The tragic history of the only diet pill that worked | Hacker News Reader

The tragic history of the only diet pill that worked

astralcodexten.substack.com

45 pointspseudolus15 comments

You might wonder how "a shady outfit called Isabella Laboratories" discovered the only diet pill that worked. They were just commercializing, recklessly, others' research. This 1933 JAMA article told the world about 2,4 DNP's striking effects:

"Actions And Uses Of Dinitrophenol: Promising Metabolic Applications"

https://jamanetwork.com/journals/jama/article-abstract/24402...

https://sci-hub.se/10.1001/jama.1933.02740280013006

2,4 DNP was being scrutinized due to its poisoning of explosives workers during the First World War.

The whole paper is worth reading. The benefit and great danger of the compound are stated very succinctly:

"When dinitrophenol is given to experimental animals, it causes an increase in metabolism within one minute after injection, or somewhat more slowly, when given gastrically. The increase in metabolism with doses of 10 mg per kilogram or less is about 50 percent. With higher doses, metabolism may be increased fourfold or more, until the animal produces heat so fast that it may be killed by the resulting fever."

This chemical has stuck in my memory since the 1990s, thanks to Uncle Al on sci.chem:

https://en.wikipedia.org/wiki/SF-6847

It is an uncoupling agent [1] with approximately 1800 times the potency of 2,4 dinitrophenol (the compound discussed in the substack post). This means that it is probably deadlier than most nerve gases in humans, milligram for milligram.

The "Uncoupler" wikipedia page I linked is a decent starting point for other chemicals in the class. Many would presumably drive weight loss like 2,4 DNP itself; and most of those would also incur similar side effects ranging from inconvenient to lethal.

[1] https://en.wikipedia.org/wiki/Uncoupler

Interesting, that sent me down a bit of a Wikipedia rabbit hole, which took me to this interesting quote: "there is no antidote or remedy for DNP once taken. In consequence, DNP has a high mortality rate — of those who presented at hospital between 2007 and 2019 with a history of having taken DNP, 18% died. This puts DNP close to cyanide in terms of its toxicity."

So that means that only a fifth or so of people who went to the hospital after taking cyanide died! Surprisingly low...

There are treatments for cyanide poisoning. Hydroxocobalamin can be used to react cyanide and form cyanocobalamin (vitamin B-12) which is nontoxic and renally excreted. The trick is to identify the cyanide poisoning quickly enough.

Isn't there a survivorship bias here? It doesn't count all the people that died before getting to the hospital.

I don't think I've laughed this much at an article in a long time;

|> There’s something quintessentially Russian about this, like a cross between the Platonic essences of AK-47s and Krokodil.

|> In fact, I just checked out a couple of bodybuilding forums and this is definitely true - one of them may have used the phrase “YOLO”.

|> And Vice (why is it always Vice?) is somehow even more melodramatic

Does anyone have any other works of writing with a similar style or subject matter? This truly made my day :)

This guy has written so much on Slate Star Codex that you could spend the next month reading it.

Derek Lowe's blog on medicinal chemistry/biopharma has a whole section on "Things I won't work with" (from a chemist's perspective):

https://blogs.sciencemag.org/pipeline/archives/category/thin...

Matt Levine’s Bloomberg column applies a similar savvy dry humor to finance topics, I don’t actually care much for finance but I read it because it’s great writing and illustrates how to make dense and uninteresting topics approachable and engaging.

Also recently covered by "chubbyemu", of the great medical clickbait youtube titles: "A Man Had An Accident With A Weight Loss Chemical. This Is What Happened To His Organs." https://www.youtube.com/watch?v=ChPeG19qKUo

I think it's likely an overstatement to say there's only one that worked.

I don't have experience with dieting or diet pills per se, but I've taken bupropion which is also a part of some weight loss formulations and it substantially counteracted the weight gain I've had from another medication.

The weight loss drug I'm thinking of combines bupropion and an opioid receptor blocker. This is not medical advice and I have not tested it, but I'm inclined to think my experience indicates it should work.

Bupropion, incidentally, is a nicotinic receptor blocker, which is why it's also prescribed as an aid to stop smoking. And an antidepressant. And a dessert topping and floor wax...

I wonder if it does anything to mitochondria though?

Amphetamines are another one that works

@perl4ever: "I don't have experience with dieting or diet pills per se"

If you need to go on a "diet" then your eating too much for the amount of physical excercise you engage in.

People who are morbidly overweight don't seem to have a "I-am-Full" switch. Or have a "I-am-always-hungry" switch that's stuck in the on position. They eat too much, the body responds by burning off the excess. They soon feel more hungry and so on. There's also a psychological component involved, comfort eating etc.

All medications come with side-effects, taking such for long periods is not wise. Certanly not to combat weight-gain. Go for a five-mile run Weekdays and on Sunday. You can have Saturday off.

I think you misunderstood me. I don't need to go on a diet, and I've never really tried. But I've felt and observed that medications change my internal thermostat that governs when I feel hungry. So, similar to lab experiments where they use an artificial proxy for a human illness, I think that bupropion's effect on my induced weight gain might be evidence it works on the natural kind - again, not medical advice, but after all, the FDA approved it for that purpose. I'm not taking it for weight loss precisely, but it is a replacement for an SSRI, and weight loss is a convenient side effect.

In my opinion, psychology, willpower, exercise, healthy foods, are all overrated as driving factors for obesity. All that really matters is your internal regulator of feelings of hunger. There may not be a perfect "diet pill" but it seems to me that if it is straightforward to induce weight gain (and eventually type 2 diabetes) with a pill, then there's no reason to doubt the feasibility of a good diet pill in principle.

Then again, if I put on my "devil's advocate" cap, there could be a fundamental difference between someone whose "thermostat" is stable at a weight that is too high and someone whose setting is stuck on "max". But very few people really gain weight without limit.

Something that really bugs me about prescription meds is, after a while you notice that drugs get invented or first approved for one thing, and then it turns out they are useful for something totally different, which really means that nobody is looking at what the drug truly is, in a holistic sense, in all its dimensions. Like, if e.g. mitochondria are important to understanding one drug, then we should be going back and looking with new eyes at all drugs that we already have to see how they affect that aspect of the body. Because not only maybe the old drugs have new possible applications, but maybe we were all wrong about why they worked in the old applications. I fear there's no incentive to, mostly, because if something's FDA approved and has a market, why bother thinking about it any more.

There are better ways to combat obesity. This is symptom treatment.

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