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]
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.
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).
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.
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.
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.
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.
Another many-purposed enzyme whose activities include DNA repair, killing cells that are beyond repair. PARP requires NAD+ as a coenzyme.
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.
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
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.
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
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).
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 firstname.lastname@example.org), 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.
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.
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.