, is the proper endogenous vasodilator. CO2 is a Lewis acid that draws excess calcium out of the cell as it diffuses out, which decalcifies soft tissues and dilates blood vessels without the inflammatory side effects of NO. Soviet research in the 1960s and 1970s used CO2 baths at therapeutic resorts to reverse cardiovascular disease and hypertension. When CO2 falls below a threshold, inducible nitric oxide synthase activates as the emergency replacement, which is why long-distance runners produce so much NO during anaerobic glycolysis that they flush red.
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There are three forms of nitric oxide synthase, and inducible NOS is the dangerous systemic one. Endothelial NOS (eNOS) keeps NO localised inside the blood vessel and is generally the safest. Neuronal NOS (nNOS) operates in the brain. Inducible NOS (iNOS) is what activates during infection or low CO2 states, releasing NO systemically into the blood where it can damage tissues throughout the body. Drugs that raise NO produce the iNOS pattern of systemic exposure, which is why they cause damage everywhere rather than just where they are needed.
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Estrogen activates the enzyme that produces nitric oxide, and progesterone inhibits it. When the uterus is exposed to either estrogen or nitric oxide, it swells up, takes on water, and shifts into oxygen-resisting metabolism. The estrogen industry and the nitric oxide industry attached themselves to each other, using each one as an argument for the other. Progesterone, pregnenolone, and the related stabilizing neurosteroids hold down nitric oxide production, partly by directly inhibiting the synthesizing enzyme and partly by blocking estrogen.
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Endotoxin from the intestine is a constant promoter of nitric oxide in the body. Anything that irritates a cell turns nitric oxide synthase on. Serotonin and histamine, which are themselves released in response to endotoxin, then increase nitric oxide formation in various tissues, creating a feedback loop. Bisphenol A and other estrogen-mimicking environmental chemicals also activate nitric oxide production.
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The safest physiological inhibitors of nitric oxide are aspirin, niacinamide, and progesterone. Aspirin has at least two or three direct and indirect routes for inhibiting it, and is safe up to several grams a day if vitamin K is taken alongside. Niacinamide also blocks nitric oxide through multiple mechanisms. Progesterone works partly by directly inhibiting the synthesizing enzyme and partly by blocking estrogen's stimulation of it.
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Methylene blue blocks nitric oxide production through about six different mechanisms. It can receive electrons in place of damaged mitochondrial enzymes and restore oxidative function. It oxidizes the sulfur groups on glutamate receptors that turn on excitotoxic nitric oxide. It increases progesterone production, inhibits estrogen, and prevents excess polymerization of microtubules. 15 milligrams a day was enough to relieve severe depression in a controlled study, and lifespan studies in rats and mice showed no harm even at doses many times higher than what Paul Ehrlich used to cure malaria a hundred years ago.
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Nitric oxide promotes cancer growth and metastasis in essentially every tissue studied. Breast cancer, prostate cancer, and probably every cancer responds badly to nitric oxide because shifting away from oxygen as the energy source defines the Warburg cancer metabolism. Recent publications show methylene blue reverses this metabolism by turning off nitric oxide production. Research going back to the 1940s found that arginine restriction stops cancer growth, and dichloroacetate (DCA) restores normal glucose oxidation in much the same way methylene blue does.
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Vasodilation from nitric oxide is a useful local response, not something to induce systemically. When an artery is pinched and the cells sense oxygen deprivation, they produce nitric oxide locally to relax the vessel and let blood through the stress point. Doing the same thing systemically with Viagra, nitroglycerin, or arginine adds to chronic inflammation, raises aldosterone (which itself drives hypertension), and promotes thickening, atherosclerosis, and hardening of the arteries. Carbon dioxide produced by good oxidative metabolism is the safe alternative for relaxing blood vessels in proportion to actual circulatory need.
Notable Quotes
"Probably the most important thing people should do is to start being critical about the tremendous amount of propaganda selling the idea that people should eat more arginine to increase their nitric oxide production."
