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)
Tl;dr I tried to run an n of 1 study on niacin and covid, and it failed to confirm or disprove anything at all.
You may remember that back in October I published a very long post investigating a niacin-based treatment protocol for long covid. My overall conclusion was “seems promising but not a slam dunk; I expect more rigorous investigation to show nothing but we should definitely check”.
Well recently I got covid and had run out of more productive things I was capable of doing, so decided to test the niacin theory. I learned nothing but it was a lot of effort and I deserve a blog post out of it null results are still results so I’m sharing anyway.
Background On Niacin
Niacin is a B-vitamin used in a ton of metabolic processes. If you’re really curious, I describe it in excruciating detail in the original post.
All B vitamins are water-soluble, and it is generaly believed that unless you take unbelievably stupid doses you will pee out any excess intake without noticing. It’s much harder to build up stores of water-soluble vitamins than fat vitamins, so you need a more regular supply. Niacin is a little weird among the water-solubles in that it gives very obvious signs of overdose: called flush, the symptoms consist of itchy skin and feeling overheated. Large doses can lead to uncontrolled shaking, but why would you ever take that much, when it’s so easy to avoid?
People regularly report response patterns that sure look like their body has a store of niacin that can be depleted and refilled over time. A dose someone has been taking for weeks or months will suddenly start giving them flush, and if they don’t lower it the flush symptoms will get worse and worse.
Some forms of niacin don’t produce flush. Open question if those offer the same benefits with no side effects, offer fewer benefits, or are completely useless.
Niacin And Long Covid
There’s an elaborate hypothesis about how covid depletes niacin (and downstream products), and this is a contributor to long covid. My full analysis is here. As of last year I hadn’t had covid (this is antibody test confirmed, I definitely didn’t have an asymptomatic case) but I did have lingering symptoms from my vaccine and not a lot else to try, so I gave the protocol a shot.
My experience was pretty consistent with the niacin-storage theory. I spent a long time at quite a high dose of the form of niacin the protocol recommends, nictonic acid. My peak dose without flush was at least 250mg (1563% RDA) and maybe even 375mg (2345% RDA). When I hit my limit I lowered my dose until I started getting flush at the new dose, and eventually went off nicotnic acid entirely (although I restarted a B-vitamin that included 313% RDA of a different form). That ended in September or early October 2021. It made no difference in my lingering vaccine symptoms.
In early 2022 I tried nicotinic acid again. Even ¼ tablet (62.5mg, 390% RDA) gave me flush.
I Get Covid
Once I developed symptoms and had done all the more obviously useful things like getting Paxlovid, I decided it would be fun to test myself with niacin (and the rest of the supplement stack discussed in my post) and see if covid had any effect. So during my two weeks of illness and week of recovery I occasionally took nicotinic acid and recorded my results. Here’s the overall timeline:
Day -2: am exposed to covid.
Day 0: test positive on a cue test (a home test that uses genetic amplification).
Lung capacity test: 470 (over 400 is considered health).
Start Fluvamoxine and the vitamin cocktail, although I’m inconsistent with both the new and existing vitamins during the worst of the illness. Vitamin cocktail includes 313% RDA of no-flush niacin, but not nicotinic acid.
Day 1: symptomatic AF. 102.3 degree fever, awake only long enough to pee, refill my water, and make sure my O2 saturation isn’t going to kill me. I eat nothing the entire day.
I monitored my O2 throughout this adventure but it never went into a dangerous zone so I’m leaving it out of the rest of the story.
Day 2: start with 99 degree fever, end day with no fever. Start Paxlovid.
Every day after this I am awake a little bit longer, eat a little bit more, and have a little more cognitive energy, although it takes a while to get back to normal.
Lung capacity troughs at 350 (considered orange zone).
Day 4: ½ tablet nictonic acid, mild flush.
Day 7: lung capacity up to 450, it will continue to vary from 430-450 for the next two weeks before occasionally going higher.
