610 Comments

I think the MAIN mediating factor is, and will soon be confirmed by independent studies - weight loss and caloric restriction. You stop eating on ozempic, don't want to, weight goes down. All of these diseases can be cured by fasting, which is natural ozempic, albeit harder to do. Caloric restriction expands lifespan in many species, it's well known.

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Addiction can be cured by fasting?

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Not sure whether there are clinical trials on this (there is no profit in doing trials on fasting), but given all the mechanisms of action, I strongly suspect that yes

https://pubmed.ncbi.nlm.nih.gov/25716779/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4725115/

There are also people that swear by it: https://waterfasting.org/overcoming-addictions/

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In graduate school I attended a seminary given by a researcher in the aging field. He mentioned that in a long-term calorie deprivation study, the participants had lost their sex drive (I have no idea what study he was referring to). Maybe drug cravings are also lost?

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It makes evolutionary sense : when food is abundand, energy is easily available - sure, go procreate, go create new generation, your individual is no longer needed for gene's survival. When food is short (starvation) - please survive until the next season, don't waste energy on sex, wait it out, your individual is needed in order for gene to survive longer until good times eventually come back.

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at least anecdotally that's a well known effect, I remember reading borderline tabloid interview with a winner of some kind of Survivor-like TV show. How they did it regarding sex/masturbation when there were so many cameras etc - and he said that after few days with little food nobody even thought about sex.

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If I was Evolution, I would definitely shut down the sex drive early when deciding what to deprioritize when there isn't enough calories to support all activities.

A pregnancy during a bad enough famine must have negative evolutionary value, and the activity itself consumes valuable calories.

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I'm not clear that shutting down male sex drives makes enough sense on a group level to outweigh the individual benefits. And alas, it only takes one to tango. :-(

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I held a water fast for a week and my libido turned to zero.

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That's more likely because starvation is associated with a decrease in testosterone.

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You mean seminar, not seminary.

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works differently for me i think. Weekdays I follow caloric deficit with heavy weight training.

My sex drive is thru the roof. Happy gf.

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Some addicts lose interest in food. This doesn't seem to help the addiction.

Any information about a relationship between anorexia and addiction?

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Right, amphetamines and heroin cause fasting.

Anorexics use amphetamines and heroin for the instrumental value. They are also said to abuse alcohol.

Does ozempic treat anorexia? Pretty tough to get approval for a study.

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Ive just spent six months working in the eating disorders space of psychiatry and anecdotally ozempic appears to be a trigger for anorexia, likely due to the act of starvation. And why we see anorexia relatively often in the context of crohns, cancer, etc

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Alcohol is pretty high in calories by itself. (But I guess the amount needed to get you drunk on an empty stomach doesn't have all that many calories.)

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But doesn't alcohol get processed by the liver, through a different pathway than normal carbohydrates? I'm not staying there's no caloric effect, but if it goes through a different pathway, it might involve a different set of metabolic signals.

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The side effects of alcohol addiction lead to many biochemical and cellular adaptations, resulting in poor nutrient intake, decreased appetite, absorption, hydrochloric acid, and amino acids. This also causes a decrease in essential nutrients needed for healthy communication and signaling necessary for ghrelin and leptin in a healthy body. Additionally, there is an extra burden of nutrient wastage. I discussed this in a recent post about the impact of alcohol on mental health, highlighting its potential to act as a mental trap by causing significant systemic changes. Regarding medications, many clinicians advise waiting a decade to see their true global side effects when they are new. Until then, healthcare providers like myself often deal with patients affected by the aftermath of quick health trends that do not prioritize lifestyle behavioral modifications for long-term, safe outcomes.

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Well yes, addiction can be cured by abstaining from the substance you are addicted to, in this case simple carbs. Who would have thought?!?

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> But an increasing body of research finds they’re also effective against stroke, heart disease, kidney disease, Parkinson’s, Alzheimer’s, alcoholism, and **drug addiction**.

I think Scott was asking about drug addiction being cured by fasting.

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Drug or behavioral. It's not implausible, but I don't know if I think it probable.

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This sarcasm seems neither necessary nor accurately aimed given that you missed Robertas's point, no?

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When people starve, they famously start craving food so much they can hardly think of anything else. People on half-starving diets get incredible interest in cooking and recipes and become quite good cooks.

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Not exactly. On an extended fast you get past the ravenous hunger in the first few days. After day two I honestly don't feel hunger anymore.

Yes, you absolutely get strong cravings though. Especially when it's been a few weeks you really start missing even the feeling of food in your mouth. I would get cravings for the feeling of biting into a burrito. And of course you miss flavour, especially since you get keto breath and your own mouth tastes disgusting. But these cravings come and go in waves. It's not like you can't think of anything else, most of the time you just go about doing normal stuff and feeling pretty normal.

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This is completely new to me. I didn't know hunger and craving for food are different things. I've fasted several times, always felt hungry/craving for food all the time. It didn't feel different when I just "almost" fasted, eating a little now and then. I thought about food most of the time. People on very low calory diet experiments still famously think about food most of the time, when of course they are not engaged in an attention-consuming task, but as soon as the task ends they think about food. Or maybe it's different for different people.

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How long have you fasted?

