Epistemic status: I spent about 5 hours looking into this, and the next day developed covid myself. I did a bit more research plus all of the writing while sick. So in addition to my normal warning that I have no medical credentials, you should keep in mind that this knowledge may be cursed.

Introduction

Nitric Oxide Nasal Spray, sold under the brand name Enovid, is a reactive compound that kills viruses (and I suspect taxes your nasal tissue). It has recently been tested and marketed for treatment of covid. The protocol I found in papers was 2 sprays per nostril every 2-3 hours, after you develop symptoms. Enovid’s instructional pamphlets say twice per day, also after you get sick. This seems a little late to me.

I suspect the real power of NONS lies in use before you develop symptoms, ideally as close to exposure as possible. This is difficult because you don’t know when you would have gotten sick, and I suspect there are costs to indefinite use (see TODO section). I initially thought (and told people, as a tentative guess) that one round of 4 total sprays after a high risk event was a good trade off. After doing the math for this post, that intervention seems much less helpful to me, and picking the right length of post-exposure prophylaxis depends on equations for which we lack good numbers. I pulled some numbers out of my ass for this post, but you should not trust them.

My guess is NONS is minimally useful once covid has reached the throat, unless you combine it with a separate disinfectant of the throat. I hope to write up a report on one such disinfectant soon, although TBH it’s not looking good.

NONS can lead to false negatives on any test based on a nasal swab, because it breaks the relationship between nasal viral load and overall load.

How does it work?

First, nitric oxide is highly reactive, which makes it destructive to anything organic. Virions are fragile to this kind of direct attack, and certain immune cells will produce nitric oxide to kill bacteria, viruses, and your own diseased cells.

First-and-a-half, nitric oxide may alter the pH of your nose, and this effect may last well past the death of the original NO molecules. This was an aside in one paper, and I haven’t followed up on it.

Second, nitric oxide is a signaling molecule within your body, probably including but definitely not limited to the immune system. I assume the immune system uses it as a signal because it serving a functional purposes. For the rest of body the selling point appears be that it crosses membranes easily but dies quickly, making it useful when the body wants the signal to fade quickly. Viagra works by indirectly increasing your body’s synthesis of nitric oxide.

How well does it work?

Good question, and it depends a lot on how you use it.

My best guess is that a single application (2 sprays in each nostril) of Envoid ~halves the viral load in your nose. Covid doubles in 3–6 hours, so that’s how much extra time you’ve bought your immune system to ramp up defenses. If you follow the more aggressive protocols in the literature and apply that treatment 6 times per day, you wipe out 95% of covid in the nose. I will attempt to translate this an efficacy estimate in that mythical future, but in the meantime siderea has a write-up on why reducing viral load is valuable even if you can’t destroy it entirely

Sometimes you will see very impressive graphs for Enovid’s impact; these are inevitably looking at the results of nasal swabs. Since even in the best case scenario NONS doesn’t affect spread once an infection has reached the throat, this doesn’t feel very relevant to me.

Sometimes you will see very unimpressive graphs, from the rare studies that looked at transmission or symptoms. These effects are so weak, in such small studies, that I consider them essentially a null result.

…Except that these studies all started treatment days after symptoms emerged. In one case it was a minimum of 4 days. Another said “0-3 days” after symptoms, but since it takes time to see a doctor and be recruited into a study I expect the average to be on the high end of that. Additionally, both studies showed a downward slope in infection in both treatment and control groups. This is a big deal because I expect the largest effect to come if NONS is used before exponential growth really takes off. If they’re seeing a decline in viral load in their control arm, they either administered treatment too late or their placebo isn’t.

[I think this reasoning holds even if immune overreaction is part of the problems with long covid. Long covid is correlated with severity of initial infection.]

To figure the impact of prophylactic use, I’m going to have to get, uh, speculative. Before I do that, let me dig into exactly what the data says.

