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FYI, Chubbyemu recently released a video regarding a DNP overdose in a young man attempting to lose weight https://youtu.be/ChPeG19qKUo

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Maybe we've gone wrong as a society if burning to death from the inside is the less risky option.

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The Texas case sounds like a large enough sample size that you could get an idea of long-term side effects from DNP usage via a survey.

Also, doesn't most modern anti-aging thought revolve around slowing the metabolism (e.g. fasting), not speeding it up? It sounds like this stuff would make you die faster, even if you didn't have any major side effects from it.

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Tried getting it off Ali baba once but it was just orange died sawdust. Also my family decided I was on meth because I was involved with a seemingly mysterious substance tied to weight loss that might explode and they didn't understand my explanations...

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Correction to "They pump protons across a membrane, creating pressure for electrons to travel the opposite direction." Actually they create pressure (potential) for electrons to travel in the *same* direction. When positive charge goes one way, negative charge also "wants" to go that way, following its potential energy gradient. Making electrons travel in the opposite direction would cost even more energy, defeating the purpose.

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It feels very weird to make drugs that make bodies less efficient. Like, if you don't need so many calories, there's a pretty easy solution!

But obviously it's not so easy in practice as human bodies are vastly complicated biochemical laboratories operating under sometimes faulty instructions.

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I've read that among a certain segment of the naturally thin population they naturally release excess calories as heat rather than storing them as fat.

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First, I am disappointed that there is no "conscious uncoupling" joke in here. A missed opportunity! Second, pretty sure that instead of "all is not lost" (implying that nothing whatsoever is lost) you mean "not all is lost" (implying not everything is lost). Sincerely yours in logical pedantry,

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There's some wonderful potential for Moloch tie-in with the only surefire weight loss pill involving burning from the inside

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Mitochondria in endotherms have proteins other mitochondria don't? And they're only expressed in certain tissue types? That strike anyone else as deeply weird?

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Is being fat the same thing as metabolic syndrome? Does DNP causing people to lose weight necessarily mean they're getting healthier?

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Not sure if I misunderstood something: how do you get from 10 000 users per death times 23 deaths to 2 300 000? Shouldn't it be 230 000, which is still more than I'd expect for the number of PED-munching bodybuilders in the UK, but at least a bit more plausible?

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Mar 2, 2021Liked by Scott Alexander

While shilling is in fashion, let me shill for Nick Lane's book *Power, Sex, Suicide: Mitochondria and the meaning of life* which is really interesting and gives you a better sense for why this whole *decoupling* business is really important and interesting. Seriously it's on of the 10 best non-fiction books I've read and I go through 25 or so a year.

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First with "Gabriel Over the White House," and now with this article, I read this piece with increasing certainty that this would turn out to be some kind of satire, which rapidly declined as no puns appeared in the last few paragraphs.

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I'm excited to see this post! Low dose DNP (2-3mg/day) has been a life saver for a number of individuals that I have spoken to in the past few months, myself included. There's a few private nootropics groups that are finding great results with it. And, a bodybuilding post on low dose DNP has some great excerpts from the recent research studies.

Low dose mitochondrial uncoupling has huge potential. DNP should not be slept on.

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"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."

Gary Taubes hardest hit.

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"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."

"Of course, if the FDA approved it for Huntington’s Disease, it would be FDA-approved, and usually that means it’s legal to prescribe for anything."

Finally I'll be able to get a prescription to get that stump out of my yard!

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Apparently non-lethal doses of this stuff shortens the lifespan of birds...

https://www.utu.fi/en/news/press-release/illegal-diet-pill-DNP-might-kill-you-on-the-long-run

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There was also recently news of a diabetes medication that causes weight-loss [1, 2]. I wonder what you think about this? The mechanism of action is allegedly loss of appetite though (and not hypercharged metabolism).

[1]: https://www.medpagetoday.com/primarycare/obesity/91146

[2]: https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

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Sounds like this indirectly adds some credence to the claim that lowering your thermostat helps lose weight

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My experience of med students is they forgot all of this ATP stuff the moment the exam is done as they claim it’s never actually useful as a doctor. As someone interested in biology, it is also intensely boring. I wonder how much Scott had to make himself look all this stuff up again. Then again, he’s been able to write about intensely boring biology before (obviously making it interesting when he writes about it, maybe he should write a textbook)

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Can we make offers, like on Shark Tank? I'll put up 25 grand for, eh....a 50% stake in the company.