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"Craving" is usually used to mean a more specific desire. E.g. a woman with pregnancy cravings doesn't just want food, she wants a *particular* kind of food.

If I eat a *low* calorie diet I'm hungry all the time and it's pretty miserable. But going all the way to a *no* calorie diet the hunger eventually goes away.

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Honest question, are you on the autism spectrum?

Because I've seen some people claim (and gotten anecdotal evidence) that for some autistic people their general interoceptive processing impairment (disconnect from bodily signals) means they don't actually experience "hunger" as a distinct sensation in the same way that allistic people do.

i.e. instead of feeling "hungry", they won't have any sensation of caloric deficit until they have stomach pain from not eating. And because this lines up with what they think allistics are describing, they assume that's what allistic people mean by "hunger". I assume the same would apply for distinguishing between "cravings" and "hunger"

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It's a problem to say "you" when you actually mean "I" or perhaps "I and many people". Your experience might not generalize to people in general.

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It's not a problem. Human bodies are mostly similar to each other, generalizations are useful. If you hit your thumb with a hammer it will hurt. That's not true for literally everyone, but it's true enough that it's a useful thing to say.

If I'm talking to someone who's about to embark on a long fast I'm going to tell them "don't trust a fart on days 2-3", because that is a useful bit of information for them to have.

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Ditto.

I also found I missed the act of eating, both somehow as a physical activity, but also as a social ritual.

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How long do you need to fast to cure your carb addiction? I've done up to three weeks and I still fricking love carbs.

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Have you tried very high fat diets?

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Nope.

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You should. Though the key is to make sure it's ALSO LOW CARB. High fat/high carb diets are arguably dangerous because of The Randall Cycle.

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Or maybe just abstaining in general? IE, if you're an alcoholic, I bet if you don't drink for a while, it gets easier to continue not to drink.

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Well, it worked for smoking. But it took several years for a real cure.

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After 46 years smoking abstinence i still get occasional urges. I sometimes miss it.

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Amphetamine addiction would be impossible...

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Though you can have a habit.

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Amphetamine (NOT methamphetamine!) addiction is actually quite hard to achieve, regardless whether its Methylphenidate salts, or street amphetamines.

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That is a pretty broad statement. Do you mean that it is hard to become addicted to because they aren't widely available? Dexedrine and benzedrine addiction were pretty common back in the 60's and 70's.

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I mean that getting addicted to regular amphetamines (again, NOT metamphetmines and their derivatives) i hard because the psychologically addictive properties kick at a bigger dose than unpleasant side effects, and the habituation effects are weak. In other words, you can get lifestyle-addicted to amphetamines giving you access to extra energy, focus and drive, but not emotionally addicted to the hedons that come from using speed, because these occur at about the same time as heart racing, jitters and anxiety.

Amphetamines are more "pragmatically useful" than "fun" and thus do not trigger addiction tot he same degree than other drugs.

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This seems like it’s closer to the root. Ozempic reduces obsessive/addictive behavior, which treats addiction and overeating. Then there are a bunch of currently common conditions that are caused by overeating, and Ozempic secondarily treats all of those.

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If you have the willpower to stop eating then you probably have the willpower to quit other addictions as well. Unless of course you're addicted to amphetamines or some other drug that suppresses your appetite.

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We actually know that weight loss is not the cause. Most beneficial "side effects" are independent from weight loss:

- People with diabetes lose way less weight than obese people without diabetes: https://x.com/EricTopol/status/1776732406340325869 That's why it took so much time to repurpose GLP-1RA for weight loss after the exenatide launch (2005).

- Similarly, in the successful phase 2 trial of lixisenatide for Parkinson's, participants did not significantly lose weight: https://www.nejm.org/doi/full/10.1056/NEJMoa2312323

- There's no evidence that calorie restriction and fasting can slow down the progression of Parkinson's disease. Quite the opposite as obesity is actually protective in the development of PD ( https://www.mdsabstracts.org/abstract/obesity-is-a-protective-factor-for-the-development-of-parkinsons-disease-in-participants-of-the-framingham-heart-study-cohort ) and PD patients are often underweight.

- Exenatide (the first approved GLP-1RA) only leads to very modest weight loss. And yet phase 2 trials showed that it could slow down the progression of Parkinson's disease (results of the larger phase 3 trial expected in 6 months). In one longitudinal study, “Each additional 30-day-equivalent claim was associated with a 2.4% relative reduction in incidence (odds ratio 0.976; 95% confidence interval 0.963–0.989; P < .001).” ( https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1002/trc2.12139 ).

So when it comes for neuroprotection (and diabetes?), we know it's not due to weight loss. Something else happens (in the brain? gut? an off-target pathway?).

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Just found this 2013 systematic review and meta-analysis that concluded: "GLP-1 analogues are associated with a small increase in heart rate and modest reductions in body weight and blood pressure" ( https://bmjopen.bmj.com/content/3/1/e001986 ) Indeed back then all studies were done on people with T2D and therefore low weight loss...

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"Having a healthy diet" is not the same thing as "being thin." Common point of confusion. I've known a few skinny people who lived on pure candy. "Right" amount of calories, "healthy" bmi - terrible health nonetheless. The answer was vegetables all along!

