[EDIT: I’m hearing that some people are considering taking DNP after reading this post. I tried to stress very hard how bad an idea that was, but apparently it didn’t sink in. PLEASE DO NOT TAKE DNP AFTER READING THIS. I tried to cover some of the risks, but there are others I didn’t mention, and it’s just generally a terrible chemical.]

In the 1930s, a shady outfit called Isabella Laboratories made a popular over-the-counter diet pill called Formula 281 (slogan: “281 for the too weighty one”). If you’re familiar with any of: the 1930s, shady pharma, or diet pills, your next question will be “did it contain amphetamines?”. Actually, no! It contained 2,4-dinitrophenol, a mitochondrial uncoupling agent.

DNP is that rarest of birds: a weight-loss pill which really works, no diet or exercise required. About 100,000 people used it in the mid-1930s. On average, they lost about 2 to 5 pounds per week, for however many weeks they wanted to keep losing it. The formula stayed popular until it was banned by the FDA in 1938, about one second after Congress passed the law saying the FDA could ban things.

What was the catch? Well, several catches, really. Many users went blind. Others got rashes, liver problems, kidney problems, or peripheral neuropathy. A few died horribly, apparently burning to death from the inside. Occasionally the DNP would just explode - the “di-nitro” of DNP is pretty similar to the “tri-nitro” of TNT, and it turns out that’s not a coincidence. As far as I know, DNP is the only substance to be banned by both the FDA and the Department of Homeland Security for unrelated reasons.

(this being the 21st century, you can still buy it online for $3/pill)

Still. A diet pill that really works! You don’t hear about too many of those these days, so let’s take a closer look.

DNP is a mitochondrial uncoupling agent. Remember, mitochondria are the powerhouse of the cell. They pump protons across a membrane, creating pressure for electrons to follow. This forms an electrical gradient which your body exploits to create the “energy currency” ATP. To “uncouple” mitochondria means to punch holes in the membrane, letting the protons leak back through and “wasting” the energy as heat. This makes your body’s energy production less efficient, meaning you have to burn more calories per amount of metabolism you want to do. Hence the weight loss. But replacing otherwise-useful energy with waste heat can have some nasty consequences.

During the 1930s, the main worry was cataracts. Estimates range from 1 in 170 users (source) to as high as 1 in 40 (source, but it’s just some guy speculating that “it could be as many as 2500 people” and me dividing that into 100,000 users). DNP cataracts are pretty striking - you could feel perfectly fine one day, and wake up with blurry vision or even blind in both eyes the next. Why? The lens of the eye needs to maintain a careful balance between different ions to stay clear. Lens epithelial cells work hard to pump some ions in and others out. These cells don’t have enough slack to be able to shrug off partially-uncoupled mitochondria. They run out of fuel - specifically ATP - and break down. The lens of the eye gets flooded with ions and clouds over.

(this all sounds really sensible when I write it out like this, but sometimes people get the cataracts weeks or months after they stop the drug, and no one knows why.)

But also, all that extra waste heat adds up. “Normal” DNP users will run a slight fever. But people who overdose will get fevers of 110 degrees plus, which are incompatible with life. This is very rare; Grundlingh et al say only 5 - 10 deaths in the ‘30s, which suggests only 1/10,000 users - but I’m not sure the 1930s had a robust drug monitoring system. During the 1980s, a sketchy Texan diet doctor gave DNP to 14,000 patients. Only one died (a suicide by deliberate overdose, though many other people experienced other side effects), which again suggests the 1/10,000 number. Still, “one in ten thousand users will burn to death from the inside” is a heck of a thing for that chirpy voice which lists side effects on drug commercials to have to say.

From a health column in the 9/26/1934 edition of the Waterloo Iowa Courier.

So after 1938, US dieters stopped using 2,4-dinitrophenol. It next shows up in history books on the Eastern Front of World War 2, where Soviet soldiers would - I can’t believe I’m writing this - take it to keep warm. There’s something quintessentially Russian about this, like a cross between the Platonic essences of AK-47s and Krokodil. Still, World War 2 ended and poor DNP vanished from the history books again.

It next shows up in the 1980s, courtesy of the aforementioned sketchy Texas diet doctor. This man - Dr. Nicholas Bachynsky - argued that the FDA had no power over him, since he wasn’t transporting it across state lines. I’m not sure of the legalities of this, but it delayed the FDA enough that they handed the case to the state of Texas. Texas also wanted to shut him down, but Bachynsky pointed to a clause in Texan law which grandfathered in chemicals sold before the 1938 act giving the FDA its regulatory powers. There was some court case about this, I don’t understand the technicalities, but the court very clearly ruled DNP was illegal in Texas and Bachynsky couldn’t prescribe it. Bachynsky ignored the order, continued prescribing DNP for several years, and made over $8 million selling it to dieters; somehow nobody bothered to shut him down until he was arrested and jailed for tax and insurance fraud years later. In conclusion, Texas truly is the greatest state.

We next encounter DNP as a supplement for British bodybuilders. This thread starts with Dan Duchaine, a bodybuilder/drug-dealer who called himself “The Steroid Guru”. He got jailed a bunch of times for selling illegal bodybuilding drugs, and during one such adventure ended up confined together with - Nicholas Bachynsky, who sold him on the wonders of DNP. Once he got out he started shilling it alongside his other wares, and it became a big hit. For whatever reason most of the articles about this are from Britain, which counts 23 DNP-related deaths in the past ten years. Based on our previous numbers, this would suggest 230,000 users. This sounds ways too high, so my guess is bodybuilders are using it much less responsibly than 1930s people or sketchy Texas diet doctor patients. 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”.

