Before we get started, this is your quarterly reminder that I have no medical credentials and my highest academic credential is a BA in a different part of biology (with a double major in computer science). In a world with a functional medical system no one would listen to me. 

Tl;dr povidone iodine probably reduces viral load when used in the mouth or nose, with corresponding decreases in symptoms and infectivity. The effect size could be as high as 90% for prophylactic use (and as low as 0% when used in late illness), but is probably much smaller. There is a long tail of side-effects. No study I read reported side effects at clinically significant levels, but I don’t think they looked hard enough. There are other gargle formulas that may have similar benefits without the risk of side effects, which are in my queue to research.

Benefits

Math

One paper found a 90% decrease in salivary viral load after mouthwash use (which probably overestimates the effect). Another found a 90% reduction in bad outcomes, with treatment (in mouth, nose, and eyes) starting soon after diagnosis. I suspect both of these are overestimates but 1. 90% reduction is a fantastic upper bound to have 2. Neither of these looked at prophylactic use. A third study found a significant reduction in viral DNA after usage, but did not quantify that by viral load or outcomes. 

I feel like if povidone iodine was actually that good we’d have heard about it before. OTOH mouthwash formulations are barely available in the US, and most of these studies were in Asia, so maybe it went to fixation there years ago and the west is just catching up. 

So I’m going to call this 9-45% reduction in illness timeXintensity when used after symptom onset. Before onset ought to be higher, my wild ass guess is up to 90%. 

One reason I think earlier use is better is that, at least with covid, most of the real damage happens when the virus reaches the lungs. If iodine gargles can form a firewall that prevents an upper respiratory infection from becoming a lower respiratory infection, you’ve prevented most (although not all) of the worst outcomes.

Papers

I livetweeted every paper I read, collected here. I don’t want to brag, but those tweets were very popular among ladies with large boobs and 10 numbers in their twitter handles. So if that’s your type you should definitely check out those threads. Everyone else will probably find them tedious, so I’m going to summarize the most relevant papers here.

Estimating salivary carriage of severe acute respiratory syndrome coronavirus 2 in nonsymptomatic people and efficacy of mouthrinse in reducing viral load: A randomized controlled trial

This study had participants rinse their mouth with one of four mouthwashes, and compared the pre-mouthwash salivary viral load with the viral load 15 and 45 minutes later. The overall effect was very strong: 3 of the washes had a 90% total reduction, and the loser of the bunch still had a 70% reduction (error bars fairly large). 

Note that despite the title, they only gave mouthwashes to participants with symptoms.

My guess is this is an overestimate of impact, because I expect an oral rinse to have a larger effect on saliva than on cellular levels. I wish they’d tested 4-6 hours later, after the virus had had some time to regrow.

Effect of 1% Povidone Iodine Mouthwash/Gargle, Nasal and Eye Drop in COVID-19 patient 

On one hand, this paper features significant ESL issues, missing data, terrible presentation of other data, and was published in a no-name journal. On the other hand, it had one of the best study designs and 30x the number of participants of other studies. I’d love to discard this paper but there aren’t better options.

We see an almost 90% reduction in testing positive on the third day. I suspect that overstates the results because it lowers salivary or nasal fluid viral load more than cellular load, so let’s look at outcomes:

90% reduction in hospitalization, 85% reduction in oxygen use, and  88% reduction in death. 

I was skeptical of these numbers at first, especially because they only tell you the total number of an age/sex group in the study, and the number of people in a demographic group with a bad outcome. Their percentages also don’t work out properly, making it hard to see the real impact. 

Luckily almost everyone in the control group was still PCR positive on day 3, which is almost like having a participant count. The number of control participants still sick on day 3 is indeed about half of every demographic. This doesn’t rule out trickier stuff like putting people at the higher end of their age band in the control group, but it’s a good deal better than that one paper where the youngest person in the control group was a year younger than the oldest person in the treatment group. 

The short-term effect of different chlorhexidine forms versus povidone iodine mouth rinse in minimizing the oral SARS-CoV-2 viral load: An open label randomized controlled clinical trial study

I originally ignored this paper, because it only reported Ct values and not outcomes or viral load.* However the previous two papers are from the same author and have shockingly concordant results, and I wanted a second opinion. 

[*Ct value = how often you have to run the PCR machine on a sample to get over a particular threshold. This corresponds to viral load but the relationship is complicated and variable. A higher Ct value means lower viral load]

The most important finding is that Ct went up by 3.3 (S genes) and 4.4 (E genes). 

