https://astralcodexten.substack.com/p/shilling-for-big-mitochondria Astral Codex TenAstral Codex Ten Subscribe * About * Archive * Mistakes * Help * Sign in Shilling For Big Mitochondria The tragic history of the only diet pill that really worked 4 hr ago 134 51 Share 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, perfectly, 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. 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. [https]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.] 134 51 Share Subscribe Discussion [https] [ ] Create your profile Set photo[ ] [ ][ ] [ ] [ ] Sign up for the newsletter Save & Post Comment Only paying subscribers can comment on this post Subscribe Already a paying subscriber? Sign in Check your email For your security, we need to re-authenticate you. Click the link we sent to , or click here to log in. Chronological * New First * Top First * Chronological [https] deleted4 hr ago deleted Notjosephconrad3 hr ago Just an FYI. For any individual thinking of investing, one [https] diligence question would be: "are any biotech/ therapeutics-focused venture capital funds investing in this round?" 4Reply Scott Alexander3 hr ago I agree with not investing in early-stage biotech startups [https] unless you are a professional early-stage biotech startup investor or know your stuff to an implausible degree. 5Reply Watchman3 hr ago Wouldn't the risk of knowing your stuff to an implausible degree be that your decision making is likely better than that of the FDA or local equivalent, making your predictions risky due to the potential behaviours of less-informed [https] agents? Of course you could be expert in the mechanisms of drug regulators, but the safe bet then is surely to hire your skills out rather than gamble on startups... Reply Melvin2 hr ago If you're going to go round investing in early-stage biotech startups then the ins and outs of the FDA is probably about 50% of the "stuff" you need to know. [https] I used to invest in (publically traded but pre-revenue) biotech companies, I made a small profit in the end but spent way too much time stressing over trial results and FDA committee meetings etc. In terms of dollars per grey hair it was the worst way of making money that I had. 1Reply dqt1 hr ago [https] What are the top ways of making money that you had? :D Reply Melvin1 hr ago For me personally, over the past ten years, the best ways of [https] making money have been (a) investing in just about anything you can think of that isn't a biotech company, and (b) going to work and doing my job. Reply dqt1 hr ago [https] OMG, awesome, thank you so much :) Reply Notjosephconrad45 min ago [https] You know the joke about the foolproof method for making a small fortune in biotech? Reply Apodidomi3 hr ago [https] Presumably youre not, but If you're an investor - direct or indirect - make sure to disclose. Reply Scott Alexander3 hr ago [https] I'm not. 2Reply Walter Sobchak, Esq.2 hr ago Scott: This is important. DO NOT Post solicitations for investments. I do not know enough of your exact situation or of the nature of the solicitation to give competent legal advice to you. [https] But. It is generally illegal to sell securities unles you are a registered securities dealer. California's laws (and I am not a California lawyer) are very strict and they are enforced aggressively. Federal law is similar. If I were you, I would take this information down. Reply Scott Alexander2 hr ago Posting an email someone sent me saying "our company is cool, [https] email us if you want to invest" is legally equivalent to selling securities? 1Reply broblawsky2 hr ago [https] There is a marginal risk here. I'd recommend against it too. Reply Scott Alexander2 hr ago All right, I've deleted. Jonah can post it himself if he [https] wants, unless someone's going to tell me even having it on the blog is a risk. 1Reply Walter Sobchak, Esq.2 hr ago I would not let anyone solicit for investments on my blog. [https] Substack might have a Section 230 defense, but a blogger probably does not. 1Reply broblawsky2 hr ago [https] I'd ask your lawyer about that. Reply Walter Sobchak, Esq.2 hr ago Perhaps. The Federal Securities Act of 1933 defines: "the term "offer to sell", "offer for sale", or "offer" shall include every attempt or offer to dispose of, or solicitation of an offer to buy, a security or interest in a security, for value." The law and administrative lore are very extensive. If you had an upside in doing this, it might be worth thinking about, but if you had an upside, that would be a fact indicating legal involvement. As you are an uncompensated volunteer, the safest thing to do is to stay far away. Back in a previous millennium when I had hair and no belly, I [https] worked in a law firm that