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It's not the obesity paradox: the protective association between obesity and Parkinson's disease is causal as proven by Mendelian randomization: https://www.neurology.org/doi/abs/10.1212/WNL.0000000000209620

On the other hand for CVD as explained in the Wikipedia article yes there is an apparent "paradox" in association studies due to many biases, but these findings are not causal.

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Not a chance

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"[Religious] fasting is good for the soul", and the whole centrality of fasting in religions might mean culture has discovered the positive benefits of fasting on the body and mind before GLP-1 researchers did. It's also uniform, if not universal, across religions. They [ancient people] just didn't have a scientific explanation.

Depends on what your addiction is. Some addictions cause you to forego eating for long periods of time.

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yes fasting can do extraordinary things (see the True North Clinic's results) but carnivore is even better as it's so easy to do. Keto is similar but not as easy as carnivore. Read Chris Palmer's book Brain Energy and look up all the Carnivore podcasters for stories of illnesses overcome. I think it was Sean Baker??? not sure but he was an orthopaedic surgeon and he cured a boy who was in ER repeatedly (over 20 times) for attempted suicide by feeding him only steak. He had to give up being a surgeon as he kept helping people through diet and the hospital didnt like that. Check it out. Also Scott please read up about Intermittent hypoxia therapy (IHT) developed by Russian Professor Arkadi Prokpov which causes rejuvenation through mitophagy. No side effects. I'm doing that with my bopolar son as well. Very exciting. Ark's book is available on Amazon. The stories of cures are MINDBLOWING! and all you need is an atltitude simulator... (expensive but worth it)

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I know a woman who quit drugs and she restricts food to feel high.

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There have been reports of people saying they feel less desire for things in general, be it alcohol, binging tv-shows, etc. Some even claim it's bordering on a depressive state. I think that doesn't seem to happen with fasting usually. Thus, I think, there's something else happening here (as well).

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Can confirm. Lost desire for everything and anything and was put in a gray haze of borderline emotional anhedonia (and enhanced depression).

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In short term, yes, you are depriving yourself of fast glucose and brain is starving. In the long term, fasting actually has an antidepressive/antianxiety action, as the liver starts to produce ketone bodies from stored fat that are alternative fuel for the brain (neurons love ketone bodies even more than glucose): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8624477/

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Think he was talking about the drug

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Yes, I was.

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Did you at least feel good about losing weight?

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FWIW, I went on a water only fast for a week. I did not feel depressed, and I also did not lose weight. This might take a bit longer than most people would want to fast.

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"Did not lose weight"?

Come on bro, that's absurd

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In principle you could replace the lost fat (and muscles) with water while you are doing your water fast? Seems a bit unlikely, though.

The commenter might also mean that they didn't keep the weight off?

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No, because the semaglutide, over the course of a month, barely accelerated weight loss from what I was already getting from adderall's appetite-suppressive side effects. It was far from "miracle weight sloughing off drug".

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Yeah, that makes sense. The appetite suppressant effect of Adderall is no joke. I can imagine stacking Semaglutide on top of that probably wouldn't do much.

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I mean, I experienced dramatically increased appetite suppression - the delayed gastric emptying was absolutely there, and it seemed like I could eat half as much and be full (when I felt like eating at all, which was pretty rare), but it didn't translate to huge weight loss in the time I was on it. On a longer timeframe, it might have.

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Weird my experience is so different - in the beginning I went from 2k calories a day to 500 easily unless I forced myself to eat. But wasn't on Adderall. And further I didn't lose drive at all, was highly productive throughout.

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From personal experience it *does* seem to happen with fasting; a big problem with losing weight is that while you are in a diet that works, all that time of being in a calorie deficit kind of sucks due to consistent low energy, lack of desire and capacity for doing things - at least for me *that* is the hard part of fasting, not any hunger or cravings.

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My big problem is that I get hangry when I diet. I get obsessive and paranoid to the point where I would be classified as mentally ill if it didn't go away. I call it the hamster wheel, because the thoughts keep running around and around in my brain, and I can't make them stop.

I'm on tirzepatide now, and I'd say the hangry has spiked at like a 2-3 out of 10, where 10 was the worst I'd get in the past.

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I haven't lost desire for anything that I aware of and I currently am on Zepbound since February.

Drugs affect people differently. Try if you can get it. If it doesn't suit you or you're in the tiny minority that encounter negative side effects, stop taking it. Simple. I have a daughter who cannot use nystatin without negative side effects. She is in a minority therefore she doesn't use it.

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that sounds suspiciously similar to the side effects of ADHD medication (amphetamine salts)

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Caloric restriction and fasting are two different things from what I remember. You can restrict your calories a lot but never enter a fasted state (higher autophagy, ketosis). On the other hand there are also fast-mimicking diets on which you restrict calories way less than fasting but still enter a fasted state.

Diets focused on reducing calories also often fail. I'd recommend taking a look at the start of A Chemical Hunger from SlimeMoldTimeMold on the current state of knowledge about obesity: https://slimemoldtimemold.com/2021/07/07/a-chemical-hunger-part-i-mysteries/. I don't agree with their conclusion that lithium is behind everything (though it sure look like it's playing a part), and there were some replies to some of their data/premises (I don't remember where). However it proves pretty well that the good old calories in calories out just doesn't work.