N=12 so I’m not thrilled with this study, but pickings are slim. 

Side Effects, Or: Should I just gargle iodine all the time then?

Barring very specific circumstances, I wouldn’t. There are several issues that give me pause about long term continuous use.

Hyperthyroidism

Povidone iodine skin washes can cause hyperthyroidism in infants. Among adults, many studies found increases in Thyroid Stimulating Hormone (an indicator of issues but not itself terrible), but not T3 or T4 (directly casual to outcomes). These studies tend to be small and in some cases used the wrong statistical test that missed a long tail clearly visible in their plots, so I assume there exist people for whom this creates a clinically significant effect, especially after prolonged use.

I didn’t include this paper when calculating health benefits, because its control group was too different from its treatment group. But it’s still potentially useful for tracking side effects (although at n=12, it’s still pretty limited). It found a 50% increase in TSH after a week of treatment, but no change in T3 or T4. TSH returned to normal within 12 days of ceasing treatment. That’s not worrisome for healthy people on its own, but could easily reach worrisome with longer use or a vulnerable patient. 

Tissue damage could leave you worse off?

There is a long history of aggressive use of topical antimicrobial treatments leaving users worse off due to long term tissue irritation. This is why proper wound treatment changes every decade. That same study looked at this and found no increase in cellular irritation in the throat after six months of use. It’s possible they didn’t look hard enough, or they didn’t have sufficient sample size to catch the effect. It’s also possible the species that invented ghost peppers for fun has a throat surface built to handle irritation and iodine is too weak to hurt us

. 

Oral microbiome damage could leave you worse off?

No one studied this at all, but it looks to me like an obvious failure point. I already use oral probiotics, but if I didn’t I would add them in while using iodine.

How to use

0.5% povidone iodine is sold under the brand name Betadine. You can also buy more concentrated povidone iodine and dilute it yourself. You might be tempted to use a higher concentration, but: 1. Remember the long tail of side-effects. 2. There’s some weird evidence that higher concentrations are less effective. I didn’t dig into this very weird claim but you probably should if you plan to try it. 

The Betadine bottle recommends gargling 10ml for 30s, 4x/day. The short term studies used 4-6x/day. Spacing that out is nontrivial attention tax, so when I was sick I just put the bottle on my bathroom sink and used it every time I used the bathroom. This probably comes out to more than 6x/day (especially when I’m sick and chugging fluids), but I also didn’t use a full 10ml and rarely made it to a full 30s, so hopefully it balanced out. 

More Data Needed

The state of existing knowledge around iodine gargles is poor. This is especially frustrating because I don’t think it should be that challenging to gather more. I’m toying with a plan to fix this, but will publish separately since it’s not specific to iodine. 

For financial support I would like to thank my Patreon supports and Lightspeed grants.

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. 

ETA 4-30-24: In this post I used “nitric oxide spray” and “enovid” as synonyms. I’ve since learned this is incorrect, NO is one of several mechanisms Enovid uses. The other mechanisms weren’t mentioned in the papers I cite so it’s possible these are accurate for NO alone.

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 suspect the 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. 

Back in 2021 I wrote a post estimating the risk of long covid. Recently a client hired me to do an update, focusing on changes induced by Paxlovid and vaccination. This was a <5h project and the literature wasn’t very rich so nothing I say here is conclusive, but nothing I said last time was conclusive either so let’s enjoy this together. 

Some caveats: 

• I spent 5 hours on this, and that includes client-specific work I’m not including here.
• Research that met my standard was really scarce; ultimately each conclusion is based on a single study. My goal was data that includes a large population not selected for having long covid, where reporting was automated so you don’t need to worry about response bias. In practice, this means I used data from large medical systems with integrated reporting, like the American Department of Veteran Affairs, national medical systems, and HMOs. Surveys from long covid support groups were ignored with prejudice. 

Summary

Vaccination helps, a bit: Given a medically diagnosed infection (which means it was serious enough to actually get you to the doctor), up-to-date vaccination lowers the risk of long covid by about 20% (this does not include the reduction in risk of having diagnosable covid in the first place, which is substantial). 

Paxlovid helps, more: Nirmatrelvir, which is one of two drugs that make up Paxlovid, reduces long covid risk by about 30% for medically diagnosed infections (which means it was serious enough to actually get you to the doctor). An optimist might hope the other drug (which is in the same class, although most commonly used as an adjuvant) is also useful and round this to 50%.

