I'm not sure it's sufficiently widely appreciated how important the liver is, and how much we stress the shit out of it by asking it to dispose of all the weird things we eat, drink, short, or inject. The more I learn about the liver does, the more I want to take tender care of the beast -- you OK in there? Need more of this, a little less o' that? Anything you want ol' buddy...
I mean, we almost all die of atherosclerosis or cancer, and you wouldn't *think* that has a lot to do with the liver, but...who's to say it does not? All those lipoproteins that people fuss over, where there's a direct connection to CAD, that's traffic to and from the liver. And the immune cells that are supposed to kill off baby cancers, they're trained in the liver. Maybe if you mistreat your liver for a few decades it starts malfunctioning in certain ways that turn up as your arterioles narrowing and your immune system slacking off. Not good.
CD56 bright NKs are trained in the liver? I mean technically it's the first site of hematopoiesis during development but they're the first cells to pop up after a bone marrow transplant. I def think it's circulating NKs that establish themselves there. Also NK cytotoxicity is based on MHC presentation/T cells are trained in the thymus/B cells either die naively or are selected for by dendritic cells through somatic hypermutation (definitely learn, don't tell the intelligent design people).
You can download Janeway's immunobiology on Libgen*/I'm hoping the pandemic increases public scientific literacy on immunology because my main goal in life is to not have job security. NKs are actually super sensitive to sleep deprivation!/will be depleted and your body will upregulate immunoglobulins across the board.
*It's super readable and fun and once you understand all the inputs into the immune system everyone saying everything makes a difference in everything makes way more sense and also there's a new edition coming out in February. Technically 17β-estradiol helps if you're exposed to COVID, but I'll eat my hat the day Bret Weinstein starts promoting that.
I just learned that circulating spike protein can induce inflammation independent of viral infection, even independent of a binding ACE2 receptor (murine). So, I have come to the realization, for the Nth time in my life, that I understand nothing of biology. It will take a while for my self-delusion to wind back up again until I have any opinion about anything biological.
This is off topic, but in another thread you said you have a very good memory because of a genetic difference... Aha, found the comment:
“...inherited two copies of protein that can only be transcribed as a specific isoform that always stabilizes this kinase involved in presynaptic facilitation so that my memory...”
If this is not too personal of a question, what protein and SNP/allele is that?
He may be DOCTOR WITH A DOT, but he doesn't seem to have heard of isomers.
I got that far in his video then skipped through the rest. If the guy honestly thinks "pooh, dropping a few bonds in this molecule versus this molecule makes no difference, they both are the same molecule and work the same way (and so this proves that Pfizer's new drug and ivermectin are one and the same, and I'm not saying there is a conspiracy to keep a cheap, sure cure hidden while the big drug company creates an expensive 'new' drug, but..... ", then he's about as reliable as a leaky bucket.
The normal convention is not to mark an abbreviation ending in a lower case letter with a full stop/period if that letter is the last one in the word. So Dr against Prof. would be correct.
And before anyone asks, I have no idea why. But it's been in every academic style guide I've ever read.
Credibility probably reaches a minimum at three titles and then starts going up again. I'd actually be interested to hear what this guy with three doctorates and a knighthood has to say.
Past three, there would need to be a rule to Google each initialism, lest you find yourself unduly impressed by the medical judgment of a Member of the Association of Accounting Technicians or a Fellow of the Institution of Agricultural Engineers.
Does a "nurse educator" require good scientific knowledge? In the UK nurses have until recently not prescribed and were expected to follow instructions on drug delivery. It seems unlikely that someone who was presumably a lecturer on nursing from three generations ago would be expected to have any expertise in pharmacology, although clearly it can't be ruled out.
His expertise looks to be physiology, which is a very different field from pharmacology. He may be good at the latter but there's nothing there to necessarily suggest it, and people on this thread are pointing out worrying weaknesses in his arguments. I am thinking there's a high probability he does not have the pharmacological expertise needed to make the claims he's making.
Note in particular his training and career were at institutions (Bolton and Cumbria) focused on training and that don't therefore prioritise staff research. In US terms you're looking at the small state college/well-ranked community college level. I'm not suggesting staff working in these places are not intelligent or competent, but Dr Campbell's career path does not look like one that involved much development of transferrable research skills, as indeed might be suggested the fact his only notable publication (admittedly according to Wikipedia) is a teaching text.
Therefore I don't think the credentials here are particulary relevant, and certainly not enough to shift my opinion of Dr Campbell's likelihood of being correct.
Are you serious? I watched the Ivermectin video. Claiming that Ivermectin has similar clinical effect to Paxlovid just because they have similar putative MOA does not reflect well on Dr. John Campbell. And, this is assuming that you actually believe the MOA is actually correct, which is pretty bold. It was a couple decades before it was shown that statins don't work (to the extent they do work) by reducing serum cholesterol, even though that was gospel for many years. This is why well run RCTs are so important. It is just not possible to fully predict how a drug will work in a human just by doing a few experiments in cell culture. It's not even possible to predict if the drug will get to the cells, let alone the right compartment in the cell, by looking at stick structures, or even full-on 3d structures. Drug discovery would be infinitely easier if it were so, but it's a real slog because Every. Little. Thing. has to be proved out in humans. Dr. John is not going to prove anything by just looking at a bunch of lab papers. Giving advice to "world leaders" based on in-silico calculations of binding affinities (which are notoriously unreliable) shows a real naivety. He also confuses Fluorine with Fluoride, a sign that he's not a chemist. I recommend Derek Lowe's blog (it's on Scotts blogroll) for the perspective of an honest-to-god, in the trenches, medicinal chemist's view of how much (or little) you can get from these MOA arguments (and in-silico calculations). Dr. John is going to need a bunch more letters after his name before I would give him a second look.
Serious about taking Dr. John seriously. He just goes through a bunch of mechanism papers, which have little relevance. The ironic thing is he actually put up the Pfizer press release (which he thinks is a paper) and then proceeds to ignore the main result, which is that Paxlovid works really well to keep people out of the hospital and alive. So well that they met their significance goal (and FDA agreed) early and could halt the trial. In the face of that, all those in vitro studies don't add or detract from the value of the drug. And if you want to cast aspersions on people's devotion to scientific truth, go back and read Scott's magnum opus on all the Ivermectin papers. He had to throw out half of them because they were so bad you couldn't draw any conclusions from them, or they were just outright fraudulent.
"Now, I don't always follow the details of these statistical analyses" @ 12:10 in the video. He appears to be confused about a very basic statistic from the bayesian analysis in the TOGETHER trial on fluvoxamine. There's a nice graph of it in Figure 2 of the paper. So now I'm convinced he's not well versed enough in either chemistry or math to be explaining the results of a clinical trial. He goes on to the result on the odds ratio of death of treatment vs control (If you're following along at home, this is line 8 of table 3), which is given as 0.68 (17 vs 25 deaths), CI95% [0.36 - 1.27], which he thinks it great because it's a 32% reduction in death! Yea!. Of course he doesn't understand that hi brow statistics stuff, so he completely ignores the p=0.24 (basically meaningless) and the fact that the CI includes a 27% INCREASE in death due to fluvoxamine. He then goes on to emphasize that this is for "very low risk" (i.e. fluvoxamine is known to be a safe drug) right after he just got showing us that the data doesn't rule out an increased risk of death due to fluvoxamine! Now, I don't believe that fluvoxamine has much effect either way, which is what that pathetic p value is saying. But if he's going to put up a bunch of stats to convince you it's safe and worthwhile to take, then he better explain why the numbers aren't agreeing with his commentary.
If you like this guy's style, then by all means watch it as light entertainment, but for God's sake, don't think you're going to get any smarter by listening to him.
Does the Recovery trial make a small step in the direction that you're suggesting, by incorporating a testing regime into ongoing medical treatment? I believe the people who designed this trial want to extend this sort of testing beyond Covid-19. https://www.recoverytrial.net/
Derek Lowe, in his blog, pointed out that that, given the success rate of new candidate drugs, if you're in a drug candidate review and just keep shaking your head saying "that will never work" (said in an Eeyore voice), you will almost certainly be right, and definitely be useless.
Sime critics od Scotts love for prediction markets told the same story recently: if one is just conservative - not important if its tomorrows weather (most people same like today) or tomorrows universe (most probable like today's) one will be mostly right in it's predictions. That's the nature of doing infinitesimal small steps on the one hand. And the nature of our pretty stable environment: no dangerous changes most of the time. The critic like Take was pointing out that most of us humans are not aware and cannot deal with long-time stable environments interrupted by very rare, extreme events. We now call it black swans after Taleb. And some of us have like a 6th sense of all kinds of black swans which could come upon us. Most others havent. Evolution is so fascinating.
When "rationalists" want to use a (presumably) less shitty/more ethical platform, they post on lesswrong.com, but the maximum (and I think also the minimum, mean, and median) number of people who will see your post on lesswrong.com is very small.
And for good reason most likely. I gave LW a second shot recently and noped out again when I noticed Eloser had insisted that a chicken can't suffer if the GPT3 can't suffer. He then went on to imply anyone who disagreed with him was stupid. Any platform featuring that guy so prominently is pretty objectively worthless.
Kidney load, cost? Also a lot of those supplements legitimately do have side-effects (though they probably attenuate with usage), I can't imagine what taking 250 would make me feel.
I wasn't really considering (or not considering!) taking 250 supplements, I was just gesturing towards the whole idea being talked about here. If 250 supplements have probabilistic costs that outweigh the potential probability of benefits, then that course of action is not even on the table for a Pascalian wager.
Depending on the condition you’re looking to treat, that kind of 500-to-one difference in chance to work vs. chance to kill might actually be reasonably attractive.
It depends on what the supplements are and the dosage. We easily take 250 supplements a day in the course of normal living - they are in the food we already eat. Some of them have pretty nasty side effects, too, especially in large doses.
“Struggling with Pascal’s wager” is the natural state of the world I think! It leads you to very strange places. Now that we have pascalian medicine, it’s time for the more extreme Roko’s Basiliskian medicine. Let’s see what supplements I can get you on by telling you there’s a small probability that not taking them will cause you to be tortured for all eternity.
I feel like the response to this is something we do every day. There are a million things I could be doing to decrease my risk of X or increase my chance of Y, but if I were to actually do all of these things that would result in an enormous cumulative cost, so the sensible thing to do is set a probability threshhold below which the cognitive load of taking everything below that seriously leads to worse outcomes and less focus on things with high confidence than the benefits of caring about all plausible things. This is why I don’t wear a cloth mask anymore
I always felt the ‘pascals’s wager’ part of this was obvious and a particularly important component in stopping COVID-19 in a world where some people will not take the new vaccines no matter what. Even if these treatments only have a 1% chance of making things better (and it seems higher than that to me), it’s better than the 0% we get in the current hyper-partisan world we inhabit. Not to mention the meta benefit of tamping down the divisive rhetoric. I’ve long felt the ‘vaccine only’ crowd is living in the world they wish existed and not the one that we’re actually inhabiting. Anyway, that’s my obscene, unenlightened $.02.
You should not overlook the cost and value of information, particularly for the future. One reason we tend to do things carefully and step by step, instead of throw everything against the wall and try to sort out post-facto what sticks, is that this is the *fastest* way to the best quality information about what works and what doesn't. We are doing massive medical experiments on people, and the way to make those experiments give the most definitive answers as fast as possible is to be very careful about the experiment and control arms.
We are, in essence, trading potential present benefit (to the lives and health of those currently alive) for the benefit of acquiring reliable information that the future can use to the lives and health of those alive then. That's the trade-off.
Information, particularly reliable information, is very, very expensive. But also of course very, very valuable. We are the beneficiaries of our forefathers' painful experiments that eventually proved disease is caused by bacteria and not miasmas, that bleeding and cupping don't work, that drinking mercury to cure your intestinal ailments is a Bad Idea, that trephining the skull to let the evil spirits out doesn't cure madness, that "hysterical" women don't have a malfunctioning uterus -- and on and on.
All the insane ideas of the past at one time seemed reasonable to the professionals and amateurs alike, and a well-informed person living in those times would've said they had more than a 5% chance of being correct. But the only way we found out they *didn't* work, at all, and put a stop to centuries of medical butchery, is by insisting on rigorous and well-controlled experiment, which approach rules out a "Why not give it a try?" approach at the social level.
I would say whether you want to try it at the individual level rests on whether you feel like random interverntion in your biochemistry is more likely to do harm than good. As someone who works occasionally with highly-tuned complex machines, like performance car engines, I find the proposition laughable -- if I randomly poke or prod something in an engine it is almost certainly going to make things worse -- but this is just an instinct, not an argument, and others can easily have different instincts for different reasons.
> As someone who works occasionally with highly-tuned complex machines, like performance car engines
I would expect engines to be very finetuned to operate in one specific way, while living organisms being far more flexible and resistant.
For example human can eat nearly pure fat or nearly pure sugar and survive at least for some time.
Liver can process a lot of problematic chemicals and so on. Though I agree with
> I would say whether you want to try it at the individual level rests on whether you feel like random interverntion in your biochemistry is more likely to do harm than good
Well, yes and no. For example, engines are designed to operate in a variety of operating temperatures, and under varying loads. That's part of the design spec, so engineers make the engine "flexible" in that it can perform well under varying load, for example. (And if you were making an engine for a different application, like a generator, you wouldn't worry about this.)
And sure arguably evolution has made our biochemistry flexible and able to perform under varying conditions, in exactly the way you describe.
But here's the thing: just as the engineer doesn't think about how to design an engine that can operate in air or under water, because he says what kind of madman would drive his car into a lake and expect it to work? Nature has *not* optimized our biochemistry to work with highly unusual chemical insults that don't occur naturally.
So we're probably indeed pretty flexible with respect to varying amounts of naturally-occuring substances[1] -- a lot or a little vitamin D, curcumin, ethanol -- it's not clear at all to me that we're flexible with respect to substances that *don't* occur naturally in our diets (like ivermectin and HCQ and SSRIs). Why would we be? Like the cars not being driven under water, this hasn't happened in our history and so the Great Designer had no occasion to design for it.
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[1] Of course, it then also logically follows that varying these things isn't likely to have a big effect. If we can maintain homeostasis in the face of widely varying levels of vitamin D, for example, that implies varying the level of vitamin D doesn't do much. So, ironically, if the body can deal easily with it, it probably doesn't do much, and if it does much (e.g. actually effective medicine) it's probably something which you have to use very carefully because the body isn't flexible about it.
FWIW, I've been told that chronic mild overdoses of vitamin D is positively associated with bone spurs. Of course, that takes a few years to show up. And chronic underdoses of vitamin D is known to cause a multitude of problems, some of which take years to show up. But there's a large area in between those two positions that isn't associated with the relevant problems. (Well, it's enough less associated with them that it can be ignored.)
Note: This is all based on "I've been told". I'm not asserting that it's true, but it sounds plausible to me.
> Nature has *not* optimized our biochemistry to work with highly unusual chemical insults that don't occur naturally.
Nature managed to produce quite wide-range generic solution which is not ideal but works relatively well.
> it's not clear at all to me that we're flexible with respect to substances that *don't* occur naturally in our diets (like ivermectin and HCQ and SSRIs). Why would we be?
To be more resistant to various novel poisons? Liver is quite amazing at dealing with wide range of chemicals.
Though, obviously, there are many thing that will be too much (try eating random mushroom and you will die).
Truly outside context chemicals like plutonium will be deadly for obvious reasons with few exception of things that evolved to handle it (or even use it!).
This presupposes that we’re capturing detailed and useful data. I’m not convinced but surely it isn’t nothing.
The other aspect is that taking Ivermectin, for example, is nothing like drinking mercury. Billions of doses have been administered over the course of this drug’s existence; it’s as safe as we can possibly make drugs. Combining it with zinc, vitamin D, etc. is super duper low on the risk table and we know it…that’s why it should have been promoted, or at least not ridiculed, mocked and disparaged.
> From the Inside View, I have a lot of trouble looking at a bunch of studies apparently supporting a thing, and no contrary evidence against the thing besides my own skepticism, and saying there’s a less than 1% chance that thing is true.
I guess I don't understand why this is the case. In particular, what propertion of things that have at least that much evidence behind them are actually true? In this domain, where low-quality studies are omnipresent, it seems like it should indeed be less than 1%, so there's no problem.
I suppose that it feels intuitively weird to look at a not-exceptionally-bad scientific study and say that there's a >99% chance that it's wrong, but in fact we deal with things like that all the time in all domains. https://www.lesswrong.com/posts/Ap4KfkHyxjYPDiqh2/pascal-s-muggle-infinitesimal-priors-and-strong-evidence seems relevant (not the part about double exponentials, that doesn't apply here, but the part about how decillion-to-one chances crop up all the time).
Maybe the problem is just that a good study and an average study intuitively look similar-ish and like they should have similar-ish effects on our beliefs, even though in fact their Bayes factors differ by orders of magnitude? Maybe a person could cure themself of this intuition by reading enough average studies whose findings were later disconfirmed by good studies?
I think Scott, of all people, has read enough studies like that that if it were going to work, it already would have. Small probabilities are just hard to think about.
Apparently this is pretty common in drugs. If you read med chem blogs, they're stuffed with bitter and cynical people who think even when it looks perfect on paper, rock-solid mechanism fully fleshed out, passed Phase I through III trials with flying colors, the FDA wet itself with enthusiasm, sales are skyrocketing -- it might still end up killing little old ladies in some completely unforeseen way and cause the entire division to be wiped out and everyone fired after the first $1 billion lawsuit is settled. They expect almost nothing to work.
Seems to be relative in some sense to the fact that biochemistry is much more complex than we know about *and* the body is sort of build in a weird Rube Goldberg way in which everything is connected to everything, even when it makes no sense from a design point of view, so you *think* you're just interfering in this pathway over here, but unknown to you some (you thought) unimportant by product plays a critical role in some regulatory pathway way the hell over here, completely different system, and your whole scheme goes up in smoke.
I work in a field in the physical sciences where there are lots of publications, but most are good quality. If I had to guess, I would say that of the papers that claim that an observation or experiment says that doing/observing A indicates that B is true, I would be 80% to 90% confident that the claim is accurate and reproducible. For top-tier journals in our field, I would raise that to 95% confidence (although I would argue that number drops back down again for Science/Nature/PNAS for complex sociological reasons).
Part of the reason for this high confidence is that we take peer review seriously, and researchers would get a pretty poor reputation if they regularly publish results that fail to reproduce. Also, if I as a referee had low confidence that a paper was reporting reliable results, in the way that Scott suggests, with 5% or 1% or less confidence, I would never recommend publication. I realize that the social and financial incentives can be different in the life sciences, and there is a different journal ecosystem. But at the fundamental level, if the studies have very low reliability, why are the referees and editors allowing them to be published?
This is Ioannides's general argument in "Most Published Research Findings are False" - if you've got a p-value of 0.05 and a power of 0.8, and you expect that half of the things people would think to study with this sort of method are true, then your posterior for a study's finding to be true should be around 96% (unless I applied Bayes' theorem wrong, which is totally possible). But if your field is such that the vast majority of hypotheses are false, then even a perfectly done study with this good power and p-value should have a posterior less than 1/2 of being true. It may be that your field is one where studies are able to establish things with p value of 0.00000001 (this is common in physical fields where you have little noise and thus don't even bother running a statistical test because the data are blindingly obvious) in which case this doesn't matter. But in noisy fields (usually anything involving humans, especially masses of humans like in macroeconomics or epidemiology) even very high quality studies can't really get better than p value of 0.05 and power of 0.8.
Thanks, that definitely helps clarify these things. That's a better encapsulation of the statistical differences between the fields than I'd seen before.
I agree with that in general, but look at figure 2 of this paper on the Pfizer vaccine: https://www.nejm.org/doi/full/10.1056/NEJMoa2110345 and tell me that the p for that isn't < 10^(-1000) (each arm of that trial is >20,000 people). A real effect does stand out of the noise in biology, even medicine. A lot of the problem is that lots of papers are published about non-existent effects.
It's not 10^{-1000} but it is quite low. I think we flipped a coin 1,165 times (total number of covid cases in the trial) and got 1,034 heads (number of those cases that occurred in the placebo group). If I calculated right, this is "only" a p value of 10^-8 against a null that the vaccine has no effect.
Perforce. Every single data point in medical research is about 10,000x more expensive to acquire than in a laser spectroscopy experiment. So if you insisted on the kind of statistical power before publication in medical research as you can just casually assume in the realm of physical science research, there'd be no need for journals, because there'd be about 2 papers per decade that were worthy of publication. So in medicine you end up with averaging 10 (ten!) measurements and trying to figure out whether you've got something significant. All the statistical tools are deployed with a vengeance, because your noise level is inherently through the roof and you're trying hard to find a signal. It's understandable, if regrettable.
I know that this is the reason, but I think it's worth seriously asking if it wouldn't be more useful to have 1-2 papers a year that are 100% rock solid and undeniable rather than however many thousand papers we have now that are functionally worthless because they have 20 patients total?
Or maybe combine the two - have tiny exploratory trials that raise hypotheses for testing, current "big" trials that are like a silver standard and get drugs licenced, and giant, actually huge trials that give you p values in the 5 sigma range and definitively settle issues such that those topics don't need to be dredged up and rehashed over an over again in an interminable replication crisis?
Well *I* think so, but I'm a smartass in physical science, so I would. No skin off my nose, I don't need to build a career on a bit of research that has to go on for 5 years to have any result at all, and then it turns out not to work for obvious (in hindsight) reasons so we all look like idiots.
There's also the major problem of participant recruitment. People are just very unwilling to coldly roll the dice on their health, regardless of the logical inconsistency this indicates with respect to their daily lifestyle choices. The only trials in which people are generally willing to participate are those in which there is zero potential downside, even if that means there is also near-zero potential upside (which accounts for the vast supplement/neutriceutical market I think).
I mean, the best possible news (for the future) would be if we had a whole series of compounds that each had a 10% chance of extending your lifespan by 100 years and a 90% chance of killing you within 12 hours. Imagine if those trials were done. Presumably one would work out and the future would be amazing. Yay! But who the heck would sign up for the trials *now* in order to acquire the information?
Maybe. I tend to think people aren't especially realistic about death even when it is fast approaching. People who actually have days to live are thinking in terms of weeks. I've seen this a few times in my life and it's often sad, e.g. someone puts off a good-bye visit "until I feel a little better" in a week or two, but in two days it's all over.
The problem with the animal models are that they don't translate as well as we could hope, but yes that would be the best way to start fore sure.
Anyway, I'm just saying that our willingness, as a species, to do the kind of cold empirical experiments that would give us definitive answers to so many important questions -- what diet makes you live longer? what form of child-rearing optimizes the next generations' success/happiness? -- is drastically lower than our willingness to do those experiments in other areas. As soon as a whole human life (or quality of human life) becomes a realistic cost in the process of doing the experiment, we shrink away. "Let's settle this one by argument, shall we? That way nobody has to go into the control arm..."
Understandable, if a bit regrettable, in the sense that if our forefathers had the courage to do these experiments, we'd be much better off, and if *we* had the courage, our descendants would be better off. (But on the other hand, I'm not going to be first in line to volunteer either, so I don't blame anyone else.)
It seems to me that Algernon's law would not be violated in cases where a person is taking in less of the particular substance than was normal in the evolutionary environment. In other words, in a world where many people are low in Vitamin D, topping up would seem to be a good strategy with an even smaller chance of side effects.
In that case ... which of Kurzweil's 100 supplements do I have a reasonable chance of being deficient in?
Most vitamins and minerals, probably; some are safer to supplement that others, though - some excesses accrete, whilst others are excreted promptly. The only cost to taking everything in the later category is monetary. My limited understanding is that modern agriculture has lower vitamin and mineral contents in vegetables than was historically the case, do to effectively optimising them for calories per month at the expense of other things.
At a first pass: Vit D unless you work outdoors is almost a no-brainer; B12 has a mutation that hinders absorption in something like 40% of the population, and thus you have decent odds of being deficient (but the 60% with functional metabolisms don't need to bother). Fish Oil (aka EPA/DHA) is also a generally recommended one.
N.B. the primary concern with the supplement market is not a rare side effect of the vitamins you think you're taking, it's the risk that what's actually in the pills is not what's been claimed. The USA in particular has a very lax regulatory environment, though if you live in a more civilised country that's less of a concern.
IIUC, in at least one study the benefits of fish oil disappeared in a double blinded study. One hypothesis was that the folks who intentionally took fish oil were in other ways more careful about their diet and health. I never encountered a followup study.
Still, it's a greater than 1% chance, at least if you're a male, and thus less able to metabolise the plant derived variant.
(I encountered this in a couple of different articles in Science New over a decade ago, so I can't provide any additional details. But I've combined at least two different studies in my memories. I think one of them was about the sex based metabolism of omega-3s.)
The thing is, there's LOTS of these different choices. My wife siezed on the studies recommending chocolate, until I pointed out that these were unsweetened chocolate. Details matter. I don't think it's really possible to assign reasonable probabilities based on most studies, because they tend to be focused on one set of properties, and ignore other properties. There are probably always tradeoffs, and you won't know most of them. Did that turkey you ate for dinner live on antibiotics? What did that do the the microbes that it carries in its corpse. (Well, they probably didn't survive, but you needed to clean the turkey before cooking it, so they may have survived in you. Or some microbes are remarkably temperature resistant. Usually they don't harm people, but perhaps this time?) And of course if it didn't live on antibiotics, you get the same argument, but with a different selection of microbes. Or people have gotten salmonella from eating raw lettuce, but it could be something worse.
We don't know most of the chances we are taking. Clearly the probabilities of somethign disasterous happening are just about always way less than 1%, but we take thousands of chances every day, and we don't just live one day.
So. You're taking a pill that is labelled as being this chemical you've decided is a good chance. What are the odds that there's something else in that pill too? Something that doesn't appear on the label. Well, actually that's a near certainty, but usually it's nothing harmful, or at least obviously harmful. Isn't titanium dioxide safe? (It won't be on the label.) But I think I read one report on a study that associated titanium dioxide with cancer. How could you figure the odds for everything you don't know about, but could if you researched sufficiently?
Heuristic shortcuts are necessary. They usually work, but in general you can't assign accurate probabilities, and even when you can it usually isn't worth the effort.
So. Pascal's wager. Consider the original Pascal's wager. He didn't consider the chance that the real god was someone else who would be offended by his choice. He didn't even consider that the official Christian god would be offended by his choice (which some theologians think (or thought) he should). The entire argument is based around a falsely constructed set of alternatives consistent with the available evidence. And I feel the same thing is true of Pascal's medicine.
Just consider, there is a common disease of cats that causes those mammals to behave recklessly. And the available evidence indicates that it affects people the same way. This is an existence proof. What are the odds that one of those medicines doesn't have this exact same property? Nobody's even tested, or at least I haven't seen any reports. Did you factor this into your "bad effects estimate"? I doubt it. And there are scores of similar kinds of effects. Say 20% of those drugs have an effect that's at 20% of measurable strength. What happens when you combine those effects? (I'm not assuming the effects are the same. Perhaps one speeds up the reaction for one kind of neuron, and another slows the recovery time for a different kind of neuron, etc. Or, of course, they could directly reinforce [or interfere].)
This *doesn't* mean you shouldn't take the chance. It means you can't calculate the risks (or benefits).
Perhaps I phrased that poorly. I was talking about Toxoplasma gondii, and you're right, I don't know that it causes cats to behave recklessly. It's quite possible that all it does is make the smell of cat urine more attractive. But there are other parasites with various known behavioral effects, including things like sacculina, so there may well be others we haven't detected.
There's a strong argument that Algernon's Law does not apply to Vitamin D. The maintenance dose for the Spanish RCT studying Vitamin D for COVID is around 8000 IU/day. This is about what someone would get from 2 hours in peak direct sunlight shirtless. Hunter-gatherers probably got this or equivalent, but we clearly don't.
(State nutritional guidelines are calibrated for the amount needed to avoid rickets, i.e. severe deficiency, but D does more than just prevent rickets.)
Similar considerations favor vegetarians taking creatine, but not randos taking Ivermectin or SSRIs.
Thinking more about this; humans who left Africa, went to colder/cloudier parts of the world, and put on clothes quickly evolved lighter-coloured skin, despite the added risk of skin cancer. Is there any plausible mechanism for this strong selection pressure apart from Vitamin D absorption?
Melanin is metabolically expensive, it takes a lot of metabolic energy and raw materials to keep your skin dark. It's only worth it if it reliably prevents you from frying in the sun.
Ancient Dna data suggests that in Europe, there was strong selection to decrease melanin but quite late, about 10 000 -5 000 years ago, well after modern humans came into Europe (about 40 000 years ago). This suggests that melanin became unfavorable in Europe only after the switch to agriculture, which points to vitamin D more than to the cost of melanin synthesis.
I would've said the reverse. The problem of the Sun being weaker in the winter is immediate on moving to norther latitudes and has nothing to do with agriculture. On the other hand, arguments have been made that the switch to agriculture was driven in part by calorie scarcity -- hunter-gatherers get considerably more calories for a given level of exertion, as long as the population density and climate support the lifestyle at all. As I recall, people got noticeably shorter when they adopted agriculture, which points to poorer average caloric intake. Lower caloric intake would put a lot of pressure on any process that was metabolically expensive.
"I would've said the reverse. The problem of the Sun being weaker in the winter is immediate on moving to norther latitudes and has nothing to do with agriculture."
The argument was that we can get some Vitamin D from food, but only from animal one, and that transition to a grain based diet forced the early Europeans to rely entirely on the Vitamin D produced in the skin through sunlight.
"As I recall, people got noticeably shorter when they adopted agriculture, which points to poorer average caloric intake. Lower caloric intake would put a lot of pressure on any process that was metabolically expensive." I don't find that likely but it is more a hunch that anything else : it seems to me that pigmentation can not be a very metabolically expensive trait, and that the "saving" coming from producing less melanin has to be small. This does not seem compatible with the very strong selection on the alleles conferring lighter pigmentation in early Europeans ( same magnitude that the selection at the most strongly selected loci in the human genome, like lactase persistence or malaria resistance).
It wouldn't have occured to me at first either, but I recall coming across arguments along those lines some time ago, and found some of them fairly impressive, e.g.:
They mention a few points against the Vit D hypothesis (which they reject), including that evidence for rickets in early skeletal remains is sparse (if it were a general problem, you'd expect that in some areas no matter what there would've been too little), that depigmentation did not occur preferentially in areas more exposed to sun, and that supposedly unpigmented skin does not generate Vit D noticeably faster or more copiously than pigmented skin. The argument is essentially that enough Vit D can be obtained through a typical Paleolithic diet (e.g. with some fish or meat intake) and relatively limited spring/summer sun exposure, and so it would not have been a major force in natural selection.
The argument for the metabolic cost of melanin manufacture is buttressed by the observation that children with protein malnutrition (kwashiorkor) exhibit noticeable depigmentation, meaning the cost of pigment production is sufficiently noticeable to the body that it's minimized in periods of malnutrition, and that in animals somewhat related outcomes seem to point to the importance of conserving energy required for pigment production, e.g. the existence of eyeless animals in dark environments, related possibly to the energy cost for visual pigment production.
I'm not taking a position on which is likely to be true, just pointing out there are alternative hypotheses that seem to be worth considering.
Better camouflage in grayer (snowy, cloudy, foggy, no foliage) environments at daytime, perhaps? Easier to paint your face with camo (I'm actually not 100% sure, that's the case)?
Camouflage is a good explanation for arctic foxes and ice bears being white (though in their case, it's fur).
So why not humans, too?
Might matter more for hunting/not being hunted by megafauna, which in Africa coevolved to stay away from dangerous humans. And outside of Africa quickly went extinct.
The Inuit murder-replaced some older group that didn't have sled dogs. Could be that they were paler?
Also the Inuit have a tendency to store fat in their face as an adaptation to the cold, which... I think might be unique among all people? Maybe you can't be pale and have that kind of adpatation at the same time?
I tried googling "Inuit without clothes", but that just showed me... Inuit clothes. It's kinda hard to get a look at anything but their faces.
So who knows what skin color people have, if they never show skin.
Though probably the same hue, as the rest of the body?
I honestly don't know. But that might be broadly the correct assumption.
Just jumping in here to say that melatonin definitely, 100 percent works for sleep in at least some people and the fact that studies can't seem to prove it must be down to some weird confounder we haven't figured out yet. I went through a period of severe insomnia that was unresponsive to any of the "proven" drugs and melatonin cured it immediately and I can use it as necessary and get the same overwhelming therapeutic effect, in a way that no other pill even resembles. So there is certainly room in my ontology for effective therapies with idosyncrasies that defy straightforward investigation in RCTs. But there had better be very large signal buried in the overall noise.
I was actually talking about melatonin for COVID! Some people claim there are a few studies that show it works, though obviously I am skeptical.
Completely unrelatedly, there *are* a few people who claim melatonin doesn't work for sleep, but as far as I know they all work in writing insomnia guidelines - no normal human being is that dumb.
Well I'm glad to see the world has made progress since I was treated for insomnia, the doctors I saw back then never even mentioned it. I got the standard drugs, not Ambien but several others, and they all did jack. A friend suggested it and it was like flipping a switch. But apparently the clinical evidence is still mixed.
Something adjacent to the "worms" hypothesis seems even better for melatonin than for ivermectin -- way more people are sleep deprived in North American than have worms in India, and it seems at least as likely that healthy sleep will have a positive effect on immune function as that worm infestation will impair it.
So if melatonin improves sleep in some people, it will probably also reduce the severity of coronavirus infection in those people.
Melatonin made me depressed the next day, I believe. I wonder if anyone has a similar experience. Being tired and feeling sad are very correlated for me, I think.
There's definitely a hangover of sorts, particularly if you don't give yourself enough time to "sleep it off", as it were. It's not a panacea but it definitely works wonders for some people, myself included.
After reading Scott's thoughts on the matter, I started taking 300ug Melatonin 7 hours before desired bedtime. Felt weird, but not alarmingly so, for the first couple days, but then something clicked and now I sleep better, at the desired time.
Aren’t *multivitamins* arguably a form of Pascalian medicine familiar from many people’s experience? I used to take them every day. I give them to my kids. For any individual vitamin in them, I’d assign a relatively small probability that supplementing it does anything good — but a higher probability that at least one does. So maybe these 30 Pascalian covid treatments could just be bundled into an “anti-covid multivitamin”?
There was a discussion about this many years ago on LW and I took the exact same stance you have taken and what the Pascalian standpoint would encourage.
Yes, although there are surprisingly many studies showing that they don't help most of the things you'd expect them to help. Also, manganese is in them and might be slightly bad for you.
The main reason you can't bundle things is 1) the FDA would think of the bundle as a separate medication and you'd have to get it approved, which they would NOT do for something like this, and 2) you can only fit so many milligrams worth of stuff into a pill, and you'd probably need to take so many pills to get the whole bundle that you'd lose a lot of the one-pill advantage from bundling.
> Yes, although there are surprisingly many studies showing that they don't help most of the things you'd expect them to help.
There are a variety of explanations proposed for this. One of the big ones I'm familiar with is that the form of the minerals in the multivitamin matters for the body's ability to absorb them in the digestive tract. Multivitamin manufacturers tend to strongly favor oxides (e.g. zinc oxide, magnesium oxide, etc) because they're cheap, but the downside is that oxides tend to be much, much less absorbable than other forms (e.g. citrates and amino acid chelations).
Another is that many micronutrients compete with one another for absorption. E.g. if you take zinc, magnesium, and manganese all at once, your body will absorb less of each than if you'd taken the same doses of each spread out hours apart.
> Also, manganese is in them and might be slightly bad for you.
Particularly if you're prone to migraines. My wife and I both have manganese as a major migraine trigger, which we discovered the hard way after trying a new brand of protein shake that consistently triggered nasty migraines for both of us and which turned out to be fortified with large amounts of manganese as its main difference in ingredients that we could find from other brands that neither of us had problems with. Poking around online turns up a bunch of stuff suggesting that manganese is a fairly common migraine trigger.
>if I “know” that onion farmers doing studies will convince me that onions have a 5% chance of curing cancer, I should just believe there’s a 5% chance onions cure cancer now.
That doesn't follow, because the fact that people are doing studies about something is itself evidence that should raise your confidence that there's substance to it. It's weak evidence, but it might not be so weak that it can't get you to 5%.
Furthermore, this should depend on the motivation for the studies. Your hypothetical assumes, as a premise, that the studies are motivated purely by a desire to sell onions. But in the scenario "what you think when you see the studies?", you don't know motivation. It may be that if you're fully informed about everything, including the motivation for the studies, you won't think there's even a 5% chance, but being partly informed may falsely lead you to think there's a 5% chance.
To get specific, onion farmers are currently not doing studies on onions curing cancer, this probably has something to do with them doubting they can convince people onions cure cancer, and this probably has something to do with onions not curing cancer. In a world where they are running the studies, maybe that's because they have some inside information that onions really do cure cancer. After all, the cabbage farmers still aren't running any studies.
Maybe in Scott's hypothetical scenario it wasn't him that came up with the onion example, he just stumbled upon studies about onions curing cancer. But yeah he didn't clarify that so him picking onions out of a hat is some evidence that the 5% figure is way too high.
Who’s gonna tell this guy that more people died in the treatment arm of Pfizer’s vaccine trial with significantly more frequent cardiovascular events? Or that only one died of Covid in the control arm vs zero in the vaxx? Or that a Pfizer whistleblower presented very serious accusations of data falsification?
I would love nothing more than to be so innocently credulous towards companies that have paid tens of billions in fines for outright lying in recent years, in an industry whose marketing budget dwarfs any industry in human history, and who are fighting tooth and nail to hide the primary data on which these trials are based from public scrutiny for 55 years.
"Anyone who tells me info I haven't read in the New York Times is making shit up."
Which part? I’ll link you. Witnessing one of the last hyper-credulous media narrative trusters discovering the media has been willfully misleading him for the first time is a very rare these experience days, so I relish the opportunity.
Facts: Pfizer vaccine trial data: “Only 3 of the people in the trial died of Covid-related illnesses - 1 who received the vaccine, and 2 who who received the saline shot. “
In terms of overall deaths there were 6 MORE deaths overall in the vaccine group than in the placebo control group.
Those numbers don't sound statistically significant. 3 out of how many over what period of time, etc. It would also be useful if you linked a source for that data, so that if I thought is seemed worth checking, I could do so.
We've now effectively done the trial on a large portion of the population in developed countries. If there is significantly higher heart attack mortality we should see this on a population-wide level, both comparing vax to unvax and comparing this year to last year.
All cause mortality is massively up in every highly-vaccinated country. Incidents of young athletes collapsing on the field from heart attacks have been skyrocketing. They are attributing barely any of vaccine-induced deaths or injuries to the vaccine, because the vaccine is “safe and effective.” Look up the “Estimating Vaccine Induced Mortality” series on the “Rounding the Earth” Substack for a deep dive from a statistician lens.
"Incidents of young athletes collapsing on the field from heart attacks have been skyrocketing"
Looking that up, the top three stories on Google are all about young athletes developing myocarditis - *after* contracting Covid, recovering, and returning to playing their sport:
I agree that Covid is very dangerous. I just go one step further: the dangerous part of the virus (the spike protein) replicating trillions of instances of itself throughout the body (the mechanism of action for the MRNA vaccines) will not provide an improved outcome.
It was a triumph of Bayesian reasoning that I could predict you would be so thoroughly ignorant about basic molecular biology. I saved myself quite a lot of suspense waiting for it to become obvious.
You of course will see this as ad hominem, but I appeal to the audience: is that an unfair characterization?
Why is the spike protein dangerous? Generally speaking, the dangerous part of a virus is the RNA or DNA inside it, which hijacks your cellular machinery and causes it to go nuts making bazillions of new viruses. The proteins that encapsulate the RNA/DNA, or which help it gain entry to the cell, are normally seen as quite harmless if they're present by themselves.
If you could say "five NFL players (or whatever, some league) had heart attacks, compared with 1 per decade usually" that would impress me as a problem. But I googled a few random names on this list and they include an amateur, a guy who was recruited to play soccer in Azerbaijan, a guy who played football for a community college. There's no established baseline for heart attack rate for people like this (particularly since "cardiac arrest" could be a euphamism in an obituary for "heroin overdose"). What's more, some of these appear to be wrong (the Azerbaijan guy died after hitting his head in a collision with another player) So no, I don't find this compelling.
Unless you search for "60X increase in pro sports adverse events since the vaccines rolled out" and then it's the 7th result.
Sometimes it feels like major misinformation sources are getting downranked these days, but if it makes you feel any better, 4 of the 6 previous results uncritically repeat the claim.
An RCT of 30,000 people is better than an observational study of 30,000 people, that's for sure. But an RCT of 30,000 people can't tell you much if anything about events that occur for 1 in a million people. An observational study of a billion people can, though it will have all sorts of potential confounds.
No one will ever do an RCT with a million or more subjects in it (at least, not in the next few years or even decades).
Nobody does these RCT in medicine, but for real important things like optimizing which ads to show people on the internet, companies do them all the time.
(I'm a bit cynical here. It's not that Google optimizing their ads is more important, it's just that these experiments are much cheaper to run.)
I've often noticed that conspiracists' supposed mistrust of experts or mainstream media goes away when they perceive the mainstream as agreeing with them.
Why cite Pfizer as an authority? Aren't you the guy who thinks Pfizer is evil?
This is a simple application of the criterion of embarrassment. It's unlikely that an organization would lie to make itself look worse than it really is. So when an untrustworthy organization reports something, we can reasonably infer the real situation is as bad or worse than they portray it.
This demonstrates one of the many flaws in the "criterion of embarrasment": the decision about whether to take something as "embarrassing" is entirely subjective. One person sees unsourced comments saying Pfizer reported negative outcomes in a trial and decides that must be embarrassing. Meanwhile another person sees the comment and thinks that Pfizer is legally required to report positive and negative outcomes in trials, the positive outcomes outweighed the negative outcomes, so it's work to be proud of.
I think you'll find plenty of pharma company skeptics here, but you're making some very bold claims without providing any evidence. And what's publicly known doesn't support what you're saying.
You didn't quote anything. You paraphrased some sort of summary. You just said "significantly more frequent cardiovascular events" but didn't say anything like "73 events among 15,000 vaccinated individuals and 24 events among 15,000 placebo recipients" or anything like that that would suggest that you knew what you were talking about.
Now it sounds like you do know something about what you're talking about, but you still haven't told us where in this long and dry document we find the information you've already found. If you've found it, you could give us those numbers so that we can interpret them too.
Cardiac-related deaths were much more frequent in the vaccinated arm.
This in combination with the whistleblower alleging they simply did not follow up on many reported adverse events should give pause, at the least.
Either the trial numbers were too small to make any substantial claims (the smallpox vaccine trial included 2 million participants), or at the least this data does not point to a resounding victory (2 died of Covid in the placebo group, vs one in the vaccine group).
I'm annoyed at the video source rather than text or still image, but since it's just one frame, I can look. I see a total of 15 deaths in one group and 14 deaths in the other, with 2 covid deaths in the vaccine group and 1 in the placebo group (if I'm reading right). That is not statistically significant evidence of anything.
The main data in the trial were the something like 170 covid cases in the placebo group and about 15 in the vaccine group. This absolutely is statistically significant at any level you can think of.
The trial numbers were too small to make any substantial claims about deaths, and they didn't make any claims about deaths on the basis of the trial. The claims about deaths were made initially as further inferences from the stunning results on infections in the trial, and then later on the basis of the very large scale data on hundreds of millions of vaccinated and unvaccinated people in observation.
So we've got four deaths by heart attack in the vaccine group, and just one in the placebo group. What's the chances of something like this popping up if the null hypothesis is true and the vaccine has no effect on heart attacks? I can't be bothered doing the maths, but it's high, for reasonable values of "something like this".
Also, consider the fact that vaccinated patients were much less likely to die of myocardial infarction or multiple organ dysfunction syndrome. Surely that reduced risk offsets the increased risk of heart attack? (The answer is no, because all of this shit is just random noise.)
Two died in the experimental arm, four died in the control arm.
"Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction)"
I would love for someone to convince a healthy young (30s) man such as myself that the risk from COVID (yes I have medications available and a testing/treatment/isolation plan) is greater than my risk from regular 6 monthly vaccines for... 1 year? 2? 5? I don't see this as a settled question and I feel justified waiting for more data (let's say til 2023) before making a decision.
I know this is a contrarian position. Am I that deep in an echo chamber? TIA
I personally know 4 people who got COVID without a vaccine. All survived, but three absolutely got their shit wrecked and spent at least a month very, very ill. One still has brain fog a year later.
I know two people who were vaccinated and got a breakthrough case. Both of them were fine after a couple of days and said it was no big deal.
I know more than two dozen people who got various vaccines and had at most a day of unpleasant side effects and felt terrific afterwards, and multiple people had no side effects whatsoever.
I've heard that and I've heard the opposite. Medical professionals are so busy during the pandemic that they haven't had time to fill in a report. (VAERS apparently take ~45 mins per report from what I've read) - I would love some papers analysing the VAERS or similar data if anyone has any.
But if you're not a medical professional and all persnickety about the truth, you can probably fill it out in under 5 minutes. I've looked at the VAERS database, had to click through 2 disclaimers that basically said "don't rely on this data, nobody has checked it and anyone can enter stuff into it." I consider it about as reliable as a Facebook page that invites people to write in their terrible experiences with vaccines.
Well if it's a moderately-sized signal, the evidence would be bodies stacked in morgues and wild-eyed TV news stories about it.
For example, let's take where I live. There are 3.2 million residents in my county, and (according to the County board of health) 2.2 million have been fully vaccinated. If the chances of the vaccine killing you were 1/10 the chance of COVID killing you (0.1% instead of 1%, averaged over all ages), then there would've been 2200 mysterious post-vaccine deaths this year, which would definitely have been noticed. (There have only been 5000 deaths from COVID itself in the past two years.)
I doubt Federal law would deter those who would enter bogus stuff into VAERS. I don't think it's possible for anyone outside FDA/CDC to remove entries in VAERS, so true data about vaccine harm is there for CDC/FDA to find and follow up on. But any conclusions based on comparing numbers of adverse events based on VAERS is suspect, to say the least.
You're in a double bind here. If VAERS is untrustworthy, then you're admitting that we have no evidence the vaccines are safe. VAERS is the official safety monitoring system the public health organizations are using to make safety determinations. You can't claim VAERS was trustworthy only when it supposedly showed that the vaccines were safe and then claim it's untrustworthy now that it's showing a huge post-vaccination mortality signal.
VAERS is untrustworthy, but VAERS in conjunction with review of personal medical records by real physicians at FDA/CDC is trustworthy. You and I and almost everyone else in the world will never see those personal medical records, for obvious reasons, so you, I, and the rest of the world cannot draw any conclusions from VAERS. That's why you have to click through two disclaimers before you can read the VAERS data. I linked to CDC's statement of what they've found below.
But reporting *deaths* to VAERS is a legal requirement, and I've certainly seen VAERS reports where it looks like somebody just spent five minutes on it, including some of the death reports.
Not crazy. I'm right there with you. If you're a male 30 - 39, the most comparable risk for you is auto accidents, so plan accordingly. According to CDC statistics there have been about 8100 deaths for that entire demographic group of 22.5M people over 20 months of pandemic.
