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.
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
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?
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.
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.
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.
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. :-(
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
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.)
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.
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.
> 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.
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.
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.
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.
"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.
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"
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.
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.
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.
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.
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.
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).
- 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?).
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...
"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!
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.
"[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.
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)
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).
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/
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.
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".
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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:
>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._
>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). )
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.
>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!
> 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.
"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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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..
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.
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?
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.
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...
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.
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.
"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.
"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.
Yes, if you don't consume calories, you will eventually waste away. But there is much, much more to the system of metabolic health and weight loss than CICO.
I agree with you on that point for sure! I am not going to analyze this guy's video (which I watched about half of) but he seems like he'd make a formidable ally (or foe) for the Debate Team...
I started on tirzepatide while barely 15lbs overweight. I have two pretty bad immune issues. Both are, completely miraculously, cured by it. I’ve gone off and now now numerous times even at perfect weight and it still has effects. Even when I eat normal calories and am not fasting on it.
> But when he dies, the coroner discovers that his head has a rock saying “[CALORIES IN CALORIES OUT]” where his brain should be.
What you’re saying is intuitive: ozempic makes users eat less. This skips all the annoying confounders when studying diets, and goes straight to the part where they really don’t take in as many calories. It’s not hard to believe that this reduces weight in most cases.
But what about the weird stuff? What does fasting have to do with Alzheimer’s? Is there stronger evidence for that than for, say, aducanumab?
I don’t know if anyone’s managed a study on heroin or amphetamine use and Alzheimer’s risk. It seems very unlikely that those drugs, which also reduce caloric intake, demonstrate any of the other benefits suggested for ozempic.
I suspect "you don't want to" is the crucial part. This article argues against calorie restriction saying it's no use if you don't "treat" you brain since the satiation feeling is some kind of guess of your hypotholamus (?) on how nutritive what you just ate was based on prior experience (which is why the hunger system can apparently be tuned) :
Really interesting pivot here into what may be the real issue. Is there any research you know of though that speaks to the ideal "happy medium" so to speak. For instance, restricting calories too much and you are unhealthy and don't get enough nutrition, but obviously an abundance of processed junk (or really any) is bad on the other end of the spectrum.
I think it might be both downstream and upstream, in the sense that other regulators (eg hormones) tell it what to do, and then it tells other things (eg the body) what to do. Maybe "center" is a better descriptor than "master".
I found myself thinking this as well. I see Scott’s explanation but I think the way he has worded the “slightly less masterful” phrasing makes downstream a more natural choice here.
The other little lesson from the SSRI experience is that in addition to benefits being overestimated, negative side effects tend to get overlooked. Just had a friend who had to get off Ozempic after developing a nasty case of pancreatitis…I’m guardedly optimistic about these drugs but reluctant to get on them until the smoke from the hype cycle has cleared a bit.
Pancreatitis as a side effect has not been ignored. It’s one of the main side effects on the label. But it happened in less than 1% of cases in clinical trials. It also was much more common if you already had risk factors for pancreatitis.
If the real world incidence of pancreatitis was over 1%, I’m confident there would be plenty of media doom cycles over it. Especially given how much they are charging for this shit. Hell, they tried to do that with suicidal ideation until further research made fairly clear that the opposite relationship is actually more likely.
Are there very common side effects besides nausea that have been shown in trials that I am unaware of? Or other side effects requiring discontinuation?
It’s 5% according to the article. Though the actual term for this symptom is gastroparesis, which is less scary sounding. I’m thinking webmd calls is “stomach paralysis” because it’s more accessible as a term.
It’s pretty treatable, though unpleasant. A friend of mine has chronic idiopathic gastroparesis, and has medication that helps. But it makes her chronically malnourished.
I only skimmed the article, but would be surprised if the symptom didn’t clear up for almost everyone within a couple of weeks. This is likely one of the symptoms that requires such a slow ramp up of your dose, so they catch it with the quickest turnaround on having it resolved.
It’s one to keep an eye on, though. And hopefully they figure out a way to get the benefits without this symptom. Because “5% of people just can’t take this drug ever” is not a good thing for such an otherwise beneficial treatment.