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It's pretty easy to make with simple chemistry equipment. But given that nitroaromatic compounds can have some pretty nasty toxicity, especially to liver, I would stay well away from DNP. https://link.springer.com/article/10.1007/s13181-011-0162-6

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In this sentence: "Treat a hundred cases of obesity in exchange for one or two cases of cataracts (and some skin rashes, and some liver issues, and maybe a small risk of explosions) - is this obviously a bad deal?" Do you mean "*Trade* a hundred cases..." instead?

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I've always found it curious that none of the easy exploits tried on the human body seem to have ever worked. Something like true nootropics, or just a good weight-loss pill, anything that would feel like cheating. As if there's some natural law preventing it. Or do we just call the working stuff medicine?

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If you are interested in obesity and weight loss, there is at least one pharmaceutical in clinical trials:

GLP-1 and Obesity By Derek Lowe 15 February, 2021

https://blogs.sciencemag.org/pipeline/archives/2021/02/15/glp-1-and-obesity

Once-Weekly Semaglutide in Adults with Overweight or Obesity

https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

That research was funded by Novo Nordisk. They are currently selling the drug as a Type II Diabetes treatment, under the trade name Ozempic. Some doctors are using it off label as a treatment for obesity.

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Typo: produg -> prodrug.

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(I had believed that) the problem with weight loss was that the body would notice what you're doing and correct for it by making you want to eat more. Weird that this pill would get around that problem.

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Why are there different endings for this post between the web version and the one that I was emailed through substack?

The email reads, "...A friend of mine works there and asked me to write a post shilling their work to potential investors. I don’t usually do this, and please don’t take this as carte blanche to ask me to shill your company. But I figured this field was interesting enough to make an exception."

While the post is "...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."

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Why no animal studies? Do mice spontaneously burst into flames when they take 2,4-DNP? Enquiring minds want to know.

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There are now obesity drugs that are safe and effective, so I have to quibble with the subtitle "the only diet pill that really worked". The latest trials of semaglutide report ~15% weight loss with modest side effects. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

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'They pump protons across a membrane, creating pressure for electrons to travel the opposite direction.' That can't be right, the electrons would have to be under pressure to travel in the same direction that the protons did.

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this seems like a $20 bill laying on the ground—why doesn’t the body do this auto-regulation on its own? Or, in other words, why isn’t this a free lunch?

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While I don't necessarily think T-Nation is the greatest source of information, this guy lists 9 other controlled substances bodybuilders use to lose weight loss in an article explicitly saying not to use DNP: https://www.t-nation.com/pharma/how-bodybuilders-really-get-ripped

You probably shouldn't use them either unless you're in a country where they're not illegal and know what you're doing, but is there any good reason to think any of these hormone-based approaches that don't manipulate your mitochondria don't work? I'm inclined to believe anything used by pro bodybuilders who make no claim to being "natural" probably works.

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I got really excited/ confused for a moment seeing DNP, as in my profession that stands for do not populate/place, then was amused/ disappointed when it was a chemical.

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I keep reading "DNP" as "Democratic Nationalist Party."

I guess that'd explain why it was banned - both Red and Blue tribes oppose some part of it.

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Moderately related: https://m.youtube.com/watch?v=kXpzp4RDGJI is a nice video that shows how a mitochondrium turns the potential difference into ATP by rotating proteins.

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Mar 2, 2021Liked by Scott Alexander

I ran the numbers on this back in 2017 and decided that since cataract surgery exists it was *totally worth* a ~2% risk of cataracts to be able to lose weight as much as I want (albeit with very careful dosing) via a mechanism distinct from the usual weight-loss mechanisms. So I bought some DNP, used it to lose ~20 lbs in 3 months...and then absolutely *did* get the cataracts! About 6 months after I’d stopped taking DNP my vision grew cloudy (like being in heavy fog), the effect going from “annoying” to “can barely see well enough to cross the street safely” over a couple months. I found a good surgery center and had my lenses replaced ASAP with a high-tech plastic equivalent. Then (as expected) my vision got cloudy *yet again* necessitating a followup “zap the rest of the haze with lasers” procedure. Now my vision is okay again, but it was touch-and-go for a while.

