Use Tools For What They're For

post by AllAmericanBreakfast · 2021-11-23T08:26:19.174Z · LW · GW · 14 comments

Maybe there isn’t and can’t be a simple heuristic you can teach everyone in school or via a PR campaign which will lead to them having making good health decisions in an adversarial information environment, without having any negative effects anywhere else. But you also don’t want people to make bad health decisions. So what do you do? - Scott Alexander, Ivermectin: Much More Than You Wanted To Know

 

The favorite catchphrase of critics of using ivermectin against COVID-19 isn’t "follow the science" or "believe the experts."

They say "IVERMECTIN IS A HORSE DEWORMER!"

And in response, ivermectin supporters say things like:

MAGAA Puppy is factually correct in the two "Me:" statements.

MAGAA Puppy's critics aren't disputing these facts. As we know, the reason they emphasize the "horse" in "horse dewormer" is that some people may have been taking horse-size doses of ivermectin and dying from it.

I am suspicious. The FDA only claims to have "received multiple reports of patients who have required medical attention, including hospitalization, after self-medicating with ivermectin intended for livestock." I see no mention of death on the FDA's web page. But if we're tentatively accepting MAGAA Puppy's claims about "numerous studies," let's also tentatively accept critics' concerns that consumption of veterinary doses of ivermectin is a serious public health concern right now.

Critics of ivermectin as a COVID-19 drug are saying that "large doses are unsafe, and small doses are probably not effective." Supporters are saying that "small doses are safe and FDA-approved for human use, and some studies suggest they may be effective."

I firmly side with the critics. But why? MAGAA Puppy has probably read more studies than I have on ivermectin as a COVID-19 treatment. It wouldn't be a high bar to clear.

I also think that the "it's a HORSE dewormer" line is missing the point and is a terrible example of public messaging. I suspect that critics misunderstand why ivermectin supporters are interested in the drug as a COVID-19 treatment, and are choosing a poor line of argument that is failing to persuade or spread necessary and true information about why we should be critical of ivermectin for COVID. My hope is not only to correct this line of thinking, but to show how a simple heuristic could have lead to better outcomes in not only this case, but in several other epistemic debacles of the COVID-19 pandemic.


Drugs are a tool.

Some tools can be effective at tasks they were never designed for. The other day, I used a the sheet of glass from a picture frame as a straight edge while cutting a mat board for the photograph I was framing. My mom puts salt on the slugs in her garden to kill them, even though salt wasn't designed by anyone, for anything.

But most of the tools we use every day were designed by a human to accomplish a specific task, and they are overwhelmingly most useful for that particular job. A hammer can be used for a few things besides hammering in a pinch, but not too many. Mostly, a hammer is for hammering. Cups are mostly for drinking out of, and for things very similar to their original purpose of holding small quantities of liquid.

Occasionally, a tool can be used for a side purpose, one for which it was not originally intended. Hammers can be for bell-ringing and battle and carnival games. In all cases, this is because the shape or mechanism of the tool happens to fit the target, such as a boxing ring bell or the skulls of one's foes.

Drugs can also be reused for a side purpose. This is called "off-label prescribing," and one in five prescriptions in America is off-label.

If we could list out all the many, many activities that people do around the world, for how many of those activities would a hammer be a useful tool? For a vanishingly small fraction. I can't use a hammer to plant roses, blow my nose, get to work, or pay my taxes, at least without a whole lot of creativity!

I forgot to mention that hammers also make excellent wall-hangers.

The reason we can often find side purposes for tools is because people understand the tool's shape and mechanical properties, the activities they do on a daily basis, and can find a few additional cases where the tool would be helpful.

That same intuition applies to drugs. We generally discover drugs in one of two ways. One is to identify a molecular target and try to design a tool that would affect the target in a desirable way. This is like choosing a location on a river, and trying to design a bridge to get across it. The other way is to screen many compounds for their medical usefulness, and see what effects they have. That's a bit like planting a packet of unlabeled, mixed seeds from all around the world and seeing what grows.

If you try to repurpose a bridge design for another river, you'll have to consider your crossing site very carefully, or else the bridge probably will not accomplish what you need it to. Likewise, if you hope that a particular seed in your packet of mystery seeds will turn out to be a daikon radish, you're likely to be disappointed.

Ivermectin, and really any drug not deliberately designed either to bolster the human immune system or to fight viruses (and more specifically COVID-19), is deeply unlikely to be directly effective against COVID-19 for the same reason your mystery seed is unlikely to be a daikon radish.