Day 9: ½ tablet nictonic acid, mild flush
Day 10-17: ⅓ tablet nictonic acid, no flush
Where by “⅓” tablet I mean “I bit off an amount of pill that was definitely >¼ and <½ and probably averaged to ~⅓ over time”
Day 12: I test positive on a home antigen test
Day 15: I test negative on a home antigen test (no tests in between)
Day 17: ⅓ tablet produces flush (and a second negative antigen test)
This was also the first day I left my house. I had thought of myself as still prone to fatigue but ended up having a lot of energy once I got out of my house and have been pretty okay since.
Conclusions
My case of covid was about as bad as you get while still technically counting as mild. Assuming I went into it with niacin stores such that 62.5mg nicotinic acid would generate flush, it looks like covid immediately took a small bite out of them. Or it reduced my absorption of vitamins, such that the same oral dosage resulted in less niacin being taken in. There’s no way to know covid had a larger effect on niacin than other illnesses, because I don’t have any to compare it to. Or maybe the whole thing was an artifact of “not eating for two days, and then only barely, and being inconsistent with my vitamins for a week”.
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.
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.
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.
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 severalfolk-wisdomlevel 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
Scatteredclaims 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).
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.
Sometimes people imply that epistemic spot checks are a waste of time, that it’s too easy to create false beliefs with statements that are literally true but fundamentally misleading. And sometimes they’re right.
On the other hand, sometimes you spend 4 hours and discover a tenet of modern parenting is based on absolutely nothing.
[EDIT: this definitely was a tenet among my friends, but apparently is less widespread than I thought.]
Sorry, did I say 4 hours? It was more like 90 minutes, but I spent another 2.5 hours checking my work just in case. It was unnecessary.
Intro
You are probably familiar with the notion that eating dirt is good for children’s immune systems, and you probably call that Hygiene Hypothesis, although that’s technically incorrect.
Hygiene Hypothesis can refer to a few different things:
A broader hypothesis that exposure to nominally harmful germs provides the immune system training and challenge that ultimately reduces allergies.
One particular form of this involves exposure to macroparasites, but that seems to have fallen out of favor.
The hypothesis that exposure to things usually considered dirty helps populate a helpful microbiome (most often gut, but plausibly also skin, and occasionally eyeball), and that reduces allergies. This is more properly known as the Old Friends hypothesis, but everyone I know combines them.
Pushback on the idea that everything children touch should be super sanitized
The idea that eatingdirt in particular is beneficial for children for vague allergy-related reasons.
I went into this research project very sold on the Hygiene Hypothesis (broad sense), and figured this would be a quick due diligence to demonstrate it and get some numbers. And it’s true, the backing for Hygiene and Old Friends Hypothesis seems reasonably good, although I didn’t dig into it because even if they’re true, the whole eating dirt thing doesn’t follow automatically. When I dug into that, what I found was spurious at best, and what gains there were had better explanations than dirt consumption.
This post is not exhaustive. Proving a negative is very tiring, and I felt like I did my due diligence checking the major books and articles making the claim, none of which had a leg to stand on. Counterevidence is welcome.
Evidence
Being born via c-section instead of vaginally impoverishes a newborn’s microbiome, and applying vaginal fluid post-birth mitigates that
This has reasonable pilot studies supporting it, to the point I mentioned it to a pregnant friend.
There are reports that a mother’s previous c-sections lower a newborn’s risks even further, but I suspect that’s caused by the fact below
Having older siblings reduces allergies
Study. The explanation given is a more germ-rich environment, although that’s not proven.
Daycare reduces later allergies, with a stronger effect the earlier you enter, unless you have older siblings in which case it doesn’t matter
Study. Again, there are other explanations, but contagious diseases sure look promising.
Living with animals when very young reduces allergies
This one is a little more contentious and I didn’t focus on it. When the animal appears seems to matter a lot.
One very popular study used to bolster Dirt Eating is a comparison of Amish and Hutterite children. Amish children get ~⅙ of the allergies Hutterite children do, which pop articles are quick to attribute to dirt “because Amish children work on farms and Hutterite children don’t.” But there are a lot of differences between the populations: dust in Amish homes have 6x the bacterial toxins of Hutterite homes, the children have much more exposure to animals, and drink unpasteurized milk.