[Ray Peat — KMUD: Nitric Oxide (November 2014)]
"Each thing (the supposed benefits of estrogen and nitric oxide) is used as an argument for the other, but when you put them in the context of thyroid and progesterone, you see that the actual problem such as high blood pressure can involve increased nitric oxide."
[Ray Peat — KMUD: Learned Helplessness, Nervous System & Thyroid (September 2013)]
"It is now being proposed to replace basically the euthanasia drugs and the death penalty drugs in the United States and several European countries because you breathe it in and you basically drop dead without even realizing it."
[Georgi Dinkov — Crucial Facts About Your Metabolism, Part 2 | Dr. Mercola Interviews Georgi Dinkov]
"Nitric oxide is the cardinal tool inside the body that the body uses to kill a pathogen invading you. So it's very toxic to living organisms. Guess what? If it's toxic to bacteria, and if it's toxic to these other organisms in large doses, don't you think it'll be toxic to you too?"
[Georgi Dinkov — Dr. Mercola Interviews Georgi Dinkov]
"Carbon dioxide, that is the proper physiological relaxant of the blood vessels, not nitric oxide. Nitric oxide, its physiological role is primarily to battle pathogens."
[Georgi Dinkov — Dr. Mercola Interviews Georgi Dinkov]
"Whenever we look at any kind of a disease currently known to men, especially chronic disease, we always notice elevated levels of NO."
[Georgi Dinkov — Generative Energy]
Important Things To Consider
L-arginine supplements are very dangerous. Arginine is an essential amino acid and any high-quality protein (eggs, milk, cheese, potatoes, meat) provides all that the body needs. Supplementing extra arginine reliably pushes nitric oxide production beyond what the body can handle, yet the bodybuilding and "male enhancement" supplement category is built on this mechanism.
Vasodilation has narrow local utility but causes systemic harm. A momentary opening of a constricted artery, as with nitroglycerin under the tongue for angina, can be helpful for a few minutes. Sustained or systemic dosing creates chronic inflammation, raises aldosterone, and worsens the underlying condition the patient is being treated for.
Aspirin above roughly two grams a day requires vitamin K co-supplementation. With vitamin K it is safe up to several grams. Two doses of 500 milligrams already give good systemic protection, so there is rarely a reason to push higher than that for general use. Vitamin K itself helps to hold down nitric oxide production through several mechanisms.
Naturally derived nitrates from celery, beets, and over-fertilized vegetables are still harmful. The "natural" framing does not change the chemistry. Celery juice marketed as a nitric oxide booster, beet products, and industrially over-fertilized spinach all create the same problem. Spinach can be safe if it is organically grown without intense nitrate fertilization, but cooking nitrate-heavy vegetables produces nitrosamines, the same carcinogens found in cigarette smoke.
Nitrous oxide canisters ("whippets") metabolize into harmful nitrogen species. The immediate effect is less harmful than nitric oxide itself, but the body converts nitrous oxide into nitrate, nitrite, and nitric oxide, so repeated exposure carries the same long-term costs as the rest of the category.
Nitric oxide synthesis rises with age starting around 40, even in healthy people. It is intensified in dementia, and it has been linked to Alzheimer's pathology. Hot flashes and night sweats during menopause are partly a vicious circle of falling progesterone, rising nitric oxide, and unstable blood sugar; a sweet snack before bed, plus progesterone, can break the cycle.
Hypothyroidism raises nitric oxide while still raising blood pressure. This contradicts the popular doctrine that nitric oxide always lowers blood pressure. A high TSH (above about 0.4) is itself a pro-inflammatory signal, and a large proportion of "high blood pressure" cases are actually hypothyroidism producing both elevated nitric oxide and vasoconstriction at once.
You can measure nitric oxide cheaply with saliva test strips. FDA-approved nitric oxide saliva test strips cost around five dollars per hundred and correlate well with blood NO levels. Test no more than once daily.
Nitric oxide is the actual trigger of multiple sclerosis demyelination. Estrogen is the underlying cause that elevates NO in the first place, but the damage to the myelin sheath is mediated by NO directly. This explains why MS is more common in women and why anti-estrogen interventions help.