Yeah, but it doesn’t contain the English word “paralysis” which most people associate with a wheelchair and a permanent condition. Gastroparesis is usually incomplete and reversible, particularly when drug induced.
“Stomach paralysis” sounds complete and permanent because of the association with the English word that is most often used to describe the consequences of a spinal cord break.
Even rational people are influenced by the context of language.
The link between suicide and SSRIs has not been disproved. A characteristic of SSRIs was that the side effects frequency were at first considered rare/low but were continually adjusted upward with post-market surveillance and patient reports. The initial trials used to get approval for a drug are often not perfect guides to what the drug effects will turn out to be when used on a mass scale.
Also, the initial trials of SSRIs did not actually include the population most affected by that side effect. (Adolescents). And only a few of them ever went through the process of doing trials in that population to get approval. The black box was added because the risk was identified as a risk of all antidepressants in pediatric populations during a metaanalysis of small RCTs of something like nine drugs (4, to my knowledge, are actually approved for pediatric use). The increased risk of suicidality at start of treatment for antidepressants is not significant in adult populations, to my recollection. (This is Scott’s wheelhouse, though, so if there is a deep dive on it from him I don’t remember please refer me.)
So, I think what we can take from that is that we should be extremely careful about off-label prescribing in populations not included in the trials. For instance, it’s probably irresponsible to start prescribing glp-1ra in non-diabetic pediatric patients until each is explicitly approved for the indication. And if they are being prescribed off-label, it should be by specialists in pediatric obesity with extra checks for weird side effects.
There's also many cases of paralyzing the stomach, class action lawsuits and most people gain all of the weight back when stopping, in some cases more. There are always negatives with prescription drugs and the FDA always winds up being wrong, zantsc just another example.
I agree, the effects of Ozempic don't seem too dissimilar from the effects of long-term, severe caloric restriction (not just casual fasting) across many animal species. Many scientists see it as a slowing of the aging process (hence the reduction of age-related diseases). There seems to be a deep evolutionary connection between energy consumption and aging, and this is one way that it manifests.
When we determine the exact mechanisms by which Ozempic prevents these diseases, we'll also understand exactly why exercise and varied, colorful vegetables (and their pigment molecules) help prevent these diseases.
Doubled the economy of Denmark? That’s ridiculous, and not mentioned in the linked article. The GDP of Denmark is $410B (yearly production), the market cap of Nova Nordisk is $560B (total value of future earnings).
Yeah, that jumped out at me, too. The closest thing that I could find (in a separate article) is:
> Danish GDP will grow by 2.7pc this year, the Ministry of Economic Affairs said – far faster than the 1.4pc it had expected in December.
> This revision has been driven in part by the runaway success of pharmaceutical company Novo Nordisk’s hit drug Ozempic, while the reopening of the Tyra gas field will also boost GDP by reducing energy imports and boosting exports.
It IS ridiculous, but it's actually a pretty widespread and oft-repeated claim. People seem to just see the two numbers, GDP and market cap, be approximately equal, and be inexorably jump to the "doubling Denmark's economy" conclusion.
A more reasonable comparison would be to the total market capitalization of Denmark's STOCK MARKET, and … huh, Nova Nordisk might about 3/4 of that.
Thanks for the article. What's behind the misleading "doubling" claim is that the market cap of Nova Nordisk, about $450bn, is bigger than the annual GDP of Denmark (about $400bn). But of course the market cap is just the value of the shares, and is not itself part of the economy. The revenue of Novo Nordisk is about $34bn which is less than 10% of the economy of Denmark, and presumably a lot of it is earned outside of Denmark. Still damn impressive that their market cap is bigger than the entire annual GDP.
Better compare something like citrus to citrus. I'll use that mkt cap compared to Denmark total wealth rather than gdp. Total wealth is 1.9 trillion. Still impressive.
I include all my organs when calculating my (personal) net worth. They are critical assets! It's part of the GAAAP (Generally Accepted Anatomic Accounting Principles).