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Lithium, huh ? Interesting angle, I'll check it out

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They made a recap article recently specifically on the lithium hypothesis: https://slimemoldtimemold.com/2024/07/27/lithium-hypothesis-of-obesity-recap/.

One interesting thing about lithium in that hypothesis is that the dose are pretty small, we're talking something like 20mg/kg at most, but it could bioaccumulate over time. Maybe there are other chemicals that are even more obesity inducing at even lower doses, and thus very hard to test for.

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Lithium hypothesis makes no sense. Lithium should be anti-suicidal and it is everywhere tested in the world. However in USA suicide increased everywhere at the same time as obesity exploded. If lithium hypothesis was true we would see at least some positive correlations (in studies even miniscule doses of lithium are antisuicidal), but now there is zero, or even negative correlation - obesity increased, while suicidal behaviour in USA also increased, so Lithium cannot mediate this

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Obesity is not everywhere; it varies across the US. Suicide also varies across the US, though for reasons (e.g., economic depression) that we at least pretend to understand.

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Correlations don't work so simply that you can make conclusions like this. Lithium could very well cause weight gain (it does in medical doses) and less suicides (it does), while some other much stronger environmental variable causes suicide rate to increase. Another example: obesity causes fertility problems in women; low-education women are more often obese; high-education women are more likely to postpone or give up having children; therefore you get a totally contra-intuitive positive correlation between obesity rate and fertility.

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I have no dog in this fight, but I suspect you'd need to control for reduced smoking, among other things.

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The lithium hypothesis got quite some pushback after the articles by SlimeMoldTimeMold, especially by LessWrong writer Natalia. I think this here is just one of a whole series of articles that she wrote.

https://www.lesswrong.com/posts/7iAABhWpcGeP5e6SB/it-s-probably-not-lithium

I still think that the general picture of A Chemical Hunger show is very interesting, but lithium as candidate doesn't look too promising.

More generally, SlimeMoldTimeMold have been accused of cherry-picking data, or at least of presenting only a weak version of more traditional hypotheses about obesity. See for example here:

https://someflow.substack.com/p/criticisms-of-a-chemical-hunger

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It might depend on which lithium salt it used. (Nobody consumes elemental lithium!) IIRC, Lithium was once used to treat depression.

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Oh thank you, those were the replies I was thinking about!

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>One interesting thing about lithium in that hypothesis is that the dose are pretty small, we're talking something like 20mg/kg at most, but _it could bioaccumulate over time._

[emphasis added for this one particular point]

From https://www.ncbi.nlm.nih.gov/books/NBK519062/

>The elimination half-life of lithium ranges from 18 to 36 hours.

I think bioaccumulation can be ruled out. ( From a chemical standpoint, bioaccumulation of any of the alkali metals would be unexpected. Their compounds tend to be soluble. They tend not to form strong complexes (crown ethers are an exception, and are very specially designed). )

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I'll be honest, I don't know enough to judge that, but they have a conversation with someone speaking about lithium pharmacokinetics here https://slimemoldtimemold.com/2022/02/19/philosophical-transactions-jp-callaghan-on-lithium-pharmacokinetics/.

One interesting part is that lithium may accumulates in the thyroid. I'm seen more and more people from the "peaters" community (that more or less follow the thinking of Ray Peat), that focus not directly on weight loss but on regaining energy through making your metabolism run faster, sometimes by focusing on trying to regain thyroid function. This by itself does not mean anything, but """maybe""" it's two group of people starting to touch two different part of the hidden Obesity Elephant.

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Many Thanks!

>JPC: It is definitely true that lithium accumulates inside cells (definitely rat neurons and human RBCs, probably human neurons, but maybe not human muscle; see e.g. that Ehrlich paper I mentioned). _The thing is, lithium kinetics seem to be pretty fast. Since it’s an ion, it doesn’t partition into fat the way other long-lasting medications and toxins do, and so it’s eliminated fairly quickly by the kidneys._

[emphasis added]

I'm not sure what he means about accumulating within cells. The "lithium kinetics" part of the comment is what I would expect. Also, not only is it an ion, it is a singly-charged ion, so it is much less prone to form complexes, or insoluble salts than more highly charged ions. Now, if the _measured_ quantities of lithium show reservoirs in cells which only slowly get cleared - experiment beats theory. And the discussion in the web page is certainly interesting!

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> However it proves pretty well that the good old calories in calories out just doesn't work.

That series does not prove anything. The authors don't even make the argument that they think they're making.

The Steelman version of A Chemical Hunger is this:

> Everyone is getting fatter. Obviously it's because we're eating too much, but why? Is it *just* our sedentary lifestyles and abundant food? Hmm. Could there be more to it? Well, we know that some psychiatric meds cause weight gain because of increased appetite. We argue that there's an industrial pollutant that's acting like a low-grade psychiatric medication and making everyone hungrier.

You would think that was the argument (it's called A Chemical *Hunger*, for crying out loud), but no. The actual words written in the post do not make that argument at all.