6.224M cases of COVID were reported among this age group as of a few weeks ago (https://www.statista.com/statistics/1254271/us-total-number-of-covid-cases-by-age-group/). According to a meta-analysis, there is a 50-50 split in risk of SARS-CoV-2 infection by gender (https://www.nature.com/articles/s41467-020-19741-6), so this leads to 3.112M cases in your age bracket. Overall, that's a 0.26% CFR, including people with pre-existing conditions that are known to affect the outcome (e.g. leukemia, obesity). Meanwhile, actual IFR is much lower because of all the asymptomatic cases and because testing was so awful early in the pandemic. I think the discourse was seriously less confused in June of 2020 than it is right now, when we were saying things like "if you know that you have a health condition that might exacerbate the effect of getting a really bad case of the flu, consider extra precautions. Otherwise, you probably don't have a lot to be afraid about."
As for my lived experience, it mostly lines up like I'd expect given all of the above. I clearly hang out with a different crowd than most SSC commenters and know a lot of people who have had COVID pre-vax. At least 50 people and this includes myself and everyone in my family. For me, COVID wrecked a good 3 days, plus I had a bronchitis that persisted for another 3 weeks after I started testing negative again, but I've felt fine for 6 months, and wouldn't call my experience atypical. My wife is legitimately immune compromised (no spleen) and she had to go to the ER for abx to treat a secondary pneumonia, but she's fine now too. I know of one person who was 40 when he got it, and seemed healthy before, but spent 15 days in the hospital. He is fine now. And of the whole social circle, one person died of COVID: she was 81, and had just recovered from a bad case of pneumonia in late 2019; if I would have made a list of all the people I knew who were likely to die from it, she'd have made the top 10. Don't know anyone in my cohort who is complaining about long COVID, although one might wonder if there's pressure to downplay those symptoms. Anyway, don't let these jokers gaslight you. Your position would have been deemed eminently reasonable in 2019 and it's still reasonable now, the only thing that's changed is the social milieu.
Just including the most unexpectedly bad outcome that I knew of from my experience for transparency sake. But given what's at stake, and we all know it's more than just health, it might not be weird for Dave s. I get that it's weird for you.
Thanks for the message. It's difficult posting about these things publicly because it's either an echo chamber in one direction or the other. I do believe my COVID risk of death is lower than 0.1% given my health status. I feel the vaccine risk is comparable but generally it's just murky knowing what data are trustworthy.
I supported my parents getting vaccinated and boostered (less so) due to their age.
I'm looking for the best analyses done by people like Scott, particular around the vaccine event reporting systems. Everyone has their biases and makes mistakes. My understanding of statistics is not what it used to be and I don't have the time or inclination to perform my own analysis.
Thanks for your "anecdata" as well as the other commenter, Ben, above.
I think this post nicely illustrates where the error lies. You suggest a comparable-to-0.1% chance of death from vaccination. In reality, it’s nothing like that. If one in a thousand people who got vaccinated were dying from it, we’d know. The chances of death from vaccination are a number of orders of magnitude lower. We know this because millions of people have now been vaccinated, and they are not dying in their thousands.
"If one in a thousand people who got vaccinated were dying from it, we’d know." I agree. I did say lower than 0.1% but yes this seems way too high for vaccine death on its own (although VAERS has captured nearly 20k deaths after a COVID vaccine). Of course we know that you can still die from COVID while vaccinated.
So in this scenario (lets only focus on death for simplicity but harm in general could be used). Options are:
Unvaxxed: Risk of death from COVID is 0.1% (this number could be orders of magnitude smaller for a healthy person with early treatment)
Vaxxed: Risk of death from COVID is reduced to X% (X = <0.1) + Risk of death from vax (Y)
Is X + Y < 0.1% ?
Does Y increase with each booster?
These are open questions, no?
As I said, a big part of my hesitation are the neverending boosters. Maybe it's 3 and done... But I believe Israel has given some vulnerable people 4 doses already. How does the risk change with subsequent shots? How long does natural immunity last in comparison to vax immunity?
Also, the analysis of VAERS I linked to and quoted in reply to SmallGnome (above) states that non-COVID deaths (and potential vaccine deaths) were counted as COVID deaths. This would skew the numbers massively if true making COVID seem more dangerous and the vaccine safer by hiding deaths caused by it.
Just to reiterate: With these unknowns, I think it is justified (if young, fit, healthy, no co-m) to wait for more data before vaccination. Or until a different vaccine is available with longer efficacy and a better safety profile. I don't think this is a crazed anti-vax position...
After reading this conversation, just weighing in here to say that I'm in a similar position to you (28 yr old male, perfect health) and I think your reasoning and skepticism are sound. No, you are not crazed anti-vax. And full disclosure - I was double vaxx'd in the Spring (Pfizer).
So... I don't think you're crazed. But I do think you're wrong. The problem is still there in the numbers, but these are numbers that are very difficult to be accurate about because they're very small.
I haven't done enough reading to be able to give you convincing numbers. But I don't think I need to. To know Covid is really bad, you just look with your eyes: they built whole new hospitals to deal with it. To know the vaccine is not really bad, you do the same thing: they haven't built whole new hospitals to deal with vaccine deaths. And more people are vaccinated now (in a shorter time) than ever got Covid. The chances of death for you (and me - I'm similar, male, 40, good health) are very low. But say it's 1 in a million (this is why it's not crazy to not get vaccinated). The chances of death from the vaccine are 1 in 100 million. Intellectually, I can barely grasp the difference between these kinds of small number. Emotionally, I can't at all. But I still think the difference is real.
And obviously there's the public benefit thing if vaccination reduces the spread, which seems to be unclear at this point.
The most important point that I hope you'll take from what I'm saying is the first line: not crazed, but wrong. I hope you won't set up this opposition where the only alternative to vaccination is crazy (and I'm sorry if pro-vaxxers sometimes make it sound like they do). You can be definitely not crazy, but still wrong.
Agree that careless unblinding is bad, but it is hard to justify refusing to give a vaccine to the people most at-risk of dying of Covid, for a long period of time and against their wishes.
Berenson calls this "destroy[ing] our best chance to compare the long-term health of a large number of vaccine recipients with a scientifically balanced group of people who had not received the drug."
I call it common decency. Carry out the vaccine trials on less at-risk people instead, and use challenge trials. (Except they don't like challenge trials, so I'm guessing they mostly did the first thing? Do you know how it was done?)
Or as FDA stated the month before: "There were no notable patterns between treatment groups for specific categories of SAEs [serious adverse events] (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2. From Dose 1 through the March 13, 2021 data cutoff date, there were a total of 38 deaths, 21 in the BNT162b2 group and 17 in the placebo group. None of the deaths were considered related to vaccination. "
Berenson seems to be implying that no no no, we mustn't use *human judgement* (gasp!) to tell which deaths were vaccine-related.
I say the sample size is too small to do otherwise. Moreover, if the FDA completely ignored indications that the deaths were unrelated to the vaccines, all kinds of people would be crying foul about that instead.
The "American Heart Association Committee on Scientific Sessions Program" has expressed "concern" about this ... um ... abstract-only paper? Are abstract-only papers a thing now wtf? https://www.ahajournals.org/doi/10.1161/CIR.0000000000001051
> The most troubling for me is the signal from VAERS, yellow card, and European system. I don't buy this "it's flooded with fake reports narrative" and I haven't seen a breakdown or attempt to analyse this, other than ones that do not support the vaccine rollout, such as this preprint
"it's flooded with fake reports"? Sounds like an argument by some dumb person that an antivaxxer found to debate them. Like maybe a journalist, hah. It took me like 30 seconds to think of a perfectly reasonable explanation that I have never seen anyone try to refute (https://dpiepgrass.medium.com/vaccine-risks-a-letter-to-my-father-d1419486e4f1), except my dad who made an assertion like "they won't give vaccines to people who might die soon", but I don't think that's true.
> I would love for someone to convince a healthy young (30s) man such as myself that the risk from COVID (yes I have medications available and a testing/treatment/isolation plan) is greater than my risk from regular 6 monthly vaccines for... 1 year? 2? 5? I don't see this as a settled question and I feel justified waiting for more data (let's say til 2023) before making a decision.
Well, all the regulatory agencies have found it safe & effective, so why not accept their findings?
By the way, the technical term for what you should be looking at in relation to VAERS / yellow card statistics is "base rate".
Any population of tens of millions of people will have deaths and sudden unexpected illnesses every single year. This is called the "base rate" of illness or death.
Any antivaxxer who talks about VAERS / yellow card, but ignores the base rates, is bullshitting you. There's no chance in hell that no one has tried to tell these people about base rates, but somehow when they talk to their fans, this issue always slips their minds.
Pfizer vaccine trial data: “Only 3 of the people in the trial died of Covid-related illnesses - 1 who received the vaccine, and 2 who who received the saline shot. “
In terms of overall deaths there were 6 MORE deaths overall in the vaccine group than in the placebo control group.
No. 1 from vaccine arm, and 6 from the placebo arm died from covid. And 16 vs 15 died during the blind trial period, through December 14. After the blind period, almost all the placebo recipients chose to get the actual jab, and through March 13, 5 more people died (3 of them original jab recipients from non-placebo arm, 2 of them original placebo recipients who later got the jab), consistent with the background mortality rate.
This is incorrect. August 12, 2021: "Only 2 people in the placebo group died of COVID-19 and 1 person in the vaccinated group died of COVID-19 pneumonia, according to additional Pfizer data obtained by The Associated Press. "
Nope. Never trust news services, go directly to the source.
From FDA's clinical review memo (August 23, 2021), page 70:
« Seven deaths were due to COVID-19 (1 BNT162b2 recipient and 6 placebo recipients). Each case had a positive COVID test (PCR or NAAT), but not all tests (including the positive PCR in the case of fatal COVID-19 pneumonia reported 109 days after Dose 2 of BNT162b2) were within the specifications of the study protocol for tests with acceptable sensitivity and specificity and were therefore not included in protocol-specified efficacy analyses of severe COVID-19 cases. Abbreviated narratives are provided for those participants who died from COVID-19 in Appendix C. »
Herzog, you're mindlessly repeating misinformation that is spread deliberately or out of unscrupulosity by certain ideology captured parties.
(1) The blind period ended on December 14, 2020. The placebo group were offered the jab (I'll refer to it as BNT from now on), and >95% chose to get it.
(2) During the blind period, 16 vs 15 people died from covid in the BNT arm vs the placebo arm.
(3) After the unblinding, through March 13, 2021, 5 more people died (3 from the original BNT arm and 2 from the placebo arm who later chose to get BNT). This is consistent with background mortality rate observed during the blind period.
(4) During the blind period 1 vs 6 people died from covid in the BNT and placebo arms, respectively.
(5) The whistleblower's complaints are about laxity and procedural irregularities she observed at one subcontractor that managed 2k participants out of 40k for Pfizer's trial. If you read the contents, this person was very conscientious, and was irritated with the minutest faults, such as late entries to patient diaries (there were some serious faults too, such as potential unblindings). Even if you throw away these 2k participants, it doesn't affect the outcome of the trial, and of course, now we have real world data from hospitals and statistics bureaus from around the world: so the RCT is not even the strongest evidence for safety and effectiveness anymore.
(6) Pfizer is not "fighting tooth and nail to hide the primary data [...] for 55 years". Here's the truth behind that oft misrepresented story: an advocacy group FOIA'd FDA for the BNT approval process documents. Their FOIA query was too broad; it returned 329k pages. The law says that, parties can either negotiate a suitable release schedule between themselves, or they can escalate and bring the dispute before a federal judge to decide. In this case, the FDA's lawyers said that the normal processing rate to appropriately redact documents is 500 pages per month. They cite case law, including one particular case where no exception was made for a really large FOIA result (in that case it was ~50k pages). So they're saying we'll give it to you 500 pages a month. The plaintiff are saying it would take 329k/500 months, about 55 years.
So Pfizer's not even involved with the case. FDA doesn't want to assign extra manpower for the redaction job, which requires 100x the regular rate to complete within 6 months. We'll see what the judge decides. But the problem here is not that FDA is being unreasonable imo (redaction really is a slow, cumbersome job), it's that the advocacy group's query is too broad. They should negotiate a properly exact and narrow query that precisely targets clinical data.
Also your #'s for total deaths of all causes are wrong. Pfizer updated these.....
On November 8, the FDA released its “Summary Basis for Regulatory Action,” a 30-page note explaining why on August 23 it granted full approval to Pfizer’s vaccine, replacing the emergency authorization from December 2020. On page 23 of the report is this sentence:
"From Dose 1 through the March 13, 2021 data cutoff date, there were a total of 38 deaths, 21 in the COMIRNATY [vaccine] group and 17 in the placebo group."
Pfizer said publicly in July it had found 15 deaths among vaccine recipients by mid-March. But it told the FDA there were 21 - at the same data cutoff end date, March 13.
21.
Not 15.
The placebo figure in the trial was also wrong. Pfizer had 17 deaths among placebo recipients, not 14. Nine extra deaths overall, six among vaccine recipients.
I've investigated this issue extensively, and you're wrong.
(1) Pfizer's July 2021 preprint says 15+1 vs 14+1 died during the blind period. They deliberately separate 1 HIV deaths in both arms. They also exclude 2 deaths in the placebo group who died before receiving their 2nd dose of placebo. So total deaths during blind period was (16 vs 17), or (16 vs 15 excluding the 2). This extra 2 deaths from the placebo arm is not mentioned in the Pfizer preprint, but is mentioned in the FDA memo.
(2) After unblinding, through March 13, 3 more original BNT162b2 recipients died, and 2 more original placebo recipients who later got BNT162b2 died. And that's it. This is clearly stated in Pfizer's July 2021 preprint.
So the 21 vs 17 framing is dishonest. After unblinding, almost everyone had received BNT162b2 shots, so 5 more BNT recipients died as expected. And going forward, ~all the deaths observed in trial participants will be BNT recipients.
Not sure, whether this analogy is valid or not, but let’s apply this logic to various types of food.
Suppose you don’t know anything about vitamins and minerals, but you know e.g. that eating lemons helps agains scurvy and some other types of food help with other things. Applying the logic from the post you’ll end up with a “Pascalian diet”: eating as diverse food as possible. And with a hindsight, it doesn’t seem to be such a bad idea.
I like the comment section of this blog because there is always someone who shows up before me and makes the point I was going to make. 😄
I was going to spin it a bit differently and argue that essentially Scott's argument here rests on the assumption that medicines are distinct from food somehow, but IMO there isn't a bright line separating the two. Is an orange a supplement or a food? It prevents scurvy, much like a vitamin C tablet would do in similar circumstances. It just happens to also give you a dose of energy (sugar) and some other miscellaneous stuff. An orange is essentially just a "multivitamin" (yes, I know I'm stretching the term vitamin here a lot but it is meant to be illustrative).
Just as with medicines, you can also die in some very rare circumstances by eating certain foods that are totally fine for everyone else basically all of the time.
In reality, there are some things that are classified as medicines due to the route they took to getting to humanity rather than due to some fundamental nature of them. Perhaps a better classification of "food" vs "medicine" would be "the probability that something bad will happen by ingesting this thing". By that measure, there are some foods that likely *should* be called medicine (blowfish?) and some medicines that should be called food (ivermectin?)
The point of this is just to argue that the pascal's wager in putting stuff in your body is one that humans make all of the time, and I think the key differentiator is (or at least should be) the risk of adverse effects. Ivermectin in this case is arguably the canonical example of something that is probably safer for you than a lot of different foods, and thus is very reasonable to make the bet on. The same goes for Vitamin D and many of those others.
Interestingly, I would argue that fluvoxamine *doesn't* make the cut for a medicine that is low risk enough to warrant making the bet on.
Erm, food is something taken for the nutritional value (other effects might happen). Medicine is taken for another effect, and generally has very minimal nutritional effects. Clearly there will be some edge cases (especially around traditional medicine) but I don't think the ven diagram here has much overlap.
How do you draw the line between "nutritional effect" and "other effect"? There are certainly some things that we need in very large quantities like calories and amino acids (in various forms), and there are some things we need in relatively small quantities like vitamins and minerals. A vitamin is just a "small molecule", and there is not a clear line between a vitamin small molecule and a medication small molecule.
Are vitamins food or medication? Most people get the majority of their vitamins from "natural" food sources, but if you don't get enough from food sources for some reason you can take them as a supplements.
I can see an argument that "food" is anything you need in large quantities (sugars and amino acids) and everything else is "medicine", but in that case we make pascal's wager every day we consume a random set of foods that are rich in vitamins and minerals and we don't just eat solely white rice and protein powder.
My argument here is that if you want to say that pascal's wager is acceptable for "food" and unacceptable for "medicine", then you need to have a much more clear line between what is food and what is medicine. I think most people intuitively make the naturalist fallacy here and essentially argue that "if it comes from a plant or animal and is not processed then it is food, else it is medicine" which I think is wrong because now vitamin A from a natural source is considered food while the exact same vitamin A from a supplement is medicine. Does this mean that it is acceptable to make pascal's wager on vitamin A only if you get it from a plant but not if you get it from a pill?
I think a real biochemist (which I am not) could pretty readily draw a line between a vitamin and a drug, for example. Vitamins are substrates for certain important metabolic factors, e.g. NAD is made from Vitamin B3 and FAD from Vitamin B2, Vitamin C is in a different category because it's a cofactor in a number of important reactions (so it gets consumed, albeit in small amounts, and should perhaps be classified as a micronutrient than a vitamin).
But in all cases, these molecules play essential and continuing roles in metabolism. I think they are not generally regulatory molecules, or messenger molecules, which are much more the kind of thing that drugs mimic, accelerate or block.
🤔 That is an interesting line to draw, it is quickly growing on me. IIUC, you are essentially saying that if the molecule is involved in regular processes that are always happening within your body, then it is a vitamin/food, and if it is a molecule that is not part of any normal processes, then it is a medicine.
I think we don't have a large enough understanding of human biology to correctly categorize everything, but I do think we are pretty close and probably "close enough" to have that be a useful delineation.
This would, of course, mean that melatonin is a vitamin and not a medicine, because it is part of regular internal processes. I don't think this breaks the general heuristic though and it likely requires us to only adjust the classification of a relatively small number of molecules.
Where things get weird is whether a gene therapy that introduces a gene into your body that your body (or the average body) already has would also be classified as "vitamin" by this. That feels a bit odd, but maybe we can draw a few more simple boundaries to handle that situation?
I don't think you can draw that line. You can say "This is more like what I think of as a vitamin" or "This is more like what I think of as a mineral" or "This is more like what I think of as a drug", but you can't draw lines between them, because you'll find things that need to fit into multiple categories. It's more like gravitational attraction than putting things in pigeonholes. And you can't really base it on mechanism, because biology is complex, and we don't really understand all the interactions.
E.g., is cobalt a mineral? Well, yes, but that's not the right way to think of B12. But it wouldn't work without the cobalt. What about hemoglobin? It's usually more like a part of the body, but if you need a transfusion it's more like a drug. (Just picking easy examples, those aren't really difficult cases, but I'm not a specialist that could explain a real edge case.)
I wouldn't say eating lemons helps with scurvy per se. Any reasonable diet has enough vitamin C to ward off scurvy. You are only at risk if you eat a highly unnatural diet for a long time, e.g. you're a Royal Navy sailor and you eat *nothing* but boiled beef and ship's biscuit for 11 months straight. Under conditions of weird privation, yeah eating lemons helps.
As someone whose shape is somewhat more spherical than ideal due to poor impulse control around food, this sounds like a bad idea. In any case where their is a clear surfeit of foodstuffs then there's a really obvious risk that a Pascalian approach leads to excessive calorie consumption, as well as increasing other potential risk groups (sugar, salt, fats etc). If you did try and fit everything into a balanced calory-controlled diet this might work, but I'd worry that if you are hoping to benefit from small traces of many things that you might have to rely on the logic of homeopathy to justify it: there's a limit to how many things you can actually eat and expect them to have an effect.
You could do this by just taking the vitamins/minerals involved, but then we're back to supplements rather than foodstuffs.
I was under the impression that it's easier to get overweight from eating a lot of the same kind of food, rather than a little of many different types of food. I suppose it might work differently for different people.
It is as far as I know, but if what you're advocating can be taken to suggest eating additional food (rather than substitution) then it probably doesn't matter how many different foods you are eating, you're likely to put on weight.
The opposite is true. It's the 'dessert stomach' phenomenon: you're able to eat much more of a varied selection of foods than if you just ate more of the same thing. Eating a burger, fries and a milkshake is easier than eating the same number of calories from fries alone.
You wouldn't have to eat all foods at all meals, but could eat different foods at different meals (maybe rotating on a weekly basis or something). Have more fruits sometimes and more meats at a different meal, etc. That intuitively seems healthier than a monochromatic diet, even if you end up eating a few items that seem "weird" to modern western tastes.
> There’s a potential compromise solution, where smart doctors come up with Pascalian medicine protocols for the few patients who would actually want them.
Do what I do, and keep a stable of general practitioners (who do not have hippa release to each other) and rotate through them, presenting slightly different versions of your current health situation in order to have a doctor sign off on your plans
I think it’s funny how hilariously irresponsible it would be for Dr Alexander to say this as advice. Gotta keep the ol’ malpractice insurers on their toes!
(But if it works for *you*, of course it works for you.)
Not sure why it would be irresponsible to seek multiple cases of qualified advice? I doubt any of them will advocate drinking mercury to solve a cold or the like, and this clearly allows you to overcome single-practioner bias.
It relies on raj not being stupid enough to say rely on homeopathy to deal with a heart irregularity, since this technique clearly allows the patient to disregard advice they don't like. But since patients normally do that anyway, and there's no ethical requirements on doctors to ensure patients do what they are told will make them better, not sure where the ethical issues leading to malpractice would be here.
Widespread adoption might stretch most healthcare systems a bit mind you. It certainly would not be a viable model for the UK's NHS for example.
Yes, I probably consume more than my 'fair' share of medical resources (despite, or perhaps especially because I'm basically healthy) which is part of the reason I do it. A lot of doctors seem to be implicitly gating/triaging care when you are operating on multiple lines of inquiry.
I don't think it's irresponsible to get second, third, or seventeenth opinions; and if that requires hiding information about your medical history, then fine, maybe it's justified...but a horde of randos doing this would *absolutely* result in some idiot relying on Tibetan vuvuzuela thwacking to treat their brain tumor, saying "This Dr Alexander guy said it was a good idea to hide tiny little bits of my medical situation to the docs!", and their heirs suing. (Dunno if said heirs would win the suit, but nobody wants to be sued at all.) And it would also increase the probability of some fatal drug interaction.
I'm not sure the inherent openess of the US legal system to groundless litigation is a good argument for anything other than making plantings pay legal fees if the case is thrown out though.
Sort of off-topic, but I strongly respect him for being willing to say what he does, being in a position with something to lose. He does exercise care by being somewhat Straussian, but could definitely also be more risk-averse (which would suck for us)
Well, if it’s true that out of 20 most promising things (by the view of a year ago) 1 really works, then 5% chance of working does seem like pretty reasonable estimate, doesn’t it?
And if that is true, then in this instance, taking 20 most promising things really is a good strategy.
I think you should just bite this bullet. I think it's OK to just say the Outside view is correct here.
"From the Inside View, I have a lot of trouble looking at a bunch of studies apparently supporting a thing, and no contrary evidence against the thing besides my own skepticism, and saying there’s a less than 1% chance that thing is true."
When low-quality studies keep piling up, eventually it should start to count against the conclusion. If nobody gets around to doing a very high-quality study despite all the low-quality ones, that starts to indicate that one can't do a high-quality study because it won't look good.
It's like if someone on Instagram post one video of themselves breaking the world squat record in their garage. Based on that, you might reasonably think they have a 20% chance of actually taking the official world record in a sanctioned event.
But if they post 20 such videos and never bother to enter a sanctioned competition to fully reap the rewards of their achievement, you'd reasonably believe there's 0% change they legitimately completed the lift.
No, it's not like that, because *lots* of scientists can *independently* choose to do a study or not. Just like that one N=12 Wakefield study saying that *parents* said that the MMR vaccine causes autism, or something, led to an explosion of other studies that said no it doesn't.
But if major ivermectin studies are being done, maybe it's too soon to expect them to be published already.
In a previous post Scott acknowledged that the current way the world works makes this not reasonably possible. Pharmaceutical companies have the capital, the skillset, and the incentive to do very large high quality RCTs, but essentially no one else does. The government has the capital, but not the incentive, and everyone else has the incentive but not the capital.
This means that the absence of a large high quality study is not indicative of it not being possible to get the desired results, because the environment simply doesn't exist to get such a large high quality study done.
Oh, very nice! It's an extension of the principle that "absense of evidence, when you can reasonably expect that evidence to exist, is indeed evidence of absense". Similarly, a bunch of weak evidence for a conclusion, when you can reasonably expect strong evidence to also exist if the conclusion is true, starts to look like evidence against the conclusion!
I agree with the general premise of "absense of evidence, when you can reasonably expect that evidence to exist, is indeed evidence of absense". What I disagree with is that it is reasonable to expect that evidence to exist in the current reality we live in (which Scott seems to also believe).
More specific to the latter half of your statement, "we do not have a reason to expect strong evidence". The medical infrastructure is setup such that we will almost *never* see a large well done DBRCT for an off-patent medication. At the least, we should not *expect* that to happen naturally even when there is good reason for such a thing to be done (like curing COVID-19 or whatever).
I think the opposite is also true though, as "high-quality studies" tend to cost a lot more than "low-quality" studies. The fact that many independent groups with far less means are pursuing studies of any size (and using their limited funds in the process) should give credence to there being some sort of effect, as something led them to initiate the study in the first place. This is predicated on "low-quality" studies normally being seen as so because of their amount of participants than other factors though.
The problem is another aspect of risk that you don't discuss. It's a kind of opportunity cost, but with a multiplier effect. Taking ivermectin *as an alternative to vaccination* presents a real cost. The ivermectin advocacy set significantly overlaps with the big pharma/medical researchers/public health officials and big tech and Dems conspiracy set. That set interacts with political sets in all sorts of realms.
Nonchalance towards ivermectin because there's a 10% chance it works with little downside risk is, in isolation, one calculation.
In the real world it interacts in complicated ways with many high damage function risks in a number of different domains. That isn't to say, don't consider ivermectin. It's only to say that you need to examine the related risks *in the full context*
??? If you're taking all the different things that have any chance of working, and willing to take 20 different drugs to maximize your chances of getting the one that works, obviously the vaccine will be on that list! This is the strategy for people who love getting as many different medical interventions as possible!
Well, group taking weird medicines likely has overrepresentation of antivaxers and other people who believe too much in their own analysis and fail in selecting good sources.
> This is the strategy for people who love getting as many different medical interventions as possible!
Ok - but in the real world context I don't see much practical utility of talking about taking "all the different things that have any chance of working." How many fit into that category? What we have in the real world in the US and some other countries, are people advocating ivermectin as a safer/cheaper alternative to vaccination.
As such, when you talk about the probability of ivermectin working - sure, it's certainly relevant to talk about it in some theoretical frame - but there's more going on than that. If there were only people trying to get as many different medical interventions as possible then your framing would be sufficient. But that's not a very prevalent situation. So just saying ivermectin has a 10% chance of working misses the real world opportunity costs (deaths and illness) involved. In the real world that actually lowers the expected return on the use of ivermectin.
Is fluvoxamine really so innocuous that you would take it if it had 5% chance of reducing your COVID mortality 30%? Would it be a good idea to take 20 drugs with fluvoxamine's side effect profile? These are genuine non-rhetorical questions. The list of side effects on Wikipedia looks like something I wouldn't eat on a whim, but side effect lists always look scary.
I also have to assume there is probably some grand correlation between "likelihood of having an unanticipated positive clinical effect" and "severity of side effects". As in, if something is bioactive, it is more likely to have both good and bad effects. Obviously there are a huge number of exceptions in either direct (penicillin, sodium cyanide) and I'm supposing this is less true for antivirals where magic bullets that affect virus but not human are more likely to exist. But for non-pathogens, Algernon's law seems like a good guide. "X is a chemical that affects your metabolism. Is X more likely to be good or bad?". Probably bad. And if you know X is completely innocuous, it almost certainly doesn't help you either. I realize this paragraph is very handwavy.
Yeah, when he said "benadryl and tylenol" I was instantly thinking this too. Even though the side effects of those things are small, they're still real. I don't want a bit of drowsiness most days, and I don't want to develop tylenol tolerance (or whatever the liver condition is that it has a tiny chance of). If I'm actually having allergies or headache, or even think I'm starting, then sure I'll take them. But it's not really Pascalian until I at least have a small chance of a condition I suspect it's helpful for.
From a personal perspective yes, go all insanity wolf and the drugs, I think the bulk of your arguments make sense.
What you ignore is the potential social consequences of hastily incorporated drugs. Any side effects not mentioned (and deliberately avoided based on your "utilitarian calculus") will meet with such damning criticism that it might jeopardise the entire medical establishment and cause people to lose faith in medicine, given how risk averse we are.
And if people start losing faith en masse, we're done more harm overall then the benefit we gain by adding a bunch of game-theoretically (for the individual) better drugs.
The biggest reason not to take any of this junk is that there are vaccines of proven efficacy and safety right now. Yet the word “vaccine” does not appear once in this essay. What is going on here?
Because it's obvious and we're trying to come up with other things that work on top of it? Do you also think Pfizer shouldn't be researching / the FDA shouldn't be approving Paxlovid because "we already have vaccines"?
Well, from comments it is obvious that it is not obvious for many people. Maybe you should make a post about vaccines "yes, it works, that is how we know that".
Or at least add a disclaimer, when you talk about alternative covid treatments, that obviously the best thing you can do is to get vaccinated. Scott already qualifies all his medical posts with a bunch of disclaimers (as well he should) so something along these lines might be worthwhile.
Come to think of it, the expected effect of any of these random drugs is far less than the expected effect of which brand of vaccine I took. If Scott really wants to do another massive covid effortpost, then a comparison of what we know about the different available brands of vaccine would be incredibly valuable. Also, boosters.
Sounds smart. Like "PS, another disclaimer that I'd thought went without saying but apparently not: if you're agonizing about Pascalian Medicine but haven't gotten the covid vaccine, you are doing it All Wrong."
I thought he was trying to smuggle the argument in. Once you get someone to agree "yes, I will take anything with a chance of working" you hit them in the face with "so here is the vaccine".
Your post wasn’t about what Pfizer and the FDA should do; it was about personal experimentation with one’s own body. In that context, the existence of safe and effective vaccines hugely alters the cost-benefit analysis of subjecting one’s self to unproven substances, making the potential upside fsr smaller. For example: If a vaccine eliminates 95% of your COVID risk, then the biggest possible upside to any of these self-experiments becomes eliminating the remaining 5% risk. Don’t you think that’s a hugely important factor in deciding whether to experiment on yourself? As for its being “obvious”: Sometimes I think smart people who like to play with ideas shy away from obvious-but-true points because they’re less fun to think about. I’m sensing that this could be happening here.
my understanding of ivermectin is that its proponents claim it is effective in reducing negative outcomes of Covid after you have contracted a severe case. I assume that most of the other treatments he listed are also in a similar boat; they’re more akin to antivirals than vaccines. if that is indeed the context (I could be wrong, I’m not a medical expert, just someone who begrudgingly obeys their doctor), then I’m not sure that the vaccine does make such an overwhelming impact on using a pascalian approach once you’ve contracted Covid
I think he's making the point that perhaps you might mention that this stuff can become incredibly marginal and it's wise to keep relative risk in mind. That is, if you are researching how to live longer by popping vitamin D pills or ordering resveratrol off the Internet *but* you smoke and don't wear a seat belt, then you need some big recalibration of your sense of relative priorities. Likewise, if you're weighing the pros and cons of experimenting on yourself if you get COVID with a variety of random small molecules drugs *but* haven't taken a vaccine because you're worried about small tail risks, then you're being rather innumerate.
Because this is for/about people who won't go near a vaccine, but demand access to a de-wormer as a miracle cure (and before anyone gets het up about "calling it horse de-wormer is a propaganda tactic!", I didn't call it that; it's also used in humans for the same reason).
So writing an article about "why, in fact, taking the juice of purple hensbane under the third full moon in Spring will not cure Covid" is for those people, or for our friends/relatives who are passing around Facebook posts about "what BIG PHARMA doesn't want you to know! This ONE WEIRD TRICK works but the doctors won't tell you!"
>Because this is for/about people who won't go near a vaccine, but demand access to a de-wormer as a miracle cure
I assumed it was about using those people and that condition as a specific example to deal with general concepts of medical decisionmaking under conditions of uncertainty and why we make the decisions we do, not attempting to dive into an active culture war with both feet and serve as a scientific missionary to the unenlightened. Like the ivermectin post, which was really about how to conduct a meta-analysis and the degree to which both the Red Tribe and Blue Tribe's biases led them astray on a question that had an interesting answer which was almost totally orthogonal to the shit they were fighting about.
I definitely struggle with this as well. I take a multivitamin but no supplements. I'm sure that there is stuff in my multivitamins I don't need and supplements that I do 'need' but I can't tell which, so I stay stuck at this mostly arbitrary equilibrium.
Tl;dr I would probably take the wager if (# of drugs for which i am ~X% confident will work) * X% * (treatments that might theoretically work) / (treatments that we reviewed to see if they work) = (the # of treatments our prior says we would expect to work). If this is true, then X is probably pretty well calibrated.
One argument against Pascallian medicine might be: I believe that thee is a 5% chance of this medicine working, but suppose i am miscalibrated by an average of 10% probability each time, which seems reasonable. Then (assuming my errors are normally distributed, of which I have no guarantee) I can be 95% confident that the probability a perfect Bayesian would hold of a drug working is… between -15% and 25%, not exactly confidence inspiring, especially when you remember Kightian uncertainty probably outweighs these numbers. So is there a way we narrow down the range of the probability of working?
… on the other hand, it seems to me that an onion farmer couldn’t get me to believe in a ~5% chance of onions curing cancer just by p hacking, so maybe, since the expected benefit of the drug is still positive, albeit barely, I should take it.
One way of resolving this problem might be this: suppose there are 10,000 chemicals that might theoretically cure cancer, but we only expect a few to work (say, 5 have really strong effects and 5 more have weak effects that are still worth having in some circumstance.) and suppose the lobbies of each drug hire some scientist to get positive results for their drugs, such that it seems to us there is a 5% chance of a given drug working. 5% of 10,000 is 500 drugs working against cancer, which is orders of magnitude than we would expect, so we should default to the outside view here. On the other hand, suppose only 400 chemicals seem to us to have a 5% chance of working, and we reject the other 9,600 out of hand after reviewing them. We find that this suggests that about 20 of the 10,000 work, which isn’t so far from our original estimate. Here, since the inside view and outside view agree, maybe we should take the 400 drugs. If this were to happen, I would think long and hard before probably taking the drugs.
I struggle to understand where 'Pascalian Medicine' would substantially differ from the alternative / complementary medicine industry, which is almost a $100b sector of the economy. The underlying ethos of both seems to be "Uncontrolled, iterative n=1 trials of pharmacologically active substances and pseudo-behavioral interventions with the primary outcome of improved subjective sense of well-being." I have no problem with this, any more than I have a problem with people finding the right exercise and diet regimen for themselves. But there's a difference between 'improving wellness' and 'treating disease'. n=1 experimentation can be great at the former, and usually pretty poor at the latter.
I think there are likely specific clinical scenarios where a Pascalian approach makes more sense - poorly understood chronic diseases, like post-infectious syndromes, or diseases where there is no good a priori evidence of effective treatment. Many of the rare disease and chronic disease communities and their treating physicians effectively take a Pascalian / Omuran approach in settings where no clinical trials are available.
The value of not dying of covid is very large. Severe side-effects, including death, have a large negative value. P(x-works) and P(x-is-bad) are both small.
expected-value-of-x = infinity * 0 - infinity * 0
You can replace whatever large/small values you want to get whatever specific result you want for your expectation value.
To put it a different way, the expected value from taking x might be good, but you can't just consider the expected value. You have to consider the whole probability distribution, which is wide and flat.
Another great post. I wish I could think like this. This methodically, this thoroughly. Why is this so rare? And then express those thoughts precisely and with humor. This is clearly even rarer.
What do you think of the heuristic that "The body can deal with surplus better than scarcity" for certain types of substances. If too much of supplement A is not a big deal but not enough of supplement A is a big deal, then we can err on the side of too much of supplement A. I think that might be the case for a lot of supplements, so taking a bit too much is reasonable. For other stuff, not so sure.
Scarcity of any given nutrient causes some specific deficiency disease. Surplus usually causes some mild impact on kidney and/or liver, right? If you ignore small effects, then it looks like avoiding scarcity is better than avoiding surplus. But if you're taking several dozen of these things, then if each one adds a little bit of strain on your liver individually, you might end up with a severe liver issue.
For poisons that obviously doesn't work, but for nutrients it probably does, since the natural supply of nutrients varies significantly -- which means the body has to have historically had ways to deal with surpluses, up to a point.
I wouldn't take it too far, though. Some substances are harder to get rid of than others, e.g. the fat-soluble vitamins, iron, and some others do ugly things along the way to being dealt with, e.g. ethanol's unfortunate waystation of acetaldehyde.
I think it's a mistake to group vitamin D in with things like Ivermectin. While the evidence that either therapy cures Covid is pretty thin the decision is not at all the same.
Vitamin D advocates are asking people to follow existing medical guidance to avoid deficiency. To maintain serum levels within 30-60 ng/ml most people will need to take a supplement in the winter, and almost everyone at risk for Covid (people with melanated skin, obese people, the elderly) will need to take one. This isn't taking some random therapy on the off chance it's helpful, it's following medical guidance that existed prior to Covid. Recommending vitamin D for these groups is a lot like recommending that they lose weight or quit smoking. It's possible that those things help with Covid, but even if they don't it's what your friendly neighbourhood endocrinologist would recommend anyway.
By contrast Ivermectin really isn't something that most people need. There's no such thing as "Ivermectin deficiency" and there aren't any medical associations who recommend that people get tested and see if they need more ivermectin in their diet.
My understanding is that the Vitamin D supplement thing is a bit faddy and tends to get out over its skis.
Also, the Vitamin D recommendation is a bit of a gateway drug to wackyness. I heard someone, I think that guy you got cancelled from Evergreen, arguing that COVID is all about Vitamin D and stay-at-home orders were responsible for the spread of COVID because they kept people from going outside and getting enough sunlight. Once your devotion to these possible cures starts encouraging you to disregard more reasonable advice, it becomes a problem.
My concern with a lot of alternative/non-standard medication is that not that it, in itself, is dangerous, but that it acts a gateway drug (pun intended) into a world that really can be harmful. E.g., I'm skeptical that acupuncture has any real value, but I also do not expect it will cause any direct harm either (other than the time and money wasted). However, I am concerned that, while an acupuncturist is treating you, he will tell you about all the dangers of modern medicine and then give you a referral to a chiropractor, who will give you a referral to a naturopath, who will give you a referral to one of those people who want to you treat your cancer with peach pits or autism with bleach.
Modern medicine isn't perfect, but it's pretty clearly better than alternative medicine (as the joke goes, if alternative medicine works, we would just call it medicine). Encouraging people to start down the alternative medicine path itself is dangerous.
Also, taking any given supplement may only cost $20/month, but that means that taking 20 supplements would cost you $400/month, which starts getting into real money.
At the same time, when my kid was sick the other day, and my wife pushed an elderberry supplement on me to try to help me avoid catching the cold, I took it because I figured "what the heck?"
Well, and there's some ethical challenges in being at all encouraging toward the natural human tendency towards magical thinking. Imagine penning a column for an AARP newsletter[1] in which you sunnily say "You know, when a stranger phones you up and offers you an incredible investment opportunity if you just read him your credit card number over the phone, there is a 1% chance he might be on the level and you'll be able to pay off your mortgage in 60 days."
You'd be shot for doing that, and quite rightly.
So ironically it's fairly ethical to encourage people to practice amateur medicine if you have no unusually high influence and the number of people likely to take it all on faith just because you said it is small, but the *more* expertise you have, the bigger your reputation, the more likely people are to take what you say and run with it, the less you want to be doing this.
Well yeah. You have to be incredibly conservative and careful if you don't want people bringing up mistakes for decades, long after the people involved are gone, and probably after it has passed into myth (e.g. I bet there are plenty of people who think the FDA *approved* thalidomide, and that just goes to show how fallible they are.)
I think the CDC in particular was caught completely flat-footed by this during COVID, because they have had essentially zero experience in pandemics in the last 75 years. So they acted as if it was business as usual for them, making flu vaccine recommendations or something on their website, very low-traffic low-weight stuff, and boy did they step in it. I would imagine they'll have a very different and far more CYA attitude for the next decade, and there will be a giant upsurge in hirings for staff lawyers and PR people.
I think rational people understand that the FDA can't give anything but the safest possible advice, the same way a cop cannot publically advise me to do anything other than obey each and every traffic law, even if I'm driving someone to the ER with chest pain or something. They're never going to even try to hit the sweet spot of the advice most likely to maximize your outcomes 'cause that involves acceptance of risk.
I thought a solid chunk of things that Algernon's law applies to have the simple drawback of "makes you need more calories" - very relevant in the evolutionary history, utterly irrelevant today. No such thing as a free lunch, but if you've got cash in your wallet there are plenty of meals to be bought.
My prior on circumin being better-than-nothing for covid was >50% because it's a weak anti-inflammatory and several other anti-inflammatories (budesonide, dexamethasone) were extremely beneficial. In some third world country that can't afford steroids, where dirt-cheap circumin is being produced locally, it might make sense. But here in the US where you can just walk into Walgreens and get a much better anti-inflammatory for $20, it's not worth trying.
Great post. Hilarious, too, and that's coming from someone who's been in the natural supplement and nootropic manufacturing world for decades. I don't blame anyone for getting burnt out from superfood and supplement consumption, and the Everest size mountains of related research. It's eye-rolling and existentially exhausting, even for those of us who are deep believers. Thanks for the perspective, Scott.
You're forgetting the placebo effect, which cuts both ways: it makes Pascalian medicine more effective, in that it actually does help whether any active ingredient actually works, and it argues for reducing the number of pills down toward an ideal of 1 magic pill.
As long as placebo effects are significant, it’s not clear why we don’t want “Doctors of Placebo”… but if they called themselves that, I guess it wouldn’t work…?
This seems like a jokey point but for me it makes all discussions of personal medicine genuinely strange. The doctors don’t have a great sense of what makes our bodies good at repairing themselves at present, even if they understand plenty of drug effects.
I'm trying to extrapolate from 1 pill down to 0, which seems like it ought to be easy, once you've gone from 20 to 1, but someone it's tough. Maybe it's because I'm afraid I'll overshoot and end up taking -1 or -2 pills a day.
Why would the placebo effect argue for reducing the number of pills? I thought it was reasonably well-established that 'bigger', more theatrical, more inconvenient and attention-getting and interesting placebos work better. It seems plausible to me that someone starting a course of five different placebos, each with their own whizbang supposedly independent mechanisms of action, would experience a stronger placebo effect than someone who just took one.
I think the principle of outsourcing decisions about what drugs are cost effective if prescribed by doctors using them only if they reasonably believe them to be cost effective for the individual patient is in principle a good system. I'd just like to see reforms in incentives that made those suppostions the case.
In the system we have FDA seems overly concerned by "side effect" costs, not concerned enough about delay of benefit costs, and not enough about resource costs. Doctors seem too much concerned with avoiding malpractice suits and not enough with cost of prescribed treatments.
The argument here seems like it can be condensed down to "I trust science, but science is contradictory, help!".
Seems like the obvious way out is to trust science less. But that feels bad, because psychologically losing trust hurts, and people will mock you for it, etc...
I don't mean to single you out specifically, you are one of a few dozen commentors who I would ask this of, but:
Did you join ACT recently? Like, within the last week or so?
Advising Scott to trust science less, and about the tribal reactions to such, just feels... idk. It feels weird, like you're maybe not aware of the context of the ten bajillion words about epistemology that scott has written, or the ten trajillion words that have been written about epistemology in our community going back to the '08 EY sequences
It feels a bit like a comment that would appear on a news opinion piece, not on a rationalist blog
I want to know if my immediate knee-jerk evaluation is right, please get back to me
No, I've been reading SSC since I guess like 2015 or so. Your knee-jerk reaction is wrong. I've become more "radicalized" by the pandemic I guess, but I've read most of the "ten bajilion word context" you refer to. In fact, when I was writing the above I was thinking of something by Eliezer Yudowski when he discusses why abandoning old belief systems is hard.
A way to make sense of "lots of good evidence for contradictory ideas" is to remove the "lots of good evidence" assumption. Scott kind of hints towards this direction in his post, but I don't think he goes far enough.
Agree, and would go further to say that if you find yourself confronted with "lots of good evidence for contradictory ideas", you're obviously mis-calibrated as to what constitutes "good evidence". My default assumption when confronted with a study that claims big benefits for some important malady is "this is either fraud or frank incompetence" and proceed to look for evidence of those before considering the hypothesis that the study is actually "good evidence". The amount of outright fraud Scott found in his Ivermectin survey increases my confidence that this is the right approach. (I also believe incompetence is more prevalent than fraud, so if there's a lot of fraud then there's a whole lot of incompetence.) This is not the nihilistic attitude that "everything is fraud and a Big Pharma conspiracy", but if you have bold claims about big things, you better have dotted all the i's and crossed all the t's. It's really a joy to read papers that do that - a sign of true craftsmanship.
My response is to ask for better standards for science (about which people more knowledgeable than me have written, e.g. peer review on methodology before data gathering starts, publication decisions before data gathering to avoid publication bias, Bayesian reasoning in addition to P-values, ...)
Most of the arguments that Scott puts forth against Pascalian medicine could equally be deployed against responses to most X-Risks. The logic is quite parallel.
Under the assumption that the "xrisk" is actually small. Also Algernons law doesn't work at all. Many interventions are obviously net beneficial. (Like how is an asteroid telescope going to increase the chance of impact?) All right, bad example for technical reasons.
For sure, I have in mind X-risks whose probability of occurrence is small.
It's not obvious that Algernon arguments may not apply in regard to social or economic effects. For example, while there are particular measures that I favor in response to climate change, there are other popular proposals (e.g., degrowth, forced restriction to non-nuclear renewables) that I see as highly counterproductive.
Well, since the sort of climate change that people are trying to prevent is itself caused by human activity, the analogy doesn't work. Human biology had many thousand of years to slowly evolve and is relatively stable, whereas the very fact that anthropogenic warming recently emerged as a potential problem itself proves that global economy rapidly changes.
That only shows that the example is not quite an Algernon argument, which I'll concede. The broader point (that measures intended to ward off an X-risk can cause social or economic harms that outweigh the benefits) still holds.
...Isn't the problem here that if there's a 0.25% chance that any given medication kills or seriously harms you, a 5% chance they cure survivable ailments, and you take 200 there's a near 100% chance you cure the ailment but a 41% chance you get killed or seriously harmed? Is that a good tradeoff?
A "bad outcome" might be much much less likely than a good one, but probably we want to avoid it much much worse.
Maybe even more likely - each of these things has a 5% chance of curing a survivable ailment, no chance of killing you by itself, but a guarantee of a mild strain on your liver (or whatever organ is used to dispose of this stuff). If you get 200 mild strains on your liver, that may lead to significant damage, even if any one of them was sure to be negligible.