> But of course the market cap is just the value of the shares
Well, more accurately it's the value of one share multiplied by the number of outstanding shares. It isn't clear how this figure relates to the value of the shares. If you want to buy all of the shares, you'll pay quite a bit more than the market cap; if you want to sell all of the shares, you'll get a lot less than the market cap.
I've been taking Ozempic and my personal theory on the addiction stuff is. Lose weight -> improved feelings of self esteem and self control (even if the self control came from a drug, you still feel good about it!) -> able to overcome other addictions.
But I don't know if that makes sense in rats! Very interesting article thank you.
That would be plausible if reduction in addiction happened only after some significant weight loss; if it happens more or less immediately, it has to be a direct effect of the drug.
Related question: Why does semaglutide, at the lowest possible start tapering upward from this dose, give me such crippling brain fog that after 3 weeks of it I was unable to think clearly enough to effectively do my job, my depressive spirals had doubled in both frequency and severity, and focusing on anything felt like dragging my brain kicking and screaming through a field of broken glass?
It also made me feel too sick to eat most of the time, which I suspect is the primary weight loss mechanism.
Anyone else experience these mental effects? Did they ever go away? I discontinued before upping the dose. Some anecdata suggests tirzepatide is less likely to do this, so that's next on the list.
I've never felt anything like this from anything else. The enhanced depression, especially, was honestly kind of terrifying, at least before I recognized that it was the drug. After a couple nights where the occasional evening self-loathing/self-worth spirals I sometimes have were set off by absolutely nothing and dropped me twice as low as usual, I Googled around some, and saw others on a few Reddit threads reporting similar mental side effects. Before that I'd been worried something was becoming dramatically worse in my brain chemistry. That went away as soon as I was off semaglutide, so I guess in a way something was.
It was kind of like having a really bad bout of Covid, for a month, with none of the physical effects of Covid (well, aside from "too sick to eat" and actually maybe some muscle fatigue now that I think of it), just the mental "I feel like I have been hit by a truck and haven't slept for days" ones.
If it lowers all reward signals somewhat, maybe your reward signals are especially weak or you are especially sensitive, such that it basically turned them all off?
I wasn't, but my blood sugar is normally far too high, which is why I was on the drug in the first place - A1C peaked over 10 and my doctor decided it was worth trying at that point (vs the 8ish I'd maintained in less stressful years). So I'm not sure I could possibly have gotten hypoglycemic enough to cause those effects, especially on the lowest dose (1/3 of what I was eventually supposed to titrate up to).
[very late reply] A1C is a summary statistic of the last 90 days of blood glucose, but there's also an instantaneous glucose test you can do at any time. You can get a take home finger prick kit.
In my case, I've had great fasting glucose (at 80) but have observed high A1C levels when tested.
If I were in this position I'd try testing my glucose a few times a day to see if it ever plummeted too low.
Sounds like my experience on liraglutide, only in my case it was more subtle. I had more trouble focusing, increased anhedonia, my ADHD got way worse, and I was sick to my stomach all the time.
I'm kind of bummed by your comment, because I had previously heard that semaglutide had a much better side effect profile than liraglutide.
FWIW, my (former) boss reported the same issues you do with liraglutide (only he was weaker or more sensitive or something, because with the exception of the ADHD, he made the symptoms sound way worse than that)...
...but when he tried semaglutide, he said it was like night & day; loved it. He got switched to tirzepatide, I think due to supply issues more than anything to do with the substance itself, and said it was even better (somehow)!
He's been going around telling everyone to get on one or the other for a good nine months+ at this point, heh. But if he couldn't handle liraglutide but got almost-no-to-no side effects with these newer suckers, might still be worth a try for you too.
My friend had a wonderful experience on Wegovy (almost sounded like she had an antidepressant effect on it too), but once her insurance company forced her doctor to switch to mounjaro, she started experiencing migraines, irritation, anxiety. She is waiting to get back on semaglutide bow, but perhaps it’s just person-dependent?
The other bit she mentioned is her Stanford doctor said they are seeing more side effects in women who get injections in their belly. It’s not playing well with our hormones, supposedly. Upper arm or leg is a better area to choose for injections.