In general, it's wise to use tools for what they're made for, unless you have a clear, compelling idea of how the shape of that tool will be useful for the physical demands of some other task. Even then, tread carefully, and only proceed if you have an opportunity to gather compelling evidence. When I used the glass sheet as a straight-edge, the ragged edge scraped ink off of the photo and permanently damaged it.


I think that critics should stop emphasizing the "horse" in "horse dewormer," and start emphasizing dewormer.

Ivermectin doesn't bolster the human immune system to help it fight against helminths. Nor does it reduce the harmful side-effects of an immune response. Ivermectin is a worm poison.

Ivermectin and its related drugs act by interfering with the nerve and muscle functions of helminths and insects. The drug binds to glutamate-gated chloride channels common to invertebrate nerve and muscle cells. The binding pushes the channels open, which increases the flow of chloride ions and hyper-polarizes the cell membranes, paralyzing and killing the invertebrate. Ivermectin is safe for mammals (at the normal therapeutic doses used to cure parasite infections) because mammalian glutamate-gated chloride channels only occur in the brain and spinal cord: the causative avermectins usually do not cross the blood–brain barrier, and are unlikely to bind to other mammalian ligand-gated channels.

So ivermectin is effective against worms because it binds and opens chloride channels in nerves and muscle cells. It's safe for humans because it doesn't have anatomical access to any of our own cells that have these channels. This mechanism of action will be completely ineffective against viruses, because viruses don't have cells at all. They're closer to the size of a single receptor than to the size of a cell, and they're not even really alive.

When critics emphasize the "horse" in "horse dewormer," they may be taken as implying three things, whether they mean to or not:

  1. People shouldn't take horse-size doses of ivermectin because it's unsafe for humans at such high dosages.
  2. People shouldn't take ivermectin because it's for animals, not humans.
  3. Ivermectin is ineffective against COVID-19 because its mechanism of action is particular to horse physiology, perhaps because ivermectin works by stimulating the horse's immune system or something.

Only the first of these implications is correct.

My guess is that many ivermectin supporters would like to take human-size doses, if they were conveniently available. But to get an ivermectin prescription, you have to go through a doctor, and they already know what kind of response they'll get if they ask their doctor for an ivermectin prescription for COVID-19. So they get it from the farm store.


Ivermectin opponents don't want to have to become biomedical experts to carry the day in this debate. Ivermectin supporters probably don't want to have to do that either. Nobody in this debate wants to catch COVID-19. Both sides think they are following the science, using their common sense, and doing their due diligence.

My guess is that much of this confusion could have been avoided if both sides stuck to a heuristic of using tools for what they're for. Focus on the tool and what it was originally designed to do. Then consider the new task for which you're considering repurposing it. Why do you think the physical shape of the tool will fit that purpose? Or what is similar about the physical dynamics of the original and new task, so that you expect the old tool will fit the new task?

Only once you've answered these questions does it help very much to gather evidence.

Imagine that you'd found 100 scientific studies showing that shovels are great for brushing your teeth. Would you believe them?

No, of course now. You can visually imagine what it would be like to brush your teeth with a shovel, and conclude that it will not work. And besides, digging holes is nothing like brushing your teeth. All those scientists are being dummies.

With ivermectin, or any other drug, you lack the ability to visualize how the drug will physically affect the new biological system you're using it against. So all you're left with is considering the task at hand.

Of course, COVID-19 and intestinal worms are both diseases, but just about anyone is aware that not every drug is good against every disease. Ivermectin is a dewormer. It is not an antiviral, and never was designed for that. Nor is it for bolstering your immune system or use as an anti-inflammatory.

So you can pretty much write off ivermectin as a COVID-19 drug in the absence of flagship-quality evidence in favor of it. If the FDA approves ivermectin for COVID-19,  and scientists come to consensus on the mechanism by which it is effective for that purpose, I'll change my mind. I don't need to know what that mechanism is, or evaluate the evidence myself.


I think this heuristic works for other pandemic debates as well.

You don't have to know exactly how the tool works. I don't know how my blender works, beyond the fact that it has blades and spins around. Why are the blades at that angle? How does the motor cause them to turn? Why are the walls shaped with that curve? I don't know, and I don't care. I just know that the manufacturer designed it to be an effective blender, and tested it out before selling it. So I start by trusting that it will blend,  until proven otherwise.

Likewise, Pfizer and Merck and all the rest of these big pharmaceutical companies designed their vaccines and drugs to fight COVID-19, and gathered lots of flagship-quality evidence to bolster their claimed success. Nobody with serious standing challenges these claims. So we should start by trusting that their products do, in fact, work.