Pre-cataract me thought having had cataract surgery would *eliminate the main risk* thereby giving DNP an even BETTER risk profile but post-cataract me thinks DNP is probably scarier than I gave it credit for, so I haven’t gotten any more.

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As grad student studying a lot of biochemical pathways in the body, I got curious about mitochondrial decoupling. I decided to experiment on myself with a seaweed extract which supposedly could have a mitochondrial decoupling effect in fat tissue. I didn't noticeably lose weight while taking it (maybe I just subconsciously increased my calorie intake since I wasn't actively dieting?) but I did get Really Uncomfortably Warm. Like, so warm that I was running like three or four degrees above my normal and it gave me trouble sleeping. I also noticed a sense of increased energy, but decided it wasn't worth the uncomfortable warmth after a few months and stopped taking it.

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From a health perspective, how useful would this really be? I am asking a causality question. If we assume that, for example, Type 2 Diabetes is caused by being overweight then losing weight by mitochondrial decoupling would be a good thing. But my understanding is that the relationship between Type 2 Diabetes and obesity is not so simply causal. So, this drug could result in a population of people who suffer the maladies normally associated with obesity but who are not obese. Not nothing, but not great either.

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In Texas, a century from now, going to jail for tax and insurance fraud will be as honorable and as much of a way of life as dying in a cattle raid was for the Irish.

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Mitochondria uncouplers sound like they could plausibly mess with the heartbeat, in potentially dangerous ways (Specifically ventricular repolarisation, ie QT interval prolongation and the like). When you prevent ventricular myocytes from accessing the energy they need, you run the risk of delaying, or otherwise altering the fairly precise electrical patterns that keep the show running.

A (very) quick google doesn’t bring up a whole lot for me; is this a concern you ran into during your research for this post?

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Chubbyemu on youtube just released a video about a DNP near-death case: https://www.youtube.com/watch?v=ChPeG19qKUo. He also has an in depth interview with the survivor: https://www.youtube.com/watch?v=o15HCjtSkug

And David Sinclair was just on the Smartless podcast, a great episode: https://www.smartless.com/episodes/episode/d2bb7c57/david-sinclair

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"Mitochondrial energy production generates various toxic byproducts which make neurological diseases worse, and making the mitochondria less efficient might produce fewer of them."

This is counterintuitive, but seems to check out. As part of their normal functioning, mitochondria generate ROS, increasing oxidative stress. If you make them less efficient, it stands to reason that they'd do more of that, but it turns out that this reduces ROS generation and oxidative stress.

I feel like I'm missing something important about the mechanism of action.

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This is a good excuse to plug my favorite crackpot biological theory: "mitonuclear match" which is basically how well the proteins that move protons across the mitochondrial membrane work together, plays a central role in the relationship between fertility and longevity across all species. https://nick-lane.net/wp-content/uploads/2016/12/Lane-Bioessays-mitonuclear-match.pdf

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I previously competed in bodybuilding at a high level. One of the most interesting protocols that I have seen for DNP involved using it to counteract accumulated insulin resistance secondary to the usage of insulin and/or growth hormone. DNP seems to very quickly restore insulin sensitivity above and beyond the effects that one would expect from weight loss. These effects persist after the user stops use of DNP. I would be interested to see whether these new mitochondrial uncouplers have similar effects, which would make them useful for a still wider population.