was located hard by Wall Street in lower Manhattan. On a clement day, if we weren't too busy, my colleagues and I would occasionally walk over to the river, and we would lunch at Sloppy Louie's immediately adjacent to the Fulton Street Fish Market. It was a very plain sort of place. The tables were picnic benches and the menu was fried or broiled fish, nothing fancy. We were sure that it was, like the Fish Market, run by the Mob. There was a sign over the cashier's seat imparting ageless Sicilian wisdom: "Even a fish can't get in trouble if it keeps its mouth shut." 2Reply Glenn1 hr ago As I posted above, general solicitation of certain private placement offerings is legal, as of 2013, under Rule 506(c) [https] of Regulation D, subject to various limitations, in particular that the issuer must take "reasonable steps" to verify accredited investor status. Reply Eol2 hr ago I have no opinion on this, but just know that I definitely [https] will never be able to read one of your comments without hearing it in Walter's voice and with his reasonable-then-screamy delivery. I appreciate it. Reply MJH59 min ago [https] Ditto and also join the chorus that exploring the edges of the securities laws is a lousy hobby. Reply Glenn1 hr ago General solicitation for private placement offerings is allowed under Rule 506(c), since the 2012 JOBS Act. (However, I don't know whether there are restrictions on _who_ is allowed to perform those solicitations. And I don't know [https] whether the company is intending to reply on 506(c), which requires them to take reasonable steps to verify the accredited investor status of their investors, or 506(b), which is more convenient because it does not require them to do that (but does not permit general solicitation.)) Reply Glenn1 hr ago [https] "reply on" should be *"rely on", obviously. Reply superporp2 hr ago I think the email is supposed to be [https] jonah@equatortherapeutics.com (you wrote puetics). Normally I wouldn't be so pedantic but I could see somebody clicking that link and failing to send an email! Reply Plutonic3 hr ago FYI, Chubbyemu recently released a video regarding a DNP [https] overdose in a young man attempting to lose weight https:// youtu.be/ChPeG19qKUo 8Reply Jilm3 hr ago [https] I came here to post this. Reply Jerdenizen3 hr ago [https] Maybe we've gone wrong as a society if burning to death from the inside is the less risky option. 9Reply Watchman3 hr ago It's always an option, just vanishingly unlikely in most [https] cases (unless you know some very sadistic people I guess...). The question with risk is not how bad is the less risky option but how horrific are the other options... Reply Aapje2 hr ago [https] Fire Walk with Me 3Reply Alex DeLarge1 hr ago The candle that burns twice as fast . . . I guess some will [https] always prefer to go out with a bang, rather than just fade away. 1Reply Demeter23 min ago Alternate use: a poetic new form of political protest? [https] In other news, the Wikipedia page on self-immolation warns: "Self-immolation does not guarantee death for the burned." Reply broblawsky3 hr ago 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. [https] 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. 5Reply Mensch3 hr ago Normally the proton gradient is used to produce ATP. With uncoupling it just makes heat and is arguably not really metabolism as it doesn't produce anything. [https] Free radical production from mitochondria is partly dependent on the proton gradient. So by uncoupling you can dissipate the gradient and reduce free radical production which may be beneficial if the cell is under oxidative stress. Of course there are lots of critiques against the free radical theory of aging. Reply Andrew Clough3 hr ago [https] Good for general health, probably, but also probably not good for male fertility though. Reply broblawsky3 hr ago That doesn't quite make sense to me. DNP is actually making the cell pump *extra* protons over the gradient, because it still needs the same minimum number of calories to operate. The DNP is just creating a parasitic side-reaction where some of the energy consumed is wasted as heat rather than used to [https] pump protons, creating a net caloric deficit. If there's a certain number of free radicals generated per proton-pumping operation, I can't see how this effect would result in less free radicals generated. If anything, it might be more. 2Reply John3 hr ago Regarding low dose DNP, from https://www.ncbi.nlm.nih.gov/pmc /articles/PMC6468406/ "DNP appears to mimic in part the neuroprotective and neurorestorative effects of exercise and fasting by increasing BDNF, lowering cellular stress and building [https] cellular resiliency by mild increases in mitochondrial bioenergetics." Basically, through slightly stressing mitochondria, you increase mitochondrial health, similar to exercise, cold exposure, and other stress related activities that have beneficial health effects. 