I think this is a good point: you're emphasizing that the way side-effects can harm you is kind of additive, more or less because everything goes through the same handful of degradation pathways in the liver, whereas the way the main effects might help you are all different and probably in some cases orthogonal. So small probabilities of benefit don't add up as fast as small probabilities of harm.
You are right about cumulative strain on the liver from taking a multitude of individually benign supplements, even with no negative interactions. My great-grandmother is a good example of this. She was obsessed with her health and took every vitamin, mineral, and supplement she could find, to the point where she was popping 150 pills a day. My mother remembers, as a little child, watching her organize her supplements each week. You know how many elderly people have pill organizers with a different compartment for each day? My great-grandmother had an entire mason jar for each day. She would also buy a 50-pound bag of carrots each week, put them through an industrial juicer, and drink the juice. (She turned orange from the beta carotene—no joke.) I'm sure each individual pill was harmless, but grandfather (an endocrinology professor) warned her that in these quantities she would wear out her liver, and eventually she did. Whereas my other three grandmothers lived to the ages of 85, 101, and 102 (I enjoyed getting to know each of them), this one died in her sixties and I never got to meet her.
> But I have to admit that given everything I know about ivermectin - and Vitamin D, melatonin, etc - I still think on net the very small chance that this stuff helps you is higher than the extremely small chance it kills you. Even if the latter isn’t quite zero.
These two are not unrelated: normally the stronger intended effects anything has on our biochemistry, the stronger the unintended ones. So the expectation of how much any specific one _might_ help should go hand in hand with the expectation of the harm if _might_ produce.
I think we are betrayed by our intuition, because we judge the low-expected-value of the negative outcomes as "come on, whatever this does, it can't be that bad" and the low-expected-value of the positives as "I don't think it'll happen, but if it does it's amazing". Something something Taleb invest some money you can live without in buying some crazy stock.
But this is not the same as going long on stock: without good evidence that any of these cures actually help, and without any reasonable model of why they may, it's basically betting on a black swan that can go _either way_. Betting on more than one (the Insanity Wolf position) doesn't improve the basically-zero expected value, just the spread.
Which is why the intuition is: it's weird to tell any single specific individual "you shouldn't do this", but it sounds like evidently bad policy to recommend it at society level. Everyone gets to decide what's their personal risk/reward balance, but as a society we'd rather avoid large stupid catastrophes.
A recommendation to single individuals could be: if you want, take more or less a couple of whatever "no proven cure but no proven side effects" that seem reasonable to you, but not too many - you may still catch the black swan, while as a society we're hedged from everyone taking everything and one of those chemicals turning out to make us sterile or whatever.
I'm not so sure about the hand waving away of side effects. Is it really so likely that a random drug is more likely to have a previously-unknown good effect than a previously-unknown bad effect?
You could respond that we have many decades of data about people taking ivermectin safely, and only a year or so of data about people with covid taking ivermectin, so we've had ample opportunity to discover ill effects and limited opportunity to discover bad side effects. On the other hand, do we have much data about people who don't already have worms taking ivermectin?
This post is about whether it would be an intelligent cost/benefit calculation to be more aggressive about the class of medications that lie in the vast gulf between 'no evidence' and 'the overwhelmingly large amount of evidence that convinces us that things Definitely Work', not literally random drugs. Troublesome as medical science often is, you can't just treat multiyear thousand-patient placebo-controlled double-blind randomized clinical trials as 1 and everything else as 0.
Given only 50% of studies in medicine can't be replicated, that should immediately halve your probabilities. We need some analysis of what proportion of studies with small effects fail replication, but I bet that too would scale down the final probabilities significantly.
Too much of the counter evidence against ivermectin is predicated on over-interpreting non-significant p-values. Alpha of 0.05 is a high bar to clear to begin with. Throw in all the complexities of treating patients for a novel disease in hospital settings while trying to run an RCT for a highly controversial repurposed drug, and it's an insanely high bar to clear. Factor in variations in dosages, days since onset of symptoms (which patients are notoriously bad at reporting accurately), severity of symptoms, and any number of factors which influence patient outcomes for Covid that can't be controlled for because they are unknowable, and you're basically set up to fail.
Keep in mind any p-value less than 0.5 means there's a greater chance of committing a Type II error than a Type I error.
When you have dozens of studies, no matter how hard it might be to compare them, consistently concluding there is a signal of efficacy for ivermectin, you *have* to change your burden of proof heuristics. Simply running a meta-analysis and interpreting the p-value @ alpha=0.05 is deeply reductionist.
This is why I am utterly unconvinced by the "debunkings" of ivermectin data. There is more than enough signal in the data, and when you have highly proficient clinicians around the world reporting success with a drug, you cannot dismiss that. You just can't.
All of this is besides the point of Pascalian Medicine, but is meant to address the probabilistic fallacy you are making in the foundation for how you've framed this argument. From my perspective, there's a 95% chance ivermectin is doing something to help treat Covid. The effect size and potential confounding variables may never be known, but it is quite clearly doing *something*.
...did you read Scott's megapost on ivermectin? This post was made in the context of that. It feels a bit like you don't know we just got done with a super long and super in-depth analysis of all of the studies on ivermectin, and concluded... well, something surprising. I won't spoil the ending for you, it's magical.
> when you have highly proficient clinicians around the world reporting success with a drug, you cannot dismiss that
when you have also highly proficient clinicians reporting testing on large scale and reporting lack of success and many positive results are from swindlers, quacks and liars it gets trickier
Many positive results are not from swindlers, quacks and liars, though. In fact, the rate of fraud in the Ivm trials is lower than the background rate of fraud, and are from countries with historically high rates of fraud. So, I'm not convinced that the ivermectin literature is particularly rife with problems to a greater degree than elsewhere.
Among weightlifters/bodybuilders, the Pascalian Medication strategy is fairly popular. It's pretty common for serious weightlifters to take oodles of different supplements and medications that are suspected with varying degrees of confidence to improve various aspects of performance. Some of it's got pretty firm scientific backing (e.g. caffeine and creatine), and some of it is off-label or illegal use of well-understood prescription meds (e.g. anabolic steroids, metformin), but a ton of it is "broscience" (a sort of oral tradition build on various combinations of highly speculative preliminary study results, laymen's extrapolations from scientific principles, and personal anecdotes). Most weightlifters will tell you that a lot of the broscience is probably nonsense (the term itself is a self-deprecating joke within the community), but they'll nevertheless take it based on an expectation that the combined effect is more likely to help than to hinder their training.
What a great time to work through my intuition's solution to pascal's wager, and see if it actually works.
Basically, my argument is that your prior for X should always be lower or equal to 1/|U(X)|, where U(X) is the expected utility of X (and |x| is the absolute value of |x|). (Yes, this means your prior is dependent on your utility function.)
We'll do our investigation with P(X) ~ 1/(2^|U(X)|). Why not P(X) ~ 1/|U(X)| directly? Because the integral doesn't converge over the reals, and while some improper priors are okay, I don't want to spend time proving that this one is. This is basically the simplest converging function that I can think of that satisfies the criteria. (The ~ symbol is pronounced "is proportional to", and means that we're eliding some possibly complicated constant that makes our priors actually proper probability functions)
Now, let's compare the hypothesis that taking some drug gives you some amount of positive utility `u`, which we'll call A_u, to the null hypothesis that it does nothing, A_0. We do a study, and find that P(study data | A_0) = 0.05, and also that the hypothesis H that best explains P(study data | H) is A_u. What are out posteriors P(A_0 | study data) and P(A_u | study data)? Well, standard frequentist methodologies don't report a P(study data | H), so this is usually impossible to compute, but if we make the VERY EXTREME assumption that the ONLY POSSIBLE hypotheses are A_0 and A_u, we can say that P(study data | A_u) = 0.95
P(A_u | study data) ~ P(A_u) * P(study data | A_u) = 1/(2^u) * 0.95
Well, what is u? Some random study online gives 1.51 QALYs (Quality Adjusted Life Years) for avoiding an infection entirely, and let's say our drug has a 10% chance of preventing any symptoms. But wait; why use QALYs and not QALDs (Quality Adjusted Life Days) or expected future earnings? This is the last part of our model that needs to be parameterized, and I have no idea how to do it, and it matters a lot: using QALYs means that we should, in fact, be ~95% sure that this thing works; using QALDs means that we require particle-physics levels of certainty before we even consider the fact that it might work.
Please comment if you have a solution to this problem!
I assume you're talking about a point prior here, rather than a prior probability distribution (i.e., your prior is that the probability of hypothesis A is P(A)=0.2, not that your prior is that P(A) ~ uniform(0,1), or P(A) ~ beta(a,b), or whatever). Note that point priors can't necessarily be coherently updated, so you should be thinking of prior distributions.
To see the problem, notice what happens when your prior is that P(A)=1 (you are 100% certain that hypothesis A is true). For you to be logically coherent, your prior probability P(D) for any study data D must necessarily be P(D)=P(D|A) (since "prior you" knows 100% that A is true, and so their prior probability of observing data D, P(D), is necessarily equal to the probability of observing D given that A is true, P(D|A)). Plugging into Bayes then gives
Mathematically, what's happened here is that the probability density for our "evidence" in A is fully concentrated at 1, and so can never change, no matter what data we observe. A distributional approach gets around this.
I'm a little confused by writing "P(A) ~ beta(a,b)". P(A) is a probability of an event A, and should be a real number, not a distribution. I might write "X ~ beta(a,b)" if X is a random variable with distribution beta(a,b), and then P(X > c) for the probability that X is greater than some constant c
In the example I worked above, I used a two-hypothesis space, where the hypotheses were A_0 and A_u, and I was using Bayesian inference to determine which hypothesis was more likely; we had priors over those hypotheses, and some evidence which had different likelihoods under the two hypotheses, and that led us to different posterior probabilities for those hypotheses. Bayes' Theorem is completely valid in finite event hypothesis spaces.
I understand that once you have a prior of 1, you can't update away from it, but I didn't do that in my example. And this doesn't have anything to do with discrete vs continuous hypotheses; Dirac deltas are just as degenerate as Kronecker deltas.
You have P(A_0) =1/(2^0) =1 as your prior for A_0, so you can't update away from that.
Bayesian updating of priors based on new evidence is based on a prior distribution; if you want to update your knowledge about the probability P(A) given some new information D, you represent your initial uncertainty in the value of P(A) via a distribution, and update that distribution. Suppose my initial prior distribution for some event A (before any observations at all) is that P(A) is equally likely have any value between 0 and 1. Then my initial distribution for P(A) is P(A) ~ beta(1,1) (beta(1,1) being the uniform distribution). If I see some data D with k occurrences of event A and N-k non-occurrences, then my updated distribution for P(A) is now P(A) ~ beta(k+1, N-k+1) (a nice property of beta as the conjungate prior for probabilities) The more observations I see, the more concentrated my distribution for P(A) becomes: I become more and more sure of it's value, but never certain! This is "Bayesian inference" for probabilities: uncertainty in the value of the probability is represented by it's distribution, which is updated as more evidence arrives.
The problem with using point-form probabilities is that they don't represent uncertainty about the probability parameter - and uncertainty is a central part of updating (the more uncertain you are about the value of the probability P(A), the more easily you should update away from that value). That's why probability distributions are used in Bayesian inference.
I'm using non-normalized probability distributions for ease of computation. I tried to be careful and use ~ instead of = everywhere, but I'm sorry it was still confusing.
The crux of the Pascalian medicine argument is the assumption that the probabilities are independent. If they are, you can sum them up and get the expected benefit. But Scott has previously argued that he thinks there's a systemic issue with the scientific process that generates this evidence. If the systemic assumption holds (and it sounds like that argument is part of the process of estimating his probability estimates), it's not valid to sum up the probabilities since a systemic failure affects all the probabilities simultaneously.
A corollary to this would be the housing market crash in '08. The assumption that killed the mortgage-backed securities was that each home foreclosure was independent. Once foreclosures became interdependent, the underlying assumption of risk was no longer valid.
And assuming you can sum up the negative effects to get the expected down side. Drug interactions are real and can be very powerful. Paxlovid is itself a combination of two drugs, PF-07321332 and ritonavir. The ritonavir is there to inhibit the P450 enzymes in the liver, which would otherwise destroy the PF-07321332, thus using drug interaction for good. on the other hand, MAO inhibitors with a side of blue cheese and pepperoni can kill. You can't just add up the side effects of Marplan with the side effects of avacados to get the expected outcome of the combination. That fact alone makes all this amateur math nonsense.
There's a bigger problem than combination effects, to my mind. I've reviewed hundreds of patient charts, and it's striking to me how many concomitant medications some patients are taking. And although Scott points out that sometimes this is exaggerated, frequently it isn't. You can tell when someone who is reportedly on two or three dozen medications (yes, really!) does indeed take those medications; if they're admitted to the hospital the nurses log each dose. I've cross checked those pages for more than a few patients and confirmed they really are taking a pharmacy home with them.
That's not to say the combination effects are moot, just that we should address it as a separate issue and maybe even as the younger sibling to a larger problem of simple over prescription. I witnessed this firsthand when my grandmother came to live with us during COVID lockdowns last year. We discovered she had been prescribed medications against both constipation and diarrhea. The insane thing is that the facility she was in had been actively giving her both! (Rx said QD PRN, but effectively they'd just treated them as QD, whether she PRN or not.) So she soiled herself literally every day. It was mortifying for this sweet old woman.
She moved into our place, we dropped both medications, and took a closer look at the other meds she was on. They had her on HTN medication, but her BP was really low. So we dropped that, too, but monitored her blood pressure so that if it became a problem we would give it to her. She went from being lethargic and weak to energetic. They had her on a benzodiazepine long-term and we said, NO to that. Got her on an antidepressant, and a Rx to treat her vascular dementia. Her thinking became clearer, and she had some happy memories in our home.
My point is that her problems stemmed from the INTENDED effects of the drugs they gave her! And the tragic part of this story is that when her dementia got bad enough that we couldn't care for her anymore, we sent her to a new facility. That new facility ignored all our notes on medications - which we got endorsed by an in-home PCP, but they didn't care - and just went back to the old routine. Now she's lethargic, and she poops her pants every day, and her memory is getting worse fast. It's a tough fight to get them to STOP treating her with drugs she doesn't need for conditions she only has because they're messing her up. And another tough fight to get them to care enough about her individual case instead of giving her the 'standard cocktail'. That's not just one facility, either, it's all the long-term care facilities. And it's not just those facilities that create the problems they then go on to treat by over prescribing.
Combination effects, to my mind, come secondary to the fact that over prescription is a huge problem for many patients. We lose not a few patients to homeopathy because replacing their current slapdash regimen with Literally Just Placebo Water is a huge step up. That's not because homeopathy 'works' so much as because throwing everything at a patient is a great way to create problems.
That's sad about your mother. On your last point, I think this is evidence that Scott is on the payroll of "Big Homeopathy", as he's obviously playing a long game to drive everyone there :)
Also that the subsequent president (Rutherford B Hayes) is a national hero in Paraguay and they have towns and holidays in his honor. And he was besties with the father of geology/John Newberry who made sure the nascent NAS was incorporated into the federal government.
Yeah, that was back before The Great War, though, when all of medicine was pretty much indistinguishable from voodoo. ^_^
People keep complaining about the FDA, as though it stepped into a nice, perfectly functioning system of evidence-based medicine. When the reality is that it wasn't that long ago when the smart move was to be cared for by a dutiful aunt, and stay far away from anyone calling themselves a physiker or a medical practitioner.
Now, I'm all for improving the current system so that it works better than it does today, but we're a long way from the days of Snake Oil salesmen. (Well, maybe not that far from it, but at least people recognize holistic voodoo as 'unproven' in some meaningful sense.)
From the wikipedia article "his given name was Doctor". Wow! Why didn't I think of that. Would have saved a lot of years in grad school! It would have been double fun if he had also become a legit physician.
IIUC, the assumption that was false was that each home foreclosure had a low probability because it was expected that the entities issuing mortgages were vetting would-be homeowners for their ability to pay, and not steering them toward homes they couldn't afford. But that wasn't true.
I think there are about a million different explanations for the '08 crisis, and likely that's because - as with so many real-life phenomena - it was multi-causal. There's certainly the issue of vetting based on ability to pay vs. ability to pay off, but banks knew many of those loans would go bust. It was part of the calculation everyone relied on to allow them to believe that detail didn't matter.
What I was referring to was how the mortgages were repackaged after they were sold. Most banks don't hold onto a mortgage after issuing it, they resell it on the open market. But there has to be a market to sell to before they'll make a bunch of loans to sell. That's why for years they didn't like making lots of sub-prime loans, because those weren't worth as much and the market for them was easily saturated. If you know a loan has a 30% probability of foreclosure within 5 years, you're unlikely to want to bet a lot of money on it. You can lower that probability be doing better vetting of the borrower's ability to pay, but then you'll make fewer loans because many borrowers will demonstrate higher risk of failure.
Then some bankers figured out that you could diversify that risk by packaging 10,000 sub-prime loans together. The law of large numbers now lets you write off 30% of the value of those loans with a 30% risk, and recalculate the risk as <1% that the whole thing is going to go belly-up. Instead, the likely value of the portfolio of loans is 70% of the nominal value of the loans (+/- <1%). With this new tool (and a few others) you can now resell as many sub-prime loans as you want, and the race is on to find new ways to get sub-sub-prime borrowers into the market.
Not only that, but these bundles of loans are now large-value, low-risk assets that can themselves be re-bundled as collateral for more risky loans. The mortgage bundle can act as a security (kind of like a co-signer) on an otherwise risky financial deal. If the original assumption holds true - that the law of large numbers allows us to reassign the risk of failure from 30% to <<1% by just writing off 30% of the value of the loan bundle - then there's nothing wrong with assigning such a high valuation (and low risk) to this bundle of loans.
Except the assumption of the bundling approach is that each of the loans in the bundle carries an independent risk of foreclosure. Out of 10,000 loans with a 30% risk of failure, we can count on about 7,000 loans to be worth exactly as much as their dollar value. If the median loan is about $200,000, the whole package is worth pretty close to $1.4 billion, plus or minus a few million. That assumption was proved wrong when there was a systemic issue. At that point the bad assumption had the market valuing those loans at <1% risk, when instead there was a ~30% risk that the whole package would collapse, which in many cases it did. Those packages then led to other packages collapsing, so that instead of being worth $1.4 billion for a package like that, it was worth a tiny fraction of its original value. Since other loans were in turn based on the value of that original mortgage-backed security, those loans were now exposed to the whole risk of the original package - a risk that had been realized, much to everyone's surprise.
That's the point I'm trying to make with the Pascalian Medicine approach. Scott is treating each of the probabilities like they are independent. But if the approach that brought you a 1% probability that Snake Oil is going to cure everything is itself flawed, then you don't get to sum up the probability for Tahitian Noni, apple cider vinegar, etc. At that point, the whole bundle has to go into the same 1% bucket. I'm not about to pump myself full of random chemicals on a 1% bet, and I don't buy the assumption that each of these percentage assessments are truly independent.
Scott seems to say that there are only two possible ways of conducting Pascalian medicine, both of them problematic:
(1) Doctors try to make all patients take all drugs that might work, which is problematic because (a) they won't, and (b) it erodes trust when doctors give patients a bunch of drugs they know are very unlikely to help.
(2) Individuals try to design their own research-based courses of action, which is problematic because (a) lay individuals don't know how to do medical research (and shouldn't have to), so (b) this path is very likely to end up with some dead or severely injured lay individuals.
Door #2 is too risky for individuals, and Door #1 is too risky for society as a whole, so we're stuck, right? I take this to be Scott's position.
Fair enough. But isn't there a middle ground?
In Door #3, doctors initially prescribe only the drugs that actually work. But if a patient *asks* (unprompted) to be prescribed curcumin or onion paste or Ivermectin or whatever, the doctor shrugs and says, "Yeah, okay, probably won't help, but sure won't hurt, either," and writes a prescription. (A doctor speaking more precisely might say, "I believe this substance is unlikely to help you, p=0.05, but I also believe it's unlikely to harm you, p<0.05.")
Society is protected because doctors only go down this path with patients who ask for it. Individuals are protected because doctors are still using their medical knowledge to protect them from their own layperson research skills. The patient is unlikely to go full Pascalian and try EVERY drug, because the great majority of these patients are only interested in one drug they heard about from some trusted source.
...and social cohesion is strengthened because we stop treating all the Ivermectin people (and all similar groups in the future) as insane pariahs obsessed with lethal horse paste. If we instead start treating them as reasonable people who made a different judgment call, not only will we have fewer chemical accidents as they try to get around the restrictions; we MIGHT even build mutual trust and respect across cultures (leading to higher vaccination rates and lower risk of civil war).
I'm a little puzzled that you write this as a hypothetical. I mean, that's exactly the relationship I have with my physician. I ask her for advice, she gives me her best opinion, then I make a decision. We both understand there's leeway here and there, about what might work the best, so she gives me the benefit of the doubt -- it's my life, after all -- and so long as she doesn't really think it's a bad idea (and I wouldn't do it anyway if that were the case) she normally supports and enables my decision. If it's a little off the beaten path, I take pains to tell her everything that happens so she can fold it into her clinical judgment with others.
I mean, clearly you need to have an established trusting relationship with an internist, but don't you need that anyway for general health? We're a long way from drive-through medicine working well.
James' suggestion is different in that the doctor didn't suggest it. I think the problem with his suggestion is that doctors are risk-averse and might unreasonably say no.
Problem: this either requires the median doctor to be educated on a wide variety of supplements/marginally effective medicines within their area of practice, which is a bit of an ask, or it requires some substantial subpopulation of doctors to advertise themselves as friendly to the supplement-curious, which...might work, at least in dense urban centers...but also strikes me as likely to generate a headline or two about a malpractice lawsuit that happens when a patient sez the doc endorsed their near-lethal megadose of thing X when what really occurred was that they said 'hey, what about X?' and the doctor cautiously said it might work without hammering on the fact that the literature focuses on 25-mg doses and under no circumstances should he go out and buy a blister pack of 0.5-g doses from Alibaba.
Fixing the second problem would involve a...somehow societally-endorsed 'second tier' of medications more regulated than food but less regulated than actual prescription drugs, I guess? There's a lot that could go wrong there, Moloch-wise.
At one point I was taking about 12 pills a day, and ran up against the limit of what would fit in one chamber of my pill organizer. Lately I've cut down to just 3 pills (all taken with breakfast):
otc lithium aspartate: This one is labeled as 5mg of elemental lithium, which I calculate is equivalent to 150mg of lithium citrate, which is about 1/6 of the lowest dose that doctors prescribe for long-term control of bipolar disorder. In spite of the low dose, it has an obvious effect on my mood. I consider it a performance-enhancing nootropic drug that helps me focus on tasks and stay calm under pressure. As of this writing it was still available on amazon, but I'm 25% confident that it gets taken off of there within 5 years.
fish oil: Mixing this into my oatmeal has induced remission of ulcerative colitis many times. Neglecting to take it for a few months has made me sick many times. There also seems to be some minor antidepressant benefit.
multivitamin: Seems to benefit my energy levels and overall well-being.
Things I used to take, which actually did something:
NAC is an interesting one. While I was on it I got rid of a few bad habits that I've had for almost my entire life, and after I got off it I resumed the same bad habits. But also while I was on it I developed some serious joint problems throughout my body, which got better when I went off of it. This one is no longer available on amazon, because the FDA acts as if noticing that someone investigated it as a pharmaceutical in the 1950s should make us update towards it being less safe than other random things people take as dietary supplements.
Creatine basically just gave me 20% more reps in the gym, with no side effects except water retention, but the dose is a few gigantic pills every day if you take it in pill form.
Probiotics seemed to help with remission of ulcerative colitis, but did nothing else. I used to play a game of "how many different species of bacteria can I find on labels in the yogurt section of the grocery store?" and buy one of each. It seemed to work.
Supplements I used to take, which had no noticeable effect on me:
My calculator says that taking 250 independent risks, each of 0.5%, results in a 71% risk of at least one hit. Liver damage, cardiac arrest, whatever. And how to tell which one? You have to either stop them all and hope that you recover from the damage, then re-introduce the (likely fake) drugs in sets while hoping you don't further damage your body
Gotta listen to William of Occam, too, and NOT multiply things unnecessarily
But you DIDN'T mention my greater concern re side-effects: a Gresham's Law where once you go down the rabbit hole of throwing stuff against the wall, you've likely lost all ability to make smart estimations of probabilities.
My two greatest sorrows were from the suicide of a family member, who had “recovered memories” of sexual assault by a man my mom was otherwise angry about
And another family member who died an agonizing death from metastasized breast cancer; when we cleaned out her apartment I found a large jar of apricot pits labeled as Laetrile.
Both women were victims of quacks; neither was able to protect herself.
Pascal would not roll dice in such crooked games. Possibly, ONE HALF MILLION Americans will die from COVID, and millions more will have suffered needlessly, due to the political assertions in favor of unlikely-at-best therapies instead of the best-available alternatives
I have yet to hear of better epistemological heuristics re self-treatment, other than the one I myself employ: “cui bono?” This doesn't override the sense that most published research is false, but it's a strong signal when a political party is using miracle cures as an adjunct to seizing power from existing medical & scientific institutions, or when somebody peddling pills on their website.
The problem is your decision-procedure is subject to exploitation.
Currently, most drugs that show this 5% chance of curing cancer (or whatever) are selected by some process that is sometimes reasonable. But if people broadly change their decision-criteria toward taking everything that shows this 5% chance of curing cancer, then the number of things that people try this with will go up significantly due to stronger adversarial pressures, because there's a lot of benefit from showing that your onions (or whatever) can do this.
...this argument suggests that the current epistemic situation is the ideal one for taking lots of these such drugs.
(I continue to wish I could edit comments post-commenting. For example I feel like my opening sentence above is too 'strident'. Just noting this for user feedback.)
Doesn't stuff like kidney/liver load and combinatorial increase in interactions give an automatic decay function on how safe is a certain combination of drugs? If you're taking 10 drugs, there are 45 possible interactions (and even more tertiary interactions) and X grams of total crap that needs to be metabolized. If you're taking 100 drugs, there's 5000 interactions and 10X grams of total crap (since you can't just take less of each drug. You may need to actually take more to keep the same bioavailability).
Also, load on off-targets: each drug alone may have too weak off-target effects to register as "bad side effect", but if they have the same off-target (more likely than not, I think - some processes are especially prone) that can accumulate.
So the solution seems to be "I'm physically limited to only this many drug candidates before the risks start outweighing the benefits (since those grow quadratically or at least supralinearly), so I'll take at most the 2-3 most effective ones"
> Should we worry that even if each drug individually is net positive, giving someone twenty medications will lead to some crazy interaction? I’m not too concerned about this; clinically significant drug interactions are rarer than most laypeople think
Seems like Birthday Paradox might apply here: chance of crazy interaction increases super-linearly with each additional drug
1) It seems to me that effects of drugs are starting typically at lower doses than its side-effects. Therefore it may be a good strategy to take a lot of small doses of drugs with similar effects (eg nootropics), so that similar effects will add up together, and side-effects are different and small, and therefore not bothersome.
2) It seems that nootropics crowd is doing something like this, when a lot of people are taking stacks of ten different things at once. It seems that they mostly do not approach it with pascalian mindset. But some (inc. myself) do.
3) I heard that Eric Drexler is also taking tens of pills a day because of similar reasons.
Why is the downside risk of taking a supplement greater than that of taking some new food, especially a food that didn't exist in our ancestral environment?
Most of the things considered for this are known to be bioactive (or else they wouldn’t be considered). On the other hand, the vast majority of food is known to not be bioactive. Ivermectin is on this list because it’s known to mess with cellular mechanisms which allows it to kill worms, and we’re just trusting that it doesn’t mess with anything in our bodies. Ivermectin is probably safe because there’s the large number of people who have taken it before. But when you go to the grocery store, you’re buying types of food that millions (or billions!) of other people have eaten before safely, and that probably dwarfs the number of people who have taken ivermectin.
If you’re talking about supplements that are already over the counter, most of those are probably closer to the food end of things but are also less plausible to help against COVID.
Is there a principled definition of 'bioactive' that firmly excludes 'gets metabolized for macro- and micronutrients'? It is trivially true that food is 'biologically active' in a boring sense.
I think the only place where I shake my head in dismay is when the same person (1) thinks tiny changes in his diet will have profound effects, like eating heirloom tomatoes instead of french fries will make him live to be 120 -- because lycopenes! -- but at the same time (2) doesn't fear unknown low-level side effects from ivermectin or HCQ because, hey, these are generally safe, right? Lots of people have taken them and I've heard of anything bad happening.
I mean, it's one or the other. Either the entire history of people eating tomatoes might have missed some subtle but important long-term benefit *and* the entire history of people eating ivermectin might have missed some subtle but important long-term harm, or in *neither* case is it likely that some subtle long-term effect has been missed. Believing
Sure it is. Everything you eat gets torn to shreds by acid and digestive enzymes in your stomach and small intestines. It has to be small enough to diffuse across the intestinal wall, which is very small indeed. The distinction between tomatoes and potatoes, in terms of what kinds of small molecules your stomach and intestines make out of them, is slight, because life has been using the same basic building blocks for a billion years.
You've got a bunch of starches that all get whacked up into a very few simple sugars, you've got some slight differences in amino acid profiles, you've got various length fatty acids with a double bond here instead of there, which slightly changes the beta oxidation pathway they go through, and -- what else? Tiny amounts of contaminents and dyes (lycopenes!) which proceed through some long complex pathway in the liver that we don't even know exists yet.
I think people wildly overestimate how much variety there is in food because they're focussed at the macroscopic level, where it looks and smells and tastes all very different. But this does not translate obviously to the microscopic level, once it all gets smashed to its building blocks. Obviously if we took it all the way down to atoms, it wouldn't translate at all -- you're basically eating carbon, hydrogen, oxygen, nitrogen, and the odd bit of phosphorus and sulfur, in varying proportions. That's too far to break it down, of course, but there's some important truth there.
> The distinction between tomatoes and potatoes, in terms of what kinds of small molecules your stomach and intestines make out of them, is slight, because life has been using the same basic building blocks for a billion years.
I was thinking about implied difference between "pile of fat + potatoes" and "tomatoes", and such change can be helpful, especially if typical person is obese.
Difference between "pile of fat + potatoes" vs "pile of fat + tomatoes" is likely negligible. It would be better to care about mountains of sugar and lakes of fat in diet.
Oh sure, agree 100%. The mix of nutrients you eat probably has, over time, a profound effect. That makes all kinds of sense to me. I'm just getting at the individuals who think there's some weird unique principle in *this* particular food, some amazingly effective micronutrient.
And I'm actually not saying that's totally impossible -- for all I know, there *is* some weird little chemical in food X that isn't found anywhere else and makes some as yet undiscovered difference over time.
But what I'm saying is, if you believe *that* I don't see how you can logically consistently be blasé about what unpleasant as yet undiscovered differences over time some other wierd little chemical (particularly one not found in the natural diet, like ivermectin) might have.
I looked this up, because my natural impulse was "Well of course this is dumb, raw whole vegetables and fruits are superior to processed foods!"
Then I found out the benefits of lycopenes only come once they have been processed into things like pasta sauces and ketchup:
"Consumption by humans
Absorption of lycopene requires that it be combined with bile salts and fat to form micelles. Intestinal absorption of lycopene is enhanced by the presence of fat and by cooking. Lycopene dietary supplements (in oil) may be more efficiently absorbed than lycopene from food.
...Ketchup is a common dietary source of lycopene. ...(T)omatoes and tomato-based sauces, juices, and ketchup account for more than 85% of the dietary intake of lycopene for most people. The lycopene content of tomatoes depends on variety and increases as the fruit ripens.
Unlike other fruits and vegetables, where nutritional content such as vitamin C is diminished upon cooking, processing of tomatoes increases the concentration of bioavailable lycopene. Lycopene in tomato paste is up to four times more bioavailable than in fresh tomatoes. Processed tomato products such as pasteurized tomato juice, soup, sauce, and ketchup contain a higher concentration of bioavailable lycopene compared to raw tomatoes."
Boy, was my face (tomato) red! The heartless Reaganite Republican budget-pinchers were, in fact, in the right!
So your friend would probably get the best benefit from consuming potatoes (say in the form of fries?) and ketchup, rather than raw tomatoes alone 😀
"Cooking and crushing tomatoes (as in the canning process) and serving in oil-rich dishes (such as spaghetti sauce or pizza) greatly increases assimilation from the digestive tract into the bloodstream. Lycopene is fat-soluble, so the oil is said to help absorption."
So if I'm stuffing my face with pizza, get off my back: I'm eating healthily, prodnose!
I think the Law Of Conservation Of Expected Evidence is vulnerable to the same problem Pascal's Wager is: our tendency to overestimate small probabilities. There is a vast sea of potential hypotheses (even pairwise-incompatible hypotheses, if you will) that you have never thought of; if you understood how vast it is, you'd probably have an appropriately-low probability estimate for a randomly selected one, but by definition you don't. Just by someone stating a hypothesis to you, it gets elevated from an unknown unknown to a known unknown, and that messes with our perception of probability.
This strikes me more as a problem of balancing one low probability (chance of a given supplement working) with another (chance of it causing harm) than of over- or under-estimating any one low probability.
Here's my naive attempt to steelman the "take a bunch of supplements" position:
Suppose there's something like a general factor of how hard your body is trying to fight illness. Think of it as an immune DEFCON. As DEFCON rises the body's effectiveness fighting infection increases. But so do things like energy use, physical weakness, and risk of long-term damage to other body systems (because the immune system is increasingly likely to attack them by mistake). This is kind of a stupid model but as far as I can tell it vaguely resembles how the immune system actually behaves, at a high level.
The Algernon principle says that raising the DEFCON isn't a free lunch in the ancient evolutionary environment. But it might be a nearly free lunch _for us_, at least under certain conditions. First, the downsides-- needing increased nutrients, decreasing out capability for strenuous physical activity-- might be things we care about less relative to a risk of e.g. serious COVID than our ancestors did. Second, modern medicine might be able to measure the risk of serious COVID better than the body (which has never seen COVID before) can.
So it could be true that supplements act-- assuming they act at all-- only by generically exciting the immune system and raising the DEFCON. And it could be that that's a net negative when we're healthy (or uncertain whether we're ill), per the Algernon principle. But it could still be a good deal to take a bunch of supplements whenever one's feeling under the weather (or better yet, isn't feeling under the weather yet but has a positive COVID test).
'Generically exciting the immune system' is not at all something I would expect to be benign in the specific context of COVID, given the hyper-inflammation and cytokine storms seen in some of the worse-off patients. The corticosteroid dexamethasone is an *immunosuppressant* and is part of the current standard of care for bad COVID cases.
This post doesn't quite get all the way to a cost-benefit analysis (even a quick back-of-the-envelope version). Let's try one:
How bad is getting covid? I've seen estimates of 1 cent per microcovid, which means that getting covid involves $10,000 of badness.
If there's a medicine that has a 5% chance of working, and cuts the expected total badness in half if it works, then: if it works then it alleviates $5,000 of badness, so its 5% chance of working gives it a $250 expected benefit.
That's... not very much.
What are the costs of taking this medicine once you get covid?
Money: let's say it costs $20
Time: maybe 30-60 minutes to figure out it's the thing to get, get it, and take it
Side effects: probably smallish, I'll guess on the order of $10
To stick with round numbers, let's say the costs add up to $50. That gives a net benefit of $200 for taking the medicine if you have covid.
But you don't have covid yet, and maybe right now you're thinking of doing some reading & thinking to figure out what you want to do if you do get covid. How likely is it that you'll get covid and be in a position to take the medicine? Maybe 5% for the next year (and if it happens more than a year from now, your research will be obsolete by then). So an expected benefit to you right now of 5% of $200, or $10, from figuring out now (when you're healthy) that a particular medicine has these expected effects on covid. And the costs of doing the research now to figure this out are more than that; even if it's just 30-60 minutes of research that time is still worth more than $10.
If you figure that out and share it widely, then it's a $10 benefit for each person who learns of it while healthy. If it just takes 2 minutes for each of those people to hear you then that's a net benefit for them of ~$9, but if they each need to spend their own 30-60 minutes of research to verify what you have to say then it's back into the negative. (Plus there's a $200 benefit for each person who learns of it after they get covid and are searching then for what to do. So there is a net benefit to creating an info hub that people can access once they get covid.)
>Should we worry that even if each drug individually is net positive, giving someone twenty medications will lead to some crazy interaction? I’m not too concerned about this; clinically significant drug interactions are rarer than most laypeople think, and usually pretty predictable. Still, giving twenty different medications at once is almost unexplored territory, and something like this might be true.
I think the risk in this sort of situation is greater than "some drugs among the twenty may have harmful interactions with each other." I think when you start taking effective doses of so many different medications at once, you'd have to start worrying whether you're going to overtax your body's mechanisms for processing drugs at all. Maybe most of the drugs have non-overlapping pathways for removal from the body, but some of them will have overlapping pathways, and you'll start seeing the sort of harmful side effects that you would if you'd greatly upped the dosage of a single drug.
I think that's a good point. My vague understanding is that almost all weird substances are dealt with by a small number of pathways in the liver. It would, after all, be very expensive for the body to maintain a wide variety of degradation pathways to deal with compounds it only rarely encounters. Much better to have a bunch of preparatory steps for the various possibilties that all feed into the same basic elimination pathway. This is rather how metabolism itself works, after all, everything feeds into the citric acid cycle with differing preparation steps.
Many life-saving medicines are using things unavailable to the body.
Also, someone deathly ill is in state where body is failing to achieve something (see IV hydration).
Strict application of Algernon's law would claim that lifesaving medicine is unlikely to work and we have piles of counterexamples (and also piles of failures!)
There's a type of drug-drug interaction you haven't considered: that the drugs could prevent each other from working. This is probably more common than you immediately think: for example, a Pascalian approach to depression treatment might naively include a psychedelic, an atypical antipsychotic, and a dopamine agonist, all of which would be fighting each other. Similarly, a Pascalian approach to smoking cessation might involve nicotine replacement therapy, varenicline, and bupropion - all of which would be fighting each other. At the beginning of the pandemic, haloperidol was actually considered as a potential COVID treatment (I can probably find a reference for this if people want me to), because of its antagonism at the sigma-1 receptor - which would, in a Pascalian approach to COVID treatment, be fighting fluvoxamine (which is an agonist at the sigma-1 receptor). Perhaps it would even be worse than nothing. Then again, a Pascalian approach to HIV treatment might lead you to taking three or more antivirals with multiple different mechanisms of action - which is in fact the standard of care. So maybe it's different in infectious disease.
Dangerous drug-drug interactions are also probably more common than you appreciate, _when the drugs actually work_. For example, the above Pascalian depression treatment would probably include both amitriptyline and an MAOI, which is either really dangerous or a great idea [1]. Even on the more benign end, a Pascalian smoking cessation treatment would probably include both bupropion and naltrexone, which together cause a lot of weight loss - that usually won't be a problem, but sometimes it will be. If you're thinking of more benign drugs, like melatonin or curcumin in the case of COVID, then this is less likely, but more benign drugs are also less likely to work, so it takes more of them to reach an expected effect similar to drugs that have evidence. That is, I would expect the probability of drug-drug interactions to be at least proportional to the expected efficacy of all the drugs taken together, perhaps even more.
Separately, starting 20 drugs at once would make it impossible to know which one is causing a side effect. If you even just tried them all separately, you would be able to discontinue the ones you don't tolerate. But if you take them all at once, if even one of them isn't tolerable, you have to stop all of them. (Maybe you could do bisection here? Probably in practice that would be too difficult to carry out.)
So why not try them all, but one after another? The core thesis of Pascalian medicine is that there's little cost to trying one more drug. But if trying one drug means you can't try another until you're done, then that doesn't apply. (In the case of an acute condition like COVID, I suppose you also won't know if it works until your symptoms are gone and you're not dead, so this also doesn't apply.)
What's the lesson here? One of the core principles of pharmacotherapy is that less is more. Pascalian medicine throws that out the window, but it's probably best we don't abandon it.
I think that you are downplaying the magnitude of algernons law. The probability that a random chemical will harm you is vastly greater than it will help. People have weird intuitions about their bodies, so let’s think about another high performing complex machine like an engine. What percentage of random chemicals could you pour in your gas tank that would make your car run better vs make it worse? In covid your chance of not dying is actually quite high, thanks to an incredibly sophisticated and complex machine in a near perfect state of balance. Your prior should be that anything you add to that is very unlikely to help more than it hurts. So anything other than a large well run RCT, no matter how positive, shouldn’t make you think benefit:harm ratio is >1. In fact probably a single RCT shouldn’t be enough to overcome what should be very pessimistic priors.
For all comers, covid ICF is about 0.6%, so even in your fluvoxamine example a 5% chance of a 30% (relative risk) reduction is 0.01%. You don’t need many unexpected harms to wipe out that benefit.
>The probability that a random chemical will harm you is vastly greater than it will help.
I would be fascinated to know if anyone has made a reasonably sophisticated crack at quantifying *how much* more likely, since that would be a decent first step towards being able to evaluate the literature on a given supplement and make an informed decision about whether or not to take it.
I’d be really interested in someone smarter than me taking a crack at quantifying it too. I’ve seen the stat that 1 in 5,000 drugs make it to market, but I’m not sure if the distribution of those that are harmful vs just lack efficacy.
An important note on harms is that they are hard to fully capture in even large RCT’s. Unless you are looking at all-cause-mortality (which very few trials do) then how you chose your endpoints is really important. It’s pretty likely that you will think of and prespecify the benefits endpoints (say, reduction in cardiovascular events), but the likelihood that you will think of and measure all of the myriad ways a drug can harm you is low (look at all the surprise harms that come out years later and lead to medical reversals)
> We don’t fret over the unknown unknowns of Benadryl or Tylenol or whatever
We absolutely fretted over ibuprofen and Tylenol possibly *increasing* covid mortality early in the pandemic. I suppose you could call it a "known unknown" as soon as people start fretting, but what about before then?
Looking from outside as a leyperson I think this discussion is often too narrow on biochemistry and statistics. These are imortant fields of sience, but talking about how to deal with problems as a society and expecially when there is no clear scientific answer (yet?), there are a few fore aspects that come to my mind:
1) people are different. I know so many stories about people reacting different to the same medication or diet. Of course with something acute like COVID there is no time to test several drugs once you are ill to see which helps you best. But with such mixed evidence like with Ivermectin it looks childish to me just to discuss who is wrong with the only options being 'it works so we recomend it to everyone' or 'its just a false positive and it harms if people have a false hope'. I think the focus should be to work together and gather as much data as possible to find out who profits from a specific treatment and who doesn't.
2) We need more public funding for independent medical research. This will not only generate more knowledge, but also improve trust in science. Many people are seeing the that the objects of research are not optimized for public good but for potential profits. So 'this is not scientifically aproved' or 'there are no good studies about it' does say more about the economic value than the medical value. This hurts trust expecially as we are often told not to use anything that has not been scientifically approved, but we know by experience that it helped i.e. traditional medicines.
If there are the voices now saying that this is the state is always inefficient in spending, we could decide publicly on the topics to be researched involving polls to see public interest or prediction markets to get the most promising candidates. We could also filter for drugs and treatments that are relatively cheap and can't be monopolized.
3) As there are so many candidates that could have a net positive effect, too many to take them all, but not a clear favorite to recomend to everyone, just let the people decide on their own. Just take care that information on risks and side-effects are easily available. This may go wrong sometimes, but i think the effect is net positive:
- if you want to stop somebody taking something, you have to show respect for opinion and his choice so he is much more likely to listen to you and your warnings.
- this builds kind experience what works and what doesn't. Of cause scientific knowledge is always better, but if there is none or not available experience is better than nothing.
- If you put force against something without good arguments, people often start to question your motives. This breaks trust and they stop believing you when even when you have good arguments next time.
- freedom always includes the freedom to take bad choices. Many people prefer freedom over safety so they will oppose anyone who wants to force them for the good. This is especially about the public pressure to get everyone vaxxed, but it also applies if you want to stop somebody from taking experimental medications with (soft) power instead of arguments.
- better people get the drugs they want to try from someone with medical knowledge knowing and telling the risks, than if they get veterinary versions without information what doses are usually save for humans.
>I think the focus should be to work together and gather as much data as possible to find out who profits from a specific treatment and who doesn't.
It is already mind-bogglingly difficult and expensive to work out whether medicines work at all on the population at large: trying to skip that step and figure out whether something works on gay male ethnic Hmong between the ages of 40 to 59 is a formidably difficult research problem with a number of well-known statistical pitfalls.
>We need more public funding for independent medical research.
'Independent' in what sense? Are you just talking about the stuff not funded by industry, or are you thinking outside mainstream academia as well?
>...just let the people decide on their own...
I don't think anyone was talking about *forcing* people to take or not take any particular medication. This post is about how people should *make* such decisions- specifically, if the average person, or the average bright ACX reader who's reasonably good at research, ought to be more aggressive about making them.
With independent my main point is independent from commercial interests. But it could also be interesting to leave some of the usual concepts. As far as i know medical research usually only looks into single chemicals, but many traditional medicines are a complex bundle, e.g. a tea of a specific herb, that could be tested as a whole protocol.
Of course it would be impossible and a waste of resources to do complete studies on every imaginable sub-group. I was more thinking of searching for patterns what could show up in the existing studies to see who did profit the most and who didn't. Just a little more of what Scott did by realizing that most of the studies showing an effect are in poor tropical countries. One factor seems to be the the worms, but perhaps it's also age, diet, lifestyle. You could also look at the cases where the drug definitely didn't help and if you see a pattern you know when better to try something else. Therefore you need as much data as possible about the study.
It does not have to be proof up to the usual standards, if you are transparent about it. It still can give hints to people deciding which supplement to try as they can't take too many.
But its also different basis for discussion if you tell the other team "Your results have to be wrong because most studies have different results." or if you say: "This is interesting, lets figure out together why your study has such a different result"
Except for vaccines there is luckily nobody taking about enforcing a particular medicine. But there is quite a force not to take something. If i go to my doctor or a medical educated friend asking about e.g. Ivermectin because i heard a lot positive about it that sounds plausible to me, there is a big difference between the possible answers: "Thats all fake news of the internet. Only stupid people believe that. You are not a horse with worms so it can only hurt you." or an alternative: "The evidence is not clear if it helps, in some studies it does have an effect in others it doesn't. But i can tell you the risks and side-effects, so i wouldn't recommend to try it."
I haven't watched the film but as it was told to me, Prof. Williams was a psychologist (I think?) that was diagnosed with glioblastoma and a one year survival timeline. He started researching anything that could possibly be effective and took them (metformin and cloroquine were two that I think ended up in his cocktail)... and 21 years later he was still around.
My first reaction to that is either he was one of the lucky ones who actually survived glioblastoma, or "diagnosed with glioblastoma" does not equate to "had malignant glioblastoma". What's the probability of a mis-diagnosis vs the probability that a bunch of random drugs would actually cure him? And, more to the point, what's the chance that if another glioblastoma patient followed the same treatment, that they would be cured, too?
As a critical care physician who has cared for dozens of Covid patients in the ICU, I saw a number of people who delayed seeking evidence based therapies such as monoclonal antibody because they were taking Ivermectin. By the time they decided to try the Monoclonal antibody—after Ivwrmectin failed—they had already developed respiratory failure and ultimately died.
I wonder if Scott could find some interesting and potentially useful things by looking into things people take to enhance performance - including doping (ie illegal).