Limitations of Farm Studies
Even if Amish children did eat more dirt and that was why they were healthier, there’s no transfer from that to urban parks treated with pesticides and highwayexhaust. They might be net positive, the contaminants might not matter that much, your park in particular might be fine, no one has proven this dirt is harmful, etc. But you should not rest your decision on the belief that that dirt has been proven beneficial, because no one has looked.
Mouse Studies
There are several very small mouse studies showing mice had fewer allergies when exposed to Amish dirt, but:
They are very small.
They are in mice.
The studies I found never involve feeding the mice dirt. Instead, they place it in bedding, or directly their nasal passages, or gently waft it into the cage with a fan.
So eating dirt is bad then?
I don’t know! It could easily be fine or even beneficial, depending on the dirt (but I suspect the source of dirt matters a lot). It could be good on the margin for some children and bad for others. Also, avoiding a constant battle to keep your toddler from doing something they extraordinarily want to do is its own reward. What I am asserting is merely that anyone who confidently tells you eating arbitrary dirt is definitely good is wrong, because we haven’t done the experiments to check.
I think any of [communicable diseases, animals, unpasteurized milk] have more support as anti-allergy interventions than dirt, but I hesitate to recommend them given that a high childhood disease load is already known to have significant downsides and the other two are not without risks either.
Epilogue
The frightening thing about this for me is how this became common knowledge even, perhaps especially, among my highly intelligent, relatively authority-skeptical friends, despite falling apart the moment anyone applied any scrutiny. I already thought the state of medical knowledge and the popular translation of that knowledge was poor, but somehow it still found a way to disappoint me.
This post was commissioned by Sid Sijbrandij. It was preregistered on Twitter. I am releasing it under the Creative Commons Attribution 4.0 license. Our initial agreement was that I would be paid before starting work to avoid the appearance of influence; in practice I had the time free and the paperwork was taking forever so I did the research right away and sat on the results for a week.
Thanks to Miranda Dixon-Luinenburg for copyediting.
Scott Alexander has published a post on long covid, which he rates as much more frequent and dangerous than I do. Scott and I spent a while hashing this out in private, and our cruxes seem to come down to:
I think his studies are too small and sample-biased to be meaningful.
He thinks my studies (especially Taquet) didn’t look at the right sequelae.
I was only looking at cognition (including mood disorders), whereas he looked at everything.
Scott also didn’t do age-specific estimates, although that’s not a crux because I expect other post-infection syndromes to worsen with age as well.
I intended to include fatigue in my analysis of cognitive symptoms but in practice the studies I weighted most highly didn’t include them. Scott’s studies, which he admits are less rigorous although we differ on how much, did include them. Why the hell aren’t the large, EHR-based studies with control groups looking at fatigue?
Also, this isn’t relevant to the covid disagreement, but I baffled by the medical systems’ decision to declare chronic Lyme in particular as the definitely psychosomatic syndrome, given that Lyme is closely related to syphilis, which we know damn well has a long dormant period and a stunning array of possible long term consequences.
Although I didn’t update much on this particular disagreement, I have a lot of respect for Scott and encourage anyone making decisions based on bloggers’ estimates of the risk of long covid to check out his post as well.
Last week I did some math on the risk/reward profile of exercising indoors (risking covid exposure) vs. outdoors (risking exposure to smoke from the CA fires), and found the numbers for the day I did the math (low-for-fire-season pollution outside, sparsely populated indoor gym) overwhelmingly favored exercise of any kind over not exercising, and any other factor was overwhelmed by how likely it was to create friction to exercising.