1Reply Andrew Clough3 hr ago After the proton gets pumped over the membrane the electron has to go through a series of complicated stages to get back to it, which each stage making its own ATP letting aerobic respiration be so much more efficient than anaerobic respiration. However, the high energy chemistry in a [https] mitochondria is potentially dangerous, sometimes things break, and if one part of the chain breaks down you have lots of electrons backing up and becoming Problematic. Letting the protons bypass the normal process more easily mitigates that danger even though it causes more of the normal operation of the mitochondria. 1Reply broblawsky2 hr ago But the same number of successful proton pumping operations [https] are still happening, right? There's just a bunch of extra unsuccessful ones as well. It's possible that my inorganic chemistry background is letting me down here. Reply Andrew Clough2 hr ago Right. The proton pumping setting up the potential happens [https] just like before. It's the electron dancing down the potential ladder making ATP that fall back on to the soft proton when they trip, to strain a metaphor. Reply broblawsky1 hr ago I think I get it - the theory here is that the extra protons create metastable states that trap rogue electrons without [https] producing free radicals, right? That makes a certain amount of sense. Thank you very much for taking the time to explain it to me. Reply Andrew Clough1 hr ago No problem. I should say, though, that this is all from a [https] popular book and that the closest I've gotten to actual chemistry since High School has been semiconductor physics. Reply Mensch2 hr ago As I understand it is the existence and magnitude of the proton gradient that increases free radical production. Thus by reducing the magnitude of the proton gradient you would get less free radical production. Cells can increase their [https] uncoupling in response to oxidative stress. All else equal this decreases ATP production but still above minimum, well except for the lens cells for some unfortunate individuals. I also imagine that uncouplers should reduce your capacity for physical labor. Reply Alephwyr3 hr ago Tried getting it off Ali baba once but it was just orange died sawdust. Also my family decided I was on meth because I [https] was involved with a seemingly mysterious substance tied to weight loss that might explode and they didn't understand my explanations... 11Reply Scott Alexander3 hr ago Props to all the good people on AliBaba who look out for [https] their customers by sending them sawdust instead of dangerous drugs that could kill them. 21Reply Alephwyr2 hr ago In my life I have still managed to buy motorcycles and guns, [https] so alas it is to limited avail; high risk tolerance, uhhh, finds a way 4Reply Cerastes2 hr ago [https] I would be very impressed with any AliBaba seller who could send you a gun or motorcycle made of sawdust. 5Reply Spiny Stellate3 hr ago 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 [https] 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. 5Reply Scott Alexander3 hr ago [https] Argh, you're right, thanks, fixed. 2Reply Anonymous50 min ago >They pump protons across a membrane, creating pressure for electrons to follow. This forms an electrical gradient... [https] I argue for removing "creating pressure for electrons to follow" entirely, because that misleadingly suggests that this pressure is somehow necessary or relevant for the potential difference. In reality, the proton concentration differential is enough. Reply Randy M3 hr ago 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! [https] But obviously it's not so easy in practice as human bodies are vastly complicated biochemical laboratories operating under sometimes faulty instructions. 4Reply aoeuhtns2 hr ago We ought to put the calories to work digging ditches and [https] filling them back in so that they'll have something to do and will have earned their wages. 6Reply Anonymous2 hr ago "Pumping protons across a membrane that diffuse back" [https] actually seems like the microbiology analogue of what you suggest. 6Reply broblawsky2 hr ago [https] Very Keynesian. I approve. 3Reply BronxZooCobra3 hr ago I've read that among a certain segment of the naturally thin [https] population they naturally release excess calories as heat rather than storing them as fat. Reply Jack C3 hr ago I have always been on the thinner side, although I can gain weight, and I also "run hot". My appendages are frequently warmer than other people's. That could be because I have a [https] higher core temperature or a higher peripheral temperature alone. I also have higher blood pressure so maybe there's just more convection of heat away from my core. Either way I'm shedding more heat than normal, and am more tolerant of cold temperatures and less tolerant of warm temperatures. 