Most symptoms are temporary: Long covid does tend to get better over time, but how quickly depends on the symptom.  At one year post-infection, the rate of heart issues is nearly indistinguishable from controls, but cognitive issues have a 50% chance of persisting. 

Calculate your absolute risk: Your absolute risk depends on your age and comorbidities. The measured risk for 70-year-old men (not controlling for comorbidities) of developing at least one serious sequelae of medically diagnosed covid n (which means it was serious enough to actually get the patient the doctor) is ~12%. If you want to norm this for your own demographic, you can get a very crude estimate by entering your demographic information in this calculator, dividing your risk of hospitalization by 3 and multiplying the total by 0.4 (which includes the 20% reduction from vaccination and the 50% reduction from Paxlovid). If you are a cis woman, multiply by 2 to account for increased risk (trans people: I have no idea, if you find good data please let me know). 

I cannot emphasize enough how crude this is. I got that 3 by making up a 70 year old man with some common comorbidities, which has a risk of hospitalization of ~36%, and noticed 36/12=3. I don’t think The Economist has been keeping up to date with the latest strains of covid or even the impact of vaccination; these proposed calculations are strictly for order-of-magnitude estimates. 

Sample calculation: a 35 year old woman with no comorbidities shows a 3.8% risk of hospitalization (with their data, which I believe is very old). 3.8%/3= 1.3%. 1.3%*0.4= 0.5%. Times 2 for being female = 1.0%. So a covid infection bad enough to require medical attention has a 1 chance in 100 of a serious persistent issue post-covid. 

Studies

Nirmatrelvir and the Risk of Post-Acute Sequelae of COVID-19 (pre-print)

This study compared people who got covid and received Nirmatrelvir (half of Paxlovid). It used data from the American Department of Veteran Affairs, which means the participants are older (average age 65), overwhelmingly male (~90%), and very white (75%). Last time I checked maleness increases the risks of short-term covid consequences but decreases the risks of long term consequences, so good luck balancing that calculation.

The distribution of medication was not random. They don’t specify beyond this, but I assume VA doctors are more likely to aggressively treat patients who are sicker or have more co-morbidities, which should lead the study to understate the impact of treatment. Additionally they were only giving nirmatrelvir, which is one of the two drugs packaged together to make Paxlovid. I’m going to be an optimistic and assume the second drug was included for good reasons, which make this study underrepresent the usefulness of Paxlovid. But they don’t give the dosage at all, so there is a wildcard.

All that said: Nirmatrelvir was quite helpful, cutting the risk of long covid (PASC) at 90 days by ~25%, which in this group translated to 2.5 percentage points. 

Survival here means “survived w/o long covid symptoms”. You might ask why that goes down over time, given some people recover between days 30 and 90. I believe the answer is that they didn’t check for symptoms’ persistence: any diagnosis of long covid issues put participants in the PASC bucket forever.

Effect by symptom:

Long COVID after breakthrough SARS-CoV-2 infection

This is another study with VA data. They compared outcomes of infection after vaccination, compared with vaccinated controls. 

Participants with infections after vaccination (aka breakthrough infections) had a 12 percentage point increase in risk of symptoms in 12 areas, compared to vaccinated people who didn’t get infected. Again, the study population is probably at higher risk than average due to age and associated comorbidities.

However, this risk is heavily concentrated among hospitalized patients:

They also compared the risks to those of infections in unvaccinated people. Vaccination clearly helped, but not by as much as one would hope.

Just for fun, here’s the long-term risks of covid relative to the flu:

Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study

This paper looked at long-term health outcomes from an Israeli HMO. It mixed vaccinated and unvaccinated participants but held infection severity constant, which is unforgivable from an absolute risk estimation standpoint but probably fine for looking at the trajectory of recovery from long covid over time. “Mild” appears to mean “did not end up in the hospital”; however the case did need to be serious enough that it made it into medical records in the first place. 

The general trend is “things get better”, with the rate of improvement varying by symptom type. Unfortunately cognitive effects are the slowest to resolve, with at best a 50% recovery rate one year out.

Thanks to anonymous patron for supporting the original research and Patreon patrons for supporting this write-up.

Epistemic status: I strongly believe this is the right conclusion given the available data. The best available data is not that good, and if better data comes out I reserve the right to change my opinion.