Apparently a quite common result is that things that enhance performance do not sum if taken together. Eg caffeine improves performance, as do nitrates, but taken together you don't get both performance boots.
idea here being that it's an area where people try to take lots of things with a similar aim, and a lot of them don't work at all and the ones that do don't necessarily add up if taken together...
"And if I’m not 95% sure this doesn’t work, doesn’t that mean there’s a 5% chance it does work?" I understand what you're trying to say, but currently the sentence is logically false. Potentially adding "at least" to both parts would do what you want.
Sigh. The mental gymnastics some people will go through in order to try (and fail) to overcome "absence of evidence is not evidence of absence" is pretty sad, especially when cloaked in a façade of rationality.
Where medicine is concerned, though, you can drive a truck through the gap between 'conventionally held by everyone to be the entirely unambiguous presence of evidence' and 'the outright absence of evidence.' Getting to the point of being Really, Really Sure takes years, often decades, and tens of millions of dollars. It is worthwhile to at least *consider* whether it's possible to parse the evidence so you can safely and responsibly pull the trigger any earlier than that.
Agreed. But in such a setting where pragmatism is prioritized, we're dealing with expected costs and benefits and the utility thereof; erroneously framing it as some kind of pure Bayesian "law" is inappropriate and also epistemologically dubious.
Exactly. It's a problem with all people who provide a service while dealing with complex systems: investment managers, meteorologists--not to mention the more scummy professionals like economists and social scientists in general. They're incentivized to pretend to know way more than they do. Probably the right approach--more accurate, at any rate-- in all these fields is much more epistemic humility, and openness to new approaches and experimentation at the margin.
I haven't nailed down a precise scenario, but I suspect if you actually went all "insanity wolf" and really took "All medication all the time" you would, in fact, die.
I have a friend who split her face open last week after passing out after she started taking a prenatal multivitamin, inositol, activated folate, and NAC all at the same because she has PCOS and is trying to get pregnant. Can confirm.
One mercy with diabetes is that you can take blood sugar measurements, which at least give you some short term information about whether something is helping. You can't test for COVID risk.
A missing dimension in this discussion is the ability to get the dose right. Even if we think about drugs in binary terms (works versus doesn't; toxicity versus not), the dose is a key determinant. It's not easy to get dosing right! Most antimalarial drugs have been introduced at the wrong dose for some key subgroups (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837842/). Chloroquine is an extremely safe drug (at the right dose) and an extremely dangerous drug (at the wrong dose - or right dose if suicide is the objective). Doctors can get the dosing wrong even for well known drugs.
An interesting example is chloroquine for COVID-19: in a clinical trial in Brazil in early 2020, the investigators got mixed up between salt and base weights (salt is the weight of the tablet; base is the weight of the active ingredient). There was a recommendation from China to use chloroquine 500 mg twice daily for 10 days, and they thought that was a base dose (chloroquine 250 salt = 150 mg base). They only had 150 mg base tablets so gave 600 mg base (4 tablets) twice daily for ten days. Turns out this gets you close to lethal concentrations and they probably killed a few people in the trial (https://elifesciences.org/articles/58631)
*Usually* things that have the kinds of promising initial studies done on them that would elevate them to your attention in the first place have at least a suggestion of what the dose should be. Agreed that you really do need to read carefully sometimes to avoid issues like the salt/base weight issue- though my personal preference when applying Pascalian stuff to myself is just to sick to the stuff with a nice, big purported therapeutic index to avoid exactly that problem.
One obvious complication is that you can't treat 20 or 100 or 250 different drugs/supplements as statistically independent, where if there's a 5% chance of each one working then there's a 1-(1-0.05)^20 = 64% chance that at least one out of twenty will work. If the first drug fails, it's possible that it failed because the postulated underlying mechanism was wrong, and three of the other drugs had similar postulated mechanisms so they're now out. Or it didn't work because the test methodology was faulty in a way that exaggerates effectiveness by 5%, and six of the other drugs were tested using the same methodology.
And on the flip side, side effects are rare and multidrug interactions are rarer, but twenty drugs gives you 380 possible multidrug interactions.
Doing a proper quantitative analysis of the linked probabilities would be almost ineffably hard. But to the extent that there's an argument for Pascalian medicine (and I think there is), it's for taking a few of the most promising and most *differently* promising drugs, not for taking everything that ever showed an effect.
What do you think of traditional Chinese medicine in this context? I had the impression that TCM had a lot of similar characteristics with this approach: the treatments are based on a combination of plausible explanations for why things might work and anecdotal evidence; patients typically take a bunch of things at the same time all of which are generally safe and might or might not help; TCM treatments sometimes turn out to do well in western-style clinical trials and sometimes they don't and also sound ridiculous. TCM doctors have some way of choosing the "right" combination of things to give each patient...
My take: from a region with a worse-than-average reputation for academic honesty, and known issues with manufacturing quality in general and heavy-metal contamination in traditional medicines in particular.
"There’s a potential compromise solution, where smart doctors come up with Pascalian medicine protocols for the few patients who would actually want them."
Congratulations. You just invented naturopathic medicine.
My mum has been recommending for years that we take Armaforce when we feel fluey. I would always refuse her offer of, as I called it, "snake oil".
Armaforce is a combination pill of andrographis, echinacea, olive leaf, vitamin C and zinc. As far as I know, none of these chemicals are really proven to help with the common cold all that much. There's a little evidence for each of them, but not a slam dunk for any.
Anyway, I finally listened to her and took the damned pill, and what do you know: it works wonders. Once I discovered how useful it was, I constructed a justification for it that approximates your description of Pascalian medicine. I now take it whenever I get that familiar scratchiness in my throat, or when I feel that a lack of sleep may have left my immune system a little off its game. And I get sick far less than I used to.
100 long-shot supplements might be too many; but for me, at least, five has hit the sweet spot.
(I still refer to it disparagingly as "snake oil", but now with a hint of irony and self-deprecation.)
Sometimes things are snake oil, and sometimes they do have benefits. Like willow bark for pain relief, before anyone knew and could synthesise salicylic acid, and then develop aspirin.
Zinc and vitamin C do have known benefits. Echinacea, olive leaf and andrographis are more in the realm of "traditional remedies, which may have a pathway of action or may not, we're not certain yet".
And then you do get snakeoil, which is "Throw together these seven things and make exaggerated claims that it will cure cancer".
OK, now I've heard of a grand total of 7 people who might (or might not) benefit from echinacea.
Obviously, there are enough people who think they benefit from echinacea tea that there are always a few facings of it at Whole Foods. On the other hand, it doesn't seem to be getting more popular or less popular. It's just bumping along, same as always over the last quarter century or so that I've been buying it.
I take an approximately Pascalian approach to depression. Not to the extent that I’m taking twenty things, but to the extent that I looked over the preliminary-noisy-low-level-promising-finding tier of treatments, picked the half-dozen or so that seemed to me to be lowest risk due to already being in *very* wide use for other purposes (creatine, fish oil, vitamin D, magnesium, melatonin, saffron), or an extremely slight chemical tweak on same (l-methylfolate). In addition to conventional antidepressants, ketamine, talk therapy, and other well-studied lifestyle stuff like intensive regular exercise and mindfulness meditation.
This was less an Insanity Wolf-style ‘REVIEW THE ENTIRE SUPPLEMENT LITERATURE AT ONCE’ thing and more a matter of a decade and a half of reading a dozen journal articles or meta-analyses a month and coming to the one-by-one decision that adding One More Thing to the regimen looked good from a risk/reward perspective. I might be a little more aggressive after reading this, actually- the ‘substantive and meaningful drug-drug interactions are rarer than you’d think’ bit is very interesting, and fear of interactions was one of the main things that kept my list of stuff to try from expanding faster (the others being the physical size of the box I use to organize my weekly medications, budget, and the desire to try only one new thing at a time to keep myself from being in the position of having significant side-effects and no idea of what to blame it on).
Certainly I’ll be looking for good reading material on polypharmacy.
I'm not really understanding the application of Algernon's Law and anyone turning people away from taking vitamin D. From what I can tell there have been a large number of very well done studies which show there is widespread vitamin D deficiency.
It just seems like the idea of warning people away from vitamin D is a pretty poor example of something to warn people away from considering it is a widely accepted issue that people don't get or have enough of it.
I think a LOT of these studies fixate too much on the already sick as well. The arguments of 'being healthy' and 'not getting sick in the first place' through things like 'having enough vitamin D'....don't really get measured in hospital admission rates or negative PCR test for people who already fell into sickness.
I don't see how we can ignore that 90% plus of people in hospitals with covid also happen to have low vitamin D which is much higher than the 60-70% background rate of people who have low vitamin D. What possible cost benefit analysis would see anyone be discouraged from the general idea of supplementing with it?
Perhaps it isn't a perfect covid cure, but so what? There's no pascalian wager associated with supplementing vitamin D when you're deficient in it...and it might also help with many other things.
What kind of Pascalaian wager of harm are we making by exposing ourselves to all the pesticides and herbicides and such. Where is Algernon's law for all the crap in our environment which has been repeatedly shown to be harming us and killing people? And still none of it is regulated or tested or examined. I'm far more concerned about the hundreds or thousands of things thrown at us from our paint to known neurotoxins in our pillows in fire retardants, to asbestos and DDT, etc.
Only a few of those are household names, but where is ANY of this analysis for those things? If I take 1,000 industrial chemicals and throw them at people, all exogenous things we never evolved around....where's Algernon?
How can Algernon's law apply to sedentary indoor modern humans whose necks are bent at odd angles looking down at their black mirrors all the time with the idea....evolution has sorted everything out for us and everything is optimised.
It just seems like such an obviously preposterous idea with no nuance. Perhaps a human 100,000 years ago living outdoors and hunting and gathering across the African savannah had no problems with Vitamin D. Perhaps they also had far far fewer problems with their jaws being under developed, or scoliosis in their spines from sitting and inactivity, not being exposed to sundry toxic substances, chemicals, and endocrine/hormonal/etc. disruptors of our various bodily systems.
There is so much that is different and has changed very rapidly in our environment.
Any reasonable evolutionary look at humans would conclude that our environment has changed far far faster than even fast evolutionary ideas would project to account for. How could we possibly have genetically adapted to these moderate and soft forces in our newly toxic environments?
Are we adapted for phthalates and our shrinking taints and plummeting sperm counts? Are all these plastics and other endless novel chemicals all utterly harmless?
If we apply the methodology of skewing towards harms being more likely than benefits, then certainly the tens of thousands of untested chemicals and the ways they degrade and interact with each other which humanity just dumped everywhere...and every so often when people start dying fast enough and in concentrated enough numbers we notice and do things like ban asbestos or any number of other banned lesser known chemicals which gave everyone cancer downstream from the factory....and the probable hundreds of other chemicals which are hurting people in such extreme degrees and in more moderate ways.
All this science and knowledge and deep long analysis of things stops at the things which get studied. The endless exemptions and lack of testing for safety for so many things we're exposed to just goes....unnoticed. Hand waive away that problem...what?
Certainly the idea that there 'is no metabolic free lunch' from taking loads of exogenous drugs and supplements is an idea. But then taking that idea to a stupid degree one wouldn't take antibiotics or anything from outside your body. And certainly looking at endogenous compounds like vitamin D or eating certain foods would make sense.
But I think there is a layering issue of complexity where no metabolic free lunch applies from one perspective, but makes no sense in another...especially when one is talking about things that are missing from your lunch, such as eating it while outside or other nutrient deficiencies in the modern western diet which has proven itself to be a huge scourge in medicine with heart disease, diabetes, and probably certain forms of depression and anxiety coming from dietary issues for some people.
Smoking cigarettes has got to be bad for you if you have covid. Whatever else is going on with covid, it does impact the lungs. Does the concept of 'patients don't do what we tell them anyway' apply here? Does it change the truth of the matter if patient compliance is high or low?
But does this mean we shouldn't ask? Or if you do smoke you shouldn't stop for at least the period while you're sick?
Do we really need a study on this when we already know how bad smoking is for you? Or how bad vitamin D deficiency is bad for you?
> There's a strong argument that Algernon's Law does not apply to Vitamin D. The maintenance dose for the Spanish RCT studying Vitamin D for COVID is around 8000 IU/day. This is about what someone would get from 2 hours in peak direct sunlight shirtless. Hunter-gatherers probably got this or equivalent, but we clearly don't.
> And still none of it is regulated or tested or examined. I'm far more concerned about the hundreds or thousands of things thrown at us from our paint to known neurotoxins in our pillows in fire retardants, to asbestos and DDT, etc.
I am pretty sure that asbestos and DDT got mostly regulated out of existence.
In Europe at least, with various more or less effective asbestos remediation programs and laws.
"I don't see how we can ignore that 90% plus of people in hospitals with covid also happen to have low vitamin D which is much higher than the 60-70% background rate of people who have low vitamin D."
But is that causation or simply correlation? If Joe didn't happen to contract Covid but was in hospital for something else, couldn't you make the same connection: "Joe is deficient in vitamin D, he's in hospital for galloping gallumphs, while Mick is also deficient in vitamin D but doesn't have it - plainly being low in vitamin D makes you more susceptible to the gallumphs"?
I agree that it's one of those things that can't hurt, but it's not so clear that it's going to be "and in this case it will make a definite difference in outcome".
Vitamin D is notorious for being corelated, but unable to be shown to be causative when you start trying to change outcomes by adding it. It's like one of the biggest now-you-see-me-now-you-don't headfakers among micronutrients, a savage little minx of a molecule.
Fascinating post, BUT I'll be a non-technical pedant and note that a Pascalian approach to medicine might also imply rejecting medical assistance out of adherence to extremely ascetic practices.
The thing I worry about with this whole poly-polypharmacy concept is EDCs - a dozen compounds that are more or less perfectly innocuous at the amounts we're routinely exposed to them (as far as the limits of their individual studies can tell), but taken together are responsible for something like a 50% decline in male fertility over the last 50 years.
What happens if you start taking 100 pills a day and then some weird additive effect like this crops up? What if you're perfectly healthy but your kids end up with some sort of weird issue due to the additive effects?
I think if you're taking 100 pills a day, that is not rational or sensible behaviour by any measure. If you're going to be taking things on the basis that "onions, garlic, turmeric are proven benefit by these studies", you're better off to incorporate them into your diet rather than try and get "multi-concentrated essence in a capsule".
Some things will help, but taking too much of anything is bad for you (let's listen to the advice of our elders in proverbs and sayings), and it's going to be down to each individual's needs and unique biochemistry anyway. You want to have more vitamin C? Eat more citrus fruit!
What, get various different things like your diet like some kind of peasant? Nah, just eat highly processed food and then try to shove all the various phytocompounds back in manually by eating a bowl's worth of pills every day. That's efficient!
Interesting view. Fact is in the beginning, people died without any treatment that can prevent them to become intubated. millions.
Its one to say, oh, we dont know if ivermectine works or not, but we dont have anything else, so why not lets just try it to save the patients.
and other to deny treatment, demonize/eliminate those doctors who were willing to treat patients and give life saving early treatment, and spread misinformation in the media about "horse dewormer"
That is criminal intent.
Especially since now we see Merck and Pfizer coming out with antiviral pills, that are supposed to tackle the same problem of early treatment, kill the virus before it becomes dangerous...
I rank these both as providing low to no evidence though, since it is well known that "everything kills cancer cells in a petri dish".
Given the incredible variety of plant extracts available with touted health benefits for various things, Scott’s scenario is not hypothetical. People will and do market the most ridiculous things as having (very dubious) health benefits.
This also makes me sceptical that e.g. Kurzweil’s use of so many supplements should be described as rational - his behaviour is indistinguishable from that of someone (like my grandmother) who has decided for some quasi-superstitious reason to take a bunch of supplements.
I practice a form of this on myself to treat depression and general fatigue. I take about 8-15 different supplements daily. I'm pretty sure half of them don't help at all, but I'm not sure which half. I can't really make myself get more than 15 pills down in a day, so if I find something else that looks promising I bump off the treatment I have the least faith in. Sometimes things immediately get worse, which provides evidence that whatever I discontinued was helping. Through this process I've found fish oil, magnesium, vitamin C, and lion's mane certainly help. No matter how much people swear up and down about it, vitamin D has no noticeable impact on my mood or health.
I think supplements and so on work when you have a small deficiency, or when you need more of something (be that because you're less/more active, getting older, pick up a minor illness).
I have found magnesium supplements very helpful with leg and muscle cramps. It's only in the last couple of years I have needed to take them, and I don't think I've changed my diet all that much. So it could be "age 30, no discernible effect; age 40, will see benefit" for many things.
I'm also taking Omega-3 fish oil because why the heck not, also my joints are getting creaky and it may help. Ditto with turmeric for anti-inflammatory properties, though given all the caveats about bioavailability, you're probably just as well off to consume it via Indian curries which at least will be tasty and enjoyable 😀
Funnily enough, Taguchi methods were developed specifically to solve issues like this. Time to queue up an orthogonal array and start filling out those BDIs, CES-Ds, EQ-5Ds...
A question I have is: What percentage of COVID patients are involved in a trial? If we have twenty to hundreds (from ivermectin and Vitamin D to onions and egg plants) of potential low risk chemicals to try out, are we? Given the number of hospitalizations in the US alone, the error bars on the effectiveness of anything that's already known to be generally safe for human consumption should be much lower than this post implies. It seems that every patient should be asked "Would you be willing to take pills from this bottle, which potentially will improve your situation, but will probably do nothing?" Each bottle would have some drug or control (eg, sugar pills), an identifier (check for allergies by entering them into a form which knows but doesn't tell which pill type it is), and after the patients illness is over one way or another, the data is recorded. This also may be the most ethical way to provide the placebo effect. Seeking better data to get the answers we want seems like a more productive line of action than choosing Omura's Wager.
An interesting question is whether crank cures tend to be wholly fallacious or if they become well known because they work for a few persuasive people (but not for most people). As I've often burbled on about, I've found the Chinese traditional remedy of echinacea tea to be helpful. But in all the years I've enthusiastically blogged about it, only about four commenters have chimed in to say it works for them too.
Now it could well be that me and my four pro-echinacea supporters are deluded about echinacea's efficacy. Or it could be that it really does work for a vanishingly small percentage of the population, such as the Chinese sage who originally promoted it, me, and four people who read me, but not for most folks.
I've long been interested in figuring out a general theory of crank cures, but haven't made much progress on the question.
If any of you want to be the Darwin or Foucault of crank cures, please have at it.
I see echinacea teas and extracts and what have you in every health food shop, so it is something that is known and recommended (over here it tends to be in German versions rather than Chinese traditional remedies, as the Germans are big on biodynamics and holistic cures and the likes).
I think the perception of it is "home remedy" like honey and lemon for coughs and sore throats, rather than "medical cure". So people may try it, but they're not going to go for it first instead of a packet of Lemsip or whatever.
One issue is the slavish adherence to the dogma that all rigourous quantification of uncertainty has to be probabilistic. So saying 75% Vitamin D doesn't work automatically implies that 25% it does work.
No. You have a lower probability bound on the chance of failure of Vitamin D, not a complete probability distribution. We simply know that at best there is a 25% percent chance that Vitamin D might work.
I read the linked article on LessWrong and this paragraph made me wonder if it is logical:
‚For a true Bayesian, it is impossible to seek evidence that confirms a theory. There is no possible plan you can devise, no clever strategy, no cunning device, by which you can legitimately expect your confidence in a fixed proposition to be higher (on average) than before. You can only ever seek evidence to test a theory, not to confirm it.‘ https://www.lesswrong.com/posts/jiBFC7DcCrZjGmZnJ/conservation-of-expected-evidence
I do not agree. Arguably, my priors are also based on a sample size. For example if my priors are based on N=1000, then one additional datapoint should adjust my believe by 1/1001 * effect size.
"‚For a true Bayesian, it is impossible to seek evidence that confirms a theory.", if by "confirms a theory" he means "posterior probability equals exactly 1.000", then he's correct. But that's a pointless, trivial observation. I read that lesswrong post. It's just a math-y sounding word salad mash-up of Law of total expectation (https://en.wikipedia.org/wiki/Law_of_total_expectation) and Bayesian jargon.
"When I reviewed Vitamin D, I said I was about 75% sure it didn’t work against COVID. When I reviewed ivermectin, I said I was about 90% sure.
Another way of looking at this is that I must think there’s a 25% chance Vitamin D works, and a 10% chance ivermectin does. Both substances are generally safe with few side effects. So (as many commenters brought up) there’s a Pascal’s Wager like argument that someone with COVID should take both. The downside is some mild inconvenience and cost (both drugs together probably cost $20 for a week-long course)."
Yes, so the good thing is, if you don't bother with Vit D & Ivermectin, even if you die, you've saved 20 bucks.
Thanks so much for all of this. I'm one who doesn't like taking drugs. But I will admit that when I feel a sniffle or there is covid peaking nearby, I'll pop a multi-vitamin, D and zinc. I'd do a prophylactic does of ivermectin if I had one. No harm, no foul. I just wanted to observe that the placebo effect is big (and useful?). By your pointing out that I'm deceiving myself abut D and zinc, I wonder if you are robbing me of the potential placebo effect. Do you ever think about it this way?
Speaking of Zinc and drug interactions, here's a little gem from ~25 years ago: https://academic.oup.com/jac/article-pdf/40/4/483/13056424/9372416.pdf It basically says, yes, zinc works, but only if it's really zinc ions. I can tell you zinc ions taste really bad and astringent. If you go to CVS to buy zinc lozenges, you'll find they're all zinc citrate, gluconate, of "chelated". Why? because all of those compounds have the zinc ion bound up really tight with an organic molecule so you don't taste it. But at the same time, there's no free zinc ion to help you fight the virus. It gets worse. There's usually excess chelator (citric acid or gluconate) in the lozenge, so it actually sequesters the zinc ions that were already in you mouth, making the viral infection worse! That's the bad interaction between zinc and citric acid (think lemons - citrus fruits). All the studies that show zinc works for colds are done with specially made, awful tasting, actual zinc ion lozenges. The stuff you get at CVS will probably make things worse. "Insanity Wolf" really is insane. This whole business of sequestering zinc to stop enzymes and other biological molecules working is a bog-standard technique in molecular biology labs. They usually use EDTA instead of citric acid, but it's the same idea and has been around since the time of The Elders. Having actual knowledge of biochemistry makes walking the aisles of CVS a depressing task.
Hmm OK thanks. I heard (on a ACX post back sometime in early 2020) about the types of zinc and I believe I bought the 'right' type of zinc. I only opened by bottle of zinc a few weeks ago, and have had two of the lozenges. They do have an astringent taste.
What brand was it? I've been looking for useful zinc lozenges without success and am about to make my own candy spiked with zinc sulphate. Zinc acetate is also good. Just make sure there's no citric acid in it.
Corrollary of Algernon Argument: Sure, you started out with a pretty convoluted balance of elements that left you in a more of less optimal state. But you've been messing with that state since the time you were born. With diet, with exercise and with drugs, usually in non-optimal ways. So it is entirely likely that most people have at least 1 or 2 imbalances that they could fix with supplements and thereby gain improvements.
Of course, if your balances are already skewed, dumping 20 odd supplements into your system is unlikely to restore it, and most side-effect statistics assume 'normal' health, and those would be amplified as well.
Also, this modelling assumes that the effects of each supplement are independant, right? Since supplements don't usually have contraindications, this might not matter at most scales, but at 20 (or 250?!), don't those interplaying effects also need to be accounted for? Is that even something we can model with accuracy?
Current hot hypothesis in autism research is that short interpregnancy intervals lead to autism via folate deficiency which vaguely is upheld by subsequent trends of osteoporosis in those mothers
(idk, but since Scott is really into birth order) Also over supplementation can be detrimental to neurodevelopment (murine models) and can allow growth of nascent tumors - it's actively discouraged for cancer patients and the elderly
Also fun fact, one of three cadavers has thyroid cancer. I think all MDs know.
This reminds me of a report I heard on NPR about a clinic in California that treats people who think they might have CTE from repeated brain injuries, but we can't prove that without an autopsy and have no treatments anyway, by basically giving them a whole bunch of random treatments that almost sound like they might work but there's no real evidence for but probably aren't harmful, from trans-cranial magnetic stimulation through dubious herbal supplements through "diet and exercise". It's probably a scam the way it's done, and you could do many of them yourself and save several thousand dollars on a consultation, but I had trouble saying confidently that it wouldn't *work*.
This feels like a cop-out to me. By conflating all early treatment medicine together and pushing it down a slippery slope you can then stand on the other side of medicine guzzling junkies and appear the more reasoned one. Though I got to admit it's funny and enjoyed reading it. Still, if we know Covid mostly strikes those with immune system deficiencies then it stands to reason all the minor things a person can do to boot their immune system could have an effect. If being outside can reduce transmission to zero, if wearing a mask or running fan can help, then having healthy levels of vitamin D can help as well. And a drug that may slow down the replication of the virus by let's say 15 to 25%, could help, which could be the difference for a given patient. Should such immune optimizations be held up as a substitute for a vaccine...no. But to dismiss them is irrational from my view.
A couple years ago I went full-scale Pascalian for my currently untreatable conditions of PSC + UC. I am taking about 10 supplements every day including berberine, SAMe, ALA, curcumin (yes) and others. On the balance, I can report it works for me so far, I am flare-free for a year now and generally feel better than at any point in the last 10 years at least. I ran my list of supplements by my doctor who recommended against one of them; a couple others I had cancelled myself after they seemed to make my liver worse.
The most obvious is kidney and liver damage. A lot of drugs are well tolerated as long as you take them in reasonable quantities, but can destroy your liver/kidneys if you take a lot of them. Taking ten drugs that all are individually well tolerated, but which can damage these organs if you OD on them, could easily basically be an OD that does the same thing - it's death by a million cuts.
The entire realm of drug interactions is also basically impossible to know, because the sheer combinatric matrix there is untestable. Take twenty meds at the same time, and you have 19+18+...+2+1 = 190 potential two-drug interactions. The higher order drug combinations are even more complicated, and may not be predictable just from the two-drug interactions. Anything which is biologically active could well have interactions, either counteracting the other things, or even counteracting something ELSE random (like, for instance, if you end up getting prescribed an antibiotic, it might have some weird interaction with some medication you are taking).
A third pontential issue is screwing up your gut microbiome. We don't exactly know what all your gut microbiome does, but throwing twenty random drugs at it at the same time seems like the sort of thing that might screw it up.
A fourth issue - especially for things like antiparasitic drugs - is that taking them all the time causes everything else to get resistant to these things. So giving these drugs all the time could easily lead to the pathogens we are trying to protect against becoming resistant or immune. This is why we don't take antibiotics 24/7 (well, one of the reasons) - it puts a kind of evolutionary pressure on pathogens we *really* don't want.
Things that you ingest normally - like, say, Vitamin D and Zinc - are PROBABLY okay if you stay relatively close to the DRA.
Taking well above the DRA is a bad idea, as some of these chemicals ARE possible to OD on - for instance, Vitamin D has both acute and chronic effects if you OD on it, and it isn't actually that hard to OD on Vitamin D - standard blood concentrations of Vitamin D are 20-50 ng/mL, and we start seeing toxic effects at 100 ng/mL. There's actually a lot of things we take where the toxic dose is only a low multiple of what the theraputic dose is.
On top of this, some micronutrients are much easier to get rid of than others, so bioaccumulation can become an issue when you oversupplement even when the acute toxicity is low.
And animal models won't always save you on this stuff.
For instance, Llamas seem to be vastly more tolerant of vitamin D overdoses than humans are. Why? Who knows. I only know this because I know one of the researchers who worked on trying to find the LD50 of Vitamin D in llamas and gave up after repeatedly doubling the dose; IIRC the final dose they gave them was completely ridiculous (IIRC 64,000 IU per kg of body mass) injected directly into their bloodstream.
For reference, the human RDA of Vitamin D is 600 or 800 IU per day. And no, that's *not* per kg for humans.
This applies to everything. There are artificial sweeteners that will cause organ damage in rats that humans are completely unaffected by. There are surely things that work in the opposite direction.
All of this is valid. If you're healthy and young, Pascalian medicine is probably not a good idea.
But if you already have an incurable condition that's going to kill you, and your choice is between whether this happens in 2 years or 20 years, I think it makes no sense not to try everything that _may_ work. Just research substances thoroughly, paying close attention to any reports of liver/kidney trouble. Introduce stuff one by one and watch closely for individual bad reactions or interactions.
I think it's worth pointing out that fluvoxamine (your example of a success) has quite a few significant side effects. I find it much less well tolerated than other SSRIs I prescribe.
A lot of this comes down to risk aversion, both at the personal and professional levels. I don't think you'd find many doctors who want to put their career at risk by prescribing experimental remedies, even if the regulatory framework was more open to this. On the patient side, who wants to take the risk that their doctor is a quack giving them something where the risks very much outweigh the potential benefit? Even if there are benefits to society from loosening up on both these fronts, it's very difficult to chip away at these biases.
You see the same thing in other fields; finance especially comes to mind. I'm a bit of an investing geek, and do some unconventional things with my portfolio. I like the risk/reward tradeoff of the unusual choices I've made, but in managing my partner's portfolio I go with something very standard, because what if I'm wrong? Professional investment managers deal with this all the time - it's called "career risk" in the field. It's very hard for them to stick to contrarian strategies when they have a benchmark to track. There's a tendency to herd in the conventional path even against one's better judgement, because performing poorly alongside everyone else looks a lot better than performing poorly on one's own.
Even if you take all twenty medicines, and doing so "works" (people who take the dosages don't get the COVID, even after multiple high-intensity exposures), what's to say that it's not the combination that "works"?
I'm a big believer in science, rationality, common sense (no question - my own type of common sense ;-) )
That said: I learned over the years that in the end its all about trust into certain people and or systems systems and distrust others. All our high IQs, information, research and much much more counts not much. In the end its about trusting or distrusting.
Thats kind of good and bad at the same time for me.
"Futurist Ray Kurzweil used to take 250 different supplements every day - but after realizing this was excessive, cut it down to only 100." was wondering the same - "maybe he really has found a secret or even the holy grail of liefe and death and I should do like he does" - some years later seeing an image of Kurzweil and thinking "looks pretty old this guy for his age - ok, let's forget that stupid 100+pills idea"
The Placebo Effect and the affects of prolonged anxiety/fear are both well established, aren't they?
Combining the beliefs that 'they put it on the test swabs' and 'God decides when its your time' would seem to be more statistically effective than fear and supplements.
"We don’t fret over the unknown unknowns of Benadryl or Tylenol or whatever, even though we know their benefits are minor."
Speak for yourself... I take Algernon's law seriously, and tend to avoid low benefit medications because the expected value doesn't favor them. I also do my best to approximate an evolutionarily informed diet (i.e. paleo, but making allowances for neolithic foods my ancestors ate for many many generations).
I have long Covid, doctors are useless, and I have had far more luck with folk/quack remedies off of the internet than I have with anything doctors have recommended. If you actually have a medical condition which doctors have not and are unlikely to help you with, Pascal's Wagers are totally rational. The way to avoid being mugged by Pascal's quacks and avoiding tail risks is to do enough research to create a hierarchic list based on a cost/plausibility ratio and go down the list.
Commenting a bit late, but this is basically my approach to supplements, with a focus on longevity and general health. I am nowhere near 100 myself (currently at around 10, peak was around 20-22), and if anyone is curious I wrote a brief (albeit slightly outdated post) outlining all of them with some reasoning as per why I take them(with the more interesting things on the bottom of the post. also keep in mind this is personal to myself!): https://nearcyan.com/supplements/
It does get interesting when you run cost/benefit analysis on things like this though, and I do have some uncertainty about the best ways to meta-manage this myself as well.
scott mentions negative interactions, but what about positive interactions? If we see a number of proxies improving in response to the drugs, maybe some of them are hitting real parts of the problem, and in combination they'll have a real effect?
That's a perfectly reasonable argument for why doctors shouldn't prescribe IVM / HCG + Zinc by default.
It's not the least justification for doctors refusing to give the prescriptions to people who want them, or for pharmacies to refuse to fill those prescriptions
Its possible for Kurzweil to be entirely rational in taking 100 supplements to slow down ageing, and for you to be entirely rational in ignoring the weak evidence for ivermectin, under certain priors. Specifically, given that you know that vaccines work generally and for covid, it is much less likely that ivermectin works than would be the case if vaccines didn't work. Vaccination validates a far from complete, but still substantial causal map of the mechanism whereby covid operates, and we can map this to facts about infectious agents that have broad support. What we know about ivermectin has no causal link to this picture, and would imply a potential large set of unknown mechanisms at work. We have a deep prior that reality displays a causal parsimoniousness (even in biology). I don't have a fully developed argument as to why, and how justified this is, but I suspect that its quite hard to do science without it, and that the success of science operates as a macro confirmation of this prior.
Normally wouldn't mind philosophical debate on fringe virus treatment, but every ounce of validation for these kinds of treatments means more folks won't get vaccinated, and more of either them or someone they contact will die. How about an essay on anticipatory regret - in effect taking every precaution so you don't unwittingly hurt someone?
I'm not sure at which point calling the approaches 'pascllian' becomes unfair (because the probabilities are much larger than that in Pascal's wager), but we still underexplore this search space in many regardless, so I think it's a good thing to encourage more usage of expected value and probabilistic approaches to these things.
> I know of only one person who takes the Pascalian argument completely seriously. Futurist Ray Kurzweil used to take 250 different supplements every day
Well, my chronically ill mother took nearly a hundred different supplements a day for 30 years. She stayed more or less sick (it's been somewhat of a roller coaster). Recently she's started to have mini-strokes and had to be placed in a care home.
some intuition for why maybe the 20-drug insanity wolf position isn't quite so crazy (aside from the efficacy claims in the meme):
We already consume tens of thousands of different chemicals every day in our food. If you plug in a prior of 0.01% that two random chemicals will have a harmful interaction, then you get a ~100% chance that our food will kill us. That prior must be wrong when applied to low doses, or when applied to chemicals that our ancestors have consumed for millennia.
Eating 20 more chemicals doesn't seem so significant in that context, as long as the dose is lower than what was well tolerated in studies. Also many/most of the supplements exist in food (like cicrumin in your curry). A thousand year history of consumption as food counts as much more evidence of safety than a few crappy studies that were probably funded by whoever is selling the supplement.
Well, Ivermectin apparently does work if you have worms and need it to fight off the worms when the corticosteroids are used to dampen the cytocine storm. So there is a possible causal effect, under which it does work.
And vitamin D does work if you lack vitamin D — just like zinc and vitamin K2 and C, it is part of what the immune system needs to work. If you are a healthy adult during summer time and take enough sunlight, you don't need vitamin D. Nor do you need K2 (produced by bacteria in the intestines) or C (because you eat enough fruits), nor zinc, when you eat enough of it. But in winter and as old aged person, you have very likely already such a severe lack of vitamin D that your bones start to crumble, and probably your eating habits are not healthy, so you lack other things, too.
And this is a condition that is far more likely than the worm infection.
So, no, you should not use this mental “chance” model. You should try to understand why a drug works, and if it only works under some conditions, use the drug only under these conditions.
Studies in worm-infected countries closer to the equator probably find more likely that Ivermectin works, while studies in northern countries have a higher chance to find vitamin D works — if the supposed effect is real. So you not only have to look if the study is performed with good standards by trustworthy people, but also where it was done, and if the underlying conditions for the drug to work are likely. Actually, the people doing the study should do that analysis in the first place.
In the end, the human body is complicated, and therefore, treatment is not always simple and unconditional. You have treats with a high success rate (like vaccination), but the one immune evading mutant during your phase III test in exactly the country where you did test it can ruin your results. You have treats with a low success rate (like Ivermectin), because the conditions under which that works is rare, at least in western countries.
Isn't the leading recommendation in medicine for a Pascalian Diet?
Your safest bet is to each as wide a variety of foods as possible(excluding those that are harmful).
Maybe I'm mistaken that's the scientific consensus, but I've never seen any argue against it or recommend a very narrow diet of a few specific things that proven to be very healthy (except as extreme weightloss diets).
So aren't the onion farmers already money pumping us with the Pascalian Diet?
Why not let them money pump us with Pascalian Medicine too?
Re. "I’m nervous about this scenario because it violates the Law Of Conservation Of Expected Evidence - if I “know” that onion farmers doing studies will convince me that onions have a 5% chance of curing cancer, I should just believe there’s a 5% chance onions cure cancer now."
There is no violation of the Law Of Conservation Of Expected Evidence. I assume you mean that the studies will conclude onions cure cancer if p < .05, so that 5% of the studies will conclude onions cure cancer if they don't, and that will convince you there's a 5% chance onions cure cancer.
No. Just do the math. A meta-review of these studies should look for the risk ratio multiplier that treatment of cancer with onions has for, say, death as outcome; then conclude that the best estimate of that risk ratio is R such that P(outcome | R) is maximum. If the studies pass a p < .05 test 5% of the time, I'm pretty sure that will work out to R = 1, meaning our best estimate is that onions have no effect on the risk. If they pass it less than 5% of the time, then R > 1, meaning our best estimate is that onions increase the risk of death from cancer.
When you phrase the question in terms of "probability onions cure cancer", you're making an asymmetric test, ignoring the possibility that onions make cancer worse. The case where R = 1 is presumably where the expected risk from onions cancels out the expect benefit from onions.
Pascal would have made a bad Boy Scout. Always gambling with the other kids and getting hopelessly lost in the woods.
Found a spammer!
I'm not sure it's sufficiently widely appreciated how important the liver is, and how much we stress the shit out of it by asking it to dispose of all the weird things we eat, drink, short, or inject. The more I learn about the liver does, the more I want to take tender care of the beast -- you OK in there? Need more of this, a little less o' that? Anything you want ol' buddy...
I mean, we almost all die of atherosclerosis or cancer, and you wouldn't *think* that has a lot to do with the liver, but...who's to say it does not? All those lipoproteins that people fuss over, where there's a direct connection to CAD, that's traffic to and from the liver. And the immune cells that are supposed to kill off baby cancers, they're trained in the liver. Maybe if you mistreat your liver for a few decades it starts malfunctioning in certain ways that turn up as your arterioles narrowing and your immune system slacking off. Not good.
CD56 bright NKs are trained in the liver? I mean technically it's the first site of hematopoiesis during development but they're the first cells to pop up after a bone marrow transplant. I def think it's circulating NKs that establish themselves there. Also NK cytotoxicity is based on MHC presentation/T cells are trained in the thymus/B cells either die naively or are selected for by dendritic cells through somatic hypermutation (definitely learn, don't tell the intelligent design people).
You can download Janeway's immunobiology on Libgen*/I'm hoping the pandemic increases public scientific literacy on immunology because my main goal in life is to not have job security. NKs are actually super sensitive to sleep deprivation!/will be depleted and your body will upregulate immunoglobulins across the board.
*It's super readable and fun and once you understand all the inputs into the immune system everyone saying everything makes a difference in everything makes way more sense and also there's a new edition coming out in February. Technically 17β-estradiol helps if you're exposed to COVID, but I'll eat my hat the day Bret Weinstein starts promoting that.
Thanks. My copy of Janeway got lost during my last move. Now I don't have to buy it again.
I just learned that circulating spike protein can induce inflammation independent of viral infection, even independent of a binding ACE2 receptor (murine). So, I have come to the realization, for the Nth time in my life, that I understand nothing of biology. It will take a while for my self-delusion to wind back up again until I have any opinion about anything biological.
This is off topic, but in another thread you said you have a very good memory because of a genetic difference... Aha, found the comment:
“...inherited two copies of protein that can only be transcribed as a specific isoform that always stabilizes this kinase involved in presynaptic facilitation so that my memory...”
If this is not too personal of a question, what protein and SNP/allele is that?
Is there a name for the effect where if you catch someone going out of their way to stress the qualifications of someone, they're probably a crackpot?
e.g. "John Campbell has written an article about Ivermectin" -- probably not crackpot
"Dr John Campbell has written an article about Ivermectin" -- probably a crackpot
He may be DOCTOR WITH A DOT, but he doesn't seem to have heard of isomers.
I got that far in his video then skipped through the rest. If the guy honestly thinks "pooh, dropping a few bonds in this molecule versus this molecule makes no difference, they both are the same molecule and work the same way (and so this proves that Pfizer's new drug and ivermectin are one and the same, and I'm not saying there is a conspiracy to keep a cheap, sure cure hidden while the big drug company creates an expensive 'new' drug, but..... ", then he's about as reliable as a leaky bucket.
The normal convention is not to mark an abbreviation ending in a lower case letter with a full stop/period if that letter is the last one in the word. So Dr against Prof. would be correct.
And before anyone asks, I have no idea why. But it's been in every academic style guide I've ever read.
How would it scale with the number of letters?
"Sir Dr. John Campbell, MA, MD, PhD, DPhil, FACP, FRS has writen an article about ivermectin..."
Credibility probably reaches a minimum at three titles and then starts going up again. I'd actually be interested to hear what this guy with three doctorates and a knighthood has to say.
Nitpick: It would be Dr Sir, not Sir Dr.
Past three, there would need to be a rule to Google each initialism, lest you find yourself unduly impressed by the medical judgment of a Member of the Association of Accounting Technicians or a Fellow of the Institution of Agricultural Engineers.
Does a "nurse educator" require good scientific knowledge? In the UK nurses have until recently not prescribed and were expected to follow instructions on drug delivery. It seems unlikely that someone who was presumably a lecturer on nursing from three generations ago would be expected to have any expertise in pharmacology, although clearly it can't be ruled out.
His expertise looks to be physiology, which is a very different field from pharmacology. He may be good at the latter but there's nothing there to necessarily suggest it, and people on this thread are pointing out worrying weaknesses in his arguments. I am thinking there's a high probability he does not have the pharmacological expertise needed to make the claims he's making.
Note in particular his training and career were at institutions (Bolton and Cumbria) focused on training and that don't therefore prioritise staff research. In US terms you're looking at the small state college/well-ranked community college level. I'm not suggesting staff working in these places are not intelligent or competent, but Dr Campbell's career path does not look like one that involved much development of transferrable research skills, as indeed might be suggested the fact his only notable publication (admittedly according to Wikipedia) is a teaching text.
Therefore I don't think the credentials here are particulary relevant, and certainly not enough to shift my opinion of Dr Campbell's likelihood of being correct.
Are you serious? I watched the Ivermectin video. Claiming that Ivermectin has similar clinical effect to Paxlovid just because they have similar putative MOA does not reflect well on Dr. John Campbell. And, this is assuming that you actually believe the MOA is actually correct, which is pretty bold. It was a couple decades before it was shown that statins don't work (to the extent they do work) by reducing serum cholesterol, even though that was gospel for many years. This is why well run RCTs are so important. It is just not possible to fully predict how a drug will work in a human just by doing a few experiments in cell culture. It's not even possible to predict if the drug will get to the cells, let alone the right compartment in the cell, by looking at stick structures, or even full-on 3d structures. Drug discovery would be infinitely easier if it were so, but it's a real slog because Every. Little. Thing. has to be proved out in humans. Dr. John is not going to prove anything by just looking at a bunch of lab papers. Giving advice to "world leaders" based on in-silico calculations of binding affinities (which are notoriously unreliable) shows a real naivety. He also confuses Fluorine with Fluoride, a sign that he's not a chemist. I recommend Derek Lowe's blog (it's on Scotts blogroll) for the perspective of an honest-to-god, in the trenches, medicinal chemist's view of how much (or little) you can get from these MOA arguments (and in-silico calculations). Dr. John is going to need a bunch more letters after his name before I would give him a second look.
Serious about taking Dr. John seriously. He just goes through a bunch of mechanism papers, which have little relevance. The ironic thing is he actually put up the Pfizer press release (which he thinks is a paper) and then proceeds to ignore the main result, which is that Paxlovid works really well to keep people out of the hospital and alive. So well that they met their significance goal (and FDA agreed) early and could halt the trial. In the face of that, all those in vitro studies don't add or detract from the value of the drug. And if you want to cast aspersions on people's devotion to scientific truth, go back and read Scott's magnum opus on all the Ivermectin papers. He had to throw out half of them because they were so bad you couldn't draw any conclusions from them, or they were just outright fraudulent.
"Now, I don't always follow the details of these statistical analyses" @ 12:10 in the video. He appears to be confused about a very basic statistic from the bayesian analysis in the TOGETHER trial on fluvoxamine. There's a nice graph of it in Figure 2 of the paper. So now I'm convinced he's not well versed enough in either chemistry or math to be explaining the results of a clinical trial. He goes on to the result on the odds ratio of death of treatment vs control (If you're following along at home, this is line 8 of table 3), which is given as 0.68 (17 vs 25 deaths), CI95% [0.36 - 1.27], which he thinks it great because it's a 32% reduction in death! Yea!. Of course he doesn't understand that hi brow statistics stuff, so he completely ignores the p=0.24 (basically meaningless) and the fact that the CI includes a 27% INCREASE in death due to fluvoxamine. He then goes on to emphasize that this is for "very low risk" (i.e. fluvoxamine is known to be a safe drug) right after he just got showing us that the data doesn't rule out an increased risk of death due to fluvoxamine! Now, I don't believe that fluvoxamine has much effect either way, which is what that pathetic p value is saying. But if he's going to put up a bunch of stats to convince you it's safe and worthwhile to take, then he better explain why the numbers aren't agreeing with his commentary.
If you like this guy's style, then by all means watch it as light entertainment, but for God's sake, don't think you're going to get any smarter by listening to him.
Thanks for the (second) shout-out. The thinking behind omura's wager led me to post this thread, which attempted to redesign a large chunk of medicine around it: https://twitter.com/alexandrosM/status/1435565853466972164?t=lOVddQ3v0IxEAv81Rub39g&s=19
Does the Recovery trial make a small step in the direction that you're suggesting, by incorporating a testing regime into ongoing medical treatment? I believe the people who designed this trial want to extend this sort of testing beyond Covid-19. https://www.recoverytrial.net/
Thanks for pointing me to that, hadn't seen it
My new pet-peeve is that Ioannidis paper because it's become an axiom in industry to disregard new findings and protocols.
Sorry about that!
Derek Lowe, in his blog, pointed out that that, given the success rate of new candidate drugs, if you're in a drug candidate review and just keep shaking your head saying "that will never work" (said in an Eeyore voice), you will almost certainly be right, and definitely be useless.
Sime critics od Scotts love for prediction markets told the same story recently: if one is just conservative - not important if its tomorrows weather (most people same like today) or tomorrows universe (most probable like today's) one will be mostly right in it's predictions. That's the nature of doing infinitesimal small steps on the one hand. And the nature of our pretty stable environment: no dangerous changes most of the time. The critic like Take was pointing out that most of us humans are not aware and cannot deal with long-time stable environments interrupted by very rare, extreme events. We now call it black swans after Taleb. And some of us have like a 6th sense of all kinds of black swans which could come upon us. Most others havent. Evolution is so fascinating.
Eww twitter. Why do "rationalists" keep ignorantly using such a shitty and unethical platform? It boggles the mind.
When "rationalists" want to use a (presumably) less shitty/more ethical platform, they post on lesswrong.com, but the maximum (and I think also the minimum, mean, and median) number of people who will see your post on lesswrong.com is very small.
And for good reason most likely. I gave LW a second shot recently and noped out again when I noticed Eloser had insisted that a chicken can't suffer if the GPT3 can't suffer. He then went on to imply anyone who disagreed with him was stupid. Any platform featuring that guy so prominently is pretty objectively worthless.
Because it's the easiest way to publicly post two sentences and a picture. Just today I was using it as a way of tacking pictures onto ACX comments...