1Reply Jaime3 hr ago hm, this is interesting. i'm also on the thinner side and have been struggling to gain weight, but I definitely feel colder to the touch than average (which i always attributed [https] to the lack of body fat to keep me warm, also im AFAB). that said, i am also more tolerant of cold temperatures than warm ones, so maybe (anecdotally ofc) there's some correlation there. Reply Migratory1 hr ago I'm thin and cold too, but I do fidget a lot - I have a tendency to twitch my leg rhythmically and such. This might contribute to excess calorie expenditure. It does seem to stop when I'm hungry, though I'm not going to claim that [https] there's an actual energy management relationship there. Every thin person is probably such due to a confluence of factors. I mostly attribute my thinness to the small portion sizes my mother fed me as a child. Reply Measure2 hr ago I'm thin, tall, and cold (which could be from lower [https] circulation due to longer limbs). I'm less tolerant of cold than of heat. Reply Fffff21 min ago Between you and Jack C's reply to the comment it feels like [https] knowing somebody is tall and thin doesn't really predict very much Reply CB2 hr ago Here's an older SSC post with something related: https://slatestarcodex.com/2017/04/26/ anorexia-and-metabolic-set-point/ The relevant quote: > Some more evidence: people with anorexia fidget like crazy. This is the conventional wisdom among generations of psychiatrists, and has been confirmed in studies - see for example *Measurement Of Fidgeting In Patients With Anorexia [https] Nervosa Using A Novel Shoe-Based Monitor*, which found anorexics fidget almost twice as much as healthy controls. This seems really damning to me. Consciously deciding to fidget is hard. If you don't believe me, try to fidget as much as possible for the next two hours (the length of the study linked above) and see how well it goes. Most people just can't do it. On the other hand, fidgeting (renamed to the more dignified "non-exercise activity thermogenesis") is the classic strategy that the lipostat uses to maintain unconscious control over weight... > A purely social paradigm of anorexia can't explain the fidgeting; a biological paradigm outright predicts it. 1Reply BronxZooCobra1 hr ago Wow! Do you mean psychological paradigm? It's not that your conscious mind holds the mistaken belief that your fat when [https] you're not. Or that you're attempting to control one part of your life when you can't control others. On a fundamental biological level your body thinks it's fat when it's not. Reply CB1 hr ago I can go on and on about the superiority of a "biological paradigm" for AN. Here are a couple tantalizing links: * https://relative-energy.tumblr.com/post/183390573416/ activity-based-anorexia-and-animal-models [https] * https://relative-energy.tumblr.com/post/182904564621/ shan-guisingers-2003-paper-adapted-to-flee See also this from SSC: https://slatestarcodex.com/2018/12/05 /giudice-on-the-self-starvation-cycle/ Reply Migratory58 min ago I would expect the social paradigm to explain the fidgeting [https] as nervous movement, the logic being that it's a stressful condition or stressed people tend to develop anorexia. I don't find the idea convincing without further explanation. Reply Steven Hales3 hr ago First, I am disappointed that there is no "conscious uncoupling" joke in here. A missed opportunity! Second, [https] 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, 1Reply Richard3 hr ago That might be logical, but "All is not lost" is a fixed phrase, logic be damned! [https] https://www.macmillandictionary.com/us/dictionary/american/ all-is-not-lost 7Reply Steven Hales1 hr ago [https] Doesn't the dictionary also allow "literally" to mean "figuratively"? So YMMV. Reply CBjust now On the danger of conflating English and logic: [https] https://journeys.dartmouth.edu/folklorearchive/2017/11/13/ a-carton-of-milk-and-some-eggs-joke/ Reply Kappa3 hr ago "All is not lost" is perfectly technically-correct if you just interpret it slightly differently - as "it is not the [https] case that all is lost" ("is all lost?" "it is not"), rather than as "it is the case that all things are not-lost" ("what is not lost?" "all is")! 