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Equator Therapeutics is a fantastic company and I am proud to be an Investor! That said, it is a private company and there are not always opportunities to invest in this or any cutting edge biotech startup. Lastly, as many commenters have correctly mentioned, startup investing is risky and you should consider the capital to be very much at risk. But, yes I think Jonah and his co-founders are brilliant and I am very encouraged by Equator's progress to date and their singleminded focus on getting this right for the sake of humanity - David Segura

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GLP-1 agonists work. https://www.nejm.org/doi/10.1056/NEJMoa2032183 The results of this recent RCT are pretty striking, though it’s over a longer time span. It kind of blows my mind that with all these crazy new onc and rare disease breakthroughs, gene therapies, immonumodulators etc. that we don’t have have an effective, safe widely available way to interrupt/circumvent metabolism. And very few seem to be working on anything despite the country being 2/3rds overweight or obese and rising and colossal health externalities. We seem to be sticking to the good old Protestant willpower model as physicians, without even adequate tools (like prescribing food) to ensure patients actually eat healthy and exercise.

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Fascinating! I've known of dnp for some time including the dangers but never knew the backstory. Where can we invest? I can't be find the link. The story was well worth making the investment IMO

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> The tragic history of the only diet pill that really worked

Scott, did you look into ephedrine hydrochloride?

Decent starting overview:

https://www.sciencedirect.com/topics/neuroscience/ephedra

If you want to research deeper, "ephedrine thermogenesis" brings up a lot of papers.

Quick summary [*] — it seems safe under MD's supervision. Certain people should never take it under any circumstances. People who can take it should do it carefully. Because people would sometimes use it recklessly and have adverse outcomes, it got banned from being prescribed or advertised as being for weight loss. Controlled status varies tremendously worldwide — it's OTC (but you have to show valid ID) in the United States; it's outright banned in some places and completely uncontrolled in others.

[*] (Relevant disclaimers: just my reading of the medical and scientific literature, but not a physician, not giving advice, might be mistaken, everyone should do their own research and talk to your physician, etc, etc, etc.)

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founding

The low theraputic index seems almost a dealbreaker in this case. You can't beat thermodynamics, and this is a particularly brute-force thermodynamic approach to weight loss. 500 kcal of the food you ate today doesn't turn into fat because it turns into heat instead, and any bit of cleverness that makes it so you don't get the heat means that this mechanism at least doesn't spare you the fat.

If the math works out that you can safely use some variant of the leaky-mitochondria trick to lose 2 lb/week, and *maybe* 5 lb/week, but 10 lb/week puts you in heatstroke territory, then the problem is that you can't have anything with the status of an FDA-approved diet pill that won't have more than a few people thinking "I *really* need to lose 10 lbs this week to fit into my wedding dress, so I'm taking the whole month's prescription this week and I promise to eat healthy after the wedding". There was apparently some of that in the 1930s, and the British bodybuilders, but I think there's a lot more pressure to be thin now than there was in the 1930s.

I say almost a dealbreaker, because the prodrug approach has an out: if you can find a prodrug where the metabolic transformation upstream of the mitochondria is a rate-limiting factor *and* saturates well below the "cause heatstroke" level, then you might be able to make this tolerably safe. That's a pretty tall order, but as you say, for an effective counter to obesity it's worth taking a look.

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1. Metformin also does something to mitochondria, right? That maybe makes them work less well? This study (https://pubmed.ncbi.nlm.nih.gov/30548390/) complained that metformin reduces how well mitochondria respond to exercise. But isn't that (at least part of) the point? Would any scientists or doctors like to explain this legibly to us social science types?

2. After I read Scott's Fussell book review, I thought, "no need to use the Greek -on to -a plural suffix for 'rhododendron.' That's a bit much for flowers. It's not like they're mitochondria." And here we are, reading about mitochondria.

2a. Rhododendrons are definitely not a high-status flower these days, at least in the DC suburbs. They are often kind of a lurid pink or red. I had them ripped out when we moved to our house and replaced with hydrangeas, which are definitely the high-status flower du jour. Something to do with the ascendancy of Mark Sikes and his mania for blue and white.

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Wait, so *Parasite Eve* was a documentary ? Live and learn.

https://parasiteeve.fandom.com/wiki/Parasite_Energy#Liberate

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> 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.

You can tell Scott has never had to survive (northern) winter without heat. :P

I absolutely would have taken DNP for warmth at the time, and I was aware of it, but had forgotten the name and couldn't find it again.

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> Remember, mitochondria are the powerhouse of the cell. They pump protons across a membrane, creating pressure for electrons to follow.