When it comes to diabetes, they got all kinds of egg on face back in the TZD era, due to their myopic focus on drugs only improving surrogate markers (in the case of diabetes, it was A1c) rather than hard outcomes (mortality; or in the cardiology case, CV death and non-fatal MI).
After that embarrassing lesson, they mandated new diabetes drugs to show cardiovascular safety via clinical outcome studies, prior to receiving regulatory approval.
So earlier, agents in the SGLT-2 inhibitor class; and now agents in the GLP-1 agonist class, have had to provide trial evidence of CV safety. It is in the course of that work that signals were seen that agents in these 2 classes were not only “safe” (ie. no increase in CV outcomes) but were in fact protective (ie. fewer CV events than placebo). And it is subsequent studies powered to show CV endpoint reductions (in CAD, HFrEF, and HFpEF for SGLT; and more recently in CAD…even without diabetes….and HFpEF for Ozempic) that have propelled both these classes into the realm of cardiac meds (even in those without diabetes, in certain indications).
But as you’ve summarized here, we still don’t know how they truly work. It remains to be seen if and when we can elucidate the mechanisms responsible to account for the observed CV outcome benefits, among others.
Nonetheless, the FDA deserves some credit, even if they stumbled into it by happenstance.
Wow, a nice story of the benefits of improved regulation.
Request: Please write “cardiovascular” if that’s what you mean. Acronyms are a negative externality - similar to pollution - of a writer saving a few keystrokes, offloading the work to everyone who needs to parse your intention.
I'm not sure I understand what we have the FDA to thank for. Is your claim that, if the FDA hadn't discovered protection against cardiac events, we would never have learned of that protection?
He wrote a book about baclofen ending his craving for alcohol-- he considered the craving to be a problem, not just the drinking. He also found, to his surprise, that he wasn't shopping compulsively any more.
I tried it, in smaller doses first than he recommended, the result was "OK not taking it today, I actually want to drink, not just crave to" and then it was the result every day. It did not fix the underlying issues, boredom, anhedonia, finding it hard to kill time.
I think it is safe to say that addictions tend to come from self-medication of issues and thus I believe it is mistake to look at the addiction only and not the cause the substance use is trying to address.
This is so obvious to me I wonder why docs, even Scott, see addiction as a thing on its own. Obviously someone starts drinking or snorting because they feel shitty, you get them to stop, they feel shitty again, so they will start again. It is really not just cravings but underlying issues of why was it even started back then when there were not yet cravings.
I don't think that's universally true - my husband had a serious drinking problem that he was only able to defeat with the help of naltrexone. He started drinking in college because that's just a common thing to do socially, and soon found that his brain chemistry *really loved alcohol* and he suffered terrible cravings whenever he tried to quit. His life post-naltrexone wasn't any different than his life pre-naltrexone, but it's been several years and he hasn't been tempted to start drinking again.
I think you're both right, and that people start addictions for a lot of reasons, often as self-medication, but many people are stuck with the addiction even after the original problem has resolved. I certainly feel like that's the case in my own life with some bad habits I find extremely difficult to shake.
Great post - GLP1s continue to be one of the most exciting areas of pharmacokinetics!
Re: second footnote on GLP-1s and libido: I did an analysis of a few hundred reddit comments from various ozempic/semaglutide communities and found that a reduction in libido was a commonly reported side-effect, but interestingly enough a large increase in libido was also reported almost as frequently. Increases were reported slightly more often by women than men, but I didn't have the statistical power one would desire here.
I think many people probably have suboptimal dosing schedules; I use custom software which roughly tracks my own blood level of it, but for mass market pharmaceuticals the one-size-fits all of "X or 2X or 4X once a week" provides for much less fine-grained control of optimizing for fewer negative side-effects.
I think it's worth noting that semaglutide and tirzepatide are much stronger than previous gen GLP-1s and may have effects that didn't show up in earlier studies of exenatide and dulaglutide.