5Reply Steven Hales1 hr ago "All is not lost" I would formalize (well, quasi formalize; [https] this is a comment section!) as (x) ~(Lx). "Not all is lost" as ~(x)(Lx). Those aren't equivalent. Would you do it differently? Reply Kappa25 min ago So to get into my position here in more detail: You can interpret "all is not lost" in one of two ways, or at least two that are clear to me at a glance. One is the way you're interpreting it; the other is the way that's equivalent to your formulation of "not all is lost". Personally, I find the latter interpretation more intuitive. To interpret "all is not lost" as "it is not the case that all is lost", logically equivalent to "not everything is lost" or "out of all things, some are not lost", I would take it as an answer to the implicit question "is all lost?", which I think is what most people tend to mean when they use the phrase. "All is not lost" under this interpretation describes a world where we were worried that all might be lost, but then found out that this isn't true, and some things still remain. I think that's the connotation the phrase is reaching for in its standard usage. (Equivalently to that implicit question, you could also read [https] it as a contradiction of an implied previous statement: "All is lost!" "No it's not!") To interpret it as "nothing is lost", I would take it as an answer to the implicit question "what is not lost?", answering with "all" i.e. "out of all things, none are lost". This interpretation feels more awkward to me, linguistically speaking. It's grammatically viable but it doesn't feel like the natural way to phrase the sentiment; an ordinary English speaker, trying to express "nothing is lost", would probably use those three words. As for "not all is lost", I think we lose something by moving to this phrasing from "all is not lost"; specifically, it muddies the connection to the implied question or statement. Sentences of the form "X is Y" negate most straightforwardly to "X is not Y" in ordinary English usage. "Not all is lost" is also a valid negation here, but in my opinion it's deemphasizing that implicit relief and instead putting more emphasis on the implication that although not all things are lost, some of them probably are. Less relieved, more foreboding. 1Reply Nissa3 hr ago There's some wonderful potential for Moloch tie-in with the [https] only surefire weight loss pill involving burning from the inside 3Reply broblawsky3 hr ago [https] Moloch, whose cells are blazing furnaces! 24Reply Daniel Speyer3 hr ago Mitochondria in endotherms have proteins other mitochondria [https] don't? And they're only expressed in certain tissue types? That strike anyone else as deeply weird? Reply Cerastes2 hr ago Uncoupling proteins are universal across Eukaryotes, but mostly seem to function to reduce the oxidative stress of cold acclimation. Mammals are unique in that UCP1 has been modified into a highly-effective non-shivering thermogenesis mechanism; it's thought similar mechanisms are occurring in birds. https://jbiol.biomedcentral.com/articles/10.1186/ jbiol155 This is also why mammals are so terribly inefficient - for the same body mass, a mammal typically uses ~10x the food and oxygen of a comparable reptile. Even unspecialized reptiles can go without food for weeks or a few months with minimal [https] weight loss, and hold their breath for hours (which makes inducing anaesthesia via gasses a real pain in the ass). Add in temperature-induced depression of the metabolism, and you get the painted turtle, which can hibernate for over 3 months at the bottom of a pond on a single lungful of air (plus some limited gas exchange across the skin and cloaca). This is also why it takes so much food to raise a cow or sheep, but so little to raise the same mass of tilapia. Interestingly, pigs are very efficient for food-mammals, and have a defect in their UCP1 which leads to difficulties generating heat. TL;DR - "Warm-blooded" species are colossally inefficient. 6Reply Nancy Lebovitz3 hr ago Is being fat the same thing as metabolic syndrome? Does DNP [https] causing people to lose weight necessarily mean they're getting healthier? 2Reply Scott Alexander3 hr ago [https] Good question, I don't know. Reply C MN3 hr ago The experiments by Jules Hirsch (which found that fat people who lost weight metabolically resembled starving people, not healthy thin people) would suggest no. Metabolic syndrome is [https] its own thing which can affect both fat and thin people, and there's at least some evidence the casuality goes the other way--some part of metabolic syndrome causes weight gain, instead of the other way around. 