Here's the actual argument, as presented:

> Everyone is getting fatter. But why? We're not eating more. (Here are some nutrition surveys that conclude that Americans aren't eating much more than they used to. Even though nutrition surveys are extremely unreliable, let's treat them as gospel.) So since we're not eating more, clearly something else must be going on. Well, we know that psychiatric medications cause weight gain because of something something chemicals. Maybe there's an industrial pollutant acting like a low-grade psychiatric medication and making everyone gain weight (because of something something chemicals). Look at us, we're so smart, we disproved CICO. Give us all the Status^tm now, please.

The post is dripping in condescension and smugness.

Which is a shame, because the idea that lithium pollution in the water supply making us hungrier is an interesting hypothesis! I would totally endorse further investigation into this. But SMTM does not present this argument. Their primary goal was to claim that weight gain is caused by something something chemicals instead of eating too much. They used a bunch of dodgy sources to do it, while being smug and condescending along the way.

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"Is it *just* our sedentary lifestyles and abundant food?"

I suggest you keep the "abundant food" but lose "sedentary lifestyles" from sentences like this. As far as I understand, the hypothesis that physical exercise reduces weight has been abandoned long ago, it's living on as a zombie theory among the general public.

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Amanda suggested the sedentary lifestyle as a reason for people *eating more*, not for failing to lose the weight gained from eating more. Possibly people sitting around at home are more likely to nibble to pass the time than people who spend their days out and about with no snacks to hand.

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Only speaking for myself, but if I'm very sedentary, I can really want to eat for the stimulation. It's not hunger, I resent feeling too full to want to eat more.

It's also not just wanting to pass the time, it's a very specific desire to eat.

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The physical exercise** -> weight loss pathway is still absolutely valid and I am frustrated that this seems to be so consistently oversimplified. Anyone who has run an ultramarathon or thru-hiked a long trail can tell you all about the high physical activity -> caloric burn -> weight loss interaction. The fundamental caloric model is not disproven or damaged in any way by evidence from exercise.

The better way to explain the issues with physical exercise as a weight loss accelerant would be thus: increased physical activity leads to direct caloric burn, but also to a widespread reallocation of energy expenditure throughout various bodily systems. Energy allocated to bodily inflammation, digestion, thermogenesis, and (famously) NEAT, among other processes, is reduced to compensate for the high energy demand of deliberate physical activity. In real terms, this means that your RMR (resting metabolic rate) decreases at a rate closely correlated to your caloric expenditure from additional exercise. Therefore, trivial-to-moderate increases in energy-intensive physical activity are roughly offset by these reallocative processes.

This is not to say that moderate levels of conscious physical activity are not worth it – the effect on low-level background inflammation alone is probably a great thing, and there are myriad other positive side effects from exercise. However, our conclusion here has to be that only *high levels* of sustained, consistent, consciously maintained activity will lead to consequently sustained and consistent weight loss.

What qualifies as sufficiently “high level” and sustained? Well, remember those compensatory pathways of energy expenditure from earlier? There’s probably an upper limit to how much energy can be reduced in those pathways, depending on the person, because the average RMR among (say) Americans varies from ~1000 to ~2500 (99% C.I.) cals per day, according to various factors including sex, body mass, body composition, genetics, etc. etc.

If you are an average American male, let’s say, with an RMR (including NEAT & digestion) pre-exercise of roughly 2000 cals/day (which is very much on the high end), and you begin to add more exercise to your daily routine, there will come a threshold where your body is unable to continue that compensatory process of reducing energy expenditure from metabolic & digestive processes. Let’s be very conservative and say that your body is able to sustain its crucial metabolic processes on only 1200 cals/day, after adapting to added exercise – you could still see a sustained weight loss effect from ramping up daily physical activity past the level equivalent to 800 cals/day, beyond which you could have no possible means of compensating for your additional energy expenditure. This example is on the extreme end, as average RMR is closer to 1400-1900 cals/day for American males, and it would be extremely unlikely for someone to have a metabolic rate capable of adjusting to that extent; that is, for the average individual, your necessary threshold for effective caloric burn from physical activity – such that you are seeing genuinely sustainable body mass reduction from exercise effects – is going to be well under 800 cals/day; perhaps closer to 400-650 cals/day for the average American male (speculative).

The point I’m making is that, even though your body will do everything it can, unconsciously and seemingly inexorably, to mitigate the effect of energy expenditure from physical activity, this is only true up to some discrete threshold, determinable at the individual level, and conscious efforts to maintain a high level of physical activity in the long term can overcome these factors. To refer back to an example from my first paragraph, people who are engaged in a long-distance thru hike (say, the Appalachian or Pacific Crest Trail) or who train for and run ultramarathons, or who bike race and bike tour, or who compete at professional or international level in other cardio-intensive sporting activities, etc. can tell you how difficult it can be to eat enough to maintain a healthy weight! At these extreme levels of sustained calorie expenditure, it becomes extremely challenging to force yourself to eat enough food to offset your level of activity. Again, for an extreme example (since that seems to be the theme), Jack “Quadzilla” Jones hiked the calendar year triple crown of American backpacking (about 8000 miles of hiking in 10 months) and lost almost 40lbs even while eating well over 5000 cals/day.

This is not especially helpful for probably the majority of people, who are unlikely to be able/willing to fit in a genuinely effective level of physical activity into their regimens, but it is genuinely helpful on the margin because it provides a pathway to weight loss for those who are desperate enough to adopt high levels of sustained activity wholesale as a lifestyle change.