It might be interesting to note that the enzyme producing ATP is quite literally a turbine (https://www.youtube.com/watch?v=kXpzp4RDGJI), although with effectively zero inertia.

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I'm not sure this is a responsible post, given the tendencies of SSC/lesswrong readers to lifehack their way into trouble and wildly overestimate their competence.

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The surprising part for me was hearing that bodybuilders are concerned with weight-loss.

I'm a skinny guy who knows I'll never have bulky muscles without serious weight gains. I guess I always assumed increased calorie intake was a natural perquisite for bodybuilding but in retrospect its obviously more complicated than that.

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How much safer would this be if the half life were only 8 hours? Or what if we targeted the effects better? Presumably our striated muscles have to be good at thermoregulation.

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BAM-15 is an unfortunate name if it does end up exploding

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But do the metabolic processes that are accelerated by these compounds produce toxins, perhaps some of the same ones causing negative consequences of obesity?

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I recall some research from the past couple of years documenting that the mitochondria of ME patients ("chronic fatigue syndrome") were producing only about 50% of the energy that normal mitochondria produce. So I've been lazily guessing that an excess reliance on stress energy might be responsible for one of the most commonly expressed complaints: the all-over burning sensation beneath the surface of the skin. But this fascinating write-up of DNP gives much food for thought.

Gabapentin is one of the most common drugs used for treating the neuropathies associated with many ME patients (and most fibromyalgia patients, who tend to have varying levels of chronic fatigue) -- and gabapentin causes weight gain pretty much no matter how much you eat.

There are so many interconnected mysteries remaining, but I'm having a hard time imagining anyone intentionally wanting to cripple the main source of normal, healthy energy production. I'm no scientist, but it strikes me as akin to, say, cutting off your hands to protect you from the dangers of smoking. And it seems super weird that anyone who is interested in athletic performance would venture down the path of punching holes in their energy factories! Surely that could never be sustainable.

When I got sick about ten years ago, I was diagnosed with central neuropathy, peripheral neuropathy, small-fiber neuropathy (which IS fibromyalgia, if you believe my neurologist) -- and also an EDS-type connective tissue disorder. But I most identify with chronic fatigue syndrome (ME -- except I doubt that mine was caused by a virus) because it better captures the utterly systemic nature of the illness.

There's a good reason ME/CFS patients use the shorthand of "flu-like symptoms": because most others can imagine what a full body/mind/energy debilitation from a bad case of the flu feels like, while they tend to associate fibromyalgia, for example, with pedestrian aches and pains. I could go on and on with a list of my other symptoms (like a full year of hives/rashes upon getting sick, and of course the burning -- there's always the burning) as well as diagnoses (IBS, orthostatic hypertension), but they all seem connected at a cellular level.

So, I do hope whoever's working on this stuff for weight-loss reasons contributes to furthering the overall science (which might also apply to Long Covid). But I also hope potential consumers remain extremely wary about playing around with such a central engine of the entire body.

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Can't quite shake fascination with Russia's industrial application of DNP as an antidote to freezing. One has to wonder, if DNP had been readily available in Texas last month, how many would have voluntarily tried it (rather than firing up barbecues and other CO2 producer heaters in enclosed spaces)?

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We are finally understanding the biology of obesity and body weight regulation. Look at semaglutide 2.4 mg with papers in NEJM, Lancet and JAMA showing ~15% weight loss on average. Why do you want to go down the sordid trail of dangerous and stupid weight loss shams, when we have medications with an evidence base to review. Semaglutide is submitted to the FDA for review this summer for a weight indication. It is already approved for diabetes and has a cardiovascular outcome trial underway. There is no need to pursue the dangerous DNP.

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My understanding is that exercise isn't great for weight loss because it makes people hungrier, canceling out the extra calories burned. Why does DNP not have the same effect?

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The general rule of thumb for steady state drug concentrations in pharmacy is around 5 half lives so if DNP has a 36 hour half life it takes around a week before it hits its stable in vivo concentration which makes it no surprise people are mucking up the dose.

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Ah, so that's why Mr. Freeze has to stay inside a cold suit.