Over on Facebook, a friend pointed out that I’d left out the biggest cost of exercise: the time in which it took place. I then realized a full accounting would also include the time to get to the gym and the risk of getting hit by a car en route. And was I sure the micromort estimate for exercise incorporated the risk of injury? (no, because the data is hidden in an appendix BJM paywalled and sci-hub doesn’t have. If you have BJM access and would like to help me out by emailing me (elizabeth@acesounderglass.com) the appendix for this article it would be much appreciated. EDIT: received and responded to. Thanks Steve!). But exercise has benefits beyond dying later, and I wasn’t fully accounting for any of those either. And time spent at or traveling to work out isn’t exactly lost: zipping around on my scooter is fun, and leaving my house regularly on some sort of schedule has been good for me. This gets unwieldy really quickly.
Nonetheless, time spent traveling and the accompanying risk of car accidents seemed really significant, so I updated the spreadsheet to incorporate it. Ignoring any positive effects beyond the microlives, this was enough to make going to my gym for cardio net costly (note: because the spreadsheet measures in micromorts a positive number is bad), although going to the gym for weights and my nearby friend’s backyard for cardio still come out ahead.
I still think gym cardio is net beneficial for me because I think my exercise is much more impactful than average. But I don’t think it’s so much more beneficial than my friend’s backyard treadmill, so I’m going to emphasize the latter except on very bad smoke days.
Since my last dental appointment (3 months ago), I’ve cleaned one half of my mouth with a water pick (in addition to brushing on both sides), with the goal of determining if it actually did anything useful. I was inspired by my dentist’s insistence that I Do Something despite not noticing when I consistently used the pick. I pre-registered on Facebook that if the hygienist spontaneously commented that one side looked better, or some objective measure like # of cavities was different, I would consider it evidence in favor of the water pick. Today was the appointment.
Final results:
Hygienist didn’t comment either way.
No new cavities on either side
Gum pocket measurements were worse on the water picked side.
Obviously one trial isn’t conclusive, but I’m giving up on the water pick. Next step: test flossing.
Edit 7/20/17: See comments from the author about this review. In particular, he believes I overstated his claims, sometimes by a lot.
This is part of an ongoing series assessing where the epistemic bar should be for self-help books.
Introduction
Thesis: increasing your physical capabilities is more often a matter of teaching your neurological system than it is anything to do with your body directly. This includes things that really really look like they’re about physical constraints, like strength and flexibility. You can treat injuries and pain and improve performance by working on the nervous system alone. More surprising, treating these physical issues will have spillover effects, improving your mental and emotional health. A Guide To Better Movement provides both specific exercises for treating those issues and general principles that can be applied to any movement art or therapy.
The first chapter of this book failed spot checking pretty hard. If I hadn’t had a very strong recommendation from a friend (“I didn’t take pain medication after two shoulder surgeries” strong), I would have tossed it aside. But I’m glad I kept going, because it turned out to be quite valuable (this is what triggered that meta post on epistemic spot checking). In accordance with the previous announcement on epistemic spot checking, I’m presenting the checks of chapter one (which failed, badly), and chapter six (which contains the best explanation of pain psychology I’ve ever seen), and a review of model quality. I’m very eager for feedback on how this works for people.
Chapter 1: Intro (of the book)
Claim: “Although we might imagine we are lengthening muscle by stretching, it is more likely that increased range of motion is caused by changes in the nervous system’s tolerance to stretch, rather than actual length changes in muscles. ” (p. 5).
Overstated, weak. (PDF). The paper’s claims to apply this up to 8 weeks, no further. Additionally, the paper draws most (all?) of its data from two studies and it doesn’t give the sample size of either.
Claim: “Research shows the forces required to deform mature connective tissue are probably impossible to create with hands, elbows or foam rollers.” (p. 5).
Misleading. (Abstract). Where by “research” the Hargrove means “mathematical model extrapolated from a single subject”.
Claim: “in hockey players, strong adductors are far more protective against groin strain than flexible adductors, which offer no benefit” (p. 14).
Misleading. (Abstract) Sample size is small, and the study was of the relative strength of adductor to abductor, not absolute strength.
Claim: “Flexibility in the muscles of the posterior chain correlates with slower running and poor running economy.” (p. 14).
Accurate citation, weak study. (Abstract) Sample size: 8. Eight. And it’s correlational.
