COVID-19: Maybe Just Say NO?

I’ve just submitted a hypothesis paper to The Lancet calling for an urgent multicenter prospective randomized controlled trial of arginine and citrulline supplementation for the purposes of pre- and post-exposure prophylaxis against the “novel coronavirus” (SARS-CoV-2). Whether or not that gets accepted, let alone, implemented, however, I feel compelled to put my thoughts forward here, possibly to a broader audience that might benefit. Right off the bat, however, let me give the disclaimer that this does not constitute medical advice — only medical hypothesis.
Here’s what we know so far:
1. Women do better than men with COVID-19. We saw that in the original SARS epidemic in 2003, where being male carried a 67% greater mortality, and we are seeing it again with data from many countries supporting similar gender-inequality. Women, of course, have a lot more estrogen, and estrogen results in increased nitric oxide (NO).
2. Laboratory research from that first SARS epidemic showed that NO not only inhibits the ability of coronavirus to attach to cells (by decreasing the adherence capability of its S or “spike” proteins to the ACE2 receptor) but also inhibits viral replication.
3. Stem cells are being actively researched right now with eight clinical trials underway at the time of this writing. Their activity is complex but seems to have a lot to do with using NO to suppress immune cell hyperreactivity.
4. Lastly, of course, there are also a handful of trials underway looking directly at the effect of nitric oxide in advanced respiratory disease from coronavirus.

So why not just give people NO? It’s a little complicated; first of all, it’s a gas (literally). Hence the inhaled trials in advanced pulmonary disease. Also for the record, it should be noted that NO is extremely complex in terms of its activities, with different and even contradictory effects in many situations depending on concentration, stage of disease, etc.
In other words, NO is potentially quite dangerous. It can have detrimental effects on the immune system or turn the immune system against a person (which is part of the issue, we think, in severe, advanced COVID-19). There is some very limited and again contradictory evidence that in some situations it may promote cancer.
Probably more pertinent from a population risk standpoint, however, is the fact that NO can really mess with blood pressure and put people’s hearts, brains and kidneys at risk if they have a lot of comorbid cardiovascular disease. That’s one reason they teach everybody in ACLS courses to ask about use of “the blue pill” before offering nitroglycerin in angina.

Speaking of sildenafil (and probably tadalafil); since they increase NO, why not try these to ward off coronavirus? First of all, there’s the whole social distancing thing (sorry). In all seriousness, it appears that those drugs may work primarily on one of the NO-synthesizing enzymes that doesn’t really have much to do with the immune system, and in fact may even suppress the important “inducible” NO synthase enzyme that seems to play a much bigger role in immune functions.
Which brings me to my main point and idea here; probably the best way to increase NO is to adopt a healthy lifestyle including regular and consistent exercise. But with time being of the essence now, supplementation with arginine and/or citrulline, two amino acids you can buy over-the-counter (or preferably online nowadays), might be the smartest way to increase NO.
Arginine is the only precursor to NO, meaning NO doesn’t get created in the body except via the transformation of arginine. Many studies over the years have shown that increasing arginine does increase NO, and also improves immune function, and I’m most familiar with that work in the context of surgery. We put a lot of people on arginine before their operation to reduce the risk of wound infections — what we call “immunonutrition.” However, arginine is poorly absorbed by the body, whereas citrulline is much more readily absorbed and serves as a precursor for arginine. In fact, some 60% or so of the NO created by the body is thought to come from citrulline.
All that to say, since I’m not a premenopausal female, I’ve started supplementing with arginine at 2 g per day and citrulline at 1.5 g per day. I’ve got my family and friends, and my staff at the office doing the same thing. I’m NOT saying everyone should do this — again, there are some risks depending on someone’s underlying health status, and those need to be taken into consideration, with consultation preferably from your physician. To reiterate — this does not constitute medical advice.
What I am doing is calling for urgent research into this simple, universally available, inexpensive means of potentially preventing this virus from replicating within hosts. If you happen to decide the potential benefit outweighs the potential risk for yourself, that’s on you. Just don’t buy up and hoard all the stock on Amazon, please.
Heath McAnally, MD, MSPH, is a board-certified anesthesiologist, pain physician, and addictionologist practicing in Alaska (the military sent him there and he decided to stay). If he wasn’t trying to guide people in improving their own lives, teaching medical students to do the same, or writing about it, he’d probably be outdoors right now slogging up a mountain with a good friend or two.
https://www.medpagetoday.com/infectiousdisease/covid19/85770