EDIT (4/27): In a development I consider deeply frustrating but probably ultimately good, the same office is now getting much more useful information from antigen tests. They aren’t tracking with same rigor so I can’t comapre results, but they are now beating the bar of “literally ever noticing covid”.

In an attempt to avoid covid without being miserable, many of my friends are hosting group events but requiring attendees to take a home covid test beforehand. Based on data from a medium-sized office, I believe testing for covid with the tests people are using, to be security theater and provide no decrease in risk. Antigen tests don’t work for covid screening. There is a more expensive home test available that provides some value, and rapid PCR may still be viable.

It’s important to distinguish between test types here: antigen tests look for viral proteins, and genetic amplification tests amplify viral RNA until it reaches detectable levels. The latter are much more sensitive. Most home tests are antigen tests, with the exception of Cue, which uses NAAT (a type of genetic amplification). An office in the bay area used aggressive testing with both Cue and antigen tests to control covid in the office and kept meticulous notes, which they were kind enough to share with me. Here are the aggregated numbers: 

• The office requested daily Cue tests from workers. I don’t know how many people this ultimately included, probably low hundreds? I expect compliance was >95% but not perfect.
  • The results are from January when the dominant strain was Omicron classic, but no one got strain tested.
• 39 people had at least one positive Cue test, all of which were either asymptomatic or ambiguously symptomatic (e.g. symptoms could be explained by allergies) at the time, and 27 of which had recent negative cue tests (often but not always the day before, sometimes the same day)
• Of these, 10 definitely went on to develop symptoms, 7 definitely did not, and 18 were ambiguous (and a few were missing data).
• 33 people with positives were retested with cue tests, of which 9 were positive. 
• Of those 24 who tested positive and then negative, 4 tested positive on tests 3 or 4.
• Of the 20 people with a single positive test followed by multiple negative retests, 6 went on to develop symptoms.
• 0 people tested positive on antigen tests. There was not a single positive antigen test across this group. They not only didn’t catch covid as early as Cue did, they did not catch any cases at all, including at least 2 people who took the tests while experiencing definitive systems.
  • Antigen tests were a mix of Binax and QuickVue.
  • Early cases took multiple antigen tests over several days, later cases stopped bothering entirely.
  • The “negative test while symptomatic” count is artificially low because I excluded people with ambiguous symptoms, and because later infectees didn’t bother with antigen tests. 
  • I suppose I can’t rule out the possibility that they had an unrelated disease with similar symptoms and a false positive on the Cue test. But it seems unlikely that that happened 10-28 times out a few hundred people without leaving other evidence.

A common defense of antigen tests is that they detect whether you’re contagious at that moment, not whether you will eventually become contagious. Given the existence of people who tested antigen-negative while Cue-positive and symptomatic, I can’t take that seriously.

Unfortunately Cue tests are very expensive. You need a dedicated reader, which is $250, and tests are $65 each (some discount if you sign up for a subscription). A reader can only run 1 test at a time and each test takes 30 minutes, so you need a lot for large gatherings even if people stagger their entrances. 

My contact’s best guess is that the aggressive testing reduced but did not eliminate in-office spread, but it’s hard to quantify because any given case could have been caught outside the office, and because they were trying so many interventions at once. Multiple people tested positive, took a second test right away, and got a negative result, some of whom went on to develop symptoms; we should probably assume the same chance of someone testing negative when a second test would have come back positive, and some of those would have been true positives. So even extremely aggressive testing has gaps.

Meanwhile, have I mentioned lately how good open windows and air purifiers are for covid? And other illnesses, and pollution? And that taping a HEPA filter to a box fan is a reasonable substitute for an air purifier achievable for a very small number of dollars? Have you changed your filter recently? 

PS. Before you throw your antigen tests out, note that they are more useful than Cue tests for determining if you’re over covid. Like PCR, NAAT can continue to pick up dead RNA for days, maybe weeks, after you have cleared the infection. A negative antigen test after symptoms have abated and there has been at least one positive test is still useful evidence to me. 

PPS. I went through some notes and back in September I estimated that antigen testing would catch 25-70% of presymptomatic covid cases. Omicron moves faster, maybe faster enough that 25% was reasonable for delta, but 70% looks obviously too high now. 

PPPS. Talked to another person at the office, their take is the Cue tests are oversensitive. I think this fits the data worse but feel obliged to pass it on since they were there and I wasn’t.