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For the past several years I've fantasized about DNP on cold winter days but this has put me off it

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Scott, what's your take on CoQ10? Lot's of new supplements of CoQ10 are hitting the shelves and they say it makes your metabolism young again -ish. Thanks

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When Scott mentions the relative risks of the drug verses obesity he's falling into a fallacy I see many doctors fall into. It's kind of related to goodharts law.

That is confusing a correlated marker of ill health with a cause.

Obesity does have some direct impacts on health but also is a correlate of other things that have serious impacts on health.

Insulin resistance and metabolic syndrome is probably the main one. Lack of exercise and an unhealthy diet is another. Stress and social social isolation correlate to obesity. Hypothyroidism, certain viral infections, certain psychological problems, and on.

To do a proper risk reward analysis we would need to run an experiment on at risk obese people and see what effects the pill has on overall morbidity and mortality. Short of that we would need to carefully try to tease apart the effects of obesity from correlates in obese individuals.

I also strongly suspect that obesity in many cases is actually a problematic adaptation of the body. A kind of lesser evil that has a purpose, like fever, inflammation or SAD. Targetting obesity with the drug not only presents the danger of the drug, and may not net the benefit of reducing all the correlated morbities, but also may undermine protective roles that obesity has.

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I did a two-week DNP cycle last year. I tried to maintain an ingested dosage of ~500-600mg at all times, using a half-life calculator I maintained using Excel. I am 6'3", 220lb, so the dosage for my body wasn't extreme, but the experience was absolutely awful. I was barely able to sleep, I sweated through my sheets and my sweat was yellow and turned everything yellow. I also had insatiable cravings for food. I only ended up losing 3–4lb. It's not a miracle drug and the sides are, in my opinion, simply not worth it. A 500-700 calorie deficit over the course of several weeks would have resulted in a similar loss of weight.

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The issue with mitochondrial uncoupling is that it acts generically across all cells, and while bodybuilding forums and old research establishes the obvious stupidity that comes with acute high usage (peripheral neuropathy, ocular damage, heat stroke), there’s indication that this has potential adverse cognitive effects.

The PNS effects come from damage to myelination of long nerves. But myelin also exists in the brain, and it’s a fair extension to assume that if DNP even has slight permeability across the BBB, this could have neurodegenerative effects long term.

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Fuck glaucoma, make pep pills debonaire again.

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Is obesity a source or a symptom? I know exercise reduces inflammation a lot, and that can look like significant weight loss.

I also know that which body types are in fashion changes mostly with which abusive partner stereotype the beauty industry is being today.

Possibly a big part of the issue is that pharmaceutical companies have a big incentive to focus on drugs rather than, say, barefoot running, and doctors usually keep up with pharmaceutical advancements more than they do with evolutionary biology and juggling and suchlike.

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Mitochondria take some time to adapt to their workload, and the dose makes the poison. There's a chance it could be safe enough if one very gradually ramped up from a nanodose to a microdose, and then gradually tapered down from a microdose to a nanodose to nothing. Someone should try this on mice and see what happens before risking any humans.

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I DID IT. It fucked me up and it was a year before my nerves and sense of taste began to recover. PURE FUCKING POISON. THIS IS the kind of evil p[rofitering gdamned BS that should be properly reported or completely banned from all media sources due to its' absolute manifestation of injurious affects.

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I took dnp 200-400mg / each day for 9 years or so, only a few small breaks. I only stopped since I now have babies (and don't want it around the house)... It's been about a year and a half since I touched it.

I used it to maintain my weight. I'll be honest, when I was on it I never ever got I'll or sick, it was weird. Had a lot of energy too. Since being "off" I've caught a couple colds.

During and since then I had my blood work taken and everything is perfectly fine... Blood tests, Liver, kidneys, etc...all normal.

The only downside is I think I'll have cataracts soon (at age 37) since it's been difficult to drive at night (seeing starbursts since about 3 months ago but had my eyes dilated in January and eye Dr said nothing..) and about 4 years ago the eye Dr told me I had deposits on my lenses.

Another reason I stopped is that bird study saying it cut life span by 20%...

Anyway just thought I would weigh in.. never had any close calls or anything since I never went above 400mg or so.. when I saw on bodybuilding forums people doing 1g+... Just madness.

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