There isn’t one, because we still don’t know how acetaminophen works.

Aspirin has been in use for thousands of years and what it does to the body was a mystery for 90% of that time. But no more: ibuprofen, diclofenac and other NSAIDs all use the same mechanism, inhibition of two enzymes that promote inflammation, cause platelets to be sticky, but also destroy your stomach lining. We tried to get cute and selectively inhibit only one of those enzymes because the other caused gastritis, but that didn’t go well. That part of the aspirin family tree was cut short. There is, however, a whole separate branch that builds on aspirin’s effect on platelets. The more we know the more we don’t know, and at the edges of our knowledge lie new drugs.

The acetaminophen family tree is a stump. On one hand this isn’t a surprise: we have only known about it for 150 or so years. But then pure aspirin was synthesized around the same time — it was just willow bark extract ⊕ Acetaminophen was derived from coal tar so it is, in fact, coal tar extract. Somewhat off-putting for something to be taken by mouth, though coal tar can do wonders for dandruff. before the late 19th century — and look at how much we have learned since then. The best we have come up with is that acetaminophen works sort of the same way as aspirin, but only in “the central nervous system”. Vagueness covering for ignorance, like ⊕ The cure? Heavy cream and butter. generic life “stress” causing stomach ulcers.

Our knowledge gaps are so large that we still can’t agree on the name. Is it acetaminophen (APAP for tired interns who hand-wrote their notes) or paracetamol? Or just Tylenol? More vagueness.

Which is to say, there can be no mechanistic arguments for APAP risks and benefits as we know nothing about the mechanism: all inferences must be made empirically. And our 150 years' worth of popping coal tar pills have shown them to be safe for everything but the liver.

Still, it is worth acknowledging that APAP is a molecule extracted from coal tar whose mechanism of action is unknown but has something to do with the central nervous system. If someone described such a drug and then asked whether it could be behind some disorders of the brain, would you find the question completely whackadoodle? I would not. And would in any case practice myself and recommend to my patients via negativa, whenever possible and sensible.

The number of ways in which one can spend money for biomedical science is infinite. America has sunk trillions into genetics research, with a few important wins to show for it but not nearly as many as hoped for in the early 2000s. ⊕ For those too young to remember, this is the time when media were full of headlines about scientists finding the gene for x, where x was everything from hypertension to obesity to being gay. None of them panned out. Would a fraction of that being allocated to figuring out how one of the most widely-used drugs actually works be such a waste?

• David Graeber: Hostile Intelligence: Reflections from a Visit to the West Bank. From 2015, but ever-more relevant. “A life of calculated degradation” was an apt description for what has been going on, and it seems to have reached the end stage.
• The WSJ Editorial Board: Dr. Prasad, the FDA’s Grim Reaper. I won’t quote from this article because it is behind a paywall. Instead, here is FDR: “I ask you to judge me by the enemies I have made.” (ᔥThe Niche)
• Chris Arnade: The meaning of, and in, McDonald’s. From December 2024 and I don’t know if I have linked to it before — likely I have — but it came to mind when reading the article below.
• Ted Gioia: David Foster Wallace Tried to Warn Us About these Eight Things. They are, as summarized by Gioia (but do read the whole article for the explanation):

1. Screen technology will cause a crisis of loneliness, especially among young people.
2. This will lead to widespread depression.
3. This will also happen at a larger scale. Society will grow more fragmented and disconnected.
4. Screen technology promises to liberate us, but the reality is that it controls us for the benefit of others.
5. The people who control the technology work to hide their purposes and goals.
6. Our survival will depend on our ability to remain independent of these forces.
7. We don’t have many tools, but kindness and compassion will be the starting point.
8. Art can help us heal.

Indeed.

• BBC: Huntington’s disease successfully treated for first time. Big if true, but still at the press release stage. Caveat lector.
• CNN: A surgical team was about to harvest this man’s organs — until his doctor intervened. Concerning. Yes, it is extremely unlikely but the number of these occurrences should be exactly 0 and the system that allows them needs to be rethought.
• NYT: She Held Her Baby for an Hour. Then the State Took Her Away. Harrowing.
• NYT: An Age of Extinction Is Coming. Here’s How to Survive. A few months old but a good one from Ross Douthat. “In this environment, survival will depend on intentionality and intensity. Any aspect of human culture that people assume gets transmitted automatically, without too much conscious deliberation, is what online slang calls NGMI — not going to make it.” We are doing our small part by introducing our kids to the pre-1980s movies and some very old books.
• FT: The young against the young. From Janan Ganesh, with whom I am — predictably — in complete agreement: “Yes, a house in E8 will cost you now, but if you think that outweighs the invention of the hepatitis B vaccine, you might investigate the option of growing up a bit.”