3Reply tgb2 hr ago In terms of literal definition, no. The International Diabetes Foundation defines it as: central obesity (i.e. large waist circumference) AND two of raised triglycerides, reduced HDL cholesterol, raised blood pressure, or raised resting fasting glucose. See Wikipedia ( https://en.wikipedia.org/wiki/Metabolic_syndrome#IDF). Definitions from WHO and others are similar. [https] So if "metabolic syndrome is when your doctor says you have metabolic syndrome", you can be obese and not have metabolic syndrome. From the "metabolic thing is the idea that we try to approximate with the IDF definition" then that's less clear. But I think researchers focusing on metabolic syndrome (I work with some of them) do not just think of it as simply obesity and would tend towards saying they're distinct phenomena. Reply FluffyBuffalo3 hr ago 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 [https] 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? 3Reply Scott Alexander3 hr ago [https] You're right, sorry. 2Reply Andrew Clough3 hr agoLiked by Scott Alexander While shilling is in fashion, let me shill for Nick Lane's book *Power, Sex, Suicide: Mitochondria and the meaning of [https] 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. 8Reply Scott Alexander3 hr ago [https] I endorse using this thread for general shilling of mitochondria. 14Reply Darius Bacon2 hr ago [https] I also found that book worthwhile. Reply Mensch2 hr ago [https] All of Nick Lane's books are great! 1Reply J Mann3 hr ago First with "Gabriel Over the White House," and now with this [https] 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. 7Reply Melvin1 hr ago [https] Instead it turned into an unexpected infomercial. Reply John3 hr ago 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 [https] 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. 2Reply Scott Alexander3 hr ago 2-3 mg/day? Isn't the normal dose more like 150? Does 2-3 [https] make you lose weight? How quickly? Or what else are people using it for? 1Reply John3 hr ago Those "normal" doses are for fat loss. However, two recent studies have shown that low doses can have profound health benefits. I've talked to people who have experienced a wide range of effects from low dose DNP, the main ones being increased energy, lessened fatigue, higher quality sleep, less need for sleep, decreased "brain fog", etc. So, nootropic, energy, and anti-aging reasons. [https] Good excerpts from the low dose studies here: https:// www.professionalmuscle.com/forums/index.php?threads/ dnp-as-nootropic-life-extension.165052/post-2896090 If you want more info on who's using low dose DNP, and where to talk to them, etc. I could make that happen. It popped up on the radar of a few nootropics groups back in October. 1Reply Ryan L3 hr ago "This makes your body's energy production less efficient, meaning you have to burn more calories per amount of [https] metabolism you want to do. Hence the weight loss." Gary Taubes hardest hit. Reply John Lehman2 hr ago Actually, I don't think so. Taube's argument has never been that caloric balance has nothing to do with weight gain or loss. His point is that it fails to explain. Like trying to explain my increasing weight by saying that I am experiencing an increased impact of gravity. Trivially true, but not the least bit useful. What I would note about this mitochondrial line of thought however, is that, though potentially [https] beneficial, it does not address the reasons for obesity or the obesity epidemic. If I were Gary Taubes, I would make that point. Which I just did. Even though I am not Gary Taubes. BTW, the idea of uncoupling mitochondria by changes in lifestyle and/or diet (as I recall) has been around the "keto-community" for a while. There are numerous YouTube lectures about it. 3Reply Ryan L1 hr ago All I'll say is that I've read at least one of his books (maybe two...can't recall) and listened to a few interviews with him. If that is his argument, he doesn't make it well. [https] To wit, quotes like this one: "The science tells us that obesity is ultimately the result of a hormonal imbalance, not a caloric one--specifically, the stimulation of insulin secretion caused by eating easily digestible, carbohydrate-rich foods" Reply Randy M1 hr ago But of course you can't literally put on mass due to the [https] secretion of hormones. The hormones have to be acting on metabolism, either getting you to want more calories, or getting you to waste fewer. 3Reply John Lehman47 min ago Sometimes the fact that something can be both true and of no explanatory value is difficult to grasp and can be difficult argument to make. In the quote you provide Taubes seems to me to be saying that caloric imbalance tells us nothing about the causes of obesity. He is not saying that the first law of thermodynamics doesn't apply to humans. Of course it does. But it tells us nothing about why some of us get fat and other don't. Here is Taubes making that point: "Why is it that from the moment you enter medical school to the moment you retire, the only disorder that you will ever diagnose with a physics textbook is obesity? This is biology folks, it's endocrinology, it's physiology - physics has nothing to do with it. The laws of thermodynamics are always true, the energy balance equation is irrelevant. [https] If someone's getting fatter I guarantee you they're taking more energy than they expend (as long as they're getting heavier). And if they're getting leaner I guarantee they're expending more than they're taking in. [It's] given, let's never discuss it again. And if you say it to your patients you're telling them nothing." Also, this: "All those who have insisted (and still do) that overeating and/or sedentary behavior must be the cause of obesity have done so on the basis of this same fundamental error: they will observe correctly that positive caloric balance must be associated with weight gain, but then they will assume without justification that positive caloric balance is the cause of weight gain. This simple misconception has led to a century of misguided obesity research." 1Reply Bullseye3 hr ago "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." [https] "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! 12Reply Doug S.3 hr ago Apparently non-lethal doses of this stuff shortens the lifespan of birds... [https] https://www.utu.fi/en/news/press-release/ illegal-diet-pill-DNP-might-kill-you-on-the-long-run 5Reply Randy M2 hr ago [https] As would lethal doses, presumably. 7Reply Thomas Kehrenberg2 hr ago 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 [https] though (and not hypercharged metabolism). [1]: https://www.medpagetoday.com/primarycare/obesity/91146 [2]: https://www.nejm.org/doi/full/10.1056/NEJMoa2032183 2Reply Scott Alexander2 hr ago [https] Seems very plausible and exciting. 2Reply J_says2 hr ago [https] Sounds like this indirectly adds some credence to the claim that lowering your thermostat helps lose weight Reply Fffff2 hr ago 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 [https] 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) Reply Scott Alexander2 hr ago [https] I had to look it all up again, and still got some of it wrong before commenters corrected me and I edited it. 4Reply Alex DeLarge52 min ago I had never heard mitochondria described as "proton pumping" [https] across a membrane before. That makes it sound like a fuel cell. Maybe that's a good analogy for the less bio inclined. Reply Randy M2 hr ago The names of, say, the intermediaries of the Kreb's cycle are indeed boring, and read like genealogies." Then Fumarate begat Oxaloacetate, who begat Citrate..." [https] But the story in broader terms is pretty cool from a logistical standpoint, with various raw materials being shuttled into the various factory like organelles and so forth. 1Reply Gordon Tremeshko2 hr ago [https] Can we make offers, like on Shark Tank? I'll put up 25 grand for, eh....a 50% stake in the company. Reply Glenn1 hr ago Well, it's a YC company, and the standard YC investment terms [https] make it worth a minimum of $2 million for the whole thing. So you're gonna have to start the bidding a bit higher. Reply Gordon Tremeshko1 hr ago [https] I'll do 30k, not a penny more. Come on, you can buy a Dodge Charger for that much! And I'm takin' all the risk, here! 3Reply Metacelsus2 hr ago It's pretty easy to make with simple chemistry equipment. But given that nitroaromatic compounds can have some pretty nasty [https] toxicity, especially to liver, I would stay well away from DNP. https://link.springer.com/article/10.1007/ s13181-011-0162-6 1Reply ipsherman2 hr ago In this sentence: "Treat a hundred cases of obesity in exchange for one or two cases of cataracts (and some skin [https] 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? Reply Oskar Fischbrotchen2 hr ago I've always found it curious that none of the easy exploits tried on the human body seem to have ever worked. Something [https] 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? 1Reply Medieval Cat1 hr ago The body is governed by a thousand fine-tuned interlocked [https] feedback loops. Changing one feedback loop without fucking up the others is hard. Reply Firanx1 hr ago Evolution had millions to billions years to optimize things. [https] So it's not really surprising that it didn't miss much of low-hanging fruit. 1Reply Adam1 hr ago Many performance enhancing drugs banned by sports leagues do work. They tend to require unsafe doses when everyone you're competing against is also taking unsafe doses, but for people [https] not trying to compete, there are fairly safe doses of most things that can get you a mostly free lunch, aside from the fact they're largely illegal and thus somewhat expensive and difficult to obtain. 