Blood sugar management lowers the risk of dementia but when you compare people who take GLP-1RAs or SGLT2 inhibitors they have half the rate of PD & AD compared to other diabetes drugs (cf. https://diabetesjournals.org/diabetes/article/72/Supplement_1/484-P/150550 & https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.15331 ). So GLP-1RAs or SGLT2is most likely have off-target effects beyond blood sugar control. Improvement of the BBB could be one thing as the BBB is more porous in neurodegenerative diseases (NDDs). Which by the way might be good for semaglutide: it's possible that semaglutide does not cross the BBB in healthy individuals but can do it in NDD patients. We'll only get the results of the semaglutide trials for AD in 2026/2027 unfortunately. The most informative will be the results of the phase 3 exenatide trial in PD (NCT04232969) that will be published in 6 months. If negative: we need to understand why it failed in phase 3 but succeeded in phase 2 (together with lixisenatide). If positive: it will make A LOT of noise and you can expect that many PD patients in existing trials will drop out and start taking exenatide off-label...
There seems to be evidence that they are inducing effects mediated by GLP-1 in the brain. Likely through the mechanism natural GLP-1 does (activating peripheral receptors that then begin telling the brain to release its own). Regular GLP-1 crosses the barrier, but it has a lot more trouble crossing the “blood” part than newer drugs do.
And not for nothing, its effects on weight loss are stronger and seemingly centrally mediated in spite of lacking BBB penetration.
I don't necessarily calibrate with other biomarkers as I'm not sure there's much to read into aside from hba1c (if you feel low energy or slightly nauseous, it's best to just note this down instead of find a blood test to prove it)
but it's useful for dosage calibration, e.g. deciding you want to take it two days later than usual, or reduce the dosage by just 15%, etc
Amazing that you did that analysis! I can imagine two opposing effects: 1/ increased libido due to increased self-confidence after weight loss and better mental health while 2/ decreased libido due to sex addiction or just sex as a coping mechanism like binge eating, drinking, smoking, etc. It would be interesting to know the baseline. I would not be surprised if semaglutide "regresses to the mean", for instance: the sex addict ends up having a lower libido (but still "normal" range) while the obese person "single for life" now has a higher libido (still in the "normal" range again).
The RR is massive. I wonder if something can happen like "Weight loss => More attractive + increased self confidence => Start dating again => Realize that they have ED => Get a prescription". Ideally we'd like to adjust by the number of sexual partners/intercourse. Alternatively, do the same study in non-obese/overweight diabetics (who don't lose that much weight: https://x.com/EricTopol/status/1776732406340325869 ) comparing GLP1-RAs users to metformin, SGLT2i, DPP4 users.
Good point - the baselines might have a strong effect here. I also found it interesting noting a very small percentage of users who basically got full anhedonia or depression from some GLP-1s, and it seems like maybe an even smaller amount got something like a minor version of the opposite. Fascinating compounds
Given natural variability in GLP-1 production, have any in-vivo studies been done in humans comparing GLP-1 production in response to food and likelihood of addictive behaviours and/or obesity?
I have significantly higher-than-average 'willpower' for stopping/reducing bad things, like overeating or addictive behaviours or drugs. I can't help but wonder if I just make a bit more GLP-1 than the average Joe or Jane.
I have, quite literally, the least self-control of anyone I've ever met, bar *maybe* a few low-IQ ex-&-future felons.
No one who knows me has ever been able to understand it, and neither have I; parents, (ex-)wife, professors, psychiatrists — hell, even my last two GPs, for some reason — have all tried to keep in touch... despite my not having enough self-discipline to sit down and write them anything back (or, in wife's case, despite the fact I cheated on her out of the blue & without being the least bit discontent 🤷♂️); and at least a couple times a year, I get several emails asking if I've finally [done the things].
I always have to say no, BUT: I'm going to tomorrow!... right after I get just one more day of slavishly adhering to all my base desires...
[*pops some pills, hits the vape, makes booty call, eats red meat (even though I think vegetarianism is the correct way to go) & entire pint of ice cream; oh look the day's over darn it–*]
It has effectively ruined my life — at least, in comparison to what it could've been — and the only reason I'm not fat is that I just (thank God) don't really care that much about food.