I've been struggling with this Pascalian *everything* for years for the exact reasons you articulate.
"Struggling" is probably not the right word, but it's always in the back of my mind.
I most don't take 250 supplements or do all the One-Weird-Trick-To-Enhance-Your-Love-Life things because...who has the time to suss out all this shit?
Just doing what Scott tells me is a lot easier.
Kidney load, cost? Also a lot of those supplements legitimately do have side-effects (though they probably attenuate with usage), I can't imagine what taking 250 would make me feel.
I wasn't really considering (or not considering!) taking 250 supplements, I was just gesturing towards the whole idea being talked about here. If 250 supplements have probabilistic costs that outweigh the potential probability of benefits, then that course of action is not even on the table for a Pascalian wager.
It seems that the more stuff you take, the more you expose yourself to a rare Vioxx/Thalidomide-style event.
That 5% chance of something working has to be weighed against a .001% (or whatever) chance it will kill you, or do something else really bad.
Depending on the condition you’re looking to treat, that kind of 500-to-one difference in chance to work vs. chance to kill might actually be reasonably attractive.
It depends on what the supplements are and the dosage. We easily take 250 supplements a day in the course of normal living - they are in the food we already eat. Some of them have pretty nasty side effects, too, especially in large doses.
“Struggling with Pascal’s wager” is the natural state of the world I think! It leads you to very strange places. Now that we have pascalian medicine, it’s time for the more extreme Roko’s Basiliskian medicine. Let’s see what supplements I can get you on by telling you there’s a small probability that not taking them will cause you to be tortured for all eternity.
Technically, hydrochloric acid
I feel like the response to this is something we do every day. There are a million things I could be doing to decrease my risk of X or increase my chance of Y, but if I were to actually do all of these things that would result in an enormous cumulative cost, so the sensible thing to do is set a probability threshhold below which the cognitive load of taking everything below that seriously leads to worse outcomes and less focus on things with high confidence than the benefits of caring about all plausible things. This is why I don’t wear a cloth mask anymore
I always felt the ‘pascals’s wager’ part of this was obvious and a particularly important component in stopping COVID-19 in a world where some people will not take the new vaccines no matter what. Even if these treatments only have a 1% chance of making things better (and it seems higher than that to me), it’s better than the 0% we get in the current hyper-partisan world we inhabit. Not to mention the meta benefit of tamping down the divisive rhetoric. I’ve long felt the ‘vaccine only’ crowd is living in the world they wish existed and not the one that we’re actually inhabiting. Anyway, that’s my obscene, unenlightened $.02.
You should not overlook the cost and value of information, particularly for the future. One reason we tend to do things carefully and step by step, instead of throw everything against the wall and try to sort out post-facto what sticks, is that this is the *fastest* way to the best quality information about what works and what doesn't. We are doing massive medical experiments on people, and the way to make those experiments give the most definitive answers as fast as possible is to be very careful about the experiment and control arms.
We are, in essence, trading potential present benefit (to the lives and health of those currently alive) for the benefit of acquiring reliable information that the future can use to the lives and health of those alive then. That's the trade-off.
Information, particularly reliable information, is very, very expensive. But also of course very, very valuable. We are the beneficiaries of our forefathers' painful experiments that eventually proved disease is caused by bacteria and not miasmas, that bleeding and cupping don't work, that drinking mercury to cure your intestinal ailments is a Bad Idea, that trephining the skull to let the evil spirits out doesn't cure madness, that "hysterical" women don't have a malfunctioning uterus -- and on and on.
All the insane ideas of the past at one time seemed reasonable to the professionals and amateurs alike, and a well-informed person living in those times would've said they had more than a 5% chance of being correct. But the only way we found out they *didn't* work, at all, and put a stop to centuries of medical butchery, is by insisting on rigorous and well-controlled experiment, which approach rules out a "Why not give it a try?" approach at the social level.
I would say whether you want to try it at the individual level rests on whether you feel like random interverntion in your biochemistry is more likely to do harm than good. As someone who works occasionally with highly-tuned complex machines, like performance car engines, I find the proposition laughable -- if I randomly poke or prod something in an engine it is almost certainly going to make things worse -- but this is just an instinct, not an argument, and others can easily have different instincts for different reasons.
> As someone who works occasionally with highly-tuned complex machines, like performance car engines
I would expect engines to be very finetuned to operate in one specific way, while living organisms being far more flexible and resistant.
For example human can eat nearly pure fat or nearly pure sugar and survive at least for some time.
Liver can process a lot of problematic chemicals and so on. Though I agree with
> I would say whether you want to try it at the individual level rests on whether you feel like random interverntion in your biochemistry is more likely to do harm than good
Well, yes and no. For example, engines are designed to operate in a variety of operating temperatures, and under varying loads. That's part of the design spec, so engineers make the engine "flexible" in that it can perform well under varying load, for example. (And if you were making an engine for a different application, like a generator, you wouldn't worry about this.)
And sure arguably evolution has made our biochemistry flexible and able to perform under varying conditions, in exactly the way you describe.
But here's the thing: just as the engineer doesn't think about how to design an engine that can operate in air or under water, because he says what kind of madman would drive his car into a lake and expect it to work? Nature has *not* optimized our biochemistry to work with highly unusual chemical insults that don't occur naturally.
So we're probably indeed pretty flexible with respect to varying amounts of naturally-occuring substances[1] -- a lot or a little vitamin D, curcumin, ethanol -- it's not clear at all to me that we're flexible with respect to substances that *don't* occur naturally in our diets (like ivermectin and HCQ and SSRIs). Why would we be? Like the cars not being driven under water, this hasn't happened in our history and so the Great Designer had no occasion to design for it.
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[1] Of course, it then also logically follows that varying these things isn't likely to have a big effect. If we can maintain homeostasis in the face of widely varying levels of vitamin D, for example, that implies varying the level of vitamin D doesn't do much. So, ironically, if the body can deal easily with it, it probably doesn't do much, and if it does much (e.g. actually effective medicine) it's probably something which you have to use very carefully because the body isn't flexible about it.
FWIW, I've been told that chronic mild overdoses of vitamin D is positively associated with bone spurs. Of course, that takes a few years to show up. And chronic underdoses of vitamin D is known to cause a multitude of problems, some of which take years to show up. But there's a large area in between those two positions that isn't associated with the relevant problems. (Well, it's enough less associated with them that it can be ignored.)
Note: This is all based on "I've been told". I'm not asserting that it's true, but it sounds plausible to me.
> Nature has *not* optimized our biochemistry to work with highly unusual chemical insults that don't occur naturally.
Nature managed to produce quite wide-range generic solution which is not ideal but works relatively well.
> it's not clear at all to me that we're flexible with respect to substances that *don't* occur naturally in our diets (like ivermectin and HCQ and SSRIs). Why would we be?
To be more resistant to various novel poisons? Liver is quite amazing at dealing with wide range of chemicals.
Though, obviously, there are many thing that will be too much (try eating random mushroom and you will die).
Truly outside context chemicals like plutonium will be deadly for obvious reasons with few exception of things that evolved to handle it (or even use it!).
I'm not sure if you're disagreeing or agreeing but in different words.
This presupposes that we’re capturing detailed and useful data. I’m not convinced but surely it isn’t nothing.
The other aspect is that taking Ivermectin, for example, is nothing like drinking mercury. Billions of doses have been administered over the course of this drug’s existence; it’s as safe as we can possibly make drugs. Combining it with zinc, vitamin D, etc. is super duper low on the risk table and we know it…that’s why it should have been promoted, or at least not ridiculed, mocked and disparaged.
There's also a similar indirect but persistent cost with promoting stupidity and fantasy.
> From the Inside View, I have a lot of trouble looking at a bunch of studies apparently supporting a thing, and no contrary evidence against the thing besides my own skepticism, and saying there’s a less than 1% chance that thing is true.
I guess I don't understand why this is the case. In particular, what propertion of things that have at least that much evidence behind them are actually true? In this domain, where low-quality studies are omnipresent, it seems like it should indeed be less than 1%, so there's no problem.
I suppose that it feels intuitively weird to look at a not-exceptionally-bad scientific study and say that there's a >99% chance that it's wrong, but in fact we deal with things like that all the time in all domains. https://www.lesswrong.com/posts/Ap4KfkHyxjYPDiqh2/pascal-s-muggle-infinitesimal-priors-and-strong-evidence seems relevant (not the part about double exponentials, that doesn't apply here, but the part about how decillion-to-one chances crop up all the time).
Maybe the problem is just that a good study and an average study intuitively look similar-ish and like they should have similar-ish effects on our beliefs, even though in fact their Bayes factors differ by orders of magnitude? Maybe a person could cure themself of this intuition by reading enough average studies whose findings were later disconfirmed by good studies?
I think Scott, of all people, has read enough studies like that that if it were going to work, it already would have. Small probabilities are just hard to think about.
I mean, yeah, but I still don't feel like I understand *why* it doesn't work.
Apparently this is pretty common in drugs. If you read med chem blogs, they're stuffed with bitter and cynical people who think even when it looks perfect on paper, rock-solid mechanism fully fleshed out, passed Phase I through III trials with flying colors, the FDA wet itself with enthusiasm, sales are skyrocketing -- it might still end up killing little old ladies in some completely unforeseen way and cause the entire division to be wiped out and everyone fired after the first $1 billion lawsuit is settled. They expect almost nothing to work.
Seems to be relative in some sense to the fact that biochemistry is much more complex than we know about *and* the body is sort of build in a weird Rube Goldberg way in which everything is connected to everything, even when it makes no sense from a design point of view, so you *think* you're just interfering in this pathway over here, but unknown to you some (you thought) unimportant by product plays a critical role in some regulatory pathway way the hell over here, completely different system, and your whole scheme goes up in smoke.
I work in a field in the physical sciences where there are lots of publications, but most are good quality. If I had to guess, I would say that of the papers that claim that an observation or experiment says that doing/observing A indicates that B is true, I would be 80% to 90% confident that the claim is accurate and reproducible. For top-tier journals in our field, I would raise that to 95% confidence (although I would argue that number drops back down again for Science/Nature/PNAS for complex sociological reasons).
Part of the reason for this high confidence is that we take peer review seriously, and researchers would get a pretty poor reputation if they regularly publish results that fail to reproduce. Also, if I as a referee had low confidence that a paper was reporting reliable results, in the way that Scott suggests, with 5% or 1% or less confidence, I would never recommend publication. I realize that the social and financial incentives can be different in the life sciences, and there is a different journal ecosystem. But at the fundamental level, if the studies have very low reliability, why are the referees and editors allowing them to be published?
This is Ioannides's general argument in "Most Published Research Findings are False" - if you've got a p-value of 0.05 and a power of 0.8, and you expect that half of the things people would think to study with this sort of method are true, then your posterior for a study's finding to be true should be around 96% (unless I applied Bayes' theorem wrong, which is totally possible). But if your field is such that the vast majority of hypotheses are false, then even a perfectly done study with this good power and p-value should have a posterior less than 1/2 of being true. It may be that your field is one where studies are able to establish things with p value of 0.00000001 (this is common in physical fields where you have little noise and thus don't even bother running a statistical test because the data are blindingly obvious) in which case this doesn't matter. But in noisy fields (usually anything involving humans, especially masses of humans like in macroeconomics or epidemiology) even very high quality studies can't really get better than p value of 0.05 and power of 0.8.
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.0020124
Thanks, that definitely helps clarify these things. That's a better encapsulation of the statistical differences between the fields than I'd seen before.
I agree with that in general, but look at figure 2 of this paper on the Pfizer vaccine: https://www.nejm.org/doi/full/10.1056/NEJMoa2110345 and tell me that the p for that isn't < 10^(-1000) (each arm of that trial is >20,000 people). A real effect does stand out of the noise in biology, even medicine. A lot of the problem is that lots of papers are published about non-existent effects.
It's not 10^{-1000} but it is quite low. I think we flipped a coin 1,165 times (total number of covid cases in the trial) and got 1,034 heads (number of those cases that occurred in the placebo group). If I calculated right, this is "only" a p value of 10^-8 against a null that the vaccine has no effect.
From those numbers, I get about 26 std dev from the mean or p~10^-149. So I was off a bit.
Perforce. Every single data point in medical research is about 10,000x more expensive to acquire than in a laser spectroscopy experiment. So if you insisted on the kind of statistical power before publication in medical research as you can just casually assume in the realm of physical science research, there'd be no need for journals, because there'd be about 2 papers per decade that were worthy of publication. So in medicine you end up with averaging 10 (ten!) measurements and trying to figure out whether you've got something significant. All the statistical tools are deployed with a vengeance, because your noise level is inherently through the roof and you're trying hard to find a signal. It's understandable, if regrettable.
I know that this is the reason, but I think it's worth seriously asking if it wouldn't be more useful to have 1-2 papers a year that are 100% rock solid and undeniable rather than however many thousand papers we have now that are functionally worthless because they have 20 patients total?
Or maybe combine the two - have tiny exploratory trials that raise hypotheses for testing, current "big" trials that are like a silver standard and get drugs licenced, and giant, actually huge trials that give you p values in the 5 sigma range and definitively settle issues such that those topics don't need to be dredged up and rehashed over an over again in an interminable replication crisis?
Well *I* think so, but I'm a smartass in physical science, so I would. No skin off my nose, I don't need to build a career on a bit of research that has to go on for 5 years to have any result at all, and then it turns out not to work for obvious (in hindsight) reasons so we all look like idiots.
There's also the major problem of participant recruitment. People are just very unwilling to coldly roll the dice on their health, regardless of the logical inconsistency this indicates with respect to their daily lifestyle choices. The only trials in which people are generally willing to participate are those in which there is zero potential downside, even if that means there is also near-zero potential upside (which accounts for the vast supplement/neutriceutical market I think).
I mean, the best possible news (for the future) would be if we had a whole series of compounds that each had a 10% chance of extending your lifespan by 100 years and a 90% chance of killing you within 12 hours. Imagine if those trials were done. Presumably one would work out and the future would be amazing. Yay! But who the heck would sign up for the trials *now* in order to acquire the information?
Someone who expects to die soon anyway? Or, more likely, a nonhuman animal that we don't have to give the option of refusing. :/
Maybe. I tend to think people aren't especially realistic about death even when it is fast approaching. People who actually have days to live are thinking in terms of weeks. I've seen this a few times in my life and it's often sad, e.g. someone puts off a good-bye visit "until I feel a little better" in a week or two, but in two days it's all over.
The problem with the animal models are that they don't translate as well as we could hope, but yes that would be the best way to start fore sure.
Anyway, I'm just saying that our willingness, as a species, to do the kind of cold empirical experiments that would give us definitive answers to so many important questions -- what diet makes you live longer? what form of child-rearing optimizes the next generations' success/happiness? -- is drastically lower than our willingness to do those experiments in other areas. As soon as a whole human life (or quality of human life) becomes a realistic cost in the process of doing the experiment, we shrink away. "Let's settle this one by argument, shall we? That way nobody has to go into the control arm..."
Understandable, if a bit regrettable, in the sense that if our forefathers had the courage to do these experiments, we'd be much better off, and if *we* had the courage, our descendants would be better off. (But on the other hand, I'm not going to be first in line to volunteer either, so I don't blame anyone else.)
It seems to me that Algernon's law would not be violated in cases where a person is taking in less of the particular substance than was normal in the evolutionary environment. In other words, in a world where many people are low in Vitamin D, topping up would seem to be a good strategy with an even smaller chance of side effects.
In that case ... which of Kurzweil's 100 supplements do I have a reasonable chance of being deficient in?
Most vitamins and minerals, probably; some are safer to supplement that others, though - some excesses accrete, whilst others are excreted promptly. The only cost to taking everything in the later category is monetary. My limited understanding is that modern agriculture has lower vitamin and mineral contents in vegetables than was historically the case, do to effectively optimising them for calories per month at the expense of other things.
At a first pass: Vit D unless you work outdoors is almost a no-brainer; B12 has a mutation that hinders absorption in something like 40% of the population, and thus you have decent odds of being deficient (but the 60% with functional metabolisms don't need to bother). Fish Oil (aka EPA/DHA) is also a generally recommended one.
N.B. the primary concern with the supplement market is not a rare side effect of the vitamins you think you're taking, it's the risk that what's actually in the pills is not what's been claimed. The USA in particular has a very lax regulatory environment, though if you live in a more civilised country that's less of a concern.
IIUC, in at least one study the benefits of fish oil disappeared in a double blinded study. One hypothesis was that the folks who intentionally took fish oil were in other ways more careful about their diet and health. I never encountered a followup study.
Still, it's a greater than 1% chance, at least if you're a male, and thus less able to metabolise the plant derived variant.
(I encountered this in a couple of different articles in Science New over a decade ago, so I can't provide any additional details. But I've combined at least two different studies in my memories. I think one of them was about the sex based metabolism of omega-3s.)
The thing is, there's LOTS of these different choices. My wife siezed on the studies recommending chocolate, until I pointed out that these were unsweetened chocolate. Details matter. I don't think it's really possible to assign reasonable probabilities based on most studies, because they tend to be focused on one set of properties, and ignore other properties. There are probably always tradeoffs, and you won't know most of them. Did that turkey you ate for dinner live on antibiotics? What did that do the the microbes that it carries in its corpse. (Well, they probably didn't survive, but you needed to clean the turkey before cooking it, so they may have survived in you. Or some microbes are remarkably temperature resistant. Usually they don't harm people, but perhaps this time?) And of course if it didn't live on antibiotics, you get the same argument, but with a different selection of microbes. Or people have gotten salmonella from eating raw lettuce, but it could be something worse.
We don't know most of the chances we are taking. Clearly the probabilities of somethign disasterous happening are just about always way less than 1%, but we take thousands of chances every day, and we don't just live one day.
So. You're taking a pill that is labelled as being this chemical you've decided is a good chance. What are the odds that there's something else in that pill too? Something that doesn't appear on the label. Well, actually that's a near certainty, but usually it's nothing harmful, or at least obviously harmful. Isn't titanium dioxide safe? (It won't be on the label.) But I think I read one report on a study that associated titanium dioxide with cancer. How could you figure the odds for everything you don't know about, but could if you researched sufficiently?
Heuristic shortcuts are necessary. They usually work, but in general you can't assign accurate probabilities, and even when you can it usually isn't worth the effort.
So. Pascal's wager. Consider the original Pascal's wager. He didn't consider the chance that the real god was someone else who would be offended by his choice. He didn't even consider that the official Christian god would be offended by his choice (which some theologians think (or thought) he should). The entire argument is based around a falsely constructed set of alternatives consistent with the available evidence. And I feel the same thing is true of Pascal's medicine.
Just consider, there is a common disease of cats that causes those mammals to behave recklessly. And the available evidence indicates that it affects people the same way. This is an existence proof. What are the odds that one of those medicines doesn't have this exact same property? Nobody's even tested, or at least I haven't seen any reports. Did you factor this into your "bad effects estimate"? I doubt it. And there are scores of similar kinds of effects. Say 20% of those drugs have an effect that's at 20% of measurable strength. What happens when you combine those effects? (I'm not assuming the effects are the same. Perhaps one speeds up the reaction for one kind of neuron, and another slows the recovery time for a different kind of neuron, etc. Or, of course, they could directly reinforce [or interfere].)
This *doesn't* mean you shouldn't take the chance. It means you can't calculate the risks (or benefits).
"Just consider, there is a common disease of cats that causes those mammals to behave recklessly." Never heard of that one, would like to learn more.
I know about the common cat parasite Toxoplasma gondii causing rodents (and maybe humans) to behave recklessly, though.
Perhaps I phrased that poorly. I was talking about Toxoplasma gondii, and you're right, I don't know that it causes cats to behave recklessly. It's quite possible that all it does is make the smell of cat urine more attractive. But there are other parasites with various known behavioral effects, including things like sacculina, so there may well be others we haven't detected.
There's a strong argument that Algernon's Law does not apply to Vitamin D. The maintenance dose for the Spanish RCT studying Vitamin D for COVID is around 8000 IU/day. This is about what someone would get from 2 hours in peak direct sunlight shirtless. Hunter-gatherers probably got this or equivalent, but we clearly don't.
(State nutritional guidelines are calibrated for the amount needed to avoid rickets, i.e. severe deficiency, but D does more than just prevent rickets.)
Similar considerations favor vegetarians taking creatine, but not randos taking Ivermectin or SSRIs.
Agreed that Vitamin D is one of the rare exceptions to this.
Thinking more about this; humans who left Africa, went to colder/cloudier parts of the world, and put on clothes quickly evolved lighter-coloured skin, despite the added risk of skin cancer. Is there any plausible mechanism for this strong selection pressure apart from Vitamin D absorption?
At some point: sexual selection, perhaps?
Melanin is metabolically expensive, it takes a lot of metabolic energy and raw materials to keep your skin dark. It's only worth it if it reliably prevents you from frying in the sun.
Ancient Dna data suggests that in Europe, there was strong selection to decrease melanin but quite late, about 10 000 -5 000 years ago, well after modern humans came into Europe (about 40 000 years ago). This suggests that melanin became unfavorable in Europe only after the switch to agriculture, which points to vitamin D more than to the cost of melanin synthesis.
I would've said the reverse. The problem of the Sun being weaker in the winter is immediate on moving to norther latitudes and has nothing to do with agriculture. On the other hand, arguments have been made that the switch to agriculture was driven in part by calorie scarcity -- hunter-gatherers get considerably more calories for a given level of exertion, as long as the population density and climate support the lifestyle at all. As I recall, people got noticeably shorter when they adopted agriculture, which points to poorer average caloric intake. Lower caloric intake would put a lot of pressure on any process that was metabolically expensive.
"I would've said the reverse. The problem of the Sun being weaker in the winter is immediate on moving to norther latitudes and has nothing to do with agriculture."
The argument was that we can get some Vitamin D from food, but only from animal one, and that transition to a grain based diet forced the early Europeans to rely entirely on the Vitamin D produced in the skin through sunlight.
"As I recall, people got noticeably shorter when they adopted agriculture, which points to poorer average caloric intake. Lower caloric intake would put a lot of pressure on any process that was metabolically expensive." I don't find that likely but it is more a hunch that anything else : it seems to me that pigmentation can not be a very metabolically expensive trait, and that the "saving" coming from producing less melanin has to be small. This does not seem compatible with the very strong selection on the alleles conferring lighter pigmentation in early Europeans ( same magnitude that the selection at the most strongly selected loci in the human genome, like lactase persistence or malaria resistance).
It wouldn't have occured to me at first either, but I recall coming across arguments along those lines some time ago, and found some of them fairly impressive, e.g.:
https://www.sciencedirect.com/science/article/pii/B9780128026526000190
They mention a few points against the Vit D hypothesis (which they reject), including that evidence for rickets in early skeletal remains is sparse (if it were a general problem, you'd expect that in some areas no matter what there would've been too little), that depigmentation did not occur preferentially in areas more exposed to sun, and that supposedly unpigmented skin does not generate Vit D noticeably faster or more copiously than pigmented skin. The argument is essentially that enough Vit D can be obtained through a typical Paleolithic diet (e.g. with some fish or meat intake) and relatively limited spring/summer sun exposure, and so it would not have been a major force in natural selection.
The argument for the metabolic cost of melanin manufacture is buttressed by the observation that children with protein malnutrition (kwashiorkor) exhibit noticeable depigmentation, meaning the cost of pigment production is sufficiently noticeable to the body that it's minimized in periods of malnutrition, and that in animals somewhat related outcomes seem to point to the importance of conserving energy required for pigment production, e.g. the existence of eyeless animals in dark environments, related possibly to the energy cost for visual pigment production.
I'm not taking a position on which is likely to be true, just pointing out there are alternative hypotheses that seem to be worth considering.
Better camouflage in grayer (snowy, cloudy, foggy, no foliage) environments at daytime, perhaps? Easier to paint your face with camo (I'm actually not 100% sure, that's the case)?
Camouflage is a good explanation for arctic foxes and ice bears being white (though in their case, it's fur).
So why not humans, too?
Might matter more for hunting/not being hunted by megafauna, which in Africa coevolved to stay away from dangerous humans. And outside of Africa quickly went extinct.
The Inuit ain't as pale as Scandinavian farmers.
[iirc from random podcasts, not expert]
The Inuit murder-replaced some older group that didn't have sled dogs. Could be that they were paler?
Also the Inuit have a tendency to store fat in their face as an adaptation to the cold, which... I think might be unique among all people? Maybe you can't be pale and have that kind of adpatation at the same time?
I tried googling "Inuit without clothes", but that just showed me... Inuit clothes. It's kinda hard to get a look at anything but their faces.
So who knows what skin color people have, if they never show skin.
Though probably the same hue, as the rest of the body?
I honestly don't know. But that might be broadly the correct assumption.
Just jumping in here to say that melatonin definitely, 100 percent works for sleep in at least some people and the fact that studies can't seem to prove it must be down to some weird confounder we haven't figured out yet. I went through a period of severe insomnia that was unresponsive to any of the "proven" drugs and melatonin cured it immediately and I can use it as necessary and get the same overwhelming therapeutic effect, in a way that no other pill even resembles. So there is certainly room in my ontology for effective therapies with idosyncrasies that defy straightforward investigation in RCTs. But there had better be very large signal buried in the overall noise.
I was actually talking about melatonin for COVID! Some people claim there are a few studies that show it works, though obviously I am skeptical.
Completely unrelatedly, there *are* a few people who claim melatonin doesn't work for sleep, but as far as I know they all work in writing insomnia guidelines - no normal human being is that dumb.
Well I'm glad to see the world has made progress since I was treated for insomnia, the doctors I saw back then never even mentioned it. I got the standard drugs, not Ambien but several others, and they all did jack. A friend suggested it and it was like flipping a switch. But apparently the clinical evidence is still mixed.
Interesting. Melatonin works for me, and so do other standard pills. But melatonin is special: the next morning I feel like I got some sleep.
Something adjacent to the "worms" hypothesis seems even better for melatonin than for ivermectin -- way more people are sleep deprived in North American than have worms in India, and it seems at least as likely that healthy sleep will have a positive effect on immune function as that worm infestation will impair it.
So if melatonin improves sleep in some people, it will probably also reduce the severity of coronavirus infection in those people.
So the Insanity Wolf is right again, I guess.
Melatonin made me depressed the next day, I believe. I wonder if anyone has a similar experience. Being tired and feeling sad are very correlated for me, I think.
There's definitely a hangover of sorts, particularly if you don't give yourself enough time to "sleep it off", as it were. It's not a panacea but it definitely works wonders for some people, myself included.
After reading Scott's thoughts on the matter, I started taking 300ug Melatonin 7 hours before desired bedtime. Felt weird, but not alarmingly so, for the first couple days, but then something clicked and now I sleep better, at the desired time.
What's your dose? For me, all doses 1mg-20mg do the same thing, but everybody's different and see SSC: https://slatestarcodex.com/2018/07/10/melatonin-much-more-than-you-wanted-to-know/
Aren’t *multivitamins* arguably a form of Pascalian medicine familiar from many people’s experience? I used to take them every day. I give them to my kids. For any individual vitamin in them, I’d assign a relatively small probability that supplementing it does anything good — but a higher probability that at least one does. So maybe these 30 Pascalian covid treatments could just be bundled into an “anti-covid multivitamin”?
There was a discussion about this many years ago on LW and I took the exact same stance you have taken and what the Pascalian standpoint would encourage.
Yes, although there are surprisingly many studies showing that they don't help most of the things you'd expect them to help. Also, manganese is in them and might be slightly bad for you.
The main reason you can't bundle things is 1) the FDA would think of the bundle as a separate medication and you'd have to get it approved, which they would NOT do for something like this, and 2) you can only fit so many milligrams worth of stuff into a pill, and you'd probably need to take so many pills to get the whole bundle that you'd lose a lot of the one-pill advantage from bundling.
Iron too. It's surprisingly easy to overdose on iron.
Although men's multivitamins usually exclude iron, for that reason.
> Yes, although there are surprisingly many studies showing that they don't help most of the things you'd expect them to help.
There are a variety of explanations proposed for this. One of the big ones I'm familiar with is that the form of the minerals in the multivitamin matters for the body's ability to absorb them in the digestive tract. Multivitamin manufacturers tend to strongly favor oxides (e.g. zinc oxide, magnesium oxide, etc) because they're cheap, but the downside is that oxides tend to be much, much less absorbable than other forms (e.g. citrates and amino acid chelations).
Another is that many micronutrients compete with one another for absorption. E.g. if you take zinc, magnesium, and manganese all at once, your body will absorb less of each than if you'd taken the same doses of each spread out hours apart.
> Also, manganese is in them and might be slightly bad for you.
Particularly if you're prone to migraines. My wife and I both have manganese as a major migraine trigger, which we discovered the hard way after trying a new brand of protein shake that consistently triggered nasty migraines for both of us and which turned out to be fortified with large amounts of manganese as its main difference in ingredients that we could find from other brands that neither of us had problems with. Poking around online turns up a bunch of stuff suggesting that manganese is a fairly common migraine trigger.
I believe Vitamin E supplementation (if you're not deficient) actually causes harm.
>if I “know” that onion farmers doing studies will convince me that onions have a 5% chance of curing cancer, I should just believe there’s a 5% chance onions cure cancer now.
That doesn't follow, because the fact that people are doing studies about something is itself evidence that should raise your confidence that there's substance to it. It's weak evidence, but it might not be so weak that it can't get you to 5%.
Furthermore, this should depend on the motivation for the studies. Your hypothetical assumes, as a premise, that the studies are motivated purely by a desire to sell onions. But in the scenario "what you think when you see the studies?", you don't know motivation. It may be that if you're fully informed about everything, including the motivation for the studies, you won't think there's even a 5% chance, but being partly informed may falsely lead you to think there's a 5% chance.
To get specific, onion farmers are currently not doing studies on onions curing cancer, this probably has something to do with them doubting they can convince people onions cure cancer, and this probably has something to do with onions not curing cancer. In a world where they are running the studies, maybe that's because they have some inside information that onions really do cure cancer. After all, the cabbage farmers still aren't running any studies.
Maybe in Scott's hypothetical scenario it wasn't him that came up with the onion example, he just stumbled upon studies about onions curing cancer. But yeah he didn't clarify that so him picking onions out of a hat is some evidence that the 5% figure is way too high.
Who’s gonna tell this guy that more people died in the treatment arm of Pfizer’s vaccine trial with significantly more frequent cardiovascular events? Or that only one died of Covid in the control arm vs zero in the vaxx? Or that a Pfizer whistleblower presented very serious accusations of data falsification?
I would love nothing more than to be so innocently credulous towards companies that have paid tens of billions in fines for outright lying in recent years, in an industry whose marketing budget dwarfs any industry in human history, and who are fighting tooth and nail to hide the primary data on which these trials are based from public scrutiny for 55 years.
My prior is that you're making shit up.
The tenor of your response has strengthened my priors to the point where no link you provide could possibly move it substantially.
For the record, I'm no great fan of the commercial media, but the enemy of my enemy is not automatically a friend, if you take my meaning.
"Anyone who tells me info I haven't read in the New York Times is making shit up."
Which part? I’ll link you. Witnessing one of the last hyper-credulous media narrative trusters discovering the media has been willfully misleading him for the first time is a very rare these experience days, so I relish the opportunity.
The NYT is crap almost across the board. That doesn't lend you the slightest shred of credibility.
Facts: Pfizer vaccine trial data: “Only 3 of the people in the trial died of Covid-related illnesses - 1 who received the vaccine, and 2 who who received the saline shot. “
In terms of overall deaths there were 6 MORE deaths overall in the vaccine group than in the placebo control group.
Those numbers don't sound statistically significant. 3 out of how many over what period of time, etc. It would also be useful if you linked a source for that data, so that if I thought is seemed worth checking, I could do so.
We've now effectively done the trial on a large portion of the population in developed countries. If there is significantly higher heart attack mortality we should see this on a population-wide level, both comparing vax to unvax and comparing this year to last year.
All cause mortality is massively up in every highly-vaccinated country. Incidents of young athletes collapsing on the field from heart attacks have been skyrocketing. They are attributing barely any of vaccine-induced deaths or injuries to the vaccine, because the vaccine is “safe and effective.” Look up the “Estimating Vaccine Induced Mortality” series on the “Rounding the Earth” Substack for a deep dive from a statistician lens.
"Incidents of young athletes collapsing on the field from heart attacks have been skyrocketing"
Looking that up, the top three stories on Google are all about young athletes developing myocarditis - *after* contracting Covid, recovering, and returning to playing their sport:
https://www.thecardiologyadvisor.com/general-cardiology/heart-inflammation-after-covid-19-infection-in-athletes/
https://www.nature.com/articles/d41586-021-01456-3
https://jamanetwork.com/journals/jamacardiology/fullarticle/2777308
Meaning, my ignorance relies upon a crutch, since I have no knowledge or learning of my own?
Ah, well, a left-handed compliment is better than none, so thank you! 😁
Surely he's about to argue that result is proof of a massive media conspiracy.
Why it's so implausible that a highly infectious novel virus would be damaging to human health will not be addressed.
I agree that Covid is very dangerous. I just go one step further: the dangerous part of the virus (the spike protein) replicating trillions of instances of itself throughout the body (the mechanism of action for the MRNA vaccines) will not provide an improved outcome.
It was a triumph of Bayesian reasoning that I could predict you would be so thoroughly ignorant about basic molecular biology. I saved myself quite a lot of suspense waiting for it to become obvious.
You of course will see this as ad hominem, but I appeal to the audience: is that an unfair characterization?
"the dangerous part of the virus (the spike protein) ". This is just wrong.
Every time I get a booster, I don't need any protein in my diet for at least a week, because I get my RDA of spike protein
Why is the spike protein dangerous? Generally speaking, the dangerous part of a virus is the RNA or DNA inside it, which hijacks your cellular machinery and causes it to go nuts making bazillions of new viruses. The proteins that encapsulate the RNA/DNA, or which help it gain entry to the cell, are normally seen as quite harmless if they're present by themselves.
Of course Google will not alert you to anything about this.
https://stevekirsch.substack.com/p/over-a-60x-increase-in-serious-adverse
If you could say "five NFL players (or whatever, some league) had heart attacks, compared with 1 per decade usually" that would impress me as a problem. But I googled a few random names on this list and they include an amateur, a guy who was recruited to play soccer in Azerbaijan, a guy who played football for a community college. There's no established baseline for heart attack rate for people like this (particularly since "cardiac arrest" could be a euphamism in an obituary for "heroin overdose"). What's more, some of these appear to be wrong (the Azerbaijan guy died after hitting his head in a collision with another player) So no, I don't find this compelling.
was discussed before, for start that even if that is trustworthy it is 60x increase in reported deaths
and blaming 100% on vaccine, and none on Covid is ridiculous
> None of these players had COVID at the time of the event since they are all tested.
they could be tested and had detected Covid! Testing is not retroactively healing!
Unless you search for "60X increase in pro sports adverse events since the vaccines rolled out" and then it's the 7th result.
Sometimes it feels like major misinformation sources are getting downranked these days, but if it makes you feel any better, 4 of the 6 previous results uncritically repeat the claim.
The one study that compared all cause mortality of demography-matched vaccinated to unvaccinated people, to my knowledge, is this one:
https://www.cdc.gov/mmwr/volumes/70/wr/mm7043e2.htm
The vaccinated people have substantially lower non-COVID mortality, which they ascribe to:
1. COVID deaths being misclassified as non-COVID.
2. Vaccinated people being more conscientious in general.
Effect 2. is so big it might dwarf all else, but this certainly doesn't look like a study from a world in which vaccines are killing lots of people.
The hell are you talking about?
https://ourworldindata.org/explorers/coronavirus-data-explorer?zoomToSelection=true&facet=none&uniformYAxis=0&pickerSort=desc&pickerMetric=total_vaccinations_per_hundred&Metric=Excess+mortality+%28%25%29&Interval=Weekly&Relative+to+Population=true&Align+outbreaks=false&country=QAT~URY~IRL~NOR~DNK~SGP~SWE~ISR~PRT~CUB~AUS~CHL~MYS~CAN~ESP~KOR~ITA~FRA~GBR~JPN
I thought RCT was the best evidence.
An RCT of 30,000 people is better than an observational study of 30,000 people, that's for sure. But an RCT of 30,000 people can't tell you much if anything about events that occur for 1 in a million people. An observational study of a billion people can, though it will have all sorts of potential confounds.
No one will ever do an RCT with a million or more subjects in it (at least, not in the next few years or even decades).
Nobody does these RCT in medicine, but for real important things like optimizing which ads to show people on the internet, companies do them all the time.
(I'm a bit cynical here. It's not that Google optimizing their ads is more important, it's just that these experiments are much cheaper to run.)
> Who’s gonna tell this guy ...
Hopefully, someone with some good evidence instead of baseless accusations?
I'm quoting Pfizer's own trial data. They report all that stuff (total deaths, by cause).
No you are not. I haven't seen any data in your comment. What is the rate of "significantly more frequent cardiovascular events" from the Pfizer data?
You are not quoting ANY data, you are not providing ANY sources.
I've often noticed that conspiracists' supposed mistrust of experts or mainstream media goes away when they perceive the mainstream as agreeing with them.
Why cite Pfizer as an authority? Aren't you the guy who thinks Pfizer is evil?
They're lying to us! But here, this fact they supplied proves that!
You must be acting intentionally obtuse, right?
This is a simple application of the criterion of embarrassment. It's unlikely that an organization would lie to make itself look worse than it really is. So when an untrustworthy organization reports something, we can reasonably infer the real situation is as bad or worse than they portray it.
This demonstrates one of the many flaws in the "criterion of embarrasment": the decision about whether to take something as "embarrassing" is entirely subjective. One person sees unsourced comments saying Pfizer reported negative outcomes in a trial and decides that must be embarrassing. Meanwhile another person sees the comment and thinks that Pfizer is legally required to report positive and negative outcomes in trials, the positive outcomes outweighed the negative outcomes, so it's work to be proud of.
I think you'll find plenty of pharma company skeptics here, but you're making some very bold claims without providing any evidence. And what's publicly known doesn't support what you're saying.
I'm quoting Pfizer's own trial data. They report all that stuff (total deaths, by cause).
You didn't quote anything. You paraphrased some sort of summary. You just said "significantly more frequent cardiovascular events" but didn't say anything like "73 events among 15,000 vaccinated individuals and 24 events among 15,000 placebo recipients" or anything like that that would suggest that you knew what you were talking about.
Now it sounds like you do know something about what you're talking about, but you still haven't told us where in this long and dry document we find the information you've already found. If you've found it, you could give us those numbers so that we can interpret them too.
Look at the data at 5:41 here: https://www.youtube.com/watch?v=NRP-_2v8mSQ
Cardiac-related deaths were much more frequent in the vaccinated arm.
This in combination with the whistleblower alleging they simply did not follow up on many reported adverse events should give pause, at the least.
Either the trial numbers were too small to make any substantial claims (the smallpox vaccine trial included 2 million participants), or at the least this data does not point to a resounding victory (2 died of Covid in the placebo group, vs one in the vaccine group).
I'm annoyed at the video source rather than text or still image, but since it's just one frame, I can look. I see a total of 15 deaths in one group and 14 deaths in the other, with 2 covid deaths in the vaccine group and 1 in the placebo group (if I'm reading right). That is not statistically significant evidence of anything.
The main data in the trial were the something like 170 covid cases in the placebo group and about 15 in the vaccine group. This absolutely is statistically significant at any level you can think of.
The trial numbers were too small to make any substantial claims about deaths, and they didn't make any claims about deaths on the basis of the trial. The claims about deaths were made initially as further inferences from the stunning results on infections in the trial, and then later on the basis of the very large scale data on hundreds of millions of vaccinated and unvaccinated people in observation.
> Look at the data at 5:41 here: https://www.youtube.com/watch?v=NRP-_2v8mSQ
Can you link data, not some videos by "Peak Prosperity" with zero credibility that could claim anything, and lie about what is in actual data?
So we've got four deaths by heart attack in the vaccine group, and just one in the placebo group. What's the chances of something like this popping up if the null hypothesis is true and the vaccine has no effect on heart attacks? I can't be bothered doing the maths, but it's high, for reasonable values of "something like this".
Also, consider the fact that vaccinated patients were much less likely to die of myocardial infarction or multiple organ dysfunction syndrome. Surely that reduced risk offsets the increased risk of heart attack? (The answer is no, because all of this shit is just random noise.)
According to Pfizer's trial data: https://www.nejm.org/doi/full/10.1056/nejmoa2034577
Two died in the experimental arm, four died in the control arm.
"Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction)"
[citation needed]
Sources to Herzog's claims:
Vaccine data (final results from Pfizer trial, 6 months in, just before control was vaccinated with non-placebo): https://www.medrxiv.org/content/10.1101/2021.07.28.21261159v1.full-text
Rationale for unblinding trials: https://www.bmj.com/content/371/bmj.m4956
Alex Berenson on the Pfizer data: https://alexberenson.substack.com/p/more-people-died-in-the-key-clinical
Cardiovascular risks: https://www.ahajournals.org/doi/abs/10.1161/circ.144.suppl_1.10712
Pfizer contractor whistleblower (this one is troubling): https://www.bmj.com/content/375/bmj.n2635
The most troubling for me is the signal from VAERS, yellow card, and European system. I don't buy this "it's flooded with fake reports narrative" and I haven't seen a breakdown or attempt to analyse this, other than ones that do not support the vaccine rollout, such as this preprint: https://www.researchgate.net/publication/352837543_Analysis_of_COVID-19_vaccine_death_reports_from_the_Vaccine_Adverse_Events_Reporting_System_VAERS_Database_Interim_Results_and_Analysis
I would love for someone to convince a healthy young (30s) man such as myself that the risk from COVID (yes I have medications available and a testing/treatment/isolation plan) is greater than my risk from regular 6 monthly vaccines for... 1 year? 2? 5? I don't see this as a settled question and I feel justified waiting for more data (let's say til 2023) before making a decision.
I know this is a contrarian position. Am I that deep in an echo chamber? TIA
I personally know 4 people who got COVID without a vaccine. All survived, but three absolutely got their shit wrecked and spent at least a month very, very ill. One still has brain fog a year later.
I know two people who were vaccinated and got a breakthrough case. Both of them were fine after a couple of days and said it was no big deal.
I know more than two dozen people who got various vaccines and had at most a day of unpleasant side effects and felt terrific afterwards, and multiple people had no side effects whatsoever.
Small n, but do with it what you will.
> The most troubling for me is the signal from VAERS, yellow card, and European system. I don't buy this "it's flooded with fake reports narrative"
How likely is that people become far more aware about it and report everything there, unlike previously?
> Despite this, there were only 14% of the cases for which a vaccine reaction could be ruled out as a contributing factor in their death.
I am surprised that even in 14% it could be definitely ruled out.
I bet that allergic reaction to spinach also would not fully ruled out in all cases.
"For many of the elderly and infirm, the description of death often asserts a pre-existing or age-related
condition as the more likely cause of death, including cancers and long-standing cardiac pathologies8
. Also,
for 12 recipients (5%) we are expressly told that one or more negative COVID-19 PCR test results were
returned in the hours or days prior to the vaccine recipient’s death. In spite of the fact that only 11 (4%)
present with a test-confirmed and current COVID-19 infection, all 250 people in this interim collection were
reported as COVID-19 deaths. This means that all, even those who received one or more negative test
results, are erroneously counted in the officially reported national COVID-19 death tally. "
This would be interesting to confirm or disprove.
I've heard that and I've heard the opposite. Medical professionals are so busy during the pandemic that they haven't had time to fill in a report. (VAERS apparently take ~45 mins per report from what I've read) - I would love some papers analysing the VAERS or similar data if anyone has any.
But if you're not a medical professional and all persnickety about the truth, you can probably fill it out in under 5 minutes. I've looked at the VAERS database, had to click through 2 disclaimers that basically said "don't rely on this data, nobody has checked it and anyone can enter stuff into it." I consider it about as reliable as a Facebook page that invites people to write in their terrible experiences with vaccines.
It's a federal crime to report inaccurate information. Don't know if it's enforced... But a bit more reliable than a facebook group.
And if you don't trust VAERS... What are you (or the CDC/FDA) using to look for a vaccine harm signal?
Well if it's a moderately-sized signal, the evidence would be bodies stacked in morgues and wild-eyed TV news stories about it.
For example, let's take where I live. There are 3.2 million residents in my county, and (according to the County board of health) 2.2 million have been fully vaccinated. If the chances of the vaccine killing you were 1/10 the chance of COVID killing you (0.1% instead of 1%, averaged over all ages), then there would've been 2200 mysterious post-vaccine deaths this year, which would definitely have been noticed. (There have only been 5000 deaths from COVID itself in the past two years.)
I doubt Federal law would deter those who would enter bogus stuff into VAERS. I don't think it's possible for anyone outside FDA/CDC to remove entries in VAERS, so true data about vaccine harm is there for CDC/FDA to find and follow up on. But any conclusions based on comparing numbers of adverse events based on VAERS is suspect, to say the least.
You're in a double bind here. If VAERS is untrustworthy, then you're admitting that we have no evidence the vaccines are safe. VAERS is the official safety monitoring system the public health organizations are using to make safety determinations. You can't claim VAERS was trustworthy only when it supposedly showed that the vaccines were safe and then claim it's untrustworthy now that it's showing a huge post-vaccination mortality signal.
VAERS is untrustworthy, but VAERS in conjunction with review of personal medical records by real physicians at FDA/CDC is trustworthy. You and I and almost everyone else in the world will never see those personal medical records, for obvious reasons, so you, I, and the rest of the world cannot draw any conclusions from VAERS. That's why you have to click through two disclaimers before you can read the VAERS data. I linked to CDC's statement of what they've found below.
But reporting *deaths* to VAERS is a legal requirement, and I've certainly seen VAERS reports where it looks like somebody just spent five minutes on it, including some of the death reports.
Not crazy. I'm right there with you. If you're a male 30 - 39, the most comparable risk for you is auto accidents, so plan accordingly. According to CDC statistics there have been about 8100 deaths for that entire demographic group of 22.5M people over 20 months of pandemic.
https://data.cdc.gov/NCHS/Provisional-COVID-19-Deaths-by-Sex-and-Age/9bhg-hcku
6.224M cases of COVID were reported among this age group as of a few weeks ago (https://www.statista.com/statistics/1254271/us-total-number-of-covid-cases-by-age-group/). According to a meta-analysis, there is a 50-50 split in risk of SARS-CoV-2 infection by gender (https://www.nature.com/articles/s41467-020-19741-6), so this leads to 3.112M cases in your age bracket. Overall, that's a 0.26% CFR, including people with pre-existing conditions that are known to affect the outcome (e.g. leukemia, obesity). Meanwhile, actual IFR is much lower because of all the asymptomatic cases and because testing was so awful early in the pandemic. I think the discourse was seriously less confused in June of 2020 than it is right now, when we were saying things like "if you know that you have a health condition that might exacerbate the effect of getting a really bad case of the flu, consider extra precautions. Otherwise, you probably don't have a lot to be afraid about."