Gift links for the last 3 — enjoy.

Yesterday, I quoted John Ioannidis’s description of how the pandemic was changing the norms of science:

There was absolutely no conspiracy or preplanning behind this hypercharged evolution. Simply, in times of crisis, the powerful thrive and the weak become more disadvantaged. Amid pandemic confusion, the powerful and the conflicted became more powerful and more conflicted, while millions of disadvantaged people have died and billions suffered.

First, note that no one person or thing (or a few countable ones) was responsible for the transformation, but rather that it was a natural property of the system. Then note that the pandemic sped up (or “hypercharged”) the system’s transition to its (breaking) endpoint. The American clinical trial ecosystem is even closer to its breaking point than science overall, and for the same reasons: its postulates make it untenable, and the influx of ZIRP-conjured pandemic-stamped money hypercharged the transition to this.

People go looking for ways to speed up clinical trials like they would for speeding up house construction. They ask: what is one key piece of legislation — the parking and zoning requirements of clinical research — that could either be tweaked or removed to break open the damn, so that trials would be as fast as they were in the 1960s? And why won’t the clinical trial hobbits tell us what those obstacles are, so that we can crush them?

But there is no one, or two, or two dozen such obstacles, the serial removal of which could speed up trial design, approvals, execution and readouts. The clinical trial path does not have boulder problem. Boulders would in fact be great: at least you can, while climbing over or making a 3-day detour around, fantasize about crushing them.

No, the problem with the path is that it runs through quicksand while being covered by a dense fog. Move too fast or stand in place and you die; move too slowly and you don’t get anywhere. Not that you know where to go: with all-encompassing fog you can only see five inches ahead anyway. There is not much time to think about anything else when you are in that kind of a quagmire, and how exactly would you imagine dealing with the fog? Drive it away with a big fan?

By “quicksand” I mean the moral, ethical and physical safety risks inherent to any clinical trail ⊕ This is why every introductory course on the topic must start with the ignominious history of experimenting on humans… and the systems we developed to deal ⊕ …immediately followed by a description of Institutional Review Boards and other regulatory matters. with them.

By “fog” I mean that much of the deliberation is not a matter of legislation but of opinion, values, principles and — the most loaded of words — comfort of people sitting on these IRBs and in the regulatory agencies. Depending on comfort level of individual members a question on whether a trial can proceed may take much deliberation or none at all. We can hardly know our own minds, and good luck about reading other people’s.

This is why I am skeptical that uncovering the FDA’s records would be of help to anyone but historians: the people who wrote them and interpreted them are no longer in play; different brains run the show, and the archives won’t reveal their thought process. Sure, sometimes there is one person sitting there that makes things worse than they should be, by being too slow, or thoughtless, or obstinate. But is “find better people” a tenable solution, when those people could be doing anything else, and with more reward of all kinds?

The pandemic hypercharge made everything worse. In addition to wading through quicksand while blinded by fog you now have to deal with many, many invisible neighbors elbowing you in the chest and kicking you in the groin, some intentionally, some out of carelessness, confusion, or not knowing any better. IRBs are overloaded and so are the regulators. What difference would any legislative change make?

Except, of course, it is to abolish one or both. It would lift the fog, sure, but would need a new kind of system to avoid making everyone sink to the bottom of the ethico-moral pit. Tearing down institutions is easy, building them is hard, as we see one but not the other being played out under our inattentive eyes.