(a commenter adds: “This supplement has gone through cycles of popularity for decades in online bodybuilding and nootropics communities. The same anecdotal stories of safety have been repeated many times over. With each surge of popularity there are waves of people who believe they’ve rediscovered a secret weight loss cheat code, and who also believe that they’re smart enough to use it correctly. And almost without fail, there are streams of reports from people who have very bad experiences or hyperreactions to what they assumed were safe doses…DNP also has a long half-life of around 36 hours or more, depending on the source. This means that daily dosing will result in build-up of DNP in your blood. The common trap occurs when people test the waters with a certain dose for a few days, but then end up accumulating uncomfortably high doses with repeated daily dosing. Or people get eager for faster weight loss, so they double up on doses. Once they’ve overdosed, it can be days before they return to normal - if they do.”)

The British tabloids had a field day with this. The Daily Mail talks about being BOILED ALIVE BY INTERNET SLIMMING PILLS! And Vice (why is it always Vice?) is somehow even more melodramatic:

DNP – this un-killable daemon soused in Satanic sulphur, dieting’s eternal bad penny – will continue to roll back round, cooking its victims from within, cell-by-cell, igniting flesh with its Mephistophelean magic.

Whenever British tabloids, Vice, and the FDA all hate a thing, I’m inclined to feel at least a little fondness towards it. So is there a case for 2,4-dinitrophenol? I think the case would look like: sure, it has a very low therapeutic index. Sure, if you take just a few times the recommended dose, you could die. But if you very carefully take exactly the recommended dose, you probably won’t. You could give it out like methadone, in a way that makes it impossible to overdose. Patients might still get cataracts. But cataracts are treatable, or at least more treatable than some of the complications of obesity.

The rashes, liver problems, and peripheral neuropathy would be my main worries, but they haven’t been studied very well and I don’t know if they’re more like 1/10 or 1/10,000. Did you know that the 1938 FDA refused to even do a cost-benefit analysis on DNP because they thought it had no benefits? This was before people really understood the dangers of obesity; they thought it was just a cosmetic problem.

I think the strongest case against re-evaluating DNP might be that most people who lose weight gain it back again; there’s no reason to think weight loss through DNP works any differently. You would have to either stay on it long-term or take a repeat course once every few months/years. This sounds like it would massively raise the danger level, unless the vulnerability was genetic or otherwise inherent such that if you weren’t the “sort of person” who got the side effects the first time, you were permanently protected. I don’t know how you would find this out, and even if it were true, long-term DNP use would mean a lot of chances to accidentally overdose.

But all is not lost. In the past few years, there’s been something of a renaissance in the mitochondrial uncoupling space.

In 2019, the FDA gave Mitochon Pharmaceuticals permission to test DNP as a treatment for Huntington’s disease. Mitochondrial energy production generates various toxic byproducts which make neurological diseases worse, and making the mitochondria less efficient might produce fewer of them. They suggest they might have some way of giving it as a prodrug with fewer side effects, but pharma companies are always saying this sort of thing.

Last year, an Australian team published a paper about a new mitochondrial uncoupler, BAM-15. They claim it’s non-toxic, doesn’t explode, and doesn’t increase body temperature (all uncouplers produce heat, but the body has a certain capacity to adjust for that, and if the heat produced is below the body’s adjustment capacity there’s no fever). Everyone involved works for Continuum Biosciences, an ambitious-looking biotech startup including anti-aging expert David Sinclair, so I’m sure they’re not missing the implications. But I haven’t seen any clear signs of where they’re going with this.

And closer to home, a team from UCSF recently figured out the specifics of natural mitochondrial uncoupling. All mitochondria contain certain uncoupling proteins - think of them as doors, in contrast to 2,4-DNP punching holes in the wall - for generating heat. These are well-understood in brown fat, a special kind of fat used to maintain body temperature, but most of the rest of the body is a mystery. The new paper suggests that uncoupling in other cells is orchestrated by the mitochondrial ADP/ATP carrier, a protein which helps shuffle the “depleted cellular battery” ADP into the mitochondria and the “recharged cellular battery” ATP out of it. At the same time, it lets a few protons escape the positively-charged side, uncoupling the mitochondrion a little bit. Depending on the relative level of ADP on either side, it might let more or fewer protons through. This forms a feedback loop that raises or lowers the level of uncoupling depending on the level of ATP in the cell.

This is a natural biological process - it’s part of how your body generates heat. It seems pretty safe - if there’s too little ATP, the feedback loop kicks in and closes the doors. A drug that modified this process could potentially replicate the fat-burning properties of DNP without its side effects. And if they targeted it to be a little less intense than DNP, it wouldn’t be able to reach the point where it caused deadly fevers either.

This group also hasn’t missed the implications - they’ve started Equator Therapeutics, a biotech company focused on developing drugs to hit this target. A friend of mine works there and shilled his company hard enough to get me interested in this. He’ll probably show up in the comments section, so you can ask him if you have any questions.

[A previous version of this post linked to a comment with a more explicit pitch for this company. Several commenters suggested I not do this, so I’ve deleted that part and will try to figure out a general policy on this.]