[A number of interesting ideas whose citations are in books and thus inaccessible to me]
Claim: “…most studies looking at measurable differences in posture between individuals find that such differences do not predict differences in chronic pain levels.” (p. 31).
Accurate citation. (Abstract). It’s a metastudy and I didn’t track down any of the 54 studies included, but the results are definitely quoted accurately.
Chapter 6: Pain
Claim: “Neuromatrix” approach to pain means the pattern of brain activity that create pain, and that pain is an output of brain activity, not an input (p93).
True, although the ability to correctly use definitions is not very impressive.
Claim: “If you think a particular stimulus will cause pain, then pain is more likely. Cancer patients will feel more pain if they believe the pain heralds the return of cancer, rather than being a natural part of the healing process.” (p93).
Claim: On taking some cure for pain, relief kicks in before the chemical has a chance to do any work (p98)
True. His source for this was a little opaque but I’ve seen this fact validated many other places.
Claim: we know you can have pain without stimulus because you can have arm pain without an arm (p102).
True, phantom limb pain is well established.
Claim: some people feel a heart attack as arm pain because the nerves are very close to each other and the heart basically never hurts, so the brain “corrects” the signal to originating in the arm (p102).
First part: True. Explanation: unsupported. The explanation certainly makes sense, but he provides no citations and I can’t find any other source on it.
Claim: Inflammation lowers the firing threshold of nociceptors (aka sensitization) (p102).
Claim: nociception is processed by the dorsal horn in the spine. The dorsal horn can also become sensitized, firing with less stimulus than it otherwise would. Constant activation is one of the things that increases sensitivity, which is one mechanism for chronic pain (p103).
Claim: people with chronic pain often have poor “body maps”, meaning that their mental model of where they are in space is inaccurate and they have less resolution when assessing where a given sensation is coming from (p107).
Accurate citation (source). This is a combination of literature review and reporting of novel results. The novel results had a sample of five.
Claim: The hidden hand in the rubber hand illusion experiences a drop in temperature (p109).
Accurate citation, tiny sample size (source). This paper, which is cited by the book’s citation, contains six experiments with sample sizes of fifteen or less. I am torn between dismissing this because cool results with tiny sample sizes are usually bullshit, and accepting it because it is super cool.
Claim: “a hand that has been disowned through use of the rubber hand illusion will suffer more inflammation in response to a physical insult than a normal hand.” (p. 109).
Almost accurate citation (source). The study was about histamine injection, not injury per se. Insult technically covers both, but I would have preferred a more precise phrasing. Also, sample size 34.
Claim: People with chronic back pain have trouble perceiving the outline of their back (p. 109).
Claim: “Watching the movements in a mirror makes the movements less painful [for people with lower back pain].” (p. 111). Better Movement. Kindle Edition.
Reminder: the model is that pain and exhaustion are a product of your brain processing a variety of information. The prediction is that improving the quality of processing via the principles explained in the book can reduce pain and increase your physical capabilities.
Simplicity: Good. This is not actually simple model, it requires a ton of explanation to a layman. But most of its assumptions come from neurology as a whole; the leap from “more or less accepted facts about neurology” to this model is quite small.
Explanation Quality: Fantastic. I’ve done some reading on pain psychology, much of which is consistent with Guide…, but Guide… has by far the best explanation I’ve read.
Explicit Predictions: Good, kept from greatness only by the fact that brains and bodies are both very complicated and there’s only so much even a very good model can do.
Useful Predictions: Okay. The testable prediction for the home-reader is that following the exercises in the back of the book, or going to a Feldenkrais class, will treat chronic pain, and increase flexibility and strength. Since the book itself admits that a lot of things offer short term relief but don’t address the real problem, helping immediately doesn’t prove very much.
Acknowledging Limitations: low. (Note: author disputes this, and it’s entirely possible he did and I forgot).GTBM doesn’t have the grandiose vision of some cure-all books, and repeatedly reminds you that your brain being involved doesn’t mean your brain is in control. But there’s no sentence along the lines of “if this doesn’t work there’s a mechanical problem and you should see a doctor.”