As for my lived experience, it mostly lines up like I'd expect given all of the above. I clearly hang out with a different crowd than most SSC commenters and know a lot of people who have had COVID pre-vax. At least 50 people and this includes myself and everyone in my family. For me, COVID wrecked a good 3 days, plus I had a bronchitis that persisted for another 3 weeks after I started testing negative again, but I've felt fine for 6 months, and wouldn't call my experience atypical. My wife is legitimately immune compromised (no spleen) and she had to go to the ER for abx to treat a secondary pneumonia, but she's fine now too. I know of one person who was 40 when he got it, and seemed healthy before, but spent 15 days in the hospital. He is fine now. And of the whole social circle, one person died of COVID: she was 81, and had just recovered from a bad case of pneumonia in late 2019; if I would have made a list of all the people I knew who were likely to die from it, she'd have made the top 10. Don't know anyone in my cohort who is complaining about long COVID, although one might wonder if there's pressure to downplay those symptoms. Anyway, don't let these jokers gaslight you. Your position would have been deemed eminently reasonable in 2019 and it's still reasonable now, the only thing that's changed is the social milieu.
"This disease put a healthy 40 year old in the hospital for two weeks, therefore you have nothing to worry about" is a truly weird train of thought.
Just including the most unexpectedly bad outcome that I knew of from my experience for transparency sake. But given what's at stake, and we all know it's more than just health, it might not be weird for Dave s. I get that it's weird for you.
What besides health is at stake?
Just curious, before I answer, what do you think I am going to say?
Thanks for the message. It's difficult posting about these things publicly because it's either an echo chamber in one direction or the other. I do believe my COVID risk of death is lower than 0.1% given my health status. I feel the vaccine risk is comparable but generally it's just murky knowing what data are trustworthy.
I supported my parents getting vaccinated and boostered (less so) due to their age.
I'm looking for the best analyses done by people like Scott, particular around the vaccine event reporting systems. Everyone has their biases and makes mistakes. My understanding of statistics is not what it used to be and I don't have the time or inclination to perform my own analysis.
Thanks for your "anecdata" as well as the other commenter, Ben, above.
So far, no gaslighting,.
I think this post nicely illustrates where the error lies. You suggest a comparable-to-0.1% chance of death from vaccination. In reality, it’s nothing like that. If one in a thousand people who got vaccinated were dying from it, we’d know. The chances of death from vaccination are a number of orders of magnitude lower. We know this because millions of people have now been vaccinated, and they are not dying in their thousands.
"If one in a thousand people who got vaccinated were dying from it, we’d know." I agree. I did say lower than 0.1% but yes this seems way too high for vaccine death on its own (although VAERS has captured nearly 20k deaths after a COVID vaccine). Of course we know that you can still die from COVID while vaccinated.
So in this scenario (lets only focus on death for simplicity but harm in general could be used). Options are:
Unvaxxed: Risk of death from COVID is 0.1% (this number could be orders of magnitude smaller for a healthy person with early treatment)
Vaxxed: Risk of death from COVID is reduced to X% (X = <0.1) + Risk of death from vax (Y)
Is X + Y < 0.1% ?
Does Y increase with each booster?
These are open questions, no?
As I said, a big part of my hesitation are the neverending boosters. Maybe it's 3 and done... But I believe Israel has given some vulnerable people 4 doses already. How does the risk change with subsequent shots? How long does natural immunity last in comparison to vax immunity?
Also, the analysis of VAERS I linked to and quoted in reply to SmallGnome (above) states that non-COVID deaths (and potential vaccine deaths) were counted as COVID deaths. This would skew the numbers massively if true making COVID seem more dangerous and the vaccine safer by hiding deaths caused by it.
Just to reiterate: With these unknowns, I think it is justified (if young, fit, healthy, no co-m) to wait for more data before vaccination. Or until a different vaccine is available with longer efficacy and a better safety profile. I don't think this is a crazed anti-vax position...
After reading this conversation, just weighing in here to say that I'm in a similar position to you (28 yr old male, perfect health) and I think your reasoning and skepticism are sound. No, you are not crazed anti-vax. And full disclosure - I was double vaxx'd in the Spring (Pfizer).
So... I don't think you're crazed. But I do think you're wrong. The problem is still there in the numbers, but these are numbers that are very difficult to be accurate about because they're very small.
I haven't done enough reading to be able to give you convincing numbers. But I don't think I need to. To know Covid is really bad, you just look with your eyes: they built whole new hospitals to deal with it. To know the vaccine is not really bad, you do the same thing: they haven't built whole new hospitals to deal with vaccine deaths. And more people are vaccinated now (in a shorter time) than ever got Covid. The chances of death for you (and me - I'm similar, male, 40, good health) are very low. But say it's 1 in a million (this is why it's not crazy to not get vaccinated). The chances of death from the vaccine are 1 in 100 million. Intellectually, I can barely grasp the difference between these kinds of small number. Emotionally, I can't at all. But I still think the difference is real.
And obviously there's the public benefit thing if vaccination reduces the spread, which seems to be unclear at this point.
The most important point that I hope you'll take from what I'm saying is the first line: not crazed, but wrong. I hope you won't set up this opposition where the only alternative to vaccination is crazy (and I'm sorry if pro-vaxxers sometimes make it sound like they do). You can be definitely not crazy, but still wrong.
I definitely take your point, but I think there's at least an outside possibility of minor lasting symptoms that would add up to a good deal of unpleasantness over time, basically https://www.dice.hhu.de/fileadmin/redaktion/Fakultaeten/Wirtschaftswissenschaftliche_Fakultaet/DICE/Discussion_Paper/368_Fischer_Reade_Schmal.pdf#page=3
> (final results from Pfizer trial...): https://www.medrxiv.org/content/10.1101/2021.07.28.21261159v1.full-text
It says "BNT162b2 had a favorable safety profile and was highly efficacious in preventing COVID-19"
> Rationale for unblinding trials: https://www.bmj.com/content/371/bmj.m4956
Agree that careless unblinding is bad, but it is hard to justify refusing to give a vaccine to the people most at-risk of dying of Covid, for a long period of time and against their wishes.
Berenson calls this "destroy[ing] our best chance to compare the long-term health of a large number of vaccine recipients with a scientifically balanced group of people who had not received the drug."
I call it common decency. Carry out the vaccine trials on less at-risk people instead, and use challenge trials. (Except they don't like challenge trials, so I'm guessing they mostly did the first thing? Do you know how it was done?)
> Alex Berenson on the Pfizer data: https://alexberenson.substack.com/p/more-people-died-in-the-key-clinical
Or as FDA stated the month before: "There were no notable patterns between treatment groups for specific categories of SAEs [serious adverse events] (including neurologic, neuro-inflammatory, and thrombotic events) that would suggest a causal relationship to BNT162b2. From Dose 1 through the March 13, 2021 data cutoff date, there were a total of 38 deaths, 21 in the BNT162b2 group and 17 in the placebo group. None of the deaths were considered related to vaccination. "
Berenson seems to be implying that no no no, we mustn't use *human judgement* (gasp!) to tell which deaths were vaccine-related.
I say the sample size is too small to do otherwise. Moreover, if the FDA completely ignored indications that the deaths were unrelated to the vaccines, all kinds of people would be crying foul about that instead.
> Cardiovascular risks: https://www.ahajournals.org/doi/abs/10.1161/circ.144.suppl_1.10712
The "American Heart Association Committee on Scientific Sessions Program" has expressed "concern" about this ... um ... abstract-only paper? Are abstract-only papers a thing now wtf? https://www.ahajournals.org/doi/10.1161/CIR.0000000000001051
> Pfizer contractor whistleblower (this one is troubling): https://www.bmj.com/content/375/bmj.n2635
Interesting. I guess that's one to watch.
> The most troubling for me is the signal from VAERS, yellow card, and European system. I don't buy this "it's flooded with fake reports narrative" and I haven't seen a breakdown or attempt to analyse this, other than ones that do not support the vaccine rollout, such as this preprint
"it's flooded with fake reports"? Sounds like an argument by some dumb person that an antivaxxer found to debate them. Like maybe a journalist, hah. It took me like 30 seconds to think of a perfectly reasonable explanation that I have never seen anyone try to refute (https://dpiepgrass.medium.com/vaccine-risks-a-letter-to-my-father-d1419486e4f1), except my dad who made an assertion like "they won't give vaccines to people who might die soon", but I don't think that's true.
> I would love for someone to convince a healthy young (30s) man such as myself that the risk from COVID (yes I have medications available and a testing/treatment/isolation plan) is greater than my risk from regular 6 monthly vaccines for... 1 year? 2? 5? I don't see this as a settled question and I feel justified waiting for more data (let's say til 2023) before making a decision.
Well, all the regulatory agencies have found it safe & effective, so why not accept their findings?
By the way, the technical term for what you should be looking at in relation to VAERS / yellow card statistics is "base rate".
Any population of tens of millions of people will have deaths and sudden unexpected illnesses every single year. This is called the "base rate" of illness or death.
Any antivaxxer who talks about VAERS / yellow card, but ignores the base rates, is bullshitting you. There's no chance in hell that no one has tried to tell these people about base rates, but somehow when they talk to their fans, this issue always slips their minds.
Pfizer vaccine trial data: “Only 3 of the people in the trial died of Covid-related illnesses - 1 who received the vaccine, and 2 who who received the saline shot. “
In terms of overall deaths there were 6 MORE deaths overall in the vaccine group than in the placebo control group.
No. 1 from vaccine arm, and 6 from the placebo arm died from covid. And 16 vs 15 died during the blind trial period, through December 14. After the blind period, almost all the placebo recipients chose to get the actual jab, and through March 13, 5 more people died (3 of them original jab recipients from non-placebo arm, 2 of them original placebo recipients who later got the jab), consistent with the background mortality rate.
This is incorrect. August 12, 2021: "Only 2 people in the placebo group died of COVID-19 and 1 person in the vaccinated group died of COVID-19 pneumonia, according to additional Pfizer data obtained by The Associated Press. "
Nope. Never trust news services, go directly to the source.
From FDA's clinical review memo (August 23, 2021), page 70:
« Seven deaths were due to COVID-19 (1 BNT162b2 recipient and 6 placebo recipients). Each case had a positive COVID test (PCR or NAAT), but not all tests (including the positive PCR in the case of fatal COVID-19 pneumonia reported 109 days after Dose 2 of BNT162b2) were within the specifications of the study protocol for tests with acceptable sensitivity and specificity and were therefore not included in protocol-specified efficacy analyses of severe COVID-19 cases. Abbreviated narratives are provided for those participants who died from COVID-19 in Appendix C. »
Herzog, you're mindlessly repeating misinformation that is spread deliberately or out of unscrupulosity by certain ideology captured parties.
(1) The blind period ended on December 14, 2020. The placebo group were offered the jab (I'll refer to it as BNT from now on), and >95% chose to get it.
(2) During the blind period, 16 vs 15 people died from covid in the BNT arm vs the placebo arm.
(3) After the unblinding, through March 13, 2021, 5 more people died (3 from the original BNT arm and 2 from the placebo arm who later chose to get BNT). This is consistent with background mortality rate observed during the blind period.
(4) During the blind period 1 vs 6 people died from covid in the BNT and placebo arms, respectively.
(5) The whistleblower's complaints are about laxity and procedural irregularities she observed at one subcontractor that managed 2k participants out of 40k for Pfizer's trial. If you read the contents, this person was very conscientious, and was irritated with the minutest faults, such as late entries to patient diaries (there were some serious faults too, such as potential unblindings). Even if you throw away these 2k participants, it doesn't affect the outcome of the trial, and of course, now we have real world data from hospitals and statistics bureaus from around the world: so the RCT is not even the strongest evidence for safety and effectiveness anymore.
(6) Pfizer is not "fighting tooth and nail to hide the primary data [...] for 55 years". Here's the truth behind that oft misrepresented story: an advocacy group FOIA'd FDA for the BNT approval process documents. Their FOIA query was too broad; it returned 329k pages. The law says that, parties can either negotiate a suitable release schedule between themselves, or they can escalate and bring the dispute before a federal judge to decide. In this case, the FDA's lawyers said that the normal processing rate to appropriately redact documents is 500 pages per month. They cite case law, including one particular case where no exception was made for a really large FOIA result (in that case it was ~50k pages). So they're saying we'll give it to you 500 pages a month. The plaintiff are saying it would take 329k/500 months, about 55 years.
So Pfizer's not even involved with the case. FDA doesn't want to assign extra manpower for the redaction job, which requires 100x the regular rate to complete within 6 months. We'll see what the judge decides. But the problem here is not that FDA is being unreasonable imo (redaction really is a slow, cumbersome job), it's that the advocacy group's query is too broad. They should negotiate a properly exact and narrow query that precisely targets clinical data.
I appreciate you putting forth the effort to write this comment.
Thanks.
Correction: Second item should read:
(2) During the blind period, 16 vs 15 people died in the BNT arm vs the placebo arm.
Also your #'s for total deaths of all causes are wrong. Pfizer updated these.....
On November 8, the FDA released its “Summary Basis for Regulatory Action,” a 30-page note explaining why on August 23 it granted full approval to Pfizer’s vaccine, replacing the emergency authorization from December 2020. On page 23 of the report is this sentence:
"From Dose 1 through the March 13, 2021 data cutoff date, there were a total of 38 deaths, 21 in the COMIRNATY [vaccine] group and 17 in the placebo group."
Pfizer said publicly in July it had found 15 deaths among vaccine recipients by mid-March. But it told the FDA there were 21 - at the same data cutoff end date, March 13.
21.
Not 15.
The placebo figure in the trial was also wrong. Pfizer had 17 deaths among placebo recipients, not 14. Nine extra deaths overall, six among vaccine recipients.
I've investigated this issue extensively, and you're wrong.
(1) Pfizer's July 2021 preprint says 15+1 vs 14+1 died during the blind period. They deliberately separate 1 HIV deaths in both arms. They also exclude 2 deaths in the placebo group who died before receiving their 2nd dose of placebo. So total deaths during blind period was (16 vs 17), or (16 vs 15 excluding the 2). This extra 2 deaths from the placebo arm is not mentioned in the Pfizer preprint, but is mentioned in the FDA memo.
(2) After unblinding, through March 13, 3 more original BNT162b2 recipients died, and 2 more original placebo recipients who later got BNT162b2 died. And that's it. This is clearly stated in Pfizer's July 2021 preprint.
So the 21 vs 17 framing is dishonest. After unblinding, almost everyone had received BNT162b2 shots, so 5 more BNT recipients died as expected. And going forward, ~all the deaths observed in trial participants will be BNT recipients.
Not sure, whether this analogy is valid or not, but let’s apply this logic to various types of food.
Suppose you don’t know anything about vitamins and minerals, but you know e.g. that eating lemons helps agains scurvy and some other types of food help with other things. Applying the logic from the post you’ll end up with a “Pascalian diet”: eating as diverse food as possible. And with a hindsight, it doesn’t seem to be such a bad idea.
I like the comment section of this blog because there is always someone who shows up before me and makes the point I was going to make. 😄
I was going to spin it a bit differently and argue that essentially Scott's argument here rests on the assumption that medicines are distinct from food somehow, but IMO there isn't a bright line separating the two. Is an orange a supplement or a food? It prevents scurvy, much like a vitamin C tablet would do in similar circumstances. It just happens to also give you a dose of energy (sugar) and some other miscellaneous stuff. An orange is essentially just a "multivitamin" (yes, I know I'm stretching the term vitamin here a lot but it is meant to be illustrative).
Just as with medicines, you can also die in some very rare circumstances by eating certain foods that are totally fine for everyone else basically all of the time.
In reality, there are some things that are classified as medicines due to the route they took to getting to humanity rather than due to some fundamental nature of them. Perhaps a better classification of "food" vs "medicine" would be "the probability that something bad will happen by ingesting this thing". By that measure, there are some foods that likely *should* be called medicine (blowfish?) and some medicines that should be called food (ivermectin?)
The point of this is just to argue that the pascal's wager in putting stuff in your body is one that humans make all of the time, and I think the key differentiator is (or at least should be) the risk of adverse effects. Ivermectin in this case is arguably the canonical example of something that is probably safer for you than a lot of different foods, and thus is very reasonable to make the bet on. The same goes for Vitamin D and many of those others.
Interestingly, I would argue that fluvoxamine *doesn't* make the cut for a medicine that is low risk enough to warrant making the bet on.
Erm, food is something taken for the nutritional value (other effects might happen). Medicine is taken for another effect, and generally has very minimal nutritional effects. Clearly there will be some edge cases (especially around traditional medicine) but I don't think the ven diagram here has much overlap.
How do you draw the line between "nutritional effect" and "other effect"? There are certainly some things that we need in very large quantities like calories and amino acids (in various forms), and there are some things we need in relatively small quantities like vitamins and minerals. A vitamin is just a "small molecule", and there is not a clear line between a vitamin small molecule and a medication small molecule.
Are vitamins food or medication? Most people get the majority of their vitamins from "natural" food sources, but if you don't get enough from food sources for some reason you can take them as a supplements.
I can see an argument that "food" is anything you need in large quantities (sugars and amino acids) and everything else is "medicine", but in that case we make pascal's wager every day we consume a random set of foods that are rich in vitamins and minerals and we don't just eat solely white rice and protein powder.
My argument here is that if you want to say that pascal's wager is acceptable for "food" and unacceptable for "medicine", then you need to have a much more clear line between what is food and what is medicine. I think most people intuitively make the naturalist fallacy here and essentially argue that "if it comes from a plant or animal and is not processed then it is food, else it is medicine" which I think is wrong because now vitamin A from a natural source is considered food while the exact same vitamin A from a supplement is medicine. Does this mean that it is acceptable to make pascal's wager on vitamin A only if you get it from a plant but not if you get it from a pill?
I think a real biochemist (which I am not) could pretty readily draw a line between a vitamin and a drug, for example. Vitamins are substrates for certain important metabolic factors, e.g. NAD is made from Vitamin B3 and FAD from Vitamin B2, Vitamin C is in a different category because it's a cofactor in a number of important reactions (so it gets consumed, albeit in small amounts, and should perhaps be classified as a micronutrient than a vitamin).
But in all cases, these molecules play essential and continuing roles in metabolism. I think they are not generally regulatory molecules, or messenger molecules, which are much more the kind of thing that drugs mimic, accelerate or block.
🤔 That is an interesting line to draw, it is quickly growing on me. IIUC, you are essentially saying that if the molecule is involved in regular processes that are always happening within your body, then it is a vitamin/food, and if it is a molecule that is not part of any normal processes, then it is a medicine.
I think we don't have a large enough understanding of human biology to correctly categorize everything, but I do think we are pretty close and probably "close enough" to have that be a useful delineation.
This would, of course, mean that melatonin is a vitamin and not a medicine, because it is part of regular internal processes. I don't think this breaks the general heuristic though and it likely requires us to only adjust the classification of a relatively small number of molecules.
Where things get weird is whether a gene therapy that introduces a gene into your body that your body (or the average body) already has would also be classified as "vitamin" by this. That feels a bit odd, but maybe we can draw a few more simple boundaries to handle that situation?
I don't think you can draw that line. You can say "This is more like what I think of as a vitamin" or "This is more like what I think of as a mineral" or "This is more like what I think of as a drug", but you can't draw lines between them, because you'll find things that need to fit into multiple categories. It's more like gravitational attraction than putting things in pigeonholes. And you can't really base it on mechanism, because biology is complex, and we don't really understand all the interactions.
E.g., is cobalt a mineral? Well, yes, but that's not the right way to think of B12. But it wouldn't work without the cobalt. What about hemoglobin? It's usually more like a part of the body, but if you need a transfusion it's more like a drug. (Just picking easy examples, those aren't really difficult cases, but I'm not a specialist that could explain a real edge case.)
A real biochemist wouldn't spend time trying to make that distinction. It doesn't lead anywhere except to Talmudic arguments over what is which.
Ha ha good point. I did say "could" though :)
You'd have to qualify it a bit maybe. Make sure not to drink all the different types of soda
I wouldn't say eating lemons helps with scurvy per se. Any reasonable diet has enough vitamin C to ward off scurvy. You are only at risk if you eat a highly unnatural diet for a long time, e.g. you're a Royal Navy sailor and you eat *nothing* but boiled beef and ship's biscuit for 11 months straight. Under conditions of weird privation, yeah eating lemons helps.
As someone whose shape is somewhat more spherical than ideal due to poor impulse control around food, this sounds like a bad idea. In any case where their is a clear surfeit of foodstuffs then there's a really obvious risk that a Pascalian approach leads to excessive calorie consumption, as well as increasing other potential risk groups (sugar, salt, fats etc). If you did try and fit everything into a balanced calory-controlled diet this might work, but I'd worry that if you are hoping to benefit from small traces of many things that you might have to rely on the logic of homeopathy to justify it: there's a limit to how many things you can actually eat and expect them to have an effect.
You could do this by just taking the vitamins/minerals involved, but then we're back to supplements rather than foodstuffs.
I was under the impression that it's easier to get overweight from eating a lot of the same kind of food, rather than a little of many different types of food. I suppose it might work differently for different people.
It is as far as I know, but if what you're advocating can be taken to suggest eating additional food (rather than substitution) then it probably doesn't matter how many different foods you are eating, you're likely to put on weight.
The opposite is true. It's the 'dessert stomach' phenomenon: you're able to eat much more of a varied selection of foods than if you just ate more of the same thing. Eating a burger, fries and a milkshake is easier than eating the same number of calories from fries alone.
Of course, that's assuming eating more calories actually has a linear relationship with becoming overweight, which you might have reason to doubt.
You wouldn't have to eat all foods at all meals, but could eat different foods at different meals (maybe rotating on a weekly basis or something). Have more fruits sometimes and more meats at a different meal, etc. That intuitively seems healthier than a monochromatic diet, even if you end up eating a few items that seem "weird" to modern western tastes.
> There’s a potential compromise solution, where smart doctors come up with Pascalian medicine protocols for the few patients who would actually want them.
Do what I do, and keep a stable of general practitioners (who do not have hippa release to each other) and rotate through them, presenting slightly different versions of your current health situation in order to have a doctor sign off on your plans
I think it’s funny how hilariously irresponsible it would be for Dr Alexander to say this as advice. Gotta keep the ol’ malpractice insurers on their toes!
(But if it works for *you*, of course it works for you.)
Not sure why it would be irresponsible to seek multiple cases of qualified advice? I doubt any of them will advocate drinking mercury to solve a cold or the like, and this clearly allows you to overcome single-practioner bias.
It relies on raj not being stupid enough to say rely on homeopathy to deal with a heart irregularity, since this technique clearly allows the patient to disregard advice they don't like. But since patients normally do that anyway, and there's no ethical requirements on doctors to ensure patients do what they are told will make them better, not sure where the ethical issues leading to malpractice would be here.
Widespread adoption might stretch most healthcare systems a bit mind you. It certainly would not be a viable model for the UK's NHS for example.
Yes, I probably consume more than my 'fair' share of medical resources (despite, or perhaps especially because I'm basically healthy) which is part of the reason I do it. A lot of doctors seem to be implicitly gating/triaging care when you are operating on multiple lines of inquiry.
I don't think it's irresponsible to get second, third, or seventeenth opinions; and if that requires hiding information about your medical history, then fine, maybe it's justified...but a horde of randos doing this would *absolutely* result in some idiot relying on Tibetan vuvuzuela thwacking to treat their brain tumor, saying "This Dr Alexander guy said it was a good idea to hide tiny little bits of my medical situation to the docs!", and their heirs suing. (Dunno if said heirs would win the suit, but nobody wants to be sued at all.) And it would also increase the probability of some fatal drug interaction.
I'm not sure the inherent openess of the US legal system to groundless litigation is a good argument for anything other than making plantings pay legal fees if the case is thrown out though.
I'm not arguing for or against change in the system; I'm just noting a likely consequence of a hypothetical act within the system we currently have.
Sort of off-topic, but I strongly respect him for being willing to say what he does, being in a position with something to lose. He does exercise care by being somewhat Straussian, but could definitely also be more risk-averse (which would suck for us)
Quite.
Well, if it’s true that out of 20 most promising things (by the view of a year ago) 1 really works, then 5% chance of working does seem like pretty reasonable estimate, doesn’t it?
And if that is true, then in this instance, taking 20 most promising things really is a good strategy.
I think you should just bite this bullet. I think it's OK to just say the Outside view is correct here.
"From the Inside View, I have a lot of trouble looking at a bunch of studies apparently supporting a thing, and no contrary evidence against the thing besides my own skepticism, and saying there’s a less than 1% chance that thing is true."
When low-quality studies keep piling up, eventually it should start to count against the conclusion. If nobody gets around to doing a very high-quality study despite all the low-quality ones, that starts to indicate that one can't do a high-quality study because it won't look good.
It's like if someone on Instagram post one video of themselves breaking the world squat record in their garage. Based on that, you might reasonably think they have a 20% chance of actually taking the official world record in a sanctioned event.
But if they post 20 such videos and never bother to enter a sanctioned competition to fully reap the rewards of their achievement, you'd reasonably believe there's 0% change they legitimately completed the lift.
No, it's not like that, because *lots* of scientists can *independently* choose to do a study or not. Just like that one N=12 Wakefield study saying that *parents* said that the MMR vaccine causes autism, or something, led to an explosion of other studies that said no it doesn't.
But if major ivermectin studies are being done, maybe it's too soon to expect them to be published already.
In a previous post Scott acknowledged that the current way the world works makes this not reasonably possible. Pharmaceutical companies have the capital, the skillset, and the incentive to do very large high quality RCTs, but essentially no one else does. The government has the capital, but not the incentive, and everyone else has the incentive but not the capital.
This means that the absence of a large high quality study is not indicative of it not being possible to get the desired results, because the environment simply doesn't exist to get such a large high quality study done.
Oh, very nice! It's an extension of the principle that "absense of evidence, when you can reasonably expect that evidence to exist, is indeed evidence of absense". Similarly, a bunch of weak evidence for a conclusion, when you can reasonably expect strong evidence to also exist if the conclusion is true, starts to look like evidence against the conclusion!
I agree with the general premise of "absense of evidence, when you can reasonably expect that evidence to exist, is indeed evidence of absense". What I disagree with is that it is reasonable to expect that evidence to exist in the current reality we live in (which Scott seems to also believe).
More specific to the latter half of your statement, "we do not have a reason to expect strong evidence". The medical infrastructure is setup such that we will almost *never* see a large well done DBRCT for an off-patent medication. At the least, we should not *expect* that to happen naturally even when there is good reason for such a thing to be done (like curing COVID-19 or whatever).
I think the opposite is also true though, as "high-quality studies" tend to cost a lot more than "low-quality" studies. The fact that many independent groups with far less means are pursuing studies of any size (and using their limited funds in the process) should give credence to there being some sort of effect, as something led them to initiate the study in the first place. This is predicated on "low-quality" studies normally being seen as so because of their amount of participants than other factors though.
The problem is another aspect of risk that you don't discuss. It's a kind of opportunity cost, but with a multiplier effect. Taking ivermectin *as an alternative to vaccination* presents a real cost. The ivermectin advocacy set significantly overlaps with the big pharma/medical researchers/public health officials and big tech and Dems conspiracy set. That set interacts with political sets in all sorts of realms.
Nonchalance towards ivermectin because there's a 10% chance it works with little downside risk is, in isolation, one calculation.
In the real world it interacts in complicated ways with many high damage function risks in a number of different domains. That isn't to say, don't consider ivermectin. It's only to say that you need to examine the related risks *in the full context*
??? If you're taking all the different things that have any chance of working, and willing to take 20 different drugs to maximize your chances of getting the one that works, obviously the vaccine will be on that list! This is the strategy for people who love getting as many different medical interventions as possible!
If you're really taking <i>all</i> the different things that have a chance of working, wouldn't there be seven different vaccines on the list?
Is that legal? I mean... even if you limit it to 3 approved vaccines in your jurisdiction...
Well, group taking weird medicines likely has overrepresentation of antivaxers and other people who believe too much in their own analysis and fail in selecting good sources.
> This is the strategy for people who love getting as many different medical interventions as possible!
Ok - but in the real world context I don't see much practical utility of talking about taking "all the different things that have any chance of working." How many fit into that category? What we have in the real world in the US and some other countries, are people advocating ivermectin as a safer/cheaper alternative to vaccination.
As such, when you talk about the probability of ivermectin working - sure, it's certainly relevant to talk about it in some theoretical frame - but there's more going on than that. If there were only people trying to get as many different medical interventions as possible then your framing would be sufficient. But that's not a very prevalent situation. So just saying ivermectin has a 10% chance of working misses the real world opportunity costs (deaths and illness) involved. In the real world that actually lowers the expected return on the use of ivermectin.
Is fluvoxamine really so innocuous that you would take it if it had 5% chance of reducing your COVID mortality 30%? Would it be a good idea to take 20 drugs with fluvoxamine's side effect profile? These are genuine non-rhetorical questions. The list of side effects on Wikipedia looks like something I wouldn't eat on a whim, but side effect lists always look scary.
I also have to assume there is probably some grand correlation between "likelihood of having an unanticipated positive clinical effect" and "severity of side effects". As in, if something is bioactive, it is more likely to have both good and bad effects. Obviously there are a huge number of exceptions in either direct (penicillin, sodium cyanide) and I'm supposing this is less true for antivirals where magic bullets that affect virus but not human are more likely to exist. But for non-pathogens, Algernon's law seems like a good guide. "X is a chemical that affects your metabolism. Is X more likely to be good or bad?". Probably bad. And if you know X is completely innocuous, it almost certainly doesn't help you either. I realize this paragraph is very handwavy.
Yeah, when he said "benadryl and tylenol" I was instantly thinking this too. Even though the side effects of those things are small, they're still real. I don't want a bit of drowsiness most days, and I don't want to develop tylenol tolerance (or whatever the liver condition is that it has a tiny chance of). If I'm actually having allergies or headache, or even think I'm starting, then sure I'll take them. But it's not really Pascalian until I at least have a small chance of a condition I suspect it's helpful for.
Penicillin allergies are no joke. They are a big potential side effect.
PS Penicillin, like all antibiotics, also messed with your gut.
From a personal perspective yes, go all insanity wolf and the drugs, I think the bulk of your arguments make sense.
What you ignore is the potential social consequences of hastily incorporated drugs. Any side effects not mentioned (and deliberately avoided based on your "utilitarian calculus") will meet with such damning criticism that it might jeopardise the entire medical establishment and cause people to lose faith in medicine, given how risk averse we are.
And if people start losing faith en masse, we're done more harm overall then the benefit we gain by adding a bunch of game-theoretically (for the individual) better drugs.
And here in the blogosphere, people debate whether to follow the medical advice of insane wolves.
The biggest reason not to take any of this junk is that there are vaccines of proven efficacy and safety right now. Yet the word “vaccine” does not appear once in this essay. What is going on here?
You could combine the vaccine with the drugs and supplements. We know the vaccine isn't perfect.
Because it's obvious and we're trying to come up with other things that work on top of it? Do you also think Pfizer shouldn't be researching / the FDA shouldn't be approving Paxlovid because "we already have vaccines"?
Well, from comments it is obvious that it is not obvious for many people. Maybe you should make a post about vaccines "yes, it works, that is how we know that".
Or at least add a disclaimer, when you talk about alternative covid treatments, that obviously the best thing you can do is to get vaccinated. Scott already qualifies all his medical posts with a bunch of disclaimers (as well he should) so something along these lines might be worthwhile.
Come to think of it, the expected effect of any of these random drugs is far less than the expected effect of which brand of vaccine I took. If Scott really wants to do another massive covid effortpost, then a comparison of what we know about the different available brands of vaccine would be incredibly valuable. Also, boosters.
Just no. Let a man blog.
Just an idea, not a demand, nor even a request.
Sounds smart. Like "PS, another disclaimer that I'd thought went without saying but apparently not: if you're agonizing about Pascalian Medicine but haven't gotten the covid vaccine, you are doing it All Wrong."
I thought he was trying to smuggle the argument in. Once you get someone to agree "yes, I will take anything with a chance of working" you hit them in the face with "so here is the vaccine".
And then they're like "but it's killed 150,000 people in the U.S. alone!" and you hit yourself in the facepalm.
Your post wasn’t about what Pfizer and the FDA should do; it was about personal experimentation with one’s own body. In that context, the existence of safe and effective vaccines hugely alters the cost-benefit analysis of subjecting one’s self to unproven substances, making the potential upside fsr smaller. For example: If a vaccine eliminates 95% of your COVID risk, then the biggest possible upside to any of these self-experiments becomes eliminating the remaining 5% risk. Don’t you think that’s a hugely important factor in deciding whether to experiment on yourself? As for its being “obvious”: Sometimes I think smart people who like to play with ideas shy away from obvious-but-true points because they’re less fun to think about. I’m sensing that this could be happening here.
my understanding of ivermectin is that its proponents claim it is effective in reducing negative outcomes of Covid after you have contracted a severe case. I assume that most of the other treatments he listed are also in a similar boat; they’re more akin to antivirals than vaccines. if that is indeed the context (I could be wrong, I’m not a medical expert, just someone who begrudgingly obeys their doctor), then I’m not sure that the vaccine does make such an overwhelming impact on using a pascalian approach once you’ve contracted Covid
Well yes, vaccines normally work only before exposure to the real virus.
I think he's making the point that perhaps you might mention that this stuff can become incredibly marginal and it's wise to keep relative risk in mind. That is, if you are researching how to live longer by popping vitamin D pills or ordering resveratrol off the Internet *but* you smoke and don't wear a seat belt, then you need some big recalibration of your sense of relative priorities. Likewise, if you're weighing the pros and cons of experimenting on yourself if you get COVID with a variety of random small molecules drugs *but* haven't taken a vaccine because you're worried about small tail risks, then you're being rather innumerate.
Because this is for/about people who won't go near a vaccine, but demand access to a de-wormer as a miracle cure (and before anyone gets het up about "calling it horse de-wormer is a propaganda tactic!", I didn't call it that; it's also used in humans for the same reason).
So writing an article about "why, in fact, taking the juice of purple hensbane under the third full moon in Spring will not cure Covid" is for those people, or for our friends/relatives who are passing around Facebook posts about "what BIG PHARMA doesn't want you to know! This ONE WEIRD TRICK works but the doctors won't tell you!"
That's what is going on.
>Because this is for/about people who won't go near a vaccine, but demand access to a de-wormer as a miracle cure
I assumed it was about using those people and that condition as a specific example to deal with general concepts of medical decisionmaking under conditions of uncertainty and why we make the decisions we do, not attempting to dive into an active culture war with both feet and serve as a scientific missionary to the unenlightened. Like the ivermectin post, which was really about how to conduct a meta-analysis and the degree to which both the Red Tribe and Blue Tribe's biases led them astray on a question that had an interesting answer which was almost totally orthogonal to the shit they were fighting about.
I definitely struggle with this as well. I take a multivitamin but no supplements. I'm sure that there is stuff in my multivitamins I don't need and supplements that I do 'need' but I can't tell which, so I stay stuck at this mostly arbitrary equilibrium.
Tl;dr I would probably take the wager if (# of drugs for which i am ~X% confident will work) * X% * (treatments that might theoretically work) / (treatments that we reviewed to see if they work) = (the # of treatments our prior says we would expect to work). If this is true, then X is probably pretty well calibrated.
One argument against Pascallian medicine might be: I believe that thee is a 5% chance of this medicine working, but suppose i am miscalibrated by an average of 10% probability each time, which seems reasonable. Then (assuming my errors are normally distributed, of which I have no guarantee) I can be 95% confident that the probability a perfect Bayesian would hold of a drug working is… between -15% and 25%, not exactly confidence inspiring, especially when you remember Kightian uncertainty probably outweighs these numbers. So is there a way we narrow down the range of the probability of working?
… on the other hand, it seems to me that an onion farmer couldn’t get me to believe in a ~5% chance of onions curing cancer just by p hacking, so maybe, since the expected benefit of the drug is still positive, albeit barely, I should take it.
One way of resolving this problem might be this: suppose there are 10,000 chemicals that might theoretically cure cancer, but we only expect a few to work (say, 5 have really strong effects and 5 more have weak effects that are still worth having in some circumstance.) and suppose the lobbies of each drug hire some scientist to get positive results for their drugs, such that it seems to us there is a 5% chance of a given drug working. 5% of 10,000 is 500 drugs working against cancer, which is orders of magnitude than we would expect, so we should default to the outside view here. On the other hand, suppose only 400 chemicals seem to us to have a 5% chance of working, and we reject the other 9,600 out of hand after reviewing them. We find that this suggests that about 20 of the 10,000 work, which isn’t so far from our original estimate. Here, since the inside view and outside view agree, maybe we should take the 400 drugs. If this were to happen, I would think long and hard before probably taking the drugs.
I struggle to understand where 'Pascalian Medicine' would substantially differ from the alternative / complementary medicine industry, which is almost a $100b sector of the economy. The underlying ethos of both seems to be "Uncontrolled, iterative n=1 trials of pharmacologically active substances and pseudo-behavioral interventions with the primary outcome of improved subjective sense of well-being." I have no problem with this, any more than I have a problem with people finding the right exercise and diet regimen for themselves. But there's a difference between 'improving wellness' and 'treating disease'. n=1 experimentation can be great at the former, and usually pretty poor at the latter.
I think there are likely specific clinical scenarios where a Pascalian approach makes more sense - poorly understood chronic diseases, like post-infectious syndromes, or diseases where there is no good a priori evidence of effective treatment. Many of the rare disease and chronic disease communities and their treating physicians effectively take a Pascalian / Omuran approach in settings where no clinical trials are available.
expected-value-of-x = value-of-x * P(x-works) + bad-from-x * P(x-is-bad)
The value of not dying of covid is very large. Severe side-effects, including death, have a large negative value. P(x-works) and P(x-is-bad) are both small.
expected-value-of-x = infinity * 0 - infinity * 0
You can replace whatever large/small values you want to get whatever specific result you want for your expectation value.
To put it a different way, the expected value from taking x might be good, but you can't just consider the expected value. You have to consider the whole probability distribution, which is wide and flat.
Another great post. I wish I could think like this. This methodically, this thoroughly. Why is this so rare? And then express those thoughts precisely and with humor. This is clearly even rarer.
What do you think of the heuristic that "The body can deal with surplus better than scarcity" for certain types of substances. If too much of supplement A is not a big deal but not enough of supplement A is a big deal, then we can err on the side of too much of supplement A. I think that might be the case for a lot of supplements, so taking a bit too much is reasonable. For other stuff, not so sure.
Scarcity of any given nutrient causes some specific deficiency disease. Surplus usually causes some mild impact on kidney and/or liver, right? If you ignore small effects, then it looks like avoiding scarcity is better than avoiding surplus. But if you're taking several dozen of these things, then if each one adds a little bit of strain on your liver individually, you might end up with a severe liver issue.
For poisons that obviously doesn't work, but for nutrients it probably does, since the natural supply of nutrients varies significantly -- which means the body has to have historically had ways to deal with surpluses, up to a point.
I wouldn't take it too far, though. Some substances are harder to get rid of than others, e.g. the fat-soluble vitamins, iron, and some others do ugly things along the way to being dealt with, e.g. ethanol's unfortunate waystation of acetaldehyde.
I think it's a mistake to group vitamin D in with things like Ivermectin. While the evidence that either therapy cures Covid is pretty thin the decision is not at all the same.
Vitamin D advocates are asking people to follow existing medical guidance to avoid deficiency. To maintain serum levels within 30-60 ng/ml most people will need to take a supplement in the winter, and almost everyone at risk for Covid (people with melanated skin, obese people, the elderly) will need to take one. This isn't taking some random therapy on the off chance it's helpful, it's following medical guidance that existed prior to Covid. Recommending vitamin D for these groups is a lot like recommending that they lose weight or quit smoking. It's possible that those things help with Covid, but even if they don't it's what your friendly neighbourhood endocrinologist would recommend anyway.
By contrast Ivermectin really isn't something that most people need. There's no such thing as "Ivermectin deficiency" and there aren't any medical associations who recommend that people get tested and see if they need more ivermectin in their diet.
My understanding is that the Vitamin D supplement thing is a bit faddy and tends to get out over its skis.
Also, the Vitamin D recommendation is a bit of a gateway drug to wackyness. I heard someone, I think that guy you got cancelled from Evergreen, arguing that COVID is all about Vitamin D and stay-at-home orders were responsible for the spread of COVID because they kept people from going outside and getting enough sunlight. Once your devotion to these possible cures starts encouraging you to disregard more reasonable advice, it becomes a problem.
My concern with a lot of alternative/non-standard medication is that not that it, in itself, is dangerous, but that it acts a gateway drug (pun intended) into a world that really can be harmful. E.g., I'm skeptical that acupuncture has any real value, but I also do not expect it will cause any direct harm either (other than the time and money wasted). However, I am concerned that, while an acupuncturist is treating you, he will tell you about all the dangers of modern medicine and then give you a referral to a chiropractor, who will give you a referral to a naturopath, who will give you a referral to one of those people who want to you treat your cancer with peach pits or autism with bleach.
Modern medicine isn't perfect, but it's pretty clearly better than alternative medicine (as the joke goes, if alternative medicine works, we would just call it medicine). Encouraging people to start down the alternative medicine path itself is dangerous.
Also, taking any given supplement may only cost $20/month, but that means that taking 20 supplements would cost you $400/month, which starts getting into real money.
At the same time, when my kid was sick the other day, and my wife pushed an elderberry supplement on me to try to help me avoid catching the cold, I took it because I figured "what the heck?"
Well, and there's some ethical challenges in being at all encouraging toward the natural human tendency towards magical thinking. Imagine penning a column for an AARP newsletter[1] in which you sunnily say "You know, when a stranger phones you up and offers you an incredible investment opportunity if you just read him your credit card number over the phone, there is a 1% chance he might be on the level and you'll be able to pay off your mortgage in 60 days."
You'd be shot for doing that, and quite rightly.
So ironically it's fairly ethical to encourage people to practice amateur medicine if you have no unusually high influence and the number of people likely to take it all on faith just because you said it is small, but the *more* expertise you have, the bigger your reputation, the more likely people are to take what you say and run with it, the less you want to be doing this.
[1] American Association of Retired People, for those not in the US.
And at the extreme edge of this is FDA/CDC. No Insanity Wolf allowed there.
Well yeah. You have to be incredibly conservative and careful if you don't want people bringing up mistakes for decades, long after the people involved are gone, and probably after it has passed into myth (e.g. I bet there are plenty of people who think the FDA *approved* thalidomide, and that just goes to show how fallible they are.)
I think the CDC in particular was caught completely flat-footed by this during COVID, because they have had essentially zero experience in pandemics in the last 75 years. So they acted as if it was business as usual for them, making flu vaccine recommendations or something on their website, very low-traffic low-weight stuff, and boy did they step in it. I would imagine they'll have a very different and far more CYA attitude for the next decade, and there will be a giant upsurge in hirings for staff lawyers and PR people.
I think rational people understand that the FDA can't give anything but the safest possible advice, the same way a cop cannot publically advise me to do anything other than obey each and every traffic law, even if I'm driving someone to the ER with chest pain or something. They're never going to even try to hit the sweet spot of the advice most likely to maximize your outcomes 'cause that involves acceptance of risk.
This all brings to mind that old post about Epistemic Learned Helplessness: https://slatestarcodex.com/2019/06/03/repost-epistemic-learned-helplessness/. All these arguments in favor of Ivermectin and curcumin and all the rest, they prove too much: https://slatestarcodex.com/2013/04/13/proving-too-much/.
what prevents algernon's law from accidentally proving stimulants don't work, when it seems like everyone who takes them loves them?
Don't most people who take stimulants regularly develop some sort of tolerance and/or dependence? Maybe it's still net good, but it's not obvious.
I thought a solid chunk of things that Algernon's law applies to have the simple drawback of "makes you need more calories" - very relevant in the evolutionary history, utterly irrelevant today. No such thing as a free lunch, but if you've got cash in your wallet there are plenty of meals to be bought.
My prior on circumin being better-than-nothing for covid was >50% because it's a weak anti-inflammatory and several other anti-inflammatories (budesonide, dexamethasone) were extremely beneficial. In some third world country that can't afford steroids, where dirt-cheap circumin is being produced locally, it might make sense. But here in the US where you can just walk into Walgreens and get a much better anti-inflammatory for $20, it's not worth trying.
On PAINS: Curcumin isn't just a PAIN, it's the worst of them all. See: https://www.science.org/content/blog-post/curcumin-waste-your-time (by Derek Lowe).
Quercetin is also pretty bad.
Great post. Hilarious, too, and that's coming from someone who's been in the natural supplement and nootropic manufacturing world for decades. I don't blame anyone for getting burnt out from superfood and supplement consumption, and the Everest size mountains of related research. It's eye-rolling and existentially exhausting, even for those of us who are deep believers. Thanks for the perspective, Scott.
You're forgetting the placebo effect, which cuts both ways: it makes Pascalian medicine more effective, in that it actually does help whether any active ingredient actually works, and it argues for reducing the number of pills down toward an ideal of 1 magic pill.
I take 5 different kinds of sugar pills, just in case
I hope you're blinded as to which sugar pill is which.
Does eating a handful of M&Ms without looking count?
Whoa! Even Insanity Wolf thinks that's kinda edgy! Were they all different colors? :)
+1
As long as placebo effects are significant, it’s not clear why we don’t want “Doctors of Placebo”… but if they called themselves that, I guess it wouldn’t work…?
This seems like a jokey point but for me it makes all discussions of personal medicine genuinely strange. The doctors don’t have a great sense of what makes our bodies good at repairing themselves at present, even if they understand plenty of drug effects.
The placebo effect still works (albeit weaker) if you know it’s a placebo.
I'm trying to extrapolate from 1 pill down to 0, which seems like it ought to be easy, once you've gone from 20 to 1, but someone it's tough. Maybe it's because I'm afraid I'll overshoot and end up taking -1 or -2 pills a day.
Why would the placebo effect argue for reducing the number of pills? I thought it was reasonably well-established that 'bigger', more theatrical, more inconvenient and attention-getting and interesting placebos work better. It seems plausible to me that someone starting a course of five different placebos, each with their own whizbang supposedly independent mechanisms of action, would experience a stronger placebo effect than someone who just took one.
I think the principle of outsourcing decisions about what drugs are cost effective if prescribed by doctors using them only if they reasonably believe them to be cost effective for the individual patient is in principle a good system. I'd just like to see reforms in incentives that made those suppostions the case.
In the system we have FDA seems overly concerned by "side effect" costs, not concerned enough about delay of benefit costs, and not enough about resource costs. Doctors seem too much concerned with avoiding malpractice suits and not enough with cost of prescribed treatments.
The argument here seems like it can be condensed down to "I trust science, but science is contradictory, help!".
Seems like the obvious way out is to trust science less. But that feels bad, because psychologically losing trust hurts, and people will mock you for it, etc...
I don't mean to single you out specifically, you are one of a few dozen commentors who I would ask this of, but:
Did you join ACT recently? Like, within the last week or so?
Advising Scott to trust science less, and about the tribal reactions to such, just feels... idk. It feels weird, like you're maybe not aware of the context of the ten bajillion words about epistemology that scott has written, or the ten trajillion words that have been written about epistemology in our community going back to the '08 EY sequences
It feels a bit like a comment that would appear on a news opinion piece, not on a rationalist blog
I want to know if my immediate knee-jerk evaluation is right, please get back to me
No, I've been reading SSC since I guess like 2015 or so. Your knee-jerk reaction is wrong. I've become more "radicalized" by the pandemic I guess, but I've read most of the "ten bajilion word context" you refer to. In fact, when I was writing the above I was thinking of something by Eliezer Yudowski when he discusses why abandoning old belief systems is hard.