PPPPS (5/02): multiple people responded across platforms that they had gotten positive antigen tests. One or two of these was even presymptomatic. I acknowledge the existence proof but will not be updating until the data has a denominator. If you’re doing a large event like a conference I encourage you to give everyone both cue, antigen, and rapid PCR tests and record their results, and who eventually gets sick. If you’d like help designing this experiment in more detail please reach out (elizabeth-at-acesounderglass.com)

Introduction

This article contains an interview with a doctor who believes NAD+ is the secret to covid’s heavy morbidity and mortality toll. The description was unusually well done for internet crackpottery. This is hard to convey rigorously, but it had a mechanistic-ness and the right level of complexity about it, and it made the right level of promises for a treatment. None of this is to say it’s definitely correct, but it had a bunch better chance of being correct than your average alt-covid-cure scribbled out in crayon. So I did some checks on it.

[Didn’t you say the risk of long covid was small? NO I SAID IT WAS TOO SMALL TO MEASURE AGAINST THE DELUGE OF CRAP THAT HAPPENS TO US EVERYDAY THAT IS NOT THE SAME]

*ahem*

This post is organized as follows:

• Description of theory. 
• Long section defining terms. These are all useful for understanding the claims I check later on, but depending on who you are they may not be helpful, and you may find the contextless infodump kind of a drag. Feel free to skip if it’s not useful to you personally, and know that it’s there if you need it.
• Deep dive onto particular claims the article makes.
• Does it work?
• Is it safe?
• My personal experience with the protocol 
• Some meta

This is your reminder that my only credential is a BA in biology and I didn’t specialize in anything relevant. It is a sign of civilizational inadequacy that this post exists at all, and you should think really hard and do your own research before putting too much weight on it.

For those of you would like to skip to the take home message: science is very hard, I’m glad they’re running larger studies to follow up on all of these because that’s a reasonable thing for a rich society to do, but I’m not super hopeful about this protocol.

The Theory

As described by Dr. Ade Wentze:

There is an extremely widely used coenzyme in your body, NAD. The more active form of this compound, NAD+, is depleted by covid (converted to NADH). In people with a preexisting deficiency or difficulty rebounding after depletion, covid infection results in a persistent NAD+ deficit. This is bad in and of itself, but causes additional problems when your body tries to make up for it by requisitioning all your tryptophan to make more. Tryptophan is also a precursor for serotonin, so this leads to either low serotonin or activation of mast cells to release their serotonin stores, accompanied by histamines (which cause allergies and other issues). 

Background

There is a lot of vocabulary in that theory and in the supporting claims, which I go over here. If you’re reading for conclusions rather than deep understanding I would skip this.

NAD+

Nicotinamide adenine dinucleotide is a coenzyme that plays an essential role in hundreds of chemical reactions in your cells, including many relating to processing energy and genetic transcription.  This is a mixed blessing as a foundation for crackpot theories go: something involved in hundreds of processes across every kind of tissue in your body can cause almost any symptom, which is great because long covid has a lot of symptoms to cover. On the other hand, it can cause almost any symptom, which means it’s hard to disprove, and you should distrust things in proportion to the difficulty to disprove them. Alas, sometimes core processes are impaired and they do express that impairment in a range of unpredictable ways that vary across people, but it’s also an easy home for crackpots. 

NAD+ has two major components, one made from either tryptophan or aspartic acid (both amino acids), or by altering niacin.

Niacin

Like many vitamins, niacin aka vitamin B3 refers to a few different closely related compounds (most commonly nicotinic acid, nicotinamide, nicotinamide riboside, and inositol nicotinate, but there are others) that are almost but not quite interchangeable.

Chemical structures of niacin compounds: (a) nicotinamide; (b) nicotinic acid; (c) nicotinamide adenine dinucleotide (NAD þ ); (d) nicotinamide adenine dinucleotide phosphate (NADP þ ) (source)

Niacin is commonly prescribed for treating high cholesterol, although a metareview found it did not reduce overall mortality and may contribute to the development of type-2 diabetes. 

Severe niacin deficiency is called pellagra, and can be caused by either insufficient consumption or problems processing the vitamin. Pellagra is mostly defined as niacin deficiency but can also be caused by tryptophan deficiency, which you may remember is another path to manufacturing NAD+. Pellagra can cause diarrhea, dermatitis, dementia, and death, which are not a great match for acute or long covid. Niacin supplementation treats pellagra, often within a few days.