1Reply Alex DeLarge1 hr ago Plain old amphetamines do a pretty good job of boosting mental acuity and causing weight loss. HGT shots will transform your body pretty dramatically. But I think we tend [https] to ban anything that seems too easy. Some people would say exercise and eating less *is* the "easy" hack. But nobody likes those people. Reply Walter Sobchak, Esq.2 hr ago 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 [https] 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. 1Reply skybrian2 hr ago [https] Typo: produg -> prodrug. Reply grumboid2 hr ago (I had believed that) the problem with weight loss was that [https] 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. Reply WhatTheHill2 hr ago 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 [https] 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." 1Reply aoeuhtns1 hr ago See this comment that convinced Scott to change the post: [https] https://astralcodexten.substack.com/p/ shilling-for-big-mitochondria#comment-1397199 4Reply Scott Alexander1 hr ago Because I edited it after some commenters expressed concerns [https] with the original version, especially that I was in violation of securities law by linking to an investment pitch. 4Reply Alex DeLarge1 hr ago [https] Why no animal studies? Do mice spontaneously burst into flames when they take 2,4-DNP? Enquiring minds want to know. Reply Scott Alexander1 hr ago There are lots of animal studies. It works more or less the [https] same way in animals as in people, although with some differences (animals don't develop cataracts unless you put a lot of work into finding the right animal model). 1Reply Stephan Guyenet1 hr ago There are now obesity drugs that are safe and effective, so I have to quibble with the subtitle "the only diet pill that [https] really worked". The latest trials of semaglutide report ~15% weight loss with modest side effects. https://www.nejm.org/ doi/full/10.1056/NEJMoa2032183 3Reply Scott Alexander1 hr ago [https] Yeah, that was just after I wrote this article, and I agree it lessens the punch. Are there any others? 1Reply IronLordByron1 hr ago The best one right now just as far as weight loss, last i [https] heard, was phentarmine+ topiramate, but that works substantially less well (with the highest dose giving like 7 percent more weight loss than placebo). Reply IronLordByron44 min ago [https] Wait, i misread the graph, it's 9 percent Reply DLR1 hr ago 'They pump protons across a membrane, creating pressure for [https] 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. Reply enoch1 hr ago this seems like a $20 bill laying on the ground--why doesn't [https] the body do this auto-regulation on its own? Or, in other words, why isn't this a free lunch? Reply Scott Alexander1 hr ago I think for obesity the answer is that almost no people outside a modern society are obese. It seems to be a completely new problem and evolution didn't need to come up with answers. I'm more surprised that the body doesn't naturally use this [https] to generate heat! There's lots of anecdotal evidence (including from the Soviet soldiers) that DNP lets you tolerate temperatures you would otherwise freeze in - how come the body just gives up and lets you die instead? I have to assume it's because we evolved in Africa and didn't need it, and actual polar animals have other better techniques they use. 8Reply Adam1 hr ago How would that function have ever evolved? The condition of long-term persistent food abundance in which it might be [https] advantageous to become less metabolically efficient and waste food on purpose has not been widely part of any animal's environment until 50 years ago or so. 1Reply Adam1 hr ago 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 [https] 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. 1Reply Woah771 hr ago I got really excited/ confused for a moment seeing DNP, as in [https] my profession that stands for do not populate/place, then was amused/ disappointed when it was a chemical. Reply Evan Th51 min ago I keep reading "DNP" as "Democratic Nationalist Party." [https] I guess that'd explain why it was banned - both Red and Blue tribes oppose some part of it. Reply Anonymous45 min ago Moderately related: https://m.youtube.com/watch?v=kXpzp4RDGJI [https] is a nice video that shows how a mitochondrium turns the potential difference into ATP by rotating proteins. Reply Glen Raphael33 min ago 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 [https] 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. 3Reply neuro morph9 min ago 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 [https] (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. Reply TopNewCommunityWhat is Astral Codex Ten?About Ready for more? [ ]Subscribe (c) 2021 Scott Alexander. See privacy, terms and information collection notice Publish on Substack This site requires JavaScript to run correctly. Please turn on JavaScript or unblock scripts