**of course, only certain kinds of physical activity are effective for burning calories; assume I’m referring to calorie-intensive exercise, i.e. cardiovascular exercise, whenever I refer to physical activity or exercise in these paragraphs

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Really interesting, thanks. Worth a write up

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Much appreciated, glad you found this worthwhile.

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Thank you! Indeed, ultra-hard exercise like this does reach uncompensat-able levels of energy loss and makes you thin. But this is not normal human activity level throughout the history of the species, right? If the claim that Kenyan men walking 30 km (or something) per day spend as much energy as an office worker, then even quite high-normal human exercise doesn't cause much weight loss. I assume our stone-age ancestors did hyper-intense exercise only sporadically, and only men (I imagine a battle would be this intense). So what I call zombie theory is when your family doctor suggests you should exercise a bit, like run an hour per day, to lose some weight. He would suggest normal human activity level of the ancestors, which is more-or-less doable for most humans. Hyper-intense exercise is doable for some small percentage (the ones who enjoy it). Anyway I think we are not in disagreement here.

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I think this is pretty much accurate, and that people who are casually interested in weight loss -- including both those who are overweight and self-interested, and people like doctors who have an interest in promoting a healthy weight -- dramatically underestimate the required level of physical activity. It makes sense to call this a zombie theory inasmuch as it seems to be a persistent error that refuses to go away... but then again, I think it is also true that some people have a fairly accurate conception of how much physical activity is required for effective, consistent weight loss and yet are unable to meet that required level just because it's a very difficult habit to sustain, understandably more difficult even than making moderate exercise a consistent habit.

It is correct to point out that plant-gatherer and premodern agricultural lifestyles would not involve anywhere near as much energy expenditure -- they were thin, as were the vast majority of pre-20th-century humans, from having had lower calorie intake -- but long-distance multi-day endurance efforts (the second human superpower, after intelligence) involved in hunting game like elk or moose (among the primary food strategies of many early tribes, such as the Coahuiltecan or San) would indeed approximate something like modern-day ultramarathon training. Of course, if you were looking at raw calorie burn, you might struggle to see that because individuals who are already thin burn fewer calories over the course of the exact same physical activity, relative to those at higher levels of body mass or those with less cardio endurance training... so it could be possible for, say, Eliud Kipchoge to walk 30km and burn fewer calories (as a raw count) than an office worker jogging 12km.

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Thanks for that writeup! More and more I'm wondering if one of the reasons people fail to lose weight by counting calories is that our estimations are not good enough at all. For example:

> However, our conclusion here has to be that only *high levels* of sustained, consistent, consciously maintained activity will lead to consequently sustained and consistent weight loss.

If you look at most calculators of calorie expenditure you can find, they'll consider that running for 80 miles will expand strictly 80 times more calories than running a mile.

I'm also wary for basing too much on very active people, as this could introduce a lot of bias due to selection effects.

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Absolutely true, as a general rule people are terrible at estimating both calorie intake (just forgetting cooking oils alone could be 100s of cals) and calorie burn from energy expenditure. Calorie expenditure calculators are extremely simplistic and should be used as rough "rules of thumb" for someone who is just getting into consistent exercise... a far more accurate estimate of one's calorie expenditure could be gleaned by using some sort of wearable GPS fitness device, which is able to take your input weight and continuously track (proxies for) physical effort during the activity, as well as difficulty (% grade) of terrain, but even that is far inferior to actual labratory calorimetry.

Very active people will generally have less body mass and significantly more sports-specific efficiency / economy of movement, which genuinely makes a significant difference in energy expenditure per [unit of distance]/[unit of output], so that could indeed be skewing results.

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As a prelude, I find many of the criticisms of the hypothesis itself that have been floating around to be reasonable and convincing.

However, the writing did not strike me as condescending or smug when I read it, and on review just now I still don't see it that way - the interlude posts come closest if I had to pick - so while interpretations of tone vary I do not think "it is very stylistically icky" is a fair line of attack here.

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After reading them (some time ago) I came away with the feeling that no matter if we eat more than in the fifties or not, our homeostasis mechanisms seem to make many of us desperately preserve and gain fat as if it was a famine. This is indeed true for many people who just never get rid of their hunger no matter how fat they grow, while other people stay thin without effort because their homeostasis mechanisms turn down appetite when they are full. Looks like something might be wrong with the homeostasis mechanisms; since such systems are mainly chemical, it seems justified to go look for a toxin. I.e. the not-so-sure fact that they ate more in the fifties is not necessary for the chemical hunger hypothesis, but if it happened to be true, it would give strong support for the hypothesis.

Smugness and other style devices should of course not affect the standing of the hypothesis, though it's easy for me to say if I don't mind smugness much.

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This is obviously a very complex topic and there's not going to be a single cause and effect. The decrease in smoking and the increase in hydrogenated oils are likely both relevant. The increase in diabetes seems relevant, which could be the result of less fresh food and more preserved and reconstituted food. Less exercise and sunlight might be relevant. I wonder if increases in genetic load have an effect. SSRIs can cause weight gain with long term use.

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My impression is that smoking only affects weight by about 15 pounds. Am I mistaken?