SIRT1

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that regulates the expression of some genes in ways that haven’t yet been made clear to me but seem to be associated with aging (more SIRT1 is associated with better outcomes, although we haven’t broken down cause and effect). As indicated by its name, it’s dependent on NAD+ to operate, which means NAD+ is involved in the regulation of expression of some genes via some mechanism, which means niacin is involved in the regulation of expression of some genes via some mechanism.

SIRT1 is downregulated in cells that have high insulin resistance and inducing its expression increases insulin sensitivity, suggesting the molecule is associated with improving insulin sensitivity.

SIRT1 may be upregulated by selenium.

PARP

Another many-purposed enzyme whose activities include DNA repair, killing cells that are beyond repair. PARP requires NAD+ as a coenzyme.

Individual Claims

Groups with low NAD+ suffer more from covid

NAD+ declines with age

NAD+ does definitely decline with age but so does literally everything bad in your body, so I don’t find this very compelling.

Correlation between NAD+ levels and Age in (A) Males (B) Females (source)

Obese people have lower NAD+ levels, leading to worse outcomes

Yes, although obese people tend to do worse on a lot of metrics. However, that paper highlights that SIRT1 seems to be involved in this correlation somehow.

Diabetics have worse NAD+ levels

Yes, although diabetics also have more immune problems generally (definitely Type 2, some pop sites said the same for Type 1 and that’s believable but I didn’t quickly find a paper I liked that backed the claim).

Low selenium is associated with bad outcomes in covid

The post cites Zhang et al, which took advantage of high variations in selenium consumption in China to do a natural experiment. Variations in the population selenium levels do seem insanely correlated with the overall cure rate (defined as not dying). The study took place in February 2020 so neither data collection nor treatment was very good, but damn that is interesting.

Moreover, this study, which came out several months after the blog post was published, took advantage of the same variation and came to the same conclusion, with a much larger sample size and much more reasonable case fatality rate (1.17% in areas with no deficiency to 3.16% in severely deficient areas, P = 0.002). (Note: several authors on that paper are also named Zhang, but I assume that’s because it’s a common name in China).

Some pharma company thinks selenium is promising enough to launch a trial for it, although recruitment hasn’t started yet.

The pre-print servers are littered with natural experiments highlighting correlations that failed as interventions, but this is very strong for a correlation.

Niacin just generally seems to help lung damage

That is indeed what their citation says, however that paper’s only source looked at the effect of niacin on lung damage in hamsters deliberately induced with a chemotherapy drug, and it’s not obvious to me that that translates to damage from infection or immune reaction. There are some other scattered studies in rodents, combining niacin with other substances, none of which looked at damage from infectious disease.

The treatment for NAD+ deficiency is niacin

Their citation backs this up: niacin supplementation led patients (n=5) and controls (healthy people given the same supplementation, n=8) to increased NAD+ levels, and arguably increased strength, although with that much variation and such a small sample size I’m not convinced. Martens et al supports this with modest benefits seen in n=24 subjects.

A few minutes investigation found some other studies:

• Dietary niacin deficiency led to NAD+ deficiency in baby rats. This paper works damn hard to hide its sample size but I think it was 10-15 per treatment group.
• The same author exposed some rats (n=6 per treatment group) to excess oxygen and found that those with a niacin deficient diet had less NAD+ in the lungs and responded less to the damage caused by excess oxygen, but had the same wet/dry ratio as their well-fed friends (wet/dry ratio is a measure of lung health).
• Ng et al found that in catfish liver NAD increased linearly with dietary niacin supplementation, but health returns like size and mortality dropped off between 6 and 9 mg/kg. They further found that tryptophan supplementation could not make up for a niacin deficiency (in catfish).

Plus niacin is so well established as a treatment for pellagra that no one bothers to cite anything for it, and that does seem to mediate through NAD+.

Nicotinic acid may act as a one of a kind bioenergetic “pump” of inflammatory molecules out of cells

They link to a preprint which has since been taken down, and I could not find it on my own. 

NAD+ problems have been indicated in chronic fatigue syndrome

Everything has been indicated in chronic fatigue syndrome; I’m not looking this up.

Low serotonin -> mast cell activation -> histamine release

Mast cells indeed produce serotonin, in mice. Note that that paper highlights fluoxetine as a way to reverse serotonin deficiency in mast-cell-deficient mice, and since the article was published fluoxetine has shown promise as a covid treatment. However this study says that while serotonin-producing mast cells are common, humans in particular don’t have them while healthy (although it still shows serotonin affecting mast cell movements). This appears to be an area of some controversy.