A way to make sense of "lots of good evidence for contradictory ideas" is to remove the "lots of good evidence" assumption. Scott kind of hints towards this direction in his post, but I don't think he goes far enough.
re-reading my post, I see why it comes accross as condescending. But this was not the intent!
Agree, and would go further to say that if you find yourself confronted with "lots of good evidence for contradictory ideas", you're obviously mis-calibrated as to what constitutes "good evidence". My default assumption when confronted with a study that claims big benefits for some important malady is "this is either fraud or frank incompetence" and proceed to look for evidence of those before considering the hypothesis that the study is actually "good evidence". The amount of outright fraud Scott found in his Ivermectin survey increases my confidence that this is the right approach. (I also believe incompetence is more prevalent than fraud, so if there's a lot of fraud then there's a whole lot of incompetence.) This is not the nihilistic attitude that "everything is fraud and a Big Pharma conspiracy", but if you have bold claims about big things, you better have dotted all the i's and crossed all the t's. It's really a joy to read papers that do that - a sign of true craftsmanship.
My response is to ask for better standards for science (about which people more knowledgeable than me have written, e.g. peer review on methodology before data gathering starts, publication decisions before data gathering to avoid publication bias, Bayesian reasoning in addition to P-values, ...)
...and until then, research carefully and be suspicious of the opinion that large numbers of obvious cranks are promoting...
There's a significant difference between:
1) what one should do;
2) what protocols doctors should prescribe.
The second, as Scott notes, involves various second-order social factors. But I, as an individual, only care about the first.
Most of the arguments that Scott puts forth against Pascalian medicine could equally be deployed against responses to most X-Risks. The logic is quite parallel.
Under the assumption that the "xrisk" is actually small. Also Algernons law doesn't work at all. Many interventions are obviously net beneficial. (Like how is an asteroid telescope going to increase the chance of impact?) All right, bad example for technical reasons.
For sure, I have in mind X-risks whose probability of occurrence is small.
It's not obvious that Algernon arguments may not apply in regard to social or economic effects. For example, while there are particular measures that I favor in response to climate change, there are other popular proposals (e.g., degrowth, forced restriction to non-nuclear renewables) that I see as highly counterproductive.
Well, since the sort of climate change that people are trying to prevent is itself caused by human activity, the analogy doesn't work. Human biology had many thousand of years to slowly evolve and is relatively stable, whereas the very fact that anthropogenic warming recently emerged as a potential problem itself proves that global economy rapidly changes.
That only shows that the example is not quite an Algernon argument, which I'll concede. The broader point (that measures intended to ward off an X-risk can cause social or economic harms that outweigh the benefits) still holds.
...Isn't the problem here that if there's a 0.25% chance that any given medication kills or seriously harms you, a 5% chance they cure survivable ailments, and you take 200 there's a near 100% chance you cure the ailment but a 41% chance you get killed or seriously harmed? Is that a good tradeoff?
A "bad outcome" might be much much less likely than a good one, but probably we want to avoid it much much worse.
Maybe even more likely - each of these things has a 5% chance of curing a survivable ailment, no chance of killing you by itself, but a guarantee of a mild strain on your liver (or whatever organ is used to dispose of this stuff). If you get 200 mild strains on your liver, that may lead to significant damage, even if any one of them was sure to be negligible.
I think this is a good point: you're emphasizing that the way side-effects can harm you is kind of additive, more or less because everything goes through the same handful of degradation pathways in the liver, whereas the way the main effects might help you are all different and probably in some cases orthogonal. So small probabilities of benefit don't add up as fast as small probabilities of harm.
You are right about cumulative strain on the liver from taking a multitude of individually benign supplements, even with no negative interactions. My great-grandmother is a good example of this. She was obsessed with her health and took every vitamin, mineral, and supplement she could find, to the point where she was popping 150 pills a day. My mother remembers, as a little child, watching her organize her supplements each week. You know how many elderly people have pill organizers with a different compartment for each day? My great-grandmother had an entire mason jar for each day. She would also buy a 50-pound bag of carrots each week, put them through an industrial juicer, and drink the juice. (She turned orange from the beta carotene—no joke.) I'm sure each individual pill was harmless, but grandfather (an endocrinology professor) warned her that in these quantities she would wear out her liver, and eventually she did. Whereas my other three grandmothers lived to the ages of 85, 101, and 102 (I enjoyed getting to know each of them), this one died in her sixties and I never got to meet her.
> But I have to admit that given everything I know about ivermectin - and Vitamin D, melatonin, etc - I still think on net the very small chance that this stuff helps you is higher than the extremely small chance it kills you. Even if the latter isn’t quite zero.
These two are not unrelated: normally the stronger intended effects anything has on our biochemistry, the stronger the unintended ones. So the expectation of how much any specific one _might_ help should go hand in hand with the expectation of the harm if _might_ produce.
I think we are betrayed by our intuition, because we judge the low-expected-value of the negative outcomes as "come on, whatever this does, it can't be that bad" and the low-expected-value of the positives as "I don't think it'll happen, but if it does it's amazing". Something something Taleb invest some money you can live without in buying some crazy stock.
But this is not the same as going long on stock: without good evidence that any of these cures actually help, and without any reasonable model of why they may, it's basically betting on a black swan that can go _either way_. Betting on more than one (the Insanity Wolf position) doesn't improve the basically-zero expected value, just the spread.
Which is why the intuition is: it's weird to tell any single specific individual "you shouldn't do this", but it sounds like evidently bad policy to recommend it at society level. Everyone gets to decide what's their personal risk/reward balance, but as a society we'd rather avoid large stupid catastrophes.
A recommendation to single individuals could be: if you want, take more or less a couple of whatever "no proven cure but no proven side effects" that seem reasonable to you, but not too many - you may still catch the black swan, while as a society we're hedged from everyone taking everything and one of those chemicals turning out to make us sterile or whatever.
I'm not so sure about the hand waving away of side effects. Is it really so likely that a random drug is more likely to have a previously-unknown good effect than a previously-unknown bad effect?
You could respond that we have many decades of data about people taking ivermectin safely, and only a year or so of data about people with covid taking ivermectin, so we've had ample opportunity to discover ill effects and limited opportunity to discover bad side effects. On the other hand, do we have much data about people who don't already have worms taking ivermectin?
This post is about whether it would be an intelligent cost/benefit calculation to be more aggressive about the class of medications that lie in the vast gulf between 'no evidence' and 'the overwhelmingly large amount of evidence that convinces us that things Definitely Work', not literally random drugs. Troublesome as medical science often is, you can't just treat multiyear thousand-patient placebo-controlled double-blind randomized clinical trials as 1 and everything else as 0.
Given only 50% of studies in medicine can't be replicated, that should immediately halve your probabilities. We need some analysis of what proportion of studies with small effects fail replication, but I bet that too would scale down the final probabilities significantly.
Too much of the counter evidence against ivermectin is predicated on over-interpreting non-significant p-values. Alpha of 0.05 is a high bar to clear to begin with. Throw in all the complexities of treating patients for a novel disease in hospital settings while trying to run an RCT for a highly controversial repurposed drug, and it's an insanely high bar to clear. Factor in variations in dosages, days since onset of symptoms (which patients are notoriously bad at reporting accurately), severity of symptoms, and any number of factors which influence patient outcomes for Covid that can't be controlled for because they are unknowable, and you're basically set up to fail.
Keep in mind any p-value less than 0.5 means there's a greater chance of committing a Type II error than a Type I error.
When you have dozens of studies, no matter how hard it might be to compare them, consistently concluding there is a signal of efficacy for ivermectin, you *have* to change your burden of proof heuristics. Simply running a meta-analysis and interpreting the p-value @ alpha=0.05 is deeply reductionist.
This is why I am utterly unconvinced by the "debunkings" of ivermectin data. There is more than enough signal in the data, and when you have highly proficient clinicians around the world reporting success with a drug, you cannot dismiss that. You just can't.
All of this is besides the point of Pascalian Medicine, but is meant to address the probabilistic fallacy you are making in the foundation for how you've framed this argument. From my perspective, there's a 95% chance ivermectin is doing something to help treat Covid. The effect size and potential confounding variables may never be known, but it is quite clearly doing *something*.
...did you read Scott's megapost on ivermectin? This post was made in the context of that. It feels a bit like you don't know we just got done with a super long and super in-depth analysis of all of the studies on ivermectin, and concluded... well, something surprising. I won't spoil the ending for you, it's magical.
Yes I read it. Did you read my post? Seems you didn't understand it.
But nobody really complained about the lack of significance. There certainly wasn't an over-interpretation of a lack of 0.05 p-values.
> when you have highly proficient clinicians around the world reporting success with a drug, you cannot dismiss that
when you have also highly proficient clinicians reporting testing on large scale and reporting lack of success and many positive results are from swindlers, quacks and liars it gets trickier
Many positive results are not from swindlers, quacks and liars, though. In fact, the rate of fraud in the Ivm trials is lower than the background rate of fraud, and are from countries with historically high rates of fraud. So, I'm not convinced that the ivermectin literature is particularly rife with problems to a greater degree than elsewhere.
> In fact, the rate of fraud in the Ivm trials is lower than the background rate of fraud
How you calculated that? Also, is background fraud really even higher then what Scott described in ivermectin post?
You have a firm, reliable figure for the background rate of fraud? This I'd like to see.
Highly proficient clinicians all through the 18the century reported success with bleeding.
Among weightlifters/bodybuilders, the Pascalian Medication strategy is fairly popular. It's pretty common for serious weightlifters to take oodles of different supplements and medications that are suspected with varying degrees of confidence to improve various aspects of performance. Some of it's got pretty firm scientific backing (e.g. caffeine and creatine), and some of it is off-label or illegal use of well-understood prescription meds (e.g. anabolic steroids, metformin), but a ton of it is "broscience" (a sort of oral tradition build on various combinations of highly speculative preliminary study results, laymen's extrapolations from scientific principles, and personal anecdotes). Most weightlifters will tell you that a lot of the broscience is probably nonsense (the term itself is a self-deprecating joke within the community), but they'll nevertheless take it based on an expectation that the combined effect is more likely to help than to hinder their training.
What a great time to work through my intuition's solution to pascal's wager, and see if it actually works.
Basically, my argument is that your prior for X should always be lower or equal to 1/|U(X)|, where U(X) is the expected utility of X (and |x| is the absolute value of |x|). (Yes, this means your prior is dependent on your utility function.)
We'll do our investigation with P(X) ~ 1/(2^|U(X)|). Why not P(X) ~ 1/|U(X)| directly? Because the integral doesn't converge over the reals, and while some improper priors are okay, I don't want to spend time proving that this one is. This is basically the simplest converging function that I can think of that satisfies the criteria. (The ~ symbol is pronounced "is proportional to", and means that we're eliding some possibly complicated constant that makes our priors actually proper probability functions)
Now, let's compare the hypothesis that taking some drug gives you some amount of positive utility `u`, which we'll call A_u, to the null hypothesis that it does nothing, A_0. We do a study, and find that P(study data | A_0) = 0.05, and also that the hypothesis H that best explains P(study data | H) is A_u. What are out posteriors P(A_0 | study data) and P(A_u | study data)? Well, standard frequentist methodologies don't report a P(study data | H), so this is usually impossible to compute, but if we make the VERY EXTREME assumption that the ONLY POSSIBLE hypotheses are A_0 and A_u, we can say that P(study data | A_u) = 0.95
P(A_0 | study data) ~ P(A_0) * P(study data | A_0) = 1/(2^0) * 0.05 = 1 * 0.05 = 0.05
P(A_u | study data) ~ P(A_u) * P(study data | A_u) = 1/(2^u) * 0.95
Well, what is u? Some random study online gives 1.51 QALYs (Quality Adjusted Life Years) for avoiding an infection entirely, and let's say our drug has a 10% chance of preventing any symptoms. But wait; why use QALYs and not QALDs (Quality Adjusted Life Days) or expected future earnings? This is the last part of our model that needs to be parameterized, and I have no idea how to do it, and it matters a lot: using QALYs means that we should, in fact, be ~95% sure that this thing works; using QALDs means that we require particle-physics levels of certainty before we even consider the fact that it might work.
Please comment if you have a solution to this problem!
I assume you're talking about a point prior here, rather than a prior probability distribution (i.e., your prior is that the probability of hypothesis A is P(A)=0.2, not that your prior is that P(A) ~ uniform(0,1), or P(A) ~ beta(a,b), or whatever). Note that point priors can't necessarily be coherently updated, so you should be thinking of prior distributions.
To see the problem, notice what happens when your prior is that P(A)=1 (you are 100% certain that hypothesis A is true). For you to be logically coherent, your prior probability P(D) for any study data D must necessarily be P(D)=P(D|A) (since "prior you" knows 100% that A is true, and so their prior probability of observing data D, P(D), is necessarily equal to the probability of observing D given that A is true, P(D|A)). Plugging into Bayes then gives
P(A|D) = P(A) * P(D|A) / P(D) = P(A) * P(D|A) / P(D|A) = P(A) =1
and so our probability for A does not change.
Mathematically, what's happened here is that the probability density for our "evidence" in A is fully concentrated at 1, and so can never change, no matter what data we observe. A distributional approach gets around this.
I suspect we're misunderstanding each other.
I'm a little confused by writing "P(A) ~ beta(a,b)". P(A) is a probability of an event A, and should be a real number, not a distribution. I might write "X ~ beta(a,b)" if X is a random variable with distribution beta(a,b), and then P(X > c) for the probability that X is greater than some constant c
In the example I worked above, I used a two-hypothesis space, where the hypotheses were A_0 and A_u, and I was using Bayesian inference to determine which hypothesis was more likely; we had priors over those hypotheses, and some evidence which had different likelihoods under the two hypotheses, and that led us to different posterior probabilities for those hypotheses. Bayes' Theorem is completely valid in finite event hypothesis spaces.
I understand that once you have a prior of 1, you can't update away from it, but I didn't do that in my example. And this doesn't have anything to do with discrete vs continuous hypotheses; Dirac deltas are just as degenerate as Kronecker deltas.
You have P(A_0) =1/(2^0) =1 as your prior for A_0, so you can't update away from that.
Bayesian updating of priors based on new evidence is based on a prior distribution; if you want to update your knowledge about the probability P(A) given some new information D, you represent your initial uncertainty in the value of P(A) via a distribution, and update that distribution. Suppose my initial prior distribution for some event A (before any observations at all) is that P(A) is equally likely have any value between 0 and 1. Then my initial distribution for P(A) is P(A) ~ beta(1,1) (beta(1,1) being the uniform distribution). If I see some data D with k occurrences of event A and N-k non-occurrences, then my updated distribution for P(A) is now P(A) ~ beta(k+1, N-k+1) (a nice property of beta as the conjungate prior for probabilities) The more observations I see, the more concentrated my distribution for P(A) becomes: I become more and more sure of it's value, but never certain! This is "Bayesian inference" for probabilities: uncertainty in the value of the probability is represented by it's distribution, which is updated as more evidence arrives.
The problem with using point-form probabilities is that they don't represent uncertainty about the probability parameter - and uncertainty is a central part of updating (the more uncertain you are about the value of the probability P(A), the more easily you should update away from that value). That's why probability distributions are used in Bayesian inference.
I'm using non-normalized probability distributions for ease of computation. I tried to be careful and use ~ instead of = everywhere, but I'm sorry it was still confusing.
The crux of the Pascalian medicine argument is the assumption that the probabilities are independent. If they are, you can sum them up and get the expected benefit. But Scott has previously argued that he thinks there's a systemic issue with the scientific process that generates this evidence. If the systemic assumption holds (and it sounds like that argument is part of the process of estimating his probability estimates), it's not valid to sum up the probabilities since a systemic failure affects all the probabilities simultaneously.
A corollary to this would be the housing market crash in '08. The assumption that killed the mortgage-backed securities was that each home foreclosure was independent. Once foreclosures became interdependent, the underlying assumption of risk was no longer valid.
And assuming you can sum up the negative effects to get the expected down side. Drug interactions are real and can be very powerful. Paxlovid is itself a combination of two drugs, PF-07321332 and ritonavir. The ritonavir is there to inhibit the P450 enzymes in the liver, which would otherwise destroy the PF-07321332, thus using drug interaction for good. on the other hand, MAO inhibitors with a side of blue cheese and pepperoni can kill. You can't just add up the side effects of Marplan with the side effects of avacados to get the expected outcome of the combination. That fact alone makes all this amateur math nonsense.
There's a bigger problem than combination effects, to my mind. I've reviewed hundreds of patient charts, and it's striking to me how many concomitant medications some patients are taking. And although Scott points out that sometimes this is exaggerated, frequently it isn't. You can tell when someone who is reportedly on two or three dozen medications (yes, really!) does indeed take those medications; if they're admitted to the hospital the nurses log each dose. I've cross checked those pages for more than a few patients and confirmed they really are taking a pharmacy home with them.
That's not to say the combination effects are moot, just that we should address it as a separate issue and maybe even as the younger sibling to a larger problem of simple over prescription. I witnessed this firsthand when my grandmother came to live with us during COVID lockdowns last year. We discovered she had been prescribed medications against both constipation and diarrhea. The insane thing is that the facility she was in had been actively giving her both! (Rx said QD PRN, but effectively they'd just treated them as QD, whether she PRN or not.) So she soiled herself literally every day. It was mortifying for this sweet old woman.
She moved into our place, we dropped both medications, and took a closer look at the other meds she was on. They had her on HTN medication, but her BP was really low. So we dropped that, too, but monitored her blood pressure so that if it became a problem we would give it to her. She went from being lethargic and weak to energetic. They had her on a benzodiazepine long-term and we said, NO to that. Got her on an antidepressant, and a Rx to treat her vascular dementia. Her thinking became clearer, and she had some happy memories in our home.
My point is that her problems stemmed from the INTENDED effects of the drugs they gave her! And the tragic part of this story is that when her dementia got bad enough that we couldn't care for her anymore, we sent her to a new facility. That new facility ignored all our notes on medications - which we got endorsed by an in-home PCP, but they didn't care - and just went back to the old routine. Now she's lethargic, and she poops her pants every day, and her memory is getting worse fast. It's a tough fight to get them to STOP treating her with drugs she doesn't need for conditions she only has because they're messing her up. And another tough fight to get them to care enough about her individual case instead of giving her the 'standard cocktail'. That's not just one facility, either, it's all the long-term care facilities. And it's not just those facilities that create the problems they then go on to treat by over prescribing.
Combination effects, to my mind, come secondary to the fact that over prescription is a huge problem for many patients. We lose not a few patients to homeopathy because replacing their current slapdash regimen with Literally Just Placebo Water is a huge step up. That's not because homeopathy 'works' so much as because throwing everything at a patient is a great way to create problems.
That's sad about your mother. On your last point, I think this is evidence that Scott is on the payroll of "Big Homeopathy", as he's obviously playing a long game to drive everyone there :)
Oops, meant grandmother.
Dementia is tough, but I feel like I'm better equipped to handle it now.
Feels almost like Big Pharma is driving people to homeopathy sometimes.
Did you know homeopathy killed a president? Probably. https://en.wikipedia.org/wiki/Doctor_Willard_Bliss
Also that the subsequent president (Rutherford B Hayes) is a national hero in Paraguay and they have towns and holidays in his honor. And he was besties with the father of geology/John Newberry who made sure the nascent NAS was incorporated into the federal government.
Yeah, that was back before The Great War, though, when all of medicine was pretty much indistinguishable from voodoo. ^_^
People keep complaining about the FDA, as though it stepped into a nice, perfectly functioning system of evidence-based medicine. When the reality is that it wasn't that long ago when the smart move was to be cared for by a dutiful aunt, and stay far away from anyone calling themselves a physiker or a medical practitioner.
Now, I'm all for improving the current system so that it works better than it does today, but we're a long way from the days of Snake Oil salesmen. (Well, maybe not that far from it, but at least people recognize holistic voodoo as 'unproven' in some meaningful sense.)
From the wikipedia article "his given name was Doctor". Wow! Why didn't I think of that. Would have saved a lot of years in grad school! It would have been double fun if he had also become a legit physician.
Oh. He was. Dr. Doctor?
IIUC, the assumption that was false was that each home foreclosure had a low probability because it was expected that the entities issuing mortgages were vetting would-be homeowners for their ability to pay, and not steering them toward homes they couldn't afford. But that wasn't true.
I think there are about a million different explanations for the '08 crisis, and likely that's because - as with so many real-life phenomena - it was multi-causal. There's certainly the issue of vetting based on ability to pay vs. ability to pay off, but banks knew many of those loans would go bust. It was part of the calculation everyone relied on to allow them to believe that detail didn't matter.
What I was referring to was how the mortgages were repackaged after they were sold. Most banks don't hold onto a mortgage after issuing it, they resell it on the open market. But there has to be a market to sell to before they'll make a bunch of loans to sell. That's why for years they didn't like making lots of sub-prime loans, because those weren't worth as much and the market for them was easily saturated. If you know a loan has a 30% probability of foreclosure within 5 years, you're unlikely to want to bet a lot of money on it. You can lower that probability be doing better vetting of the borrower's ability to pay, but then you'll make fewer loans because many borrowers will demonstrate higher risk of failure.
Then some bankers figured out that you could diversify that risk by packaging 10,000 sub-prime loans together. The law of large numbers now lets you write off 30% of the value of those loans with a 30% risk, and recalculate the risk as <1% that the whole thing is going to go belly-up. Instead, the likely value of the portfolio of loans is 70% of the nominal value of the loans (+/- <1%). With this new tool (and a few others) you can now resell as many sub-prime loans as you want, and the race is on to find new ways to get sub-sub-prime borrowers into the market.
Not only that, but these bundles of loans are now large-value, low-risk assets that can themselves be re-bundled as collateral for more risky loans. The mortgage bundle can act as a security (kind of like a co-signer) on an otherwise risky financial deal. If the original assumption holds true - that the law of large numbers allows us to reassign the risk of failure from 30% to <<1% by just writing off 30% of the value of the loan bundle - then there's nothing wrong with assigning such a high valuation (and low risk) to this bundle of loans.
Except the assumption of the bundling approach is that each of the loans in the bundle carries an independent risk of foreclosure. Out of 10,000 loans with a 30% risk of failure, we can count on about 7,000 loans to be worth exactly as much as their dollar value. If the median loan is about $200,000, the whole package is worth pretty close to $1.4 billion, plus or minus a few million. That assumption was proved wrong when there was a systemic issue. At that point the bad assumption had the market valuing those loans at <1% risk, when instead there was a ~30% risk that the whole package would collapse, which in many cases it did. Those packages then led to other packages collapsing, so that instead of being worth $1.4 billion for a package like that, it was worth a tiny fraction of its original value. Since other loans were in turn based on the value of that original mortgage-backed security, those loans were now exposed to the whole risk of the original package - a risk that had been realized, much to everyone's surprise.
That's the point I'm trying to make with the Pascalian Medicine approach. Scott is treating each of the probabilities like they are independent. But if the approach that brought you a 1% probability that Snake Oil is going to cure everything is itself flawed, then you don't get to sum up the probability for Tahitian Noni, apple cider vinegar, etc. At that point, the whole bundle has to go into the same 1% bucket. I'm not about to pump myself full of random chemicals on a 1% bet, and I don't buy the assumption that each of these percentage assessments are truly independent.
Scott seems to say that there are only two possible ways of conducting Pascalian medicine, both of them problematic:
(1) Doctors try to make all patients take all drugs that might work, which is problematic because (a) they won't, and (b) it erodes trust when doctors give patients a bunch of drugs they know are very unlikely to help.
(2) Individuals try to design their own research-based courses of action, which is problematic because (a) lay individuals don't know how to do medical research (and shouldn't have to), so (b) this path is very likely to end up with some dead or severely injured lay individuals.
Door #2 is too risky for individuals, and Door #1 is too risky for society as a whole, so we're stuck, right? I take this to be Scott's position.
Fair enough. But isn't there a middle ground?
In Door #3, doctors initially prescribe only the drugs that actually work. But if a patient *asks* (unprompted) to be prescribed curcumin or onion paste or Ivermectin or whatever, the doctor shrugs and says, "Yeah, okay, probably won't help, but sure won't hurt, either," and writes a prescription. (A doctor speaking more precisely might say, "I believe this substance is unlikely to help you, p=0.05, but I also believe it's unlikely to harm you, p<0.05.")
Society is protected because doctors only go down this path with patients who ask for it. Individuals are protected because doctors are still using their medical knowledge to protect them from their own layperson research skills. The patient is unlikely to go full Pascalian and try EVERY drug, because the great majority of these patients are only interested in one drug they heard about from some trusted source.
...and social cohesion is strengthened because we stop treating all the Ivermectin people (and all similar groups in the future) as insane pariahs obsessed with lethal horse paste. If we instead start treating them as reasonable people who made a different judgment call, not only will we have fewer chemical accidents as they try to get around the restrictions; we MIGHT even build mutual trust and respect across cultures (leading to higher vaccination rates and lower risk of civil war).
I was hoping I'd find a comment like this and was not disappointed. Thanks for writing this up! :)
I'm a little puzzled that you write this as a hypothetical. I mean, that's exactly the relationship I have with my physician. I ask her for advice, she gives me her best opinion, then I make a decision. We both understand there's leeway here and there, about what might work the best, so she gives me the benefit of the doubt -- it's my life, after all -- and so long as she doesn't really think it's a bad idea (and I wouldn't do it anyway if that were the case) she normally supports and enables my decision. If it's a little off the beaten path, I take pains to tell her everything that happens so she can fold it into her clinical judgment with others.
I mean, clearly you need to have an established trusting relationship with an internist, but don't you need that anyway for general health? We're a long way from drive-through medicine working well.
James' suggestion is different in that the doctor didn't suggest it. I think the problem with his suggestion is that doctors are risk-averse and might unreasonably say no.
Problem: this either requires the median doctor to be educated on a wide variety of supplements/marginally effective medicines within their area of practice, which is a bit of an ask, or it requires some substantial subpopulation of doctors to advertise themselves as friendly to the supplement-curious, which...might work, at least in dense urban centers...but also strikes me as likely to generate a headline or two about a malpractice lawsuit that happens when a patient sez the doc endorsed their near-lethal megadose of thing X when what really occurred was that they said 'hey, what about X?' and the doctor cautiously said it might work without hammering on the fact that the literature focuses on 25-mg doses and under no circumstances should he go out and buy a blister pack of 0.5-g doses from Alibaba.
Fixing the second problem would involve a...somehow societally-endorsed 'second tier' of medications more regulated than food but less regulated than actual prescription drugs, I guess? There's a lot that could go wrong there, Moloch-wise.
At one point I was taking about 12 pills a day, and ran up against the limit of what would fit in one chamber of my pill organizer. Lately I've cut down to just 3 pills (all taken with breakfast):
otc lithium aspartate: This one is labeled as 5mg of elemental lithium, which I calculate is equivalent to 150mg of lithium citrate, which is about 1/6 of the lowest dose that doctors prescribe for long-term control of bipolar disorder. In spite of the low dose, it has an obvious effect on my mood. I consider it a performance-enhancing nootropic drug that helps me focus on tasks and stay calm under pressure. As of this writing it was still available on amazon, but I'm 25% confident that it gets taken off of there within 5 years.
fish oil: Mixing this into my oatmeal has induced remission of ulcerative colitis many times. Neglecting to take it for a few months has made me sick many times. There also seems to be some minor antidepressant benefit.
multivitamin: Seems to benefit my energy levels and overall well-being.
Things I used to take, which actually did something:
NAC is an interesting one. While I was on it I got rid of a few bad habits that I've had for almost my entire life, and after I got off it I resumed the same bad habits. But also while I was on it I developed some serious joint problems throughout my body, which got better when I went off of it. This one is no longer available on amazon, because the FDA acts as if noticing that someone investigated it as a pharmaceutical in the 1950s should make us update towards it being less safe than other random things people take as dietary supplements.
Creatine basically just gave me 20% more reps in the gym, with no side effects except water retention, but the dose is a few gigantic pills every day if you take it in pill form.
Probiotics seemed to help with remission of ulcerative colitis, but did nothing else. I used to play a game of "how many different species of bacteria can I find on labels in the yogurt section of the grocery store?" and buy one of each. It seemed to work.
Supplements I used to take, which had no noticeable effect on me:
Vitamin D+K, Zinc, Green Tea extract, Glycine, Spirulina, Propionyl-L-Carnitine, Theanine, Magnesium, Calcium, Circumin
My calculator says that taking 250 independent risks, each of 0.5%, results in a 71% risk of at least one hit. Liver damage, cardiac arrest, whatever. And how to tell which one? You have to either stop them all and hope that you recover from the damage, then re-introduce the (likely fake) drugs in sets while hoping you don't further damage your body
Gotta listen to William of Occam, too, and NOT multiply things unnecessarily
But you DIDN'T mention my greater concern re side-effects: a Gresham's Law where once you go down the rabbit hole of throwing stuff against the wall, you've likely lost all ability to make smart estimations of probabilities.
My two greatest sorrows were from the suicide of a family member, who had “recovered memories” of sexual assault by a man my mom was otherwise angry about
And another family member who died an agonizing death from metastasized breast cancer; when we cleaned out her apartment I found a large jar of apricot pits labeled as Laetrile.
Both women were victims of quacks; neither was able to protect herself.
Pascal would not roll dice in such crooked games. Possibly, ONE HALF MILLION Americans will die from COVID, and millions more will have suffered needlessly, due to the political assertions in favor of unlikely-at-best therapies instead of the best-available alternatives
I have yet to hear of better epistemological heuristics re self-treatment, other than the one I myself employ: “cui bono?” This doesn't override the sense that most published research is false, but it's a strong signal when a political party is using miracle cures as an adjunct to seizing power from existing medical & scientific institutions, or when somebody peddling pills on their website.
The problem is your decision-procedure is subject to exploitation.
Currently, most drugs that show this 5% chance of curing cancer (or whatever) are selected by some process that is sometimes reasonable. But if people broadly change their decision-criteria toward taking everything that shows this 5% chance of curing cancer, then the number of things that people try this with will go up significantly due to stronger adversarial pressures, because there's a lot of benefit from showing that your onions (or whatever) can do this.
...this argument suggests that the current epistemic situation is the ideal one for taking lots of these such drugs.
(I continue to wish I could edit comments post-commenting. For example I feel like my opening sentence above is too 'strident'. Just noting this for user feedback.)
Doesn't stuff like kidney/liver load and combinatorial increase in interactions give an automatic decay function on how safe is a certain combination of drugs? If you're taking 10 drugs, there are 45 possible interactions (and even more tertiary interactions) and X grams of total crap that needs to be metabolized. If you're taking 100 drugs, there's 5000 interactions and 10X grams of total crap (since you can't just take less of each drug. You may need to actually take more to keep the same bioavailability).
Also, load on off-targets: each drug alone may have too weak off-target effects to register as "bad side effect", but if they have the same off-target (more likely than not, I think - some processes are especially prone) that can accumulate.
So the solution seems to be "I'm physically limited to only this many drug candidates before the risks start outweighing the benefits (since those grow quadratically or at least supralinearly), so I'll take at most the 2-3 most effective ones"
> Should we worry that even if each drug individually is net positive, giving someone twenty medications will lead to some crazy interaction? I’m not too concerned about this; clinically significant drug interactions are rarer than most laypeople think
Seems like Birthday Paradox might apply here: chance of crazy interaction increases super-linearly with each additional drug
1) It seems to me that effects of drugs are starting typically at lower doses than its side-effects. Therefore it may be a good strategy to take a lot of small doses of drugs with similar effects (eg nootropics), so that similar effects will add up together, and side-effects are different and small, and therefore not bothersome.
2) It seems that nootropics crowd is doing something like this, when a lot of people are taking stacks of ten different things at once. It seems that they mostly do not approach it with pascalian mindset. But some (inc. myself) do.
3) I heard that Eric Drexler is also taking tens of pills a day because of similar reasons.
hu, I scrolled through this list and suddenly had this shock moment of: ähm, I didn't comment to this post yet, did I???
>It seems to me that effects of drugs are starting typically at lower doses than its side-effects.
wikipedian_protestor.jpg
Why is the downside risk of taking a supplement greater than that of taking some new food, especially a food that didn't exist in our ancestral environment?
Not sure is it greater. But eating random wild plants and mushrooms and animals is a great way to die quickly and horribly.
Even nowadays there are deaths from eating mushrooms (at least in Central Europe).
What about a new food you get at a supermarket?
Then I guess that new food is likely much safer, as supplements can be concentrated into extreme much more easily.
At least as long as new food is not mostly sugar which is a different danger.
I also would bet that supplements are more likely to be contaminated/have unwanted impurities but I am wildly guessing here
Most of the things considered for this are known to be bioactive (or else they wouldn’t be considered). On the other hand, the vast majority of food is known to not be bioactive. Ivermectin is on this list because it’s known to mess with cellular mechanisms which allows it to kill worms, and we’re just trusting that it doesn’t mess with anything in our bodies. Ivermectin is probably safe because there’s the large number of people who have taken it before. But when you go to the grocery store, you’re buying types of food that millions (or billions!) of other people have eaten before safely, and that probably dwarfs the number of people who have taken ivermectin.
If you’re talking about supplements that are already over the counter, most of those are probably closer to the food end of things but are also less plausible to help against COVID.
Is there a principled definition of 'bioactive' that firmly excludes 'gets metabolized for macro- and micronutrients'? It is trivially true that food is 'biologically active' in a boring sense.
I think the only place where I shake my head in dismay is when the same person (1) thinks tiny changes in his diet will have profound effects, like eating heirloom tomatoes instead of french fries will make him live to be 120 -- because lycopenes! -- but at the same time (2) doesn't fear unknown low-level side effects from ivermectin or HCQ because, hey, these are generally safe, right? Lots of people have taken them and I've heard of anything bad happening.
I mean, it's one or the other. Either the entire history of people eating tomatoes might have missed some subtle but important long-term benefit *and* the entire history of people eating ivermectin might have missed some subtle but important long-term harm, or in *neither* case is it likely that some subtle long-term effect has been missed. Believing
> tiny changes in his diet will have profound effects, like eating heirloom tomatoes instead of french fries
This is not a tiny change, but switching to regular tomatoes will likely have basically the same effect.
If they were obese then reducing calories can help to live longer (but 120 is a pipedream).
Sure it is. Everything you eat gets torn to shreds by acid and digestive enzymes in your stomach and small intestines. It has to be small enough to diffuse across the intestinal wall, which is very small indeed. The distinction between tomatoes and potatoes, in terms of what kinds of small molecules your stomach and intestines make out of them, is slight, because life has been using the same basic building blocks for a billion years.
You've got a bunch of starches that all get whacked up into a very few simple sugars, you've got some slight differences in amino acid profiles, you've got various length fatty acids with a double bond here instead of there, which slightly changes the beta oxidation pathway they go through, and -- what else? Tiny amounts of contaminents and dyes (lycopenes!) which proceed through some long complex pathway in the liver that we don't even know exists yet.
I think people wildly overestimate how much variety there is in food because they're focussed at the macroscopic level, where it looks and smells and tastes all very different. But this does not translate obviously to the microscopic level, once it all gets smashed to its building blocks. Obviously if we took it all the way down to atoms, it wouldn't translate at all -- you're basically eating carbon, hydrogen, oxygen, nitrogen, and the odd bit of phosphorus and sulfur, in varying proportions. That's too far to break it down, of course, but there's some important truth there.
> The distinction between tomatoes and potatoes, in terms of what kinds of small molecules your stomach and intestines make out of them, is slight, because life has been using the same basic building blocks for a billion years.
I was thinking about implied difference between "pile of fat + potatoes" and "tomatoes", and such change can be helpful, especially if typical person is obese.
Difference between "pile of fat + potatoes" vs "pile of fat + tomatoes" is likely negligible. It would be better to care about mountains of sugar and lakes of fat in diet.
Oh sure, agree 100%. The mix of nutrients you eat probably has, over time, a profound effect. That makes all kinds of sense to me. I'm just getting at the individuals who think there's some weird unique principle in *this* particular food, some amazingly effective micronutrient.
And I'm actually not saying that's totally impossible -- for all I know, there *is* some weird little chemical in food X that isn't found anywhere else and makes some as yet undiscovered difference over time.
But what I'm saying is, if you believe *that* I don't see how you can logically consistently be blasé about what unpleasant as yet undiscovered differences over time some other wierd little chemical (particularly one not found in the natural diet, like ivermectin) might have.
Way back in the days of "tomato ketchup is classed as a vegetable" controversy around school meals
https://en.wikipedia.org/wiki/Ketchup_as_a_vegetable
https://online.ucpress.edu/gastronomica/article/21/1/17/116213/Ketchup-as-a-VegetableCondiments-and-the-Politics
I looked this up, because my natural impulse was "Well of course this is dumb, raw whole vegetables and fruits are superior to processed foods!"
Then I found out the benefits of lycopenes only come once they have been processed into things like pasta sauces and ketchup:
"Consumption by humans
Absorption of lycopene requires that it be combined with bile salts and fat to form micelles. Intestinal absorption of lycopene is enhanced by the presence of fat and by cooking. Lycopene dietary supplements (in oil) may be more efficiently absorbed than lycopene from food.
...Ketchup is a common dietary source of lycopene. ...(T)omatoes and tomato-based sauces, juices, and ketchup account for more than 85% of the dietary intake of lycopene for most people. The lycopene content of tomatoes depends on variety and increases as the fruit ripens.
Unlike other fruits and vegetables, where nutritional content such as vitamin C is diminished upon cooking, processing of tomatoes increases the concentration of bioavailable lycopene. Lycopene in tomato paste is up to four times more bioavailable than in fresh tomatoes. Processed tomato products such as pasteurized tomato juice, soup, sauce, and ketchup contain a higher concentration of bioavailable lycopene compared to raw tomatoes."
Boy, was my face (tomato) red! The heartless Reaganite Republican budget-pinchers were, in fact, in the right!
So your friend would probably get the best benefit from consuming potatoes (say in the form of fries?) and ketchup, rather than raw tomatoes alone 😀
I forgot to include this bit!
https://en.wikipedia.org/wiki/Lycopene#Diet
"Cooking and crushing tomatoes (as in the canning process) and serving in oil-rich dishes (such as spaghetti sauce or pizza) greatly increases assimilation from the digestive tract into the bloodstream. Lycopene is fat-soluble, so the oil is said to help absorption."
So if I'm stuffing my face with pizza, get off my back: I'm eating healthily, prodnose!
I think the Law Of Conservation Of Expected Evidence is vulnerable to the same problem Pascal's Wager is: our tendency to overestimate small probabilities. There is a vast sea of potential hypotheses (even pairwise-incompatible hypotheses, if you will) that you have never thought of; if you understood how vast it is, you'd probably have an appropriately-low probability estimate for a randomly selected one, but by definition you don't. Just by someone stating a hypothesis to you, it gets elevated from an unknown unknown to a known unknown, and that messes with our perception of probability.
This strikes me more as a problem of balancing one low probability (chance of a given supplement working) with another (chance of it causing harm) than of over- or under-estimating any one low probability.
Here's my naive attempt to steelman the "take a bunch of supplements" position:
Suppose there's something like a general factor of how hard your body is trying to fight illness. Think of it as an immune DEFCON. As DEFCON rises the body's effectiveness fighting infection increases. But so do things like energy use, physical weakness, and risk of long-term damage to other body systems (because the immune system is increasingly likely to attack them by mistake). This is kind of a stupid model but as far as I can tell it vaguely resembles how the immune system actually behaves, at a high level.
The Algernon principle says that raising the DEFCON isn't a free lunch in the ancient evolutionary environment. But it might be a nearly free lunch _for us_, at least under certain conditions. First, the downsides-- needing increased nutrients, decreasing out capability for strenuous physical activity-- might be things we care about less relative to a risk of e.g. serious COVID than our ancestors did. Second, modern medicine might be able to measure the risk of serious COVID better than the body (which has never seen COVID before) can.
So it could be true that supplements act-- assuming they act at all-- only by generically exciting the immune system and raising the DEFCON. And it could be that that's a net negative when we're healthy (or uncertain whether we're ill), per the Algernon principle. But it could still be a good deal to take a bunch of supplements whenever one's feeling under the weather (or better yet, isn't feeling under the weather yet but has a positive COVID test).
'Generically exciting the immune system' is not at all something I would expect to be benign in the specific context of COVID, given the hyper-inflammation and cytokine storms seen in some of the worse-off patients. The corticosteroid dexamethasone is an *immunosuppressant* and is part of the current standard of care for bad COVID cases.
Good point, COVID is a bad example in this respect.
This post doesn't quite get all the way to a cost-benefit analysis (even a quick back-of-the-envelope version). Let's try one:
How bad is getting covid? I've seen estimates of 1 cent per microcovid, which means that getting covid involves $10,000 of badness.
If there's a medicine that has a 5% chance of working, and cuts the expected total badness in half if it works, then: if it works then it alleviates $5,000 of badness, so its 5% chance of working gives it a $250 expected benefit.
That's... not very much.
What are the costs of taking this medicine once you get covid?
Money: let's say it costs $20
Time: maybe 30-60 minutes to figure out it's the thing to get, get it, and take it
Side effects: probably smallish, I'll guess on the order of $10
To stick with round numbers, let's say the costs add up to $50. That gives a net benefit of $200 for taking the medicine if you have covid.
But you don't have covid yet, and maybe right now you're thinking of doing some reading & thinking to figure out what you want to do if you do get covid. How likely is it that you'll get covid and be in a position to take the medicine? Maybe 5% for the next year (and if it happens more than a year from now, your research will be obsolete by then). So an expected benefit to you right now of 5% of $200, or $10, from figuring out now (when you're healthy) that a particular medicine has these expected effects on covid. And the costs of doing the research now to figure this out are more than that; even if it's just 30-60 minutes of research that time is still worth more than $10.
If you figure that out and share it widely, then it's a $10 benefit for each person who learns of it while healthy. If it just takes 2 minutes for each of those people to hear you then that's a net benefit for them of ~$9, but if they each need to spend their own 30-60 minutes of research to verify what you have to say then it's back into the negative. (Plus there's a $200 benefit for each person who learns of it after they get covid and are searching then for what to do. So there is a net benefit to creating an info hub that people can access once they get covid.)
>Should we worry that even if each drug individually is net positive, giving someone twenty medications will lead to some crazy interaction? I’m not too concerned about this; clinically significant drug interactions are rarer than most laypeople think, and usually pretty predictable. Still, giving twenty different medications at once is almost unexplored territory, and something like this might be true.
I think the risk in this sort of situation is greater than "some drugs among the twenty may have harmful interactions with each other." I think when you start taking effective doses of so many different medications at once, you'd have to start worrying whether you're going to overtax your body's mechanisms for processing drugs at all. Maybe most of the drugs have non-overlapping pathways for removal from the body, but some of them will have overlapping pathways, and you'll start seeing the sort of harmful side effects that you would if you'd greatly upped the dosage of a single drug.
I think that's a good point. My vague understanding is that almost all weird substances are dealt with by a small number of pathways in the liver. It would, after all, be very expensive for the body to maintain a wide variety of degradation pathways to deal with compounds it only rarely encounters. Much better to have a bunch of preparatory steps for the various possibilties that all feed into the same basic elimination pathway. This is rather how metabolism itself works, after all, everything feeds into the citric acid cycle with differing preparation steps.
Does Algernon's law apply when you're deathly ill?
Immune systems are finely-tuned beasties which have gotten a *lot* of evolutionary optimizing. If anything, I would bet it applies more strongly.
Many life-saving medicines are using things unavailable to the body.
Also, someone deathly ill is in state where body is failing to achieve something (see IV hydration).
Strict application of Algernon's law would claim that lifesaving medicine is unlikely to work and we have piles of counterexamples (and also piles of failures!)
Joe Rogan is a proponent of Pascalian medicine for covid
https://www.instagram.com/tv/CTSsA8wAR2-/
I guess you could call "eat a varied diet" a Pascal's Wager but that isn't an argument against it.
There's a type of drug-drug interaction you haven't considered: that the drugs could prevent each other from working. This is probably more common than you immediately think: for example, a Pascalian approach to depression treatment might naively include a psychedelic, an atypical antipsychotic, and a dopamine agonist, all of which would be fighting each other. Similarly, a Pascalian approach to smoking cessation might involve nicotine replacement therapy, varenicline, and bupropion - all of which would be fighting each other. At the beginning of the pandemic, haloperidol was actually considered as a potential COVID treatment (I can probably find a reference for this if people want me to), because of its antagonism at the sigma-1 receptor - which would, in a Pascalian approach to COVID treatment, be fighting fluvoxamine (which is an agonist at the sigma-1 receptor). Perhaps it would even be worse than nothing. Then again, a Pascalian approach to HIV treatment might lead you to taking three or more antivirals with multiple different mechanisms of action - which is in fact the standard of care. So maybe it's different in infectious disease.
Dangerous drug-drug interactions are also probably more common than you appreciate, _when the drugs actually work_. For example, the above Pascalian depression treatment would probably include both amitriptyline and an MAOI, which is either really dangerous or a great idea [1]. Even on the more benign end, a Pascalian smoking cessation treatment would probably include both bupropion and naltrexone, which together cause a lot of weight loss - that usually won't be a problem, but sometimes it will be. If you're thinking of more benign drugs, like melatonin or curcumin in the case of COVID, then this is less likely, but more benign drugs are also less likely to work, so it takes more of them to reach an expected effect similar to drugs that have evidence. That is, I would expect the probability of drug-drug interactions to be at least proportional to the expected efficacy of all the drugs taken together, perhaps even more.
Separately, starting 20 drugs at once would make it impossible to know which one is causing a side effect. If you even just tried them all separately, you would be able to discontinue the ones you don't tolerate. But if you take them all at once, if even one of them isn't tolerable, you have to stop all of them. (Maybe you could do bisection here? Probably in practice that would be too difficult to carry out.)
So why not try them all, but one after another? The core thesis of Pascalian medicine is that there's little cost to trying one more drug. But if trying one drug means you can't try another until you're done, then that doesn't apply. (In the case of an acute condition like COVID, I suppose you also won't know if it works until your symptoms are gone and you're not dead, so this also doesn't apply.)
What's the lesson here? One of the core principles of pharmacotherapy is that less is more. Pascalian medicine throws that out the window, but it's probably best we don't abandon it.
[1] https://jamanetwork.com/journals/jamapsychiatry/article-abstract/491926
I think that you are downplaying the magnitude of algernons law. The probability that a random chemical will harm you is vastly greater than it will help. People have weird intuitions about their bodies, so let’s think about another high performing complex machine like an engine. What percentage of random chemicals could you pour in your gas tank that would make your car run better vs make it worse? In covid your chance of not dying is actually quite high, thanks to an incredibly sophisticated and complex machine in a near perfect state of balance. Your prior should be that anything you add to that is very unlikely to help more than it hurts. So anything other than a large well run RCT, no matter how positive, shouldn’t make you think benefit:harm ratio is >1. In fact probably a single RCT shouldn’t be enough to overcome what should be very pessimistic priors.
For all comers, covid ICF is about 0.6%, so even in your fluvoxamine example a 5% chance of a 30% (relative risk) reduction is 0.01%. You don’t need many unexpected harms to wipe out that benefit.
>The probability that a random chemical will harm you is vastly greater than it will help.
I would be fascinated to know if anyone has made a reasonably sophisticated crack at quantifying *how much* more likely, since that would be a decent first step towards being able to evaluate the literature on a given supplement and make an informed decision about whether or not to take it.