Note that this heuristic also often allows us to come to the right conclusion when the experts are right and when they're wrong, without putting much thought into it.


This heuristic will have some failure modes.

It won't work as well against an (at best) mediocre tool, like aducanumab. This drug was designed for the purpose of treating Alzheimer's, and it got FDA approved for that purpose. The fact that this was immensely controversial doesn't helps, by this heuristic. How do we know that the detractors aren't just the equivalent of anti-vaxxers? 

It also won't work well against externalities, as we see with climate change. Gas-powered cars work perfectly well for their advertised purpose of driving, and the CO2 you release from your own personal driving will barely affect you.

And it won't work well when the experts are misguided, make mistakes, or lack integrity. Perhaps their tests are inadequate, or the tool's real purpose is not what it seems. We deal with this daily, when we consider issues like inadequate testing of the effects of herbicides on wildlife, or the effects of a social media ecosystem that is built primarily to generate advertising revenue rather than to improve social relations.

 But a rule of thumb isn't meant to be a conclusive answer. Ideally, we use it with other heuristics, other forms of common sense, to come to a sensible decision.

Perhaps "trust your tools, and use them for what they're for" is a neglected piece of common sense in our era. Many people are surrounded by messages of concern that our tools are making us unhealthy, poisoning the planet, motivating or facilitating murder and suicide, alienating people from one another, causing addictions and unhealthy obsessions, spreading misinformation, and putting the future of humanity at risk.

While acknowledging that these problems exist, we don't have to blame the tools that give rise to them. Instead, we can focus on the tools that solve them.

Exercise and a healthy diet promote health. Carbon taxes and solar panels can help solve climate change. Adequate and compassionate policing and mental health services can reduce murder and suicide. Friendship and anti-anxiety medications can reduce alienation. Hobbies and drug treatment programs can help dissolve destructive habits and form better ones. Reading credible sources and consulting with experts helps reduce misinformation, even if it doesn't remove all the risk of going wrong. And there's lots of research and action going on into safeguarding the future of humanity.

The problem is perhaps not inherent in our tools, but lies in our failure to understand their purpose or make adequate and timely use them.

14 comments

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comment by ChristianKl · 2021-11-23T10:10:10.361Z · LW(p) · GW(p)

The FDA not liking people using the horse version to treat illnesses that people have has nothing to do with ivermectin being ineffective for the illnesses in question.

We know that because in 2019 that already was the FDA position to be concerned about it's usage for Rosacea. The FDA just opposes US citizens to use cheaper versions to treat their diseases then the human versions that they approve. 

Ivermectin, and really any drug not deliberately designed either to bolster the human immune system or to fight viruses (and more specifically COVID-19), is deeply unlikely to be directly effective against COVID-19 for the same reason your mystery seed is unlikely to be a daikon radish.

This ignores the apriori reasons to believe that Ivermectin is a good candidate as a treatment.

From a paper in The Journal of Antibiotics from 2017:

Ivermectin has also been demonstrated to be a potent broad-spectrum specific inhibitor of importin α/β-mediated nuclear transport and demonstrates antiviral activity against several RNA viruses by blocking the nuclear trafficking of viral proteins. It has been shown to have potent antiviral action against HIV-1 and dengue viruses, both of which are dependent on the importin protein superfamily for several key cellular processes. Ivermectin may be of import in disrupting HIV-1 integrase in HIV-1 as well as NS-5 (non-structural protein 5) polymerase in dengue viruses.

From another paper in 2018:

Ivermectin has long been clinically administered for the treatment of parasitosis (63), but has recently come to attention as a potential inhibitor of IMPα/β (64). Ivermectin inhibition of IMPα/β has shown to inhibit the replication of RNA viruses such as dengue virus and HIV-1 (64). Ivermectin was recently tested for the inhibition of IAV in vitro, with nuclear import of vRNP complex (of both wild-type and antiviral MxA escape mutant) efficiently inhibited (65). Given ivermectin’s longstanding record of clinical applications and FDA-approved status, repurposing of this drug for the treatment of IAV should be considered, especially while under threat of pandemic IAV outbreak.

When COVID-19 came around and we started discussing what could be done on LessWrong, in April 2020 there were positions [LW · GW]like:

What kind of treatments and vaccines might we expect? Derek Lowe outlines “The Order of the Battle” where first we try repurposing existing drugs (e.g., remdesivir, hydroxychloroquine, azithromycin, falapirivir, ivermectin), then monoclonal antibodies, then vaccines, and then potentially new treatments. It’s possible existing drugs or new treatments could greatly reduce the danger of COVID and allow for faster reopening, but it would take a vaccine to truly make it go away.