• Bart’s Watch Stories on YouTube: How Casio Made the Most Sold Watch Ever. It is about Casio F-91W, my default watch, and I can attest to its — excuse the pun — timelessness.
• @StatisticUrban on X: What states do Americans most approve of? DC is the lowest at +1 net approval.
• Ruxandra Teslo: Your newborn is not Hepatitis B vaccinated because of wokeness. See also her exchange on X with Curtis Yarvin, aka Mencius Moldbug, aka Mr Head-Up-Ass who loves the sound of his one voice even as he recommends disastrous remedies for obvious problems.
• Marioun Fourcade and Kieran Healy: Authenticate thyself. The subheading is “The sovereign individual and the paradox of the digital age”. It is more highfalutin than what I usually read — “The combination of epistemological self-centredness and hyperconnectivity makes people susceptible to diffuse forms of ‘supersense’-making (to borrow a term from Hannah Arendt).”, reads one sentence — but the essay does some important sense-making of its own:

As the deployment of digital technologies continues to generate ever-more stratospheric concentrations of wealth, the masses sink deeper into the void left by the evisceration of social solidarity and the rise of automation. The often-missed point about sovereign individuals is that not everyone gets to be one. But everyone should aspire to be one, and in the meantime follow one, as they walk down the road to selfdom.

Worth reading for that last sentence alone.

Out today in Annals of Clinical and Translational Neurology: Durability of Response to B-Cell Maturation Antigen-Directed mRNA Cell Therapy in Myasthenia Gravis. It only took 18 months to get here from the pre-print but hey, we were able to get longer follow-up!

Whatever you think of medicalization of moderate obesity, the GLP-1 inhibitors semaglutide and tirzeparide (aka Ozempic, Wegowy and Zepbound) are truly groundbreaking. It takes a lot for me to admit something approaches imatinib in innovation and importance, and they are there! Incredibly, the drug companies that developed them are considered losers in the upside-down world of American finance:

Since their peak last year, the decline is more pronounced. Novo Nordisk has lost $367bn in value since its peak in June 2024, a fall of more than two-thirds, while Lilly has fallen 29 per cent from a record valuation last year, wiping $250bn off its market capitalisation.

In a decision that was short-termist and reactionary to the extreme, Novo Nordisk even fired their longstanding CEO over it.

The kicker comes from a healthcare fund manager quoted near the end of the article:

“If you’re a generalist investor, why are you putting money here, versus buying an AI stock, [given] the headwinds of both tariffs and the most favoured nation policy?” he added.

What are we even doing here?

The Occasional Human Sacrifice puts faces, personalities, anxieties and neuroses to the names of people who acted as whistleblowers to some of the biggest ethical failures in clinical trials. Some are textbook, like Tuskegee or the Willowbrook hepatitis studies, but many were either new to me, or just barely registered when they were briefly covered.

Elliott was himself a whistleblower in the case of Dan Markingson so he is hardly impartial to their cause — caveat lector — but the cases presented seem truly egregious. And not all of them are ancient history: Paolo Machiarrini experimented on humans without oversight as recently as 2014.

The picture you get is bleak and does not fill one with confidence about clinical research anywhere in the world. Physician-scientists are careless at best, selfish profiteers at worst, people who sit on ethics committees are a bunch of box-checkers, institutions are insular and protective of their own. Of course, there is major selection bias going on: yes, institutions protect their own but then there are many of their members who are accused daily of misconduct by conspiracy theorists, biopharma lobbyists, and the occasional psychopath. Some IRBs are indeed approval mills, but then there are those which truly protect research subjects, though alas what they do doesn’t make it into a book. How to tell where the equilibrium should lie?

In fairness to the book, it does not pretend to be a grand unifying theory of what is wrong with medical research. It is a collection of vignettes, no more and no less, and as such is an important source of “real-world” information to the research community. It is also a big honking red flag to any person thinking to blow the whistle on wrongdoings medical or not: it is a difficult path to take, with no vindication at the end.

Is lithium deficiency an important factor in developing Alzheimer’s disease? A recent paper in Nature provides some convincing evidence, mostly from mice. For example:

Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice.

I know quite a few doctors who would say lithium (carbonate) deficiency is responsible for many behavioral issues in adults, but this is not what they had in mind! (↬Derek Lowe)

Well that was fast:

“At the FDA’s request, Dr. Vinay Prasad is resuming leadership of the Center for Biologics Evaluation and Research,” HHS spokesperson Andrew Nixon said. “Neither the White House nor HHS will allow the fake news media to distract from the critical work the FDA is carrying out under the Trump administration.”

Maybe lobbying isn’t as effective as I thought? I am sure there are stories to be told about what happened during these two weeks.