(Diet's shit; just go long periods of time with no food also.)
I wonder if this could be (part of) the explanation.
I appreciate the advice! I probably didn't write the above with the correct tone, wanting it to be amusing or at least not "weak"-sounding, but in truth I'm at the end of my rope and will probably end up dead within a year or two if I can't manage to make myself DO the things I want to do (instead of the things I compulsively do, if you know what I mean).
I haven't been able to stick with meditation, very much — though I managed to for a brief while, in the past, and it did seem to help a bit; keep meaning to get back into it...
I have indeed tried amphetamine & co., and in fact, I'm trying them again right now: just took my dose, and we'll see if I manage anything. One thing I've noticed is that if I let myself do something pleasurable, I become "stuck" worse than ever when on amphetamine — need someone to watch me and smack me every time I focus on the wrong thing, heh.
Hang in there. And yeah, try this stuff, it sounds like it might have a chance of helping.
I didn't use to be like that, but then shit happened, and all the advanced coping skills utterly failed to work, and now I've got a lot of bad habits...
I appreciate that, amigo. 👊 Same to you — hey, if we developed bad habits, that's actually just proof we're good at developing habits, I say! Good ones will be a cinch!
(I know what you mean, too... it's like every attempt at — and then failure at — improving has actually just made me much, much worse. A sort of hopelessness has set in. If you feel like telling your story, I'm interested to hear it; if it's the sort that's actually unhelpful to you to vent/re-tell, of course, then never mind about that!)
You could try beeminder, boss as a service, or stickk. Also, if you can manage it, a large dose of meditation (concentration meditation like breath watching or Vipassana or noting, not the more mental types like looking for the self) (an hour a day, in one sitting, for 2-3 months). Medication in conjunction with meditation might make it more bearable. For me the effects last around a year. Or get a dominatrix that beat you if you eat a pint of ice cream?
I remember when Beeminder first came out (or first entered my awareness, maybe) some years ago, but IIRC I concluded that probably I'd just fail to meet the goals I set a bunch & then stop using it, rather than actually modify my behavior to avoid the fines (if I'm thinking of the right app here—the one that fines you for not meeting deadlines right)...
...but I've never heard of the other two. Since I'm extremely diligent at work, somehow — don't even ask me why it becomes easy in that context, heh — BaaS sounds very promising...
I appreciate it, mi amigo! 🫡
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(...and, uh, hey, if anyone knows of some dominatrices in Texas, I... my friend, that is, would be interested for sure—)
And after you have some general coping strategies or confidence, you could start on strategies for specific circumstances. Atomic Habits is also a useful book, probably the only useful book I've encountered.
Red meat has gotten a bad rap. I'd try a low to zero carb diet. Beef, butter, bacon, eggs, fish, fowl. Fruits & vegetables are overrated; but if you do them make sure they are low glycemic.
Here is the hack: You can't cheat. If you have urges, just eat more of the above until you are satiated.
But yeah, I understand a life without pizza and french fries, to say nothing about buns for your burgers and sandwiches, just isn't worth living to some/many folks.
Hmm, interesting to hear this — my buddy is trying this sort of diet, and claims it has made him feel better than ever; he's certainly fitter than ever, so I guess it's working...
...but I feel bad about killing all the innocent animals...
...just not enough, apparently, to stop eating meat anyway, heh.
Low carb/keto/carnivore diets work. Even its skeptics and detractors are starting to admit they do in the short term (weight loss and reversal of chronic diseases). Though, they then focus on the unknown long term effects, about which I'm still agnostic.
I too sympathize with the ethics of eating animals. There are three separate issues involved. Carbon footprint is another. And nutrition science is the third. I focus mainly on the third.
That's not what this article says, and it's not true. Obesity isn't a risk factor for addiction, and is only a very weak risk factor for things like Parkinson's. Most of the people in these studies are probably diabetics taking it for diabetes and may not have even been obese to begin with.
That sounds like the opposite mechanism. This reduces addiction, and obesity is an outcome of a particular addiction, so this reduces obesity. Rather than the hypothesis upthread, which says that the obesity effect was mediating the addiction effect.