That was the position because we knew that ivermectin does more then just deworming. If we had a pro-Science administration in any Western country the reaction to COVID-19 would have been by that point to immediately fund powered trails for those candidates. 

Unfortunately, that doesn't happen but other people did fund the trials and as of June  [LW · GW]quality meta reviews of the available trial suggested it works. The problem is that the trials are mostly not run in Western countries and thus not as trustworthy then those that would have been run if the CDC would be pro-Science at the beginning of the pandemic. 

The favorite catchphrase of critics of using ivermectin against COVID-19 don't say "follow the science" or "believe the experts."

The reason to not take ivermectin is essentially "don't follow the science, because some of it is fraudulent" at this point in time. Back in the highest quality meta analysis were pro-ivermectin.

Note that this heuristic also often allows us to come to the right conclusion when the experts are right and when they're wrong, without putting much thought into it.

The heuristics likely gets you to results such as not using various drugs such as SSRI's when depressed because those hit a bunch of different targets and produce complex interactions which we don't fully understand. Not taking drugs where there's good evidence that they work but where the workings are complex enough that we don't fully understand them gets you to a wrong conclusion many times.

Replies from: AllAmericanBreakfast
comment by AllAmericanBreakfast · 2021-11-23T16:27:55.435Z · LW(p) · GW(p)

With any heuristic, it’s going to have failure modes and will only get you so far. This is meant as a common-sense guideline for lay people, not as an intellectual stopping point for scientists, regulators, and clinicians.

Here, I’m aiming at people who are ivermectin partisans, both critics and supporters. Those who’d reject other treatments in favor of ivermectin, and those who think ivermectin has no possible relevance to COVID-19 and yet yet don’t seem to be thinking even at a baseline level of wisdom in their criticism.

This post is a tool, and I advocate using it only for what it’s for!

comment by Vanilla_cabs · 2021-11-24T13:39:29.862Z · LW(p) · GW(p)

I find it misleading to call drugs tools. It is not uncommon to find unexpected uses for drugs.

Here is an example I just saw in a documentary last week:

Avastin, a treatment for certain types of cancer, was found out to cure AMD very cost-efficiently. Novartis was so miffed that they successfully lobbied for forbidding using Avastin in AMD cases, then they repackaged it into Lucentis and now they sell it at 40 times Avastin's price. It's the same product, but doctors are forbidden to use the cancer treatment to cure people's eyes. (Correction: Novartis and Roche tried to have the use of Avastin in AMD cases outlawed in France, but failed. Still, doctors are discouraged from doing that by the complexity of administrative procedures, and presently the overwhelming majority of case are treated with Lucentis.)

Likewise, Pfizer and Merck and all the rest of these big pharmaceutical companies designed their vaccines and drugs to fight COVID-19, and gathered lots of flagship-quality evidence to bolster their claimed success. Nobody with serious standing challenges these claims.

If they are so confident that their vaccines are stellar successes, why did they specify in their contracts with European governments that they could not be held liable for side effects?

Replies from: ChristianKl, ChristianKl, Dustin
comment by ChristianKl · 2021-11-25T00:56:53.834Z · LW(p) · GW(p)

Novartis was so miffed that they successfully lobbied for forbidding using Avastin in AMD cases

Can you be more specific to what you are referring to? What specific regulatory are you calling "forbidding using Avastin in AMD cases". What forbids off-label use here?

Replies from: Vanilla_cabs
comment by Vanilla_cabs · 2021-11-25T01:51:02.882Z · LW(p) · GW(p)

My bad, I rewatched the documentary and it's actually less clear. The two swiss labs Novartis and Roche, who respectively commercialize Lucentis and Avastin in Europe (undistinguishable treatments both created by Genetech, an American lab bought back by Roche - also, Novartis owns 33.33% of Roche), tried a legal action against France. I assume it was to outlaw the use of Avastin in the eyes. But it eventually failed. However, in the meantime, the habit had taken root to use Lucentis to cure AMD. It's not explained exactly why. The interviewed person says "the difficulty nowadays for the healthcare system, is that they set up a system that is so complex for eye doctors to manage that in the end, everyone gave up." I interpret that as "it's possible, but there's so much red tape that it's impractical". I will correct my original comment.

Replies from: ChristianKl
comment by ChristianKl · 2021-11-25T09:23:00.920Z · LW(p) · GW(p)

The two swiss labs Novartis and Roche, who respectively commercialize Lucentis and Avastin in Europe (undistinguishable treatments both created by Genetech, an American lab bought back by Roche - also, Novartis owns 33.33% of Roche), tried a legal action against France. I assume it was to outlaw the use of Avastin in the eyes. 