Mast cells releasing histamine in response to allergens is uncontroversial. Moreover, histamines and serotonin are stored in the same compartments (in mice). Second source (still in mice). 

Some Guy did an informal study based on this theory and it worked

Some guy (Birth name: Gez Mendinger) did indeed report this, and I have to say, for an uncredentialed dude on youtube recommending OTC supplements to treat a nebulously defined disease, this guy looks really credible, and his reasonably good analysis was quite promising. He shared his results with me, and it continued to look promising when I first dug into it with assistance from a statistician, but the deeper we drilled the less promising it looked (details). By the end, the most I could say is “yeah, worth a harder look”, but the history of things that look promising in small, poorly organized studies that wilt under large, well-organized ones is just too dismal to ignore. 

Mouse study shows low NAD+ hurts you via SIRT1

The interview also cites this mouse study featuring a direct NAD+ drip and a slightly different coronavirus. They show improved symptoms but not viral load. They don’t list the sample size anywhere I can find, judging from the low-resolution graph it looks like 7 mice in the control group and maybe 12 in the treatment group? Except for the embolism test which had many more mice.

(apologies for poor image quality, the PDF was crap)

(note: that article was up when I started this post but disappeared before I verified the SIRT1-specific part of the claim)

Quercetin increases NAD+ levels 

Yes, in rats and mice. Specifically, it speeds up the transition from NADH to NAD+

Male pattern balding and low vitamin D are both associated with poor covid outcomes and low NAD+.

The balding citation does indeed say that, but it only looked at hospitalized patients so it’s useless. Moreover, balding is associated with a testosterone derivative, and testosterone weakens the immune system. But when I went to find some cites for those, I found that within hospitalized patients, low testosterone was associated with worse outcomes. However these patients were already hospitalized, so the causality could easily go the other way.

Meanwhile I found several folk-wisdom level comments indicating a link between NAD+ and male pattern balding, but nothing rigorous.

Low vitamin D does seem to be associated with poor covid outcomes, maybe, but treatment doesn’t seem to help (at least not if you wait until patients are hospitalized). 

Chang and Kim assert that Vitamin D activates the NAD-SIRT1 pathway in fat cells in vitro, which if it held up elsewhere would be even stronger evidence for the overall theory than this claim attempts. Byers et al found that vitamin D did not protect guinea pigs against the NAD+ depleting effects of mustard gas. This is not a slam dunk.

Covid depletes NAD+ by activating PARP

Curtin et al lay out a theoretical case for using PARP-inhibitors to treat covid-caused ARDS.

Heer et al “we show that SARS-CoV-2 infection strikingly upregulates MARylating PARPs and induces the expression of genes encoding enzymes for salvage NAD synthesis from nicotinamide (NAM) and nicotinamide riboside (NR), while downregulating other NAD biosynthetic pathways” (notably, the forms not used in the protocol), “overexpression of PARP10 is sufficient to depress cellular NAD and that the activities of the transcriptionally induced enzymes PARP7, PARP10, PARP12 and PARP14 are limited by cellular NAD and can be enhanced by pharmacological activation of NAD synthesis”, “MHV induces a severe attack on host cell NAD+ and NADP+.” (MHV being used as a model)

Long covid and Pellagra share a lot of symptoms, including hyponosmia

Scattered claims pellagra causes hyponosmia but you have to look really hard, it doesn’t show up on any of the common descriptions. I checked in Spanish and didn’t find anything either.

Sen (published only last month) suggests that serotonin deficiency causes anosmia and other neuro symptoms in covid. They propose a different method for the depletion (ACE2 is a mechanism for moving serotonin into the cell), but it’s not mutually exclusive with Wentzel’s theory (that NAD+ depletion causes the body to use up tryptophan trying to produce more NAD+).

Your body hijacks tryptophan to make NAD+ at the expense of serotonin

Tryptophan can indeed be used to make NAD (albeit niacin is better) and serotonin. How your body prioritizes under a given set of circumstances is anyone’s guess.

NAD+ and the immune system

Probably at least some of long covid stems from autoimmune issues, as witnessed by the fact that it’s much more common in women and sometimes helped by steroids. The post and paper don’t make any claims on this beyond the effect of NAD+ on mast cells, which are implicated in autoimmune disorders, but out of curiosity I did some quick googling and found that NAD+ downregulate inflammation via CD4 cells (in mice) and activating SIRT1, the pathway mentioned previously (still in mice).