I’d be really interested in someone smarter than me taking a crack at quantifying it too. I’ve seen the stat that 1 in 5,000 drugs make it to market, but I’m not sure if the distribution of those that are harmful vs just lack efficacy.
An important note on harms is that they are hard to fully capture in even large RCT’s. Unless you are looking at all-cause-mortality (which very few trials do) then how you chose your endpoints is really important. It’s pretty likely that you will think of and prespecify the benefits endpoints (say, reduction in cardiovascular events), but the likelihood that you will think of and measure all of the myriad ways a drug can harm you is low (look at all the surprise harms that come out years later and lead to medical reversals)
> We don’t fret over the unknown unknowns of Benadryl or Tylenol or whatever
We absolutely fretted over ibuprofen and Tylenol possibly *increasing* covid mortality early in the pandemic. I suppose you could call it a "known unknown" as soon as people start fretting, but what about before then?
Looking from outside as a leyperson I think this discussion is often too narrow on biochemistry and statistics. These are imortant fields of sience, but talking about how to deal with problems as a society and expecially when there is no clear scientific answer (yet?), there are a few fore aspects that come to my mind:
1) people are different. I know so many stories about people reacting different to the same medication or diet. Of course with something acute like COVID there is no time to test several drugs once you are ill to see which helps you best. But with such mixed evidence like with Ivermectin it looks childish to me just to discuss who is wrong with the only options being 'it works so we recomend it to everyone' or 'its just a false positive and it harms if people have a false hope'. I think the focus should be to work together and gather as much data as possible to find out who profits from a specific treatment and who doesn't.
2) We need more public funding for independent medical research. This will not only generate more knowledge, but also improve trust in science. Many people are seeing the that the objects of research are not optimized for public good but for potential profits. So 'this is not scientifically aproved' or 'there are no good studies about it' does say more about the economic value than the medical value. This hurts trust expecially as we are often told not to use anything that has not been scientifically approved, but we know by experience that it helped i.e. traditional medicines.
If there are the voices now saying that this is the state is always inefficient in spending, we could decide publicly on the topics to be researched involving polls to see public interest or prediction markets to get the most promising candidates. We could also filter for drugs and treatments that are relatively cheap and can't be monopolized.
3) As there are so many candidates that could have a net positive effect, too many to take them all, but not a clear favorite to recomend to everyone, just let the people decide on their own. Just take care that information on risks and side-effects are easily available. This may go wrong sometimes, but i think the effect is net positive:
- if you want to stop somebody taking something, you have to show respect for opinion and his choice so he is much more likely to listen to you and your warnings.
- this builds kind experience what works and what doesn't. Of cause scientific knowledge is always better, but if there is none or not available experience is better than nothing.
- If you put force against something without good arguments, people often start to question your motives. This breaks trust and they stop believing you when even when you have good arguments next time.
- freedom always includes the freedom to take bad choices. Many people prefer freedom over safety so they will oppose anyone who wants to force them for the good. This is especially about the public pressure to get everyone vaxxed, but it also applies if you want to stop somebody from taking experimental medications with (soft) power instead of arguments.
- better people get the drugs they want to try from someone with medical knowledge knowing and telling the risks, than if they get veterinary versions without information what doses are usually save for humans.
>I think the focus should be to work together and gather as much data as possible to find out who profits from a specific treatment and who doesn't.
It is already mind-bogglingly difficult and expensive to work out whether medicines work at all on the population at large: trying to skip that step and figure out whether something works on gay male ethnic Hmong between the ages of 40 to 59 is a formidably difficult research problem with a number of well-known statistical pitfalls.
>We need more public funding for independent medical research.
'Independent' in what sense? Are you just talking about the stuff not funded by industry, or are you thinking outside mainstream academia as well?
>...just let the people decide on their own...
I don't think anyone was talking about *forcing* people to take or not take any particular medication. This post is about how people should *make* such decisions- specifically, if the average person, or the average bright ACX reader who's reasonably good at research, ought to be more aggressive about making them.
With independent my main point is independent from commercial interests. But it could also be interesting to leave some of the usual concepts. As far as i know medical research usually only looks into single chemicals, but many traditional medicines are a complex bundle, e.g. a tea of a specific herb, that could be tested as a whole protocol.
Of course it would be impossible and a waste of resources to do complete studies on every imaginable sub-group. I was more thinking of searching for patterns what could show up in the existing studies to see who did profit the most and who didn't. Just a little more of what Scott did by realizing that most of the studies showing an effect are in poor tropical countries. One factor seems to be the the worms, but perhaps it's also age, diet, lifestyle. You could also look at the cases where the drug definitely didn't help and if you see a pattern you know when better to try something else. Therefore you need as much data as possible about the study.
It does not have to be proof up to the usual standards, if you are transparent about it. It still can give hints to people deciding which supplement to try as they can't take too many.
But its also different basis for discussion if you tell the other team "Your results have to be wrong because most studies have different results." or if you say: "This is interesting, lets figure out together why your study has such a different result"
Except for vaccines there is luckily nobody taking about enforcing a particular medicine. But there is quite a force not to take something. If i go to my doctor or a medical educated friend asking about e.g. Ivermectin because i heard a lot positive about it that sounds plausible to me, there is a big difference between the possible answers: "Thats all fake news of the internet. Only stupid people believe that. You are not a horse with worms so it can only hurt you." or an alternative: "The evidence is not clear if it helps, in some studies it does have an effect in others it doesn't. But i can tell you the risks and side-effects, so i wouldn't recommend to try it."
This reminds me of Ben Williams' "Surviving Terminal Cancer:" https://www.survivingterminalcancer.com/
I haven't watched the film but as it was told to me, Prof. Williams was a psychologist (I think?) that was diagnosed with glioblastoma and a one year survival timeline. He started researching anything that could possibly be effective and took them (metformin and cloroquine were two that I think ended up in his cocktail)... and 21 years later he was still around.
My first reaction to that is either he was one of the lucky ones who actually survived glioblastoma, or "diagnosed with glioblastoma" does not equate to "had malignant glioblastoma". What's the probability of a mis-diagnosis vs the probability that a bunch of random drugs would actually cure him? And, more to the point, what's the chance that if another glioblastoma patient followed the same treatment, that they would be cured, too?
Forget about Bayes' rule... did you see the meme? Checkmate!
I don't know why everybody is so critical of curcumin. Within living memory it has cured the British people of their worst affliction: bland food.
As a critical care physician who has cared for dozens of Covid patients in the ICU, I saw a number of people who delayed seeking evidence based therapies such as monoclonal antibody because they were taking Ivermectin. By the time they decided to try the Monoclonal antibody—after Ivwrmectin failed—they had already developed respiratory failure and ultimately died.
That is definitely not what Scott is talking about here, though. The Pascalian position would be to get the monoclonal *and* ivermectin.
I wonder if Scott could find some interesting and potentially useful things by looking into things people take to enhance performance - including doping (ie illegal).
Apparently a quite common result is that things that enhance performance do not sum if taken together. Eg caffeine improves performance, as do nitrates, but taken together you don't get both performance boots.
*sporting performance
idea here being that it's an area where people try to take lots of things with a similar aim, and a lot of them don't work at all and the ones that do don't necessarily add up if taken together...
"And if I’m not 95% sure this doesn’t work, doesn’t that mean there’s a 5% chance it does work?" I understand what you're trying to say, but currently the sentence is logically false. Potentially adding "at least" to both parts would do what you want.
"Conservation of Expected Evidence"
Sigh. The mental gymnastics some people will go through in order to try (and fail) to overcome "absence of evidence is not evidence of absence" is pretty sad, especially when cloaked in a façade of rationality.
Where medicine is concerned, though, you can drive a truck through the gap between 'conventionally held by everyone to be the entirely unambiguous presence of evidence' and 'the outright absence of evidence.' Getting to the point of being Really, Really Sure takes years, often decades, and tens of millions of dollars. It is worthwhile to at least *consider* whether it's possible to parse the evidence so you can safely and responsibly pull the trigger any earlier than that.
Agreed. But in such a setting where pragmatism is prioritized, we're dealing with expected costs and benefits and the utility thereof; erroneously framing it as some kind of pure Bayesian "law" is inappropriate and also epistemologically dubious.
Exactly. It's a problem with all people who provide a service while dealing with complex systems: investment managers, meteorologists--not to mention the more scummy professionals like economists and social scientists in general. They're incentivized to pretend to know way more than they do. Probably the right approach--more accurate, at any rate-- in all these fields is much more epistemic humility, and openness to new approaches and experimentation at the margin.
I haven't nailed down a precise scenario, but I suspect if you actually went all "insanity wolf" and really took "All medication all the time" you would, in fact, die.
I have a friend who split her face open last week after passing out after she started taking a prenatal multivitamin, inositol, activated folate, and NAC all at the same because she has PCOS and is trying to get pregnant. Can confirm.
One mercy with diabetes is that you can take blood sugar measurements, which at least give you some short term information about whether something is helping. You can't test for COVID risk.
A missing dimension in this discussion is the ability to get the dose right. Even if we think about drugs in binary terms (works versus doesn't; toxicity versus not), the dose is a key determinant. It's not easy to get dosing right! Most antimalarial drugs have been introduced at the wrong dose for some key subgroups (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837842/). Chloroquine is an extremely safe drug (at the right dose) and an extremely dangerous drug (at the wrong dose - or right dose if suicide is the objective). Doctors can get the dosing wrong even for well known drugs.
An interesting example is chloroquine for COVID-19: in a clinical trial in Brazil in early 2020, the investigators got mixed up between salt and base weights (salt is the weight of the tablet; base is the weight of the active ingredient). There was a recommendation from China to use chloroquine 500 mg twice daily for 10 days, and they thought that was a base dose (chloroquine 250 salt = 150 mg base). They only had 150 mg base tablets so gave 600 mg base (4 tablets) twice daily for ten days. Turns out this gets you close to lethal concentrations and they probably killed a few people in the trial (https://elifesciences.org/articles/58631)
*Usually* things that have the kinds of promising initial studies done on them that would elevate them to your attention in the first place have at least a suggestion of what the dose should be. Agreed that you really do need to read carefully sometimes to avoid issues like the salt/base weight issue- though my personal preference when applying Pascalian stuff to myself is just to sick to the stuff with a nice, big purported therapeutic index to avoid exactly that problem.
One obvious complication is that you can't treat 20 or 100 or 250 different drugs/supplements as statistically independent, where if there's a 5% chance of each one working then there's a 1-(1-0.05)^20 = 64% chance that at least one out of twenty will work. If the first drug fails, it's possible that it failed because the postulated underlying mechanism was wrong, and three of the other drugs had similar postulated mechanisms so they're now out. Or it didn't work because the test methodology was faulty in a way that exaggerates effectiveness by 5%, and six of the other drugs were tested using the same methodology.
And on the flip side, side effects are rare and multidrug interactions are rarer, but twenty drugs gives you 380 possible multidrug interactions.
Doing a proper quantitative analysis of the linked probabilities would be almost ineffably hard. But to the extent that there's an argument for Pascalian medicine (and I think there is), it's for taking a few of the most promising and most *differently* promising drugs, not for taking everything that ever showed an effect.
What do you think of traditional Chinese medicine in this context? I had the impression that TCM had a lot of similar characteristics with this approach: the treatments are based on a combination of plausible explanations for why things might work and anecdotal evidence; patients typically take a bunch of things at the same time all of which are generally safe and might or might not help; TCM treatments sometimes turn out to do well in western-style clinical trials and sometimes they don't and also sound ridiculous. TCM doctors have some way of choosing the "right" combination of things to give each patient...
My take: from a region with a worse-than-average reputation for academic honesty, and known issues with manufacturing quality in general and heavy-metal contamination in traditional medicines in particular.
"There’s a potential compromise solution, where smart doctors come up with Pascalian medicine protocols for the few patients who would actually want them."
Congratulations. You just invented naturopathic medicine.
My mum has been recommending for years that we take Armaforce when we feel fluey. I would always refuse her offer of, as I called it, "snake oil".
Armaforce is a combination pill of andrographis, echinacea, olive leaf, vitamin C and zinc. As far as I know, none of these chemicals are really proven to help with the common cold all that much. There's a little evidence for each of them, but not a slam dunk for any.
Anyway, I finally listened to her and took the damned pill, and what do you know: it works wonders. Once I discovered how useful it was, I constructed a justification for it that approximates your description of Pascalian medicine. I now take it whenever I get that familiar scratchiness in my throat, or when I feel that a lack of sleep may have left my immune system a little off its game. And I get sick far less than I used to.
100 long-shot supplements might be too many; but for me, at least, five has hit the sweet spot.
(I still refer to it disparagingly as "snake oil", but now with a hint of irony and self-deprecation.)
Sometimes things are snake oil, and sometimes they do have benefits. Like willow bark for pain relief, before anyone knew and could synthesise salicylic acid, and then develop aspirin.
Zinc and vitamin C do have known benefits. Echinacea, olive leaf and andrographis are more in the realm of "traditional remedies, which may have a pathway of action or may not, we're not certain yet".
And then you do get snakeoil, which is "Throw together these seven things and make exaggerated claims that it will cure cancer".
OK, now I've heard of a grand total of 7 people who might (or might not) benefit from echinacea.
Obviously, there are enough people who think they benefit from echinacea tea that there are always a few facings of it at Whole Foods. On the other hand, it doesn't seem to be getting more popular or less popular. It's just bumping along, same as always over the last quarter century or so that I've been buying it.
I take an approximately Pascalian approach to depression. Not to the extent that I’m taking twenty things, but to the extent that I looked over the preliminary-noisy-low-level-promising-finding tier of treatments, picked the half-dozen or so that seemed to me to be lowest risk due to already being in *very* wide use for other purposes (creatine, fish oil, vitamin D, magnesium, melatonin, saffron), or an extremely slight chemical tweak on same (l-methylfolate). In addition to conventional antidepressants, ketamine, talk therapy, and other well-studied lifestyle stuff like intensive regular exercise and mindfulness meditation.
This was less an Insanity Wolf-style ‘REVIEW THE ENTIRE SUPPLEMENT LITERATURE AT ONCE’ thing and more a matter of a decade and a half of reading a dozen journal articles or meta-analyses a month and coming to the one-by-one decision that adding One More Thing to the regimen looked good from a risk/reward perspective. I might be a little more aggressive after reading this, actually- the ‘substantive and meaningful drug-drug interactions are rarer than you’d think’ bit is very interesting, and fear of interactions was one of the main things that kept my list of stuff to try from expanding faster (the others being the physical size of the box I use to organize my weekly medications, budget, and the desire to try only one new thing at a time to keep myself from being in the position of having significant side-effects and no idea of what to blame it on).
Certainly I’ll be looking for good reading material on polypharmacy.
>When I reviewed ivermectin, I said I was about 90% sure.
When you make statements about ivermectin are you careful to separate its use as a prophylactic from its use as a cure?
Or not?
Give the grant money to ivmmeta.com to research 10000 substances' effects on COVID. Overwhelm the system. DOS the science. Get a value for that prior.
I'm not really understanding the application of Algernon's Law and anyone turning people away from taking vitamin D. From what I can tell there have been a large number of very well done studies which show there is widespread vitamin D deficiency.
It just seems like the idea of warning people away from vitamin D is a pretty poor example of something to warn people away from considering it is a widely accepted issue that people don't get or have enough of it.
I think a LOT of these studies fixate too much on the already sick as well. The arguments of 'being healthy' and 'not getting sick in the first place' through things like 'having enough vitamin D'....don't really get measured in hospital admission rates or negative PCR test for people who already fell into sickness.
I don't see how we can ignore that 90% plus of people in hospitals with covid also happen to have low vitamin D which is much higher than the 60-70% background rate of people who have low vitamin D. What possible cost benefit analysis would see anyone be discouraged from the general idea of supplementing with it?
Perhaps it isn't a perfect covid cure, but so what? There's no pascalian wager associated with supplementing vitamin D when you're deficient in it...and it might also help with many other things.
What kind of Pascalaian wager of harm are we making by exposing ourselves to all the pesticides and herbicides and such. Where is Algernon's law for all the crap in our environment which has been repeatedly shown to be harming us and killing people? And still none of it is regulated or tested or examined. I'm far more concerned about the hundreds or thousands of things thrown at us from our paint to known neurotoxins in our pillows in fire retardants, to asbestos and DDT, etc.
Only a few of those are household names, but where is ANY of this analysis for those things? If I take 1,000 industrial chemicals and throw them at people, all exogenous things we never evolved around....where's Algernon?
How can Algernon's law apply to sedentary indoor modern humans whose necks are bent at odd angles looking down at their black mirrors all the time with the idea....evolution has sorted everything out for us and everything is optimised.
It just seems like such an obviously preposterous idea with no nuance. Perhaps a human 100,000 years ago living outdoors and hunting and gathering across the African savannah had no problems with Vitamin D. Perhaps they also had far far fewer problems with their jaws being under developed, or scoliosis in their spines from sitting and inactivity, not being exposed to sundry toxic substances, chemicals, and endocrine/hormonal/etc. disruptors of our various bodily systems.
There is so much that is different and has changed very rapidly in our environment.
Any reasonable evolutionary look at humans would conclude that our environment has changed far far faster than even fast evolutionary ideas would project to account for. How could we possibly have genetically adapted to these moderate and soft forces in our newly toxic environments?
Are we adapted for phthalates and our shrinking taints and plummeting sperm counts? Are all these plastics and other endless novel chemicals all utterly harmless?
If we apply the methodology of skewing towards harms being more likely than benefits, then certainly the tens of thousands of untested chemicals and the ways they degrade and interact with each other which humanity just dumped everywhere...and every so often when people start dying fast enough and in concentrated enough numbers we notice and do things like ban asbestos or any number of other banned lesser known chemicals which gave everyone cancer downstream from the factory....and the probable hundreds of other chemicals which are hurting people in such extreme degrees and in more moderate ways.
All this science and knowledge and deep long analysis of things stops at the things which get studied. The endless exemptions and lack of testing for safety for so many things we're exposed to just goes....unnoticed. Hand waive away that problem...what?
Certainly the idea that there 'is no metabolic free lunch' from taking loads of exogenous drugs and supplements is an idea. But then taking that idea to a stupid degree one wouldn't take antibiotics or anything from outside your body. And certainly looking at endogenous compounds like vitamin D or eating certain foods would make sense.
But I think there is a layering issue of complexity where no metabolic free lunch applies from one perspective, but makes no sense in another...especially when one is talking about things that are missing from your lunch, such as eating it while outside or other nutrient deficiencies in the modern western diet which has proven itself to be a huge scourge in medicine with heart disease, diabetes, and probably certain forms of depression and anxiety coming from dietary issues for some people.
Smoking cigarettes has got to be bad for you if you have covid. Whatever else is going on with covid, it does impact the lungs. Does the concept of 'patients don't do what we tell them anyway' apply here? Does it change the truth of the matter if patient compliance is high or low?
But does this mean we shouldn't ask? Or if you do smoke you shouldn't stop for at least the period while you're sick?
Do we really need a study on this when we already know how bad smoking is for you? Or how bad vitamin D deficiency is bad for you?
> Agreed that Vitamin D is one of the rare exceptions to this.
-- Scott Alexander
https://astralcodexten.substack.com/p/pascalian-medicine/comments#comment-3751320
replying to
> There's a strong argument that Algernon's Law does not apply to Vitamin D. The maintenance dose for the Spanish RCT studying Vitamin D for COVID is around 8000 IU/day. This is about what someone would get from 2 hours in peak direct sunlight shirtless. Hunter-gatherers probably got this or equivalent, but we clearly don't.
https://astralcodexten.substack.com/p/pascalian-medicine/comment/3751040
> And still none of it is regulated or tested or examined. I'm far more concerned about the hundreds or thousands of things thrown at us from our paint to known neurotoxins in our pillows in fire retardants, to asbestos and DDT, etc.
I am pretty sure that asbestos and DDT got mostly regulated out of existence.
In Europe at least, with various more or less effective asbestos remediation programs and laws.
I suspect that not enough is done ( https://www.nytimes.com/2020/12/03/climate/salmon-kill-washington.html https://news.ycombinator.com/item?id=25431550 ) but giving asbestos as example to "none of it is regulated" is weird. AFAIK it is also regulated in USA.
"I don't see how we can ignore that 90% plus of people in hospitals with covid also happen to have low vitamin D which is much higher than the 60-70% background rate of people who have low vitamin D."
But is that causation or simply correlation? If Joe didn't happen to contract Covid but was in hospital for something else, couldn't you make the same connection: "Joe is deficient in vitamin D, he's in hospital for galloping gallumphs, while Mick is also deficient in vitamin D but doesn't have it - plainly being low in vitamin D makes you more susceptible to the gallumphs"?
I agree that it's one of those things that can't hurt, but it's not so clear that it's going to be "and in this case it will make a definite difference in outcome".
Vitamin D is notorious for being corelated, but unable to be shown to be causative when you start trying to change outcomes by adding it. It's like one of the biggest now-you-see-me-now-you-don't headfakers among micronutrients, a savage little minx of a molecule.
Fascinating post, BUT I'll be a non-technical pedant and note that a Pascalian approach to medicine might also imply rejecting medical assistance out of adherence to extremely ascetic practices.
The thing I worry about with this whole poly-polypharmacy concept is EDCs - a dozen compounds that are more or less perfectly innocuous at the amounts we're routinely exposed to them (as far as the limits of their individual studies can tell), but taken together are responsible for something like a 50% decline in male fertility over the last 50 years.
What happens if you start taking 100 pills a day and then some weird additive effect like this crops up? What if you're perfectly healthy but your kids end up with some sort of weird issue due to the additive effects?
I think if you're taking 100 pills a day, that is not rational or sensible behaviour by any measure. If you're going to be taking things on the basis that "onions, garlic, turmeric are proven benefit by these studies", you're better off to incorporate them into your diet rather than try and get "multi-concentrated essence in a capsule".
Some things will help, but taking too much of anything is bad for you (let's listen to the advice of our elders in proverbs and sayings), and it's going to be down to each individual's needs and unique biochemistry anyway. You want to have more vitamin C? Eat more citrus fruit!
What, get various different things like your diet like some kind of peasant? Nah, just eat highly processed food and then try to shove all the various phytocompounds back in manually by eating a bowl's worth of pills every day. That's efficient!
Interesting view. Fact is in the beginning, people died without any treatment that can prevent them to become intubated. millions.
Its one to say, oh, we dont know if ivermectine works or not, but we dont have anything else, so why not lets just try it to save the patients.
and other to deny treatment, demonize/eliminate those doctors who were willing to treat patients and give life saving early treatment, and spread misinformation in the media about "horse dewormer"
That is criminal intent.
Especially since now we see Merck and Pfizer coming out with antiviral pills, that are supposed to tackle the same problem of early treatment, kill the virus before it becomes dangerous...
> life saving early treatment
It is quite dubious and unclear is it actually effective treatment (in cases where you are free from worms, as dewormer it works fine).
> but we dont have anything else, so why not lets just try it to save the patients
As this post itself discusses trying all medicines at once will not necessarily help and is not some golder bullet
> that are supposed to tackle the same problem of early treatment, kill the virus before it becomes dangerous
The difference is that Paxlovid for example clearly works: https://astralcodexten.substack.com/p/when-will-the-fda-approve-paxlovid (and FDA drags its feet without clear explanation so there is anyway place to complain!)
So ironically people have actually run studies that ended up claiming positive anti-cancer properties of both onions and pumpkins…
https://www.sciencedirect.com/science/article/abs/pii/S0963996917301060
https://pubmed.ncbi.nlm.nih.gov/33978471/
I rank these both as providing low to no evidence though, since it is well known that "everything kills cancer cells in a petri dish".
Given the incredible variety of plant extracts available with touted health benefits for various things, Scott’s scenario is not hypothetical. People will and do market the most ridiculous things as having (very dubious) health benefits.
This also makes me sceptical that e.g. Kurzweil’s use of so many supplements should be described as rational - his behaviour is indistinguishable from that of someone (like my grandmother) who has decided for some quasi-superstitious reason to take a bunch of supplements.
It's very on-brand for him, though, so there's that.
I practice a form of this on myself to treat depression and general fatigue. I take about 8-15 different supplements daily. I'm pretty sure half of them don't help at all, but I'm not sure which half. I can't really make myself get more than 15 pills down in a day, so if I find something else that looks promising I bump off the treatment I have the least faith in. Sometimes things immediately get worse, which provides evidence that whatever I discontinued was helping. Through this process I've found fish oil, magnesium, vitamin C, and lion's mane certainly help. No matter how much people swear up and down about it, vitamin D has no noticeable impact on my mood or health.
I think supplements and so on work when you have a small deficiency, or when you need more of something (be that because you're less/more active, getting older, pick up a minor illness).
I have found magnesium supplements very helpful with leg and muscle cramps. It's only in the last couple of years I have needed to take them, and I don't think I've changed my diet all that much. So it could be "age 30, no discernible effect; age 40, will see benefit" for many things.
I'm also taking Omega-3 fish oil because why the heck not, also my joints are getting creaky and it may help. Ditto with turmeric for anti-inflammatory properties, though given all the caveats about bioavailability, you're probably just as well off to consume it via Indian curries which at least will be tasty and enjoyable 😀
Funnily enough, Taguchi methods were developed specifically to solve issues like this. Time to queue up an orthogonal array and start filling out those BDIs, CES-Ds, EQ-5Ds...
Fun fact, magnesium competes with calcium in oxalate binding to prevent kidney stones
A question I have is: What percentage of COVID patients are involved in a trial? If we have twenty to hundreds (from ivermectin and Vitamin D to onions and egg plants) of potential low risk chemicals to try out, are we? Given the number of hospitalizations in the US alone, the error bars on the effectiveness of anything that's already known to be generally safe for human consumption should be much lower than this post implies. It seems that every patient should be asked "Would you be willing to take pills from this bottle, which potentially will improve your situation, but will probably do nothing?" Each bottle would have some drug or control (eg, sugar pills), an identifier (check for allergies by entering them into a form which knows but doesn't tell which pill type it is), and after the patients illness is over one way or another, the data is recorded. This also may be the most ethical way to provide the placebo effect. Seeking better data to get the answers we want seems like a more productive line of action than choosing Omura's Wager.
An interesting question is whether crank cures tend to be wholly fallacious or if they become well known because they work for a few persuasive people (but not for most people). As I've often burbled on about, I've found the Chinese traditional remedy of echinacea tea to be helpful. But in all the years I've enthusiastically blogged about it, only about four commenters have chimed in to say it works for them too.
Now it could well be that me and my four pro-echinacea supporters are deluded about echinacea's efficacy. Or it could be that it really does work for a vanishingly small percentage of the population, such as the Chinese sage who originally promoted it, me, and four people who read me, but not for most folks.
I've long been interested in figuring out a general theory of crank cures, but haven't made much progress on the question.
If any of you want to be the Darwin or Foucault of crank cures, please have at it.
I see echinacea teas and extracts and what have you in every health food shop, so it is something that is known and recommended (over here it tends to be in German versions rather than Chinese traditional remedies, as the Germans are big on biodynamics and holistic cures and the likes).
I think the perception of it is "home remedy" like honey and lemon for coughs and sore throats, rather than "medical cure". So people may try it, but they're not going to go for it first instead of a packet of Lemsip or whatever.
One issue is the slavish adherence to the dogma that all rigourous quantification of uncertainty has to be probabilistic. So saying 75% Vitamin D doesn't work automatically implies that 25% it does work.
No. You have a lower probability bound on the chance of failure of Vitamin D, not a complete probability distribution. We simply know that at best there is a 25% percent chance that Vitamin D might work.
If "Insanity Wolf" really does have a valid argument for taking every medication all the time, shouldn't you call him(?) "Cooly Rational Wolf"?
I read the linked article on LessWrong and this paragraph made me wonder if it is logical:
‚For a true Bayesian, it is impossible to seek evidence that confirms a theory. There is no possible plan you can devise, no clever strategy, no cunning device, by which you can legitimately expect your confidence in a fixed proposition to be higher (on average) than before. You can only ever seek evidence to test a theory, not to confirm it.‘ https://www.lesswrong.com/posts/jiBFC7DcCrZjGmZnJ/conservation-of-expected-evidence
I do not agree. Arguably, my priors are also based on a sample size. For example if my priors are based on N=1000, then one additional datapoint should adjust my believe by 1/1001 * effect size.
No?
"‚For a true Bayesian, it is impossible to seek evidence that confirms a theory.", if by "confirms a theory" he means "posterior probability equals exactly 1.000", then he's correct. But that's a pointless, trivial observation. I read that lesswrong post. It's just a math-y sounding word salad mash-up of Law of total expectation (https://en.wikipedia.org/wiki/Law_of_total_expectation) and Bayesian jargon.
i am partial to the explanation that one should put lower probabilities on things with shody studies working.
to a bayesian the details matter a lot.
what is the probability that an egyptian study with n=22 finds an effect size of X of dryg z on sickness y, GIVEN the true effect size is T?
the above is the question one should truly ask
also noting that the interaction probability scales at least quadraticly in the number of medications.
(depending on your prior on interactions requireing more than 2 medications it could increase exponentially)
Oh, got it. Many thanks for the clarification!
"When I reviewed Vitamin D, I said I was about 75% sure it didn’t work against COVID. When I reviewed ivermectin, I said I was about 90% sure.
Another way of looking at this is that I must think there’s a 25% chance Vitamin D works, and a 10% chance ivermectin does. Both substances are generally safe with few side effects. So (as many commenters brought up) there’s a Pascal’s Wager like argument that someone with COVID should take both. The downside is some mild inconvenience and cost (both drugs together probably cost $20 for a week-long course)."
Yes, so the good thing is, if you don't bother with Vit D & Ivermectin, even if you die, you've saved 20 bucks.
Thanks so much for all of this. I'm one who doesn't like taking drugs. But I will admit that when I feel a sniffle or there is covid peaking nearby, I'll pop a multi-vitamin, D and zinc. I'd do a prophylactic does of ivermectin if I had one. No harm, no foul. I just wanted to observe that the placebo effect is big (and useful?). By your pointing out that I'm deceiving myself abut D and zinc, I wonder if you are robbing me of the potential placebo effect. Do you ever think about it this way?
Dang, prophylactic dose.
Speaking of Zinc and drug interactions, here's a little gem from ~25 years ago: https://academic.oup.com/jac/article-pdf/40/4/483/13056424/9372416.pdf It basically says, yes, zinc works, but only if it's really zinc ions. I can tell you zinc ions taste really bad and astringent. If you go to CVS to buy zinc lozenges, you'll find they're all zinc citrate, gluconate, of "chelated". Why? because all of those compounds have the zinc ion bound up really tight with an organic molecule so you don't taste it. But at the same time, there's no free zinc ion to help you fight the virus. It gets worse. There's usually excess chelator (citric acid or gluconate) in the lozenge, so it actually sequesters the zinc ions that were already in you mouth, making the viral infection worse! That's the bad interaction between zinc and citric acid (think lemons - citrus fruits). All the studies that show zinc works for colds are done with specially made, awful tasting, actual zinc ion lozenges. The stuff you get at CVS will probably make things worse. "Insanity Wolf" really is insane. This whole business of sequestering zinc to stop enzymes and other biological molecules working is a bog-standard technique in molecular biology labs. They usually use EDTA instead of citric acid, but it's the same idea and has been around since the time of The Elders. Having actual knowledge of biochemistry makes walking the aisles of CVS a depressing task.
tl/dr: solve your vitamin D and zinc deficiency simultaneously and definitely just eat your sunscreen
That's definitely an Insanity Wolf hall-of-fame level idea :)
Grin, OK. I've almost never use sun screen anymore. Only when I'm, say, out sailing on a lake all day.
Is your name a reference to a Kugelrohr?
No my real name.
Hmm OK thanks. I heard (on a ACX post back sometime in early 2020) about the types of zinc and I believe I bought the 'right' type of zinc. I only opened by bottle of zinc a few weeks ago, and have had two of the lozenges. They do have an astringent taste.
What brand was it? I've been looking for useful zinc lozenges without success and am about to make my own candy spiked with zinc sulphate. Zinc acetate is also good. Just make sure there's no citric acid in it.
Corrollary of Algernon Argument: Sure, you started out with a pretty convoluted balance of elements that left you in a more of less optimal state. But you've been messing with that state since the time you were born. With diet, with exercise and with drugs, usually in non-optimal ways. So it is entirely likely that most people have at least 1 or 2 imbalances that they could fix with supplements and thereby gain improvements.
Of course, if your balances are already skewed, dumping 20 odd supplements into your system is unlikely to restore it, and most side-effect statistics assume 'normal' health, and those would be amplified as well.
Also, this modelling assumes that the effects of each supplement are independant, right? Since supplements don't usually have contraindications, this might not matter at most scales, but at 20 (or 250?!), don't those interplaying effects also need to be accounted for? Is that even something we can model with accuracy?
Non-sequiturs:
Current hot hypothesis in autism research is that short interpregnancy intervals lead to autism via folate deficiency which vaguely is upheld by subsequent trends of osteoporosis in those mothers
https://pubmed.ncbi.nlm.nih.gov/29164825/
(idk, but since Scott is really into birth order) Also over supplementation can be detrimental to neurodevelopment (murine models) and can allow growth of nascent tumors - it's actively discouraged for cancer patients and the elderly
Also fun fact, one of three cadavers has thyroid cancer. I think all MDs know.
I'll do my best to not become a cadaver.
So what is your estimate of the chance that that folate-autism link is real?
This reminds me of a report I heard on NPR about a clinic in California that treats people who think they might have CTE from repeated brain injuries, but we can't prove that without an autopsy and have no treatments anyway, by basically giving them a whole bunch of random treatments that almost sound like they might work but there's no real evidence for but probably aren't harmful, from trans-cranial magnetic stimulation through dubious herbal supplements through "diet and exercise". It's probably a scam the way it's done, and you could do many of them yourself and save several thousand dollars on a consultation, but I had trouble saying confidently that it wouldn't *work*.
https://www.nprillinois.org/2021-11-22/a-market-of-dubious-remedies-has-sprung-up-as-more-everyday-people-fear-they-have-cte
And I bet they can't find a doctor to give them an autopsy so they can know for sure if they should get treatment.
This feels like a cop-out to me. By conflating all early treatment medicine together and pushing it down a slippery slope you can then stand on the other side of medicine guzzling junkies and appear the more reasoned one. Though I got to admit it's funny and enjoyed reading it. Still, if we know Covid mostly strikes those with immune system deficiencies then it stands to reason all the minor things a person can do to boot their immune system could have an effect. If being outside can reduce transmission to zero, if wearing a mask or running fan can help, then having healthy levels of vitamin D can help as well. And a drug that may slow down the replication of the virus by let's say 15 to 25%, could help, which could be the difference for a given patient. Should such immune optimizations be held up as a substitute for a vaccine...no. But to dismiss them is irrational from my view.
A couple years ago I went full-scale Pascalian for my currently untreatable conditions of PSC + UC. I am taking about 10 supplements every day including berberine, SAMe, ALA, curcumin (yes) and others. On the balance, I can report it works for me so far, I am flare-free for a year now and generally feel better than at any point in the last 10 years at least. I ran my list of supplements by my doctor who recommended against one of them; a couple others I had cancelled myself after they seemed to make my liver worse.
So what are the downsides?
Oh, there's lots!
The most obvious is kidney and liver damage. A lot of drugs are well tolerated as long as you take them in reasonable quantities, but can destroy your liver/kidneys if you take a lot of them. Taking ten drugs that all are individually well tolerated, but which can damage these organs if you OD on them, could easily basically be an OD that does the same thing - it's death by a million cuts.
The entire realm of drug interactions is also basically impossible to know, because the sheer combinatric matrix there is untestable. Take twenty meds at the same time, and you have 19+18+...+2+1 = 190 potential two-drug interactions. The higher order drug combinations are even more complicated, and may not be predictable just from the two-drug interactions. Anything which is biologically active could well have interactions, either counteracting the other things, or even counteracting something ELSE random (like, for instance, if you end up getting prescribed an antibiotic, it might have some weird interaction with some medication you are taking).
A third pontential issue is screwing up your gut microbiome. We don't exactly know what all your gut microbiome does, but throwing twenty random drugs at it at the same time seems like the sort of thing that might screw it up.
A fourth issue - especially for things like antiparasitic drugs - is that taking them all the time causes everything else to get resistant to these things. So giving these drugs all the time could easily lead to the pathogens we are trying to protect against becoming resistant or immune. This is why we don't take antibiotics 24/7 (well, one of the reasons) - it puts a kind of evolutionary pressure on pathogens we *really* don't want.
Things that you ingest normally - like, say, Vitamin D and Zinc - are PROBABLY okay if you stay relatively close to the DRA.
Taking well above the DRA is a bad idea, as some of these chemicals ARE possible to OD on - for instance, Vitamin D has both acute and chronic effects if you OD on it, and it isn't actually that hard to OD on Vitamin D - standard blood concentrations of Vitamin D are 20-50 ng/mL, and we start seeing toxic effects at 100 ng/mL. There's actually a lot of things we take where the toxic dose is only a low multiple of what the theraputic dose is.
On top of this, some micronutrients are much easier to get rid of than others, so bioaccumulation can become an issue when you oversupplement even when the acute toxicity is low.
And animal models won't always save you on this stuff.
For instance, Llamas seem to be vastly more tolerant of vitamin D overdoses than humans are. Why? Who knows. I only know this because I know one of the researchers who worked on trying to find the LD50 of Vitamin D in llamas and gave up after repeatedly doubling the dose; IIRC the final dose they gave them was completely ridiculous (IIRC 64,000 IU per kg of body mass) injected directly into their bloodstream.
For reference, the human RDA of Vitamin D is 600 or 800 IU per day. And no, that's *not* per kg for humans.
This applies to everything. There are artificial sweeteners that will cause organ damage in rats that humans are completely unaffected by. There are surely things that work in the opposite direction.
All of this is valid. If you're healthy and young, Pascalian medicine is probably not a good idea.
But if you already have an incurable condition that's going to kill you, and your choice is between whether this happens in 2 years or 20 years, I think it makes no sense not to try everything that _may_ work. Just research substances thoroughly, paying close attention to any reports of liver/kidney trouble. Introduce stuff one by one and watch closely for individual bad reactions or interactions.
I think it's worth pointing out that fluvoxamine (your example of a success) has quite a few significant side effects. I find it much less well tolerated than other SSRIs I prescribe.
Not that any SSRI is without side effects.
A lot of this comes down to risk aversion, both at the personal and professional levels. I don't think you'd find many doctors who want to put their career at risk by prescribing experimental remedies, even if the regulatory framework was more open to this. On the patient side, who wants to take the risk that their doctor is a quack giving them something where the risks very much outweigh the potential benefit? Even if there are benefits to society from loosening up on both these fronts, it's very difficult to chip away at these biases.
You see the same thing in other fields; finance especially comes to mind. I'm a bit of an investing geek, and do some unconventional things with my portfolio. I like the risk/reward tradeoff of the unusual choices I've made, but in managing my partner's portfolio I go with something very standard, because what if I'm wrong? Professional investment managers deal with this all the time - it's called "career risk" in the field. It's very hard for them to stick to contrarian strategies when they have a benchmark to track. There's a tendency to herd in the conventional path even against one's better judgement, because performing poorly alongside everyone else looks a lot better than performing poorly on one's own.
Even if you take all twenty medicines, and doing so "works" (people who take the dosages don't get the COVID, even after multiple high-intensity exposures), what's to say that it's not the combination that "works"?
I'm a big believer in science, rationality, common sense (no question - my own type of common sense ;-) )
That said: I learned over the years that in the end its all about trust into certain people and or systems systems and distrust others. All our high IQs, information, research and much much more counts not much. In the end its about trusting or distrusting.
Thats kind of good and bad at the same time for me.
"Futurist Ray Kurzweil used to take 250 different supplements every day - but after realizing this was excessive, cut it down to only 100." was wondering the same - "maybe he really has found a secret or even the holy grail of liefe and death and I should do like he does" - some years later seeing an image of Kurzweil and thinking "looks pretty old this guy for his age - ok, let's forget that stupid 100+pills idea"
The Placebo Effect and the affects of prolonged anxiety/fear are both well established, aren't they?
Combining the beliefs that 'they put it on the test swabs' and 'God decides when its your time' would seem to be more statistically effective than fear and supplements.
"We don’t fret over the unknown unknowns of Benadryl or Tylenol or whatever, even though we know their benefits are minor."
Speak for yourself... I take Algernon's law seriously, and tend to avoid low benefit medications because the expected value doesn't favor them. I also do my best to approximate an evolutionarily informed diet (i.e. paleo, but making allowances for neolithic foods my ancestors ate for many many generations).
I have long Covid, doctors are useless, and I have had far more luck with folk/quack remedies off of the internet than I have with anything doctors have recommended. If you actually have a medical condition which doctors have not and are unlikely to help you with, Pascal's Wagers are totally rational. The way to avoid being mugged by Pascal's quacks and avoiding tail risks is to do enough research to create a hierarchic list based on a cost/plausibility ratio and go down the list.
Commenting a bit late, but this is basically my approach to supplements, with a focus on longevity and general health. I am nowhere near 100 myself (currently at around 10, peak was around 20-22), and if anyone is curious I wrote a brief (albeit slightly outdated post) outlining all of them with some reasoning as per why I take them(with the more interesting things on the bottom of the post. also keep in mind this is personal to myself!): https://nearcyan.com/supplements/
It does get interesting when you run cost/benefit analysis on things like this though, and I do have some uncertainty about the best ways to meta-manage this myself as well.
scott mentions negative interactions, but what about positive interactions? If we see a number of proxies improving in response to the drugs, maybe some of them are hitting real parts of the problem, and in combination they'll have a real effect?
That's a perfectly reasonable argument for why doctors shouldn't prescribe IVM / HCG + Zinc by default.
It's not the least justification for doctors refusing to give the prescriptions to people who want them, or for pharmacies to refuse to fill those prescriptions
Its possible for Kurzweil to be entirely rational in taking 100 supplements to slow down ageing, and for you to be entirely rational in ignoring the weak evidence for ivermectin, under certain priors. Specifically, given that you know that vaccines work generally and for covid, it is much less likely that ivermectin works than would be the case if vaccines didn't work. Vaccination validates a far from complete, but still substantial causal map of the mechanism whereby covid operates, and we can map this to facts about infectious agents that have broad support. What we know about ivermectin has no causal link to this picture, and would imply a potential large set of unknown mechanisms at work. We have a deep prior that reality displays a causal parsimoniousness (even in biology). I don't have a fully developed argument as to why, and how justified this is, but I suspect that its quite hard to do science without it, and that the success of science operates as a macro confirmation of this prior.
Normally wouldn't mind philosophical debate on fringe virus treatment, but every ounce of validation for these kinds of treatments means more folks won't get vaccinated, and more of either them or someone they contact will die. How about an essay on anticipatory regret - in effect taking every precaution so you don't unwittingly hurt someone?
Wrote a short response to this arguing in favor of this approach for personal health/longevity if anyone is interested: https://nearcyan.com/pascalian-longevity-why-not/
I'm not sure at which point calling the approaches 'pascllian' becomes unfair (because the probabilities are much larger than that in Pascal's wager), but we still underexplore this search space in many regardless, so I think it's a good thing to encourage more usage of expected value and probabilistic approaches to these things.
> I know of only one person who takes the Pascalian argument completely seriously. Futurist Ray Kurzweil used to take 250 different supplements every day
Well, my chronically ill mother took nearly a hundred different supplements a day for 30 years. She stayed more or less sick (it's been somewhat of a roller coaster). Recently she's started to have mini-strokes and had to be placed in a care home.
some intuition for why maybe the 20-drug insanity wolf position isn't quite so crazy (aside from the efficacy claims in the meme):
We already consume tens of thousands of different chemicals every day in our food. If you plug in a prior of 0.01% that two random chemicals will have a harmful interaction, then you get a ~100% chance that our food will kill us. That prior must be wrong when applied to low doses, or when applied to chemicals that our ancestors have consumed for millennia.
Eating 20 more chemicals doesn't seem so significant in that context, as long as the dose is lower than what was well tolerated in studies. Also many/most of the supplements exist in food (like cicrumin in your curry). A thousand year history of consumption as food counts as much more evidence of safety than a few crappy studies that were probably funded by whoever is selling the supplement.
Well, Ivermectin apparently does work if you have worms and need it to fight off the worms when the corticosteroids are used to dampen the cytocine storm. So there is a possible causal effect, under which it does work.
And vitamin D does work if you lack vitamin D — just like zinc and vitamin K2 and C, it is part of what the immune system needs to work. If you are a healthy adult during summer time and take enough sunlight, you don't need vitamin D. Nor do you need K2 (produced by bacteria in the intestines) or C (because you eat enough fruits), nor zinc, when you eat enough of it. But in winter and as old aged person, you have very likely already such a severe lack of vitamin D that your bones start to crumble, and probably your eating habits are not healthy, so you lack other things, too.
And this is a condition that is far more likely than the worm infection.
So, no, you should not use this mental “chance” model. You should try to understand why a drug works, and if it only works under some conditions, use the drug only under these conditions.
Studies in worm-infected countries closer to the equator probably find more likely that Ivermectin works, while studies in northern countries have a higher chance to find vitamin D works — if the supposed effect is real. So you not only have to look if the study is performed with good standards by trustworthy people, but also where it was done, and if the underlying conditions for the drug to work are likely. Actually, the people doing the study should do that analysis in the first place.
In the end, the human body is complicated, and therefore, treatment is not always simple and unconditional. You have treats with a high success rate (like vaccination), but the one immune evading mutant during your phase III test in exactly the country where you did test it can ruin your results. You have treats with a low success rate (like Ivermectin), because the conditions under which that works is rare, at least in western countries.
1 Million supplements with1 Gram each makes you take in 100 Kg of supplements every day. Killing you with high probability.
Isn't the leading recommendation in medicine for a Pascalian Diet?
Your safest bet is to each as wide a variety of foods as possible(excluding those that are harmful).
Maybe I'm mistaken that's the scientific consensus, but I've never seen any argue against it or recommend a very narrow diet of a few specific things that proven to be very healthy (except as extreme weightloss diets).
So aren't the onion farmers already money pumping us with the Pascalian Diet?
Why not let them money pump us with Pascalian Medicine too?
Re. "I’m nervous about this scenario because it violates the Law Of Conservation Of Expected Evidence - if I “know” that onion farmers doing studies will convince me that onions have a 5% chance of curing cancer, I should just believe there’s a 5% chance onions cure cancer now."
There is no violation of the Law Of Conservation Of Expected Evidence. I assume you mean that the studies will conclude onions cure cancer if p < .05, so that 5% of the studies will conclude onions cure cancer if they don't, and that will convince you there's a 5% chance onions cure cancer.
No. Just do the math. A meta-review of these studies should look for the risk ratio multiplier that treatment of cancer with onions has for, say, death as outcome; then conclude that the best estimate of that risk ratio is R such that P(outcome | R) is maximum. If the studies pass a p < .05 test 5% of the time, I'm pretty sure that will work out to R = 1, meaning our best estimate is that onions have no effect on the risk. If they pass it less than 5% of the time, then R > 1, meaning our best estimate is that onions increase the risk of death from cancer.
When you phrase the question in terms of "probability onions cure cancer", you're making an asymmetric test, ignoring the possibility that onions make cancer worse. The case where R = 1 is presumably where the expected risk from onions cancels out the expect benefit from onions.