That seems unlikely to me. Our health system doesn't work in a way that there's a normal process for outlawing drugs for being used for certain purposes. 

Let's start with, Lucentis and Avastin are similar but the are not undistinguishable. They are both monoclononal antibodies against the same target but not the same. That's why you have for example two different English Wikipedia pages for them which you don't have for drugs were the same substance gets marketed under different brand names.

https://go.drugbank.com/drugs/DB01270 and https://go.drugbank.com/drugs/DB00112 give you the sequences of the antibodies and even without comparing every letter you see that the molecular weight of one is a third of the other.

When repacking a drug that intravenously into one that's optimized for intravitreal delievery it's plausible that some optimization can be made. Wikipedia suggests that there's  review that even suggests low certainty evidence that there are clinically relevant differences. While those difference might be just the result of p-hacking it's plausible that they are real.

Even the French Wikipedia doesn't go into detail but a more likely scenario is that someone in the French health service thought that covering Lucentis with public health insurance is a waste of money when Avastin exists that costs 1/40 as much and that they ran a lawsuit to get French public health insurance to cover Lucentis. 

If money wouldn't be any concern, then the act of repackaging drugs to be better for a given clinical application makes a lot of sense. The key issue is how much profit a company deserves for doing that and the amount feels excessive for the service that's provided.

comment by ChristianKl · 2021-11-25T09:45:39.899Z · LW(p) · GW(p)

If they are so confident that their vaccines are stellar successes, why did they specify in their contracts with European governments that they could not be held liable for side effects?

Courts of law can make companies liable for "side effects" whether or not there's scientific evidence that the "side effects" are caused by the drugs. 

If you for example look at LYMErix it's not clear that the side effects were really that severe but they were still enough to get the vaccine withdrawn.

comment by Dustin · 2021-11-25T00:19:00.395Z · LW(p) · GW(p)

If they are so confident that their vaccines are stellar successes, why did they specify in their contracts with European governments that they could not be held liable for side effects?

 

I mean, that's just good practice.  No one can be 100% sure of anything, and you always want to take as little liability as possible...particularly when the costs of taking less liability are low.

comment by Gunnar_Zarncke · 2021-11-23T09:30:11.611Z · LW(p) · GW(p)

Scotty: How many times do I have to tell you? The right tool for the right job!

-- https://getyarn.io/yarn-clip/ff8609de-278d-48bf-8c0e-036749f825de 

comment by Big Tony · 2021-11-24T18:40:35.525Z · LW(p) · GW(p)

Haha, I'm seeing a lot of people noticing confusion between the prevailing opinions of the society they live in (Ivermectin is a HORSE DEWORMER and DOESN'T WORK) and their own thoughts (there's weak evidence that it may work in some cases, perhaps we shouldn't treat it with such vitriol).

This post is a good attempt to reconcile the two.

comment by Richard_Kennaway · 2021-11-23T12:43:45.460Z · LW(p) · GW(p)

As we know, the reason they emphasize the "horse" in "horse dewormer" is that some people may have been taking horse-size doses of ivermectin and dying from it.

I thought the people saying "horse dewormer" were emphasising it because "Haw! Haw! HORSE DEWORMER!!! Lookit the stoopid Rethuglicans using HORSE DEWORMER!!! HORSE DEWORMER!!! HORSE DEWORMER!!! Haw! Haw! Haw! HORSE DEWORMER!!! Haw! Haw! Stoopids going to the ER cos they took HORSE DEWORMER!!! Serves them right I hope they die die die HORSE DEWORMER!!!"

Replies from: Richard_Kennaway
comment by Richard_Kennaway · 2021-11-23T17:44:57.708Z · LW(p) · GW(p)

For example [LW(p) · GW(p)].

Replies from: rosyatrandom
comment by rosyatrandom · 2021-11-24T10:02:23.336Z · LW(p) · GW(p)

No, not really, Richard, but at least you tried. 

If you tried harder, you might notice that my contempt did not actually bring with it any malice or schadenfreude, or even any mention of 'horse dewormer', which seems to be the entirety of your take. So... yeah, very well done there.

comment by rosyatrandom · 2021-11-23T12:34:19.878Z · LW(p) · GW(p)

Let's face it -- anything promoted by reactionary-moron-targeting snake-oil grifters, especially those with 'MAGA' in their names, can basically be written off immediately with little loss of value.