Measurability: low. This book expects you to put in a lot of time before seeing results, and does not make a specific prediction of the form they will come in. Worse, I don’t think you can skip straight to the exercises. If I hadn’t read the entire preceding book I wouldn’t have approached them in the correct spirit of attention and curiosity.
Hmmm, if I’d assigned a gestalt rating it would have been higher than what I now think is merited based on the subscores. I deliberately wrote this mostly before trying the exercises, so I can’t give an effectiveness score. If you do decide to try it, please let me know how it goes so I can further calibrate my reviews to actual effectiveness.
You might like this book if…
…you suffer from chronic pain or musculoskeletal issues, or find the mind-body connection fascinating.
How much would it suck to be the guy who invented sulfa drugs? You dedicate your life to preventing a repeat of the horrors you saw in the war, succeed in that and so much more, and then 10 years later some idiot leaves a petri dish open and completely replaces you as the father of man’s triumph against bacteria. Actually he left the lid off before you found your thing, but ignored the result until you hit it big because everyone knew you couldn’t fight disease with chemicals, until you proved you could. It’s the ultimate silver medal. The Demon Under the Microscope is the tale of that guy.
It’s by the same author (Thomas Hager) as The Alchemy of Air. It’s also set in the same corporation, and about field that was transforming from science to industry. The writing style is similar. I originally didn’t intend to fact check this book very hard because I already knew what to expect from the author (a little too invested in the subject but basically accurate), but the habit is too ingrained at this point and I couldn’t keep reading until I’d checked out the first few chapters.
Evaluation
Claim: “Domagk [the researcher] had the ability to see. He watched everything, noted slight variations, quietly filed it all away.” (p. 18).
The wounds themselves he accepted as the results of war. But the infections that followed—surely science could do something to stop those. He focused on the bacteria, his personal demons, “these terrible enemies of man that murder him maliciously and treacherously without giving him a chance.” “I swore before God and myself,” he later wrote, “to counter this destructive madness.” (p. 20).
Who knows but it’s pretty. Someone in the same position as thousands of others (in this case a WW1 medic), caring more , and going to fix it (via sulfa drugs) is my moral aesthetic. Of course there could be another surgeon in the same place with just as much care and potential who got blow up or gassed. The Alchemy of Airprioritized poetry over provability, so I don’t entirely trust this, but I like it.
Claim: Cholera was a big problem for German soldiers.
This would be a weird thing to make up, but I’m a little confused. There had been a cholera vaccine for over 20 years by that point.
Claim: Gas gangrene is bad.
True.
Claim: Sir Almroth Wright created a typhoid vaccine that was deployed during WW1, saving may lives. During WW1 he established a laboratory researching wound infections.
True. He was also prescient enough to foresee the risk of drug-resistant bacteria. Of course he also thought that bacteria were associated with but not the cause of disease, and that scurvy was caused by poorly preserved meat. Being right is hard.
Claim: Doctors at the time thought that a dry wound was more resistant to infection; however dryness inhibited white blood cells and thus ultimately increased infections. They also thought wounds needed to be completely covered to prevent reinfection, but this created the ideal environment for anaerobic bacteria like Clostridium perfringens (which causes gas gangrene).
True. I was surprised to find ideal wound moistness still isn’t entirely settled, but the book’s description seems essentially in good faith. Demon goes on to say that by the 1920s, doctors believed they were basically powerless and their job was to get the body’s own healing systems a pillow and some tea. They took this so far that:
“A physician doing drug research was a physician taken away from patient care. There was an unsavory aspect to a physician’s developing a drug for money. There were ethical questions about testing drugs on patients. Developing new drug therapies smacked of a return to the discredited age of bleedings and purgings.”
To repeat: researching new treatments was considered distasteful at best and morally outrageous at worst. And brain differentiation was once considered phrenology redux. I just don’t think we’re very good at seeing where medicine is going (p40).