The Paper

Not that good. Feels associational rather than mechanistic. However Bordoni et al (published after the cited paper) found covid-19 was associated with diminished SIRT1- but Pinto et al found covid-19 upregulated SIRT1 and cite another study claiming that under conditions of energetic stress (which would imply low NAD+), SIRT1 substitutes for ACE2 (the receptor covid uses to enter the cell. Smith suggests that downregulating SIRT1 is good for fighting covid. So SIRT1, NAD+, and covid are probably related, but the first two items are very common so this isn’t damning.

Notably, this paper doesn’t explain why covid would deplete NAD+ more than other infectious diseases, which is an enormous hole.

Does it work? 

The mechanism and empirical data are definitely enough to merit more rigorous follow-up studies (which are in progress) and definitely not slam dunks. But you may need to make a decision before that’s in, so the real question is “should I take this stack if I get sick? Should my parents?”

My tentative answer is: the prescribed stack probably won’t physically hurt you (but see the next section), and it’s fairly cheap, so the limiting factor is probably “what do you have the energy to try”. This is a better thing to try than the interventions whose proof was actively made up or have been investigated and discarded, but there undoubtedly are or will be equally probable things floating around, and choosing between them will be a matter of taste..  

If you do end up giving this a shot, for covid long or acute, I invite you to preregister your complaints and intention with me (a comment here or email elizabeth@acesounderglass.com), so I can create my own little study. If you don’t feel like doing that I still encourage you to announce the intention somewhere, as a general good practice (I did so here). 

So you’re saying it’s safe then?

Anything that does anything is dangerous to you in sufficient dosages. If you’re considering an unverified supplement stack, you should carefully investigate the potential side effects of each substance and consider it in light of what you know of your own health (especially other medications you’re taking). Consider talking to a doctor, if you have a good one.

If any of you are thinking “oh niacin’s a water-soluble vitamin it must be fine”: that’s a pretty good heuristic but it doesn’t hold for niacin in particular.

My experience

As mentioned previously, I acquired lingering progressive chest congestion/inflammation from (probably) my covid vaccine. It’s always possible there was another reason but the timing and symptoms really do not match anything else. 

Since I never had covid (probably), my reaction can’t come from the infection itself, only my immune response to it. Since the theory doesn’t specify a mechanism that’s not disqualifying, but they do make it sound like it starts as a covid problem not an immune problem.

I started this supplement stack before doing any deep verification. The original blog post pattern matched to the kind of thing that was worth trying, everything on the list I either knew was generally safe or confirmed with a quick check (my doctor later confirmed my opinion on safety without endorsing the stack for any particular use), and I had a lot of client work to do. Shoemaker’s children go barefoot, and all that.  So by the time I was writing this I had been on the recommended supplement stack (and some other things besides) for 3 weeks, and was beginning to wean down. 

Overall: my chest pain got better but the timing fits better with attribution to a different intervention. The rash I got on matches very well with the supplement stack. I nonetheless was craving it after I weaned off, so probably there’s at least one thing in it I need, which hopefully isn’t the same as the thing causing the rash. 

[Alert twitter readers may have questions, since I previously was more positive on the stack. I had a major regression when I got a non-covid cold, and had to go back on the other treatment]

Interestingly, my tolerance for niacin increased and then plummeted. Originally I could take 250mg (the smallest size I could find in the right form) with only very mild flush, and that got better over time, to the point I tried 500 mg once (a mistake). But around week 3 my flush was getting worse. Lowering the dose helped, but it’s getting worse again, so I’m continuing to titrate down. This is extremely consistent with filling up NAD+ reserves over time, although very far from conclusive.

Meta

I was originally much more positive on this treatment/theory. I gave it more credit on Twitter, but that’s nothing compared to the excited messages I sent a few friends after an initial lit review. I wrote several much more positive versions of this post (and the forthcoming study analysis), but there kept being one more thing to check, until I talked my way down to what you see here. Some of my downgrade stemmed from asking better statistical questions, but some of it was just the emotional process of talking myself down from something that initially looked so promising, but ultimately had a similar amount of holes to many other things that looked equally promising and failed to pay off. This represents dozens of hours of work from me and my statistician, for the very disappointing result of “fringe treatment probably doesn’t do very much but can’t rule it out”. Reality is infinitely disappointing. 

Thanks to Alex Ray and my Patreon Patrons for partially funding this investigation, and Miranda Dixon-Luinenburg⁩ for copyediting.