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Up here in the North, preserved and reconstituted foods were much more prevalent in the past, we now can eat fresh stuff through the whole winter and spring, which would have been unthinkable. I don't know about their diabetes rates in past, could've been high, noone measured.

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I don't really believe in "steelman version" as I found that it's often a way to not listen to what is actually written/said. For example "obviously it's because we're eating too much", that's not obvious. You could imagine that for some reason the body maintain homeostasis and digest less energy giving things when eating more.

CICO itself doesn't mean anything and acts more like a motte-and-bailey to allow some people to feel smug because they're themselves not obese, at least in my experience of the use online. It has proven completely insufficient as a model to fight against the obesity epidemic, and its defender spend most of their time in denial of anything that was proven ("Even though nutrition studies are extremely unreliable, let's treat them like gospel").

I don't really see the condescension and smugness in those posts, to each their own.

Again, CICO has been mostly useless. It's time to find a better model, one that actually works, and that doesn't imply that everyone is lying about everything.

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CICO doesn’t really imply widespread lying, nor is it consistently disproven. If anything, I find “CICO is disproven” to be a consistent canard signaling that the observer is uncomfortable with complexity. Saying that CICO is disproven by anecdotes about dieting or moderate exercise is equivalent to disproving the law of gravity by dropping a feather and a bowling ball. The fact that the feather drops more slowly, in other words, has nothing to do with gravity whatsoever.

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No, I don't think they're equivalent at all. The bailey of CICO is something like "if you reduce your caloric consumption by X every day/week, you'll lose a pound of fat every ~X/4500 day/week. Your caloric consumption can be estimated by one of those online calculators". This is false, for a few reasons: metabolism can/will slow down to adapt to getting less calories, online calculators overestimate calories lost through physical exercise, online calculators don't take into account differences in basal metabolic rate, your body may decide to eat its own muscle which will leave you with less muscle and thus decrease your metabolic rate, etc.

"Counting calories and reducing your caloric intake by a fixed amount every day/week that still leaves you with enough energy to properly function and doesn't reduce your metabolic rate in the long run" is something like the motte of CICO, but even then, it does not work for anyone. People for whom it works love saying that it worked for them, just like people that did X to get out of depression love telling you to "just do X", even though we know different things work differently for different people (except for weight gain/obesity the average duration isn't six months, you can't wait around and expect it to improve).

One other big issue of CICO is that it doesn't mean anything, really. Some people will do fasts, not eat anything for a few days, and get results. Some "pro-CICO" people will tell them it worked because of CICO, even though the numbers don't match. Some others will tell them they are crazy and they're going to ruin their metabolism and CICO doesn't work like that.

But my main point isn't even that it's "proven" or "disproven". It's that at scale it doesn't work, plain and simple. We can argue for a long while about all the details but the truth is right there. Now we can keep diving into why/if CICO does/does not work, but I'm more interested into exploring other options that do actually work.

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Check out Bart Kay's work. He disproves CICO. Those who believe in CICO don't understand the first law of thermodynamics.

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I think we're touching on two subtly different things, actually -- one is whether CICO is a valid and parsimonious model of caloric effect on weight, in a scientific context, and one is whether internalizing the concepts of CICO is a valid and helpful step in someone's individual path to losing weight.

I still believe CICO to be perfectly helpful as a fundamental mental model of caloric effect on weight over time**. It serves as a foundation, upon which the rest of the edifice of the model must be built; the issue comes with the rest of the complexity that is necessary to come anywhere near an accurate understanding of someone's weight over time on the individual level. As you accurately mention, metabolic adaptation will vary on the level of the individual and will significantly mitigate expected weight loss from calorie restriction. Without resistance training and adequate protein intake, and other hypertrophic interventions, the actual body mass lost will include desirable musculature along with undesirable excess fat. NEAT will often fall in tandem with increased conscious physical exertion, or will calorie restriction, etc... and as with any other simplistic online tool, diet calculators are completely inaccurate often enough to be worse than useless (actively discouraging) for a large fraction of the population.

My sense is that those who often find success with simple calorie restriction are those for whom metabolic adaptation or unconscious NEAT reduction are less affected, and they are, in some sense, just lucky to have systems that are conducive to using CICO alone as a dieting strategy. I suspect you would say the same, and to be fair, this will be a significant enough proportion of the population that it doesn't make sense to throw the baby out with the bathwater. Keep CICO around, not just for diet and exercise scientists, but in the popular understanding. Just build from there. I'm not convinced there is any other conception/explanation of caloric effect on weight over time that is simultaneously more parsimonious and more intelligible than CICO.

Again, I want to be very clear -- CICO, by itself, is an inadequate model for understanding the effect of calorie intake on weight over time. It is plainly flawed. It ignores a vast amount of complexity. I think of it as similar to the Bohr model, or democratic peace theory, or "homo economicus"-- on a technical level, it is so simplified as to be essentially incorrect in a vast proportion of individual cases. Nevertheless, there is utility in a framework so simple that still kind of works by itself for some people, and for others is part of the foundational understanding we have of calorimetry that all people could benefit from.

**Of course there are wholesale exceptions to even this; in the case of hypothyroidism, or patients who are sarcopenic/cachexic, or in other medical edge cases, CICO is not even necessarily useful as a building block because the entire metabolic architecture is compromised or changed in such a fundamental way.