Claim: Section on Leeuwenhoek.
True but missing time data. Given that everything discussed so far happened in the range of 1890-1920, I would have have explicitly mentioned I was going 250 years into the past. As it was, the only reason I noticed was that I recognized some of the names on the list of Leeuwenhoek’s contemporaries. The kindle edition may have made this worse. But everything Hager actually says on Leeuwenhoek’s work in inventing the microscope seems accurate.
Claim: [crickets] (no page)
There’s no false statements, but I found the absence of discussion of the 1918 Spanish Flu epidemic puzzling. Demon’s narrative is that seeing the horror of infected wounds in World War 1 drove Domangk to dedicate his life to preventing them. Spanish Flu killed 5% of the entire world over the course of three years, and had a massive effect on troop movements and training in WW1. From a military perspective it might have been more important. We know now that the flu is really hard to vaccinate against, but at the time they didn’t even know it was a virus. If you were a motivated medic looking for something to care about, Spanish Flu was a really obvious choice. Demon mentions Spanish Flu in passing but not as an influence on Domangk, and that feels incomplete to me. Why gangrene in particular, when there were so many horrors happening at the time?
Claim: Streptococcus is the cause of everything bad.
True. I knew it was possible to die from a scratch, but reading about everything strep causes really made me appreciate how few technological innovations are between us humans and mass die offs. Strep causes childbed fever, St. Anthony’s Fire, meningitis, scarlet fever, pink eye, necrotizing fasciitis… Strep is the cockroach of human-infecting bacteria. And for a while, all we had to do was take a pill and it was completely harmless.
Of course now we have MRSA (Methicillin-resistant Staphylococcus aureus) (whose natural habitat is the hospital, just like strep). And multiply resistant gonorrhea. And tuberculosis resistant to most known antibiotics. The bad old days are on our heels, is what I’m saying.
One weird thing is I finished this book with the vague impression that sulfa drugs had saved a lot of lives but not actually knowing how many. This article estimates that sulfa drugs led to a 2-3% drop in overall mortality, which translated to a 0.4-0.7 year increase in life expectancy. That only covers up until 1943: presumably it had a bigger impact as distribution increased, or at least would have if penicillin had not taken over.
Overall Verdict
Pretty good, with some oversights. Like Alchemy of Air the beginning is the best part, and if you find your attention flagging I’d just let it go. I found the subject matter more innately interesting than Alchemy of Air but the writing a little less so. Demon spends less time on the personal lives of the scientists, which was a selling point for my roommate but a disappointment for me.
I am in the middle of a post on Dreamland (Sam Quinones) and how it is so wrong, but honestly I don’t think I can wait that long so here’s an easily encapsulated teaser.
On page 39 Quinones says “Most drugs are easily reduced to water-soluble glucose…Alone in nature, the morphine molecule rebelled.” I am reasonably certain that is horseshit. Glucose contains three kinds of atoms- carbon, oxygen, and hydrogen. The big three of organic chemicals. Your body is incapable of atomic fusion, so the atoms it starts with are the atoms it ends up with, it can only rearrange them into different molecules. Morphine is carbon, oxygen, hydrogen, and nitrogen, and that nitrogen has to go somewhere, so I guess technically you can’t reform it into just sugar. But lots of other medications have non-big-3 atoms too (although, full disclosure, when I spot checked there was a lot less variety than I expected).
This valorization of morphine as the indigestible molecule is equally bizarre. Morphine has a half-life of 2-3 hours (meaning that if you have N morphine in your body to start with, 2-3 hours later you will have N/2). In fact that’s one of the things that makes it so addictive- you get a large spike, tied tightly it with the act of ingestion, and then it goes away quickly, without giving your body time to adjust. Persistence is the opposite of morphine’s problem.
This is so unbelievably wrong I would normally assume the author meant something entirely different and I was misreading. I’d love to check this, but the book cites no sources, and the online bibliography doesn’t discuss this particular factoid. I am also angry at the book for being terrible in general, so it gets no charity here.
Aceso Under Glass 