Effect size on nasal viral load

This has very solid data: even under the unfavorable circumstances of a strong infection, a day of usage drops viral load by 90-95%

Paper 1 says 95% reduction in one day, 99% in two. They took samples from the nose and throat but don’t clarify which location that applies to. If I had the energy I’d be very angry about that right now.

(Their placebo was a saline spray, which other people claim is an antimicrobial in its own right, so this may understate the effect)

Paper 2 finds an adjusted 93-98% decline after 1 day’s use of NONS.

Effect on symptoms/transmission, as measured by poorly designed studies

Paper 1 did track time to cure, but with a 40% response rate on a sample size of 40 in the treatment arm I can’t bring myself to care.

Paper 2 reported a couple of metrics. One is “Time to cure (as defined by PCR results)” which is still worthless because it’s still using a nasal swab. Another is clinician-assessed improvement; this effect seemed real but not huge.

They also checked for spread to close contacts, but not very well. Contacts had to take the initiative to get tested themselves, and AFAICT they didn’t establish if they were infected before or after treatment started. You can try to factor that out by only looking at the last day of recorded data, but the difference appears to start on day 1 of treatment, when there absolutely shouldn’t be an effect.

Other Diseases

NONS has been studied against other infections and I fully meant to look at that data. Now that I have actual covid I consider it kind of a race to get this post out before I’m too tired, so this will come later if at all.

My wild ass guess of impact

What does a single dose do? I did a very stupid model assuming six doses over 24 hours each having the same proportionate effect, and found that halving viral load with each application was a perfect match with the data. I expect the first dose of the day has a larger effect and each one is a little less effective until you sleep and the virus has some time to marshal forces, but barring better data I’m going to treat Enovid as rolling back one doubling.

[I want to emphasize I didn’t massage this to make the math easier. I tried .9 in my naive spreadsheet knowing it wouldn’t work, and then tried 0.5 to find it perfectly matched the data]

If my covid infection starts in the nose and I take a full course of treatment immediately after exposure, <10% chance I get sick. But that’s unachievable without constant use, which I think is a bad idea (see below).

What if you’re infected, but only in your nose? It’s a 95% reduction per day. It’s anyone’s guess how much that reduces the chance of spread to your throat; I’d say 95% is the upper bound, and am very arbitrarily setting 50% as the lower bound for the first day (this time I am trying to make the math easier). But you’re also reducing the cumulative load; on day three (after two days of treatment), your viral load is 99% lower than it would otherwise be, before you take any new doses.

I suspectthe real killer app here is combining Enovid with a throat disinfectant, and am prioritizing a review of at least one throat disinfectant in a future post.

Can I get this effect for free, without the painful stinging or logistical hassle of a nasal spray?

Maybe. Your nose already naturally produces nitric oxide, and you can increase this by 15x by humming. I haven’t been able to find the dosage of a single spray of Enovid to compare, but humming doesn’t sting so I assume it’s a lot less. On the other hand, you can hum more often than six times per day. On the third hand, I can’t tell if humming causes you to produce more NO or just release it faster, in which case chronic humming might deplete your stores.

A quick search found multiple published articles suggesting this, but none actually studying it. The cynic in me says this is because there’s no money in it, but this study would take pennies to run and be so high impact if it worked that I suspect this is less promising than it seems.

Thank you to Michael Tontchev on twitter for pointing me towards humming.

Should I just use this all the time?

I don’t regularly use Envoid, despite having a shit immune system. The history of treatments like this is that long term use causes more problems than it solves. They dry out mucous membranes, or kill your own immune cells. I think the rest of you should seriously consider developing a humming habit; alas I have nerve damage in my jaw that makes vibration painful so not an option for me.

I do think there’s a case for prophylactic use during high risk situations like conferences or taking care of a sick loved one.

Where can I buy Enovid?

Amazon has it, but at $100/bottle it’s quite expensive. You can get it from other websites for half the price but longer shipping times; my friend used israelpharm.com and confirms he got his shipment.

Nitric oxide for covid and other viral infections