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Professor Bart Kay has disproven CICO.

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I'm familiar with his perspective. The uncharitable response would be that the insult-ridden claims of a carnivore advocate with mental health issues have absolutely zero bearing on this conversation. The slightly more polite version would be that he is so far outside of the mainstream that I would love to see considerably more gold-standard scientific experimentation showing his preferred mechanism of calorie-metabolic interaction to be genuinely, replicably, meaningfully different from the current paradigm measured by direct calorimetry.

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Anecdotally, calories in/calories out has worked quite well for me. 3 months of running a >=5k qod, >=10 push-ups qod, no etoh (down from ~1 light beer qhs), and 1 less bean-and-cheese quesadilla per night -> BP 135/85 down to 122/82, weight 196 lbs down to 180 lbs..

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Good for you and I hope that it keeps working! But there are plenty of people for whom it doesn't work at all (you can take a look at Yudkowsky's twitter feed to see his struggles). And it doesn't seem to work at the population level.

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I think "working" is being confounded with "completing the necessary steps for it to work." To say it "doesn't work at all" is misleading when what isn't working is the individual themselves - specifically, the individual applying effort in an amount sufficient to effect weight loss. To make an imperfect parallel, I could say "my job pays very little money - look at my small paycheck;" my paycheck shows I make $100/hour, which is not typically considered to be a low hourly wage, multiplied by 5, the number of hours I worked for the pay period. Clearly, my paycheck is small because I've only worked 5 hours, versus 40 hours, which is what might be considered a normal week's work. So, to continue the example, it would be erroneous to conclude that my job pays very little when in reality I am just not working for enough time to effect a certain magnitude of paycheck.

Another mediocre parallel is driving a very fast car, yet only ever driving under 30 mph. Is it accurate to say "my car is so slow," when the only reason it doesn't go over 30 mph is because I fail to sufficiently depress the accelerator?

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If some method is supposed to produce a net gain in quality of life for the people who apply it, and yet people keep abandoning that method, maybe there's something wrong with it.

On the other hand, if weight loss is the most important thing, more important than quality of life, then I think you're leaving out something important.

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Where the balance lies - how much time or effort to spend on each aspect of their lives - is for each individual to decide. Ultimately, in my case, Stage 1 hypertension has numerous negative effects. One of them is increased risk of MI/stroke. Alcohol use is also associated with negative outcomes. I -now- (haven't for many years) make a choice daily to do these things because they, as evidenced by my BP alone, are steps (haha) towards potentially maximizing my longevity and qol. This ofc is so I can be around for family/kids/improving the world/etc. To your comment, high attrition rates could indeed indicate an issue with the process. That said, another plausible explanation is that it is simply "difficult" to "be healthy," and there is not an issue with the process - individuals are just not willing to do it. This definitely describes my behavior for the last idk how many years...hopefully I still have some metaphorical telomere left...

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I would appreciate it if it wasn't assumed that every time a method fails for losing weight it's because people don't apply it or follow it correctly. Sure, there are people that fail to apply it. But there are people that do apply it correctly and for whom it fails. When you consider that everyone that fails is lying/not doing things properly that means you are never going to consider that your method might be flawed. You're not interested in searching for truth anymore.

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Caloric restriction and increased caloric expenditure through physical activity are both well-supported by scientific evidence as effective strategies for achieving weight loss...the fundamental principle of energy balance applies universally. If weight is not lost, consuming fewer calories and expending more calories will at some point effect this end. If you would provide evidence to refute these facts I would be interested. Please understand also that I am not accusing anyone of 'lying,' nor am I passing value judgment. As to seeking truth, it is possible I am misunderstanding the vast corpus of evidence that supports my statement. Again, I would be very interested to see evidence against this. Also, let's not forget that the decrease in blood pressure is what I initially wanted to highlight.

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"I think "working" is being confounded with "completing the necessary steps for it to work." "

This would be better without the passive voice. Who is doing the confounding? When, where, under what circumstances? Would the following be an example?

"Anecdotally, calories in/calories out has worked quite well for me."

Because perhaps I misinterpreted, but I took that claim to mean "I found the method to be useful and reasonable to apply for practical benefits." As opposed to the much more modest "I didn't find it literally impossible to get results this way."

I think the trouble here is with the phrase "completing the necessary steps." It elides quite a lot of individual variation. The "necessary steps" can vary on the one end from "doing nothing, I maintain a healthy weight without effort" to "rendering myself almost totally unable to function" on the other end. The job parallel was *this close* to the point. Yes, "I earn very little money" could indeed mean you earn $100 an hour but only work 5 hours a week. It could also mean you earn $5 and hour and work 100 hour weeks. Assuming that it must mean one or the other based only on the initial phrasing isn't particularly reasonable.

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"Working" is quantitated in my posts (blood pressure, weight loss that puts me in a non-overweight category) and sufficiently in the massive corpus of evidence that supports the positive association with sufficient application of the aforementioned strategies and weight loss/decreases in blood pressure.

It appears that you are interested more in attempting to refute *me* than in perusing the referenced evidence and refuting those multitudinous examples supporting my statements.

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Yeah, for sure it works. The problem is that people are unable to maintain it for the long term.

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