Most probably a troll job by the tone of the writing, but anyway: The connection between GLP-1 agonists and Parkinson's is "modulation of dopamine" if anything - nothing to do with obesity, as Scott already pipped me to say obesity was never found to be a risk factor, and most Parkinson's patient I've met tend to decline in weight on their own as the disease progresses. Also, while obesity in younger years increases the risk of dementia, if a 5-year trial alleviates symptoms of patients already experiencing Alzheimer's, it can't possibly be because the drug affected them aged 35-65, when the drug and the trial weren't in existence...
There are metagenomic studies on Parkinson's that have found an association with an altered gut microbiome. Of course, it could well be that Parkinson affects gastrointestinal mobility and that changes the biome.
But if it goes the other way, there could be a causal chain something like constant feeding -> dysbiosis -> Parkinson. Ozempic would act on the first, and the causative pathogen would be s.t. it would not thrive with less food or longer breaks between meals.
Always a possibility - but constant feeding that doesn't cause a caloric surplus and so isn't represented as obesity? In that case the Vagal hypothesis makes more sense, Occam's Razor-wise. Gut microbiome is currently in the "over-saturated as an explanation for everything, because we don't understand it at all" phase. Not saying it's not possible, mind you.
It's effects certainly are not just from fasting/obesity. I took it at a healthy weight and it entirely cured some very nasty immune system issues I've dealt with my whole life (Ehlers Danlos + Familial Mediterranean Fever).
That is very much not the conclusion of the article lol. The interesting thing about the article is that this is unexpectedly *not* the case. Did you *read* the article?
So I've been thinking about taking Ozempic, but now I'm scared that I do I'll lose interest and joy in all my hobbies and not accomplish anything anymore. Or that I'll no longer care if whatever I'm entertaining myself with is good or bad.
Is this a rational fear or is it my anxiety projecting nightmare scenarios from a few studies?
As far as I know, zero people have ever reported that on this med. As I said above, it's mysterious that the reward circuitry seems to separate out "addictive" reward from "wholesome" reward, but it sure does seem to do this.
Could it have something to do with the difference in "wanting" vs "liking" circuits in the brain? I vaguely remember reading something along the lines that both are parts of the dopaminergic system, but are nonetheless separate. Anecdotally, advanced meditators often report that decreasing "wanting" not only does not inhibit "liking" but actually boosts it.
See my comments above. I experienced more or less precisely what Ghatanathoah is afraid of - "lost interest and joy in all my hobbies" is the least of it, "not accomplishing anything anymore" (due to horrible brain fog/low energy) was what made me discontinue. It seems to be somewhat rare, but it is a possibility.
Maybe it just prevents some kind of runaway loop in reward circuitry. Sweetness is a good way to think about it. Sweet things are enjoyable, but they don’t induce compulsive seeking behavior for sweetness. A behavior that is well-established and I argue analogous to addiction just at lower intensity.
As I said, I wasn't on it long enough or at high enough doses, so I didn't get the "wow, suddenly I don't want to eat the tasty food I usually crave!" effects.
So I imagine you won't get the effects you fear. But if you only want 'quick easy way to lose a few excess pounds', I'd avoid Ozempic. Why take it unless you really need it? On the other hand, if you're extremely overweight/diabetic and nothing else has worked, take it.
N=1, obviously, but this didn't happen to me at all. I still enjoy all kinds of things. Actually I still enjoy food, I just feel full faster so I stop eating.
Maybe you could pre-commit to doing it for a month (or whatever a couple of administrations is), and then stopping for a month (ditto), and taking notes along the way? That way you'd have your subjective memory of the time on the drug, and your records from the time, and you could compare the two to see if they match up.
(I suppose that wouldn't tell you whether the drug turned you into a homo economicus p-zombie, but I don't know that anything would work for that...)
"The results were unequivocal: Ozempic and its relatives work in the brain. Although they have some effects in the body, these are short-lived and not really relevant to their mechanism of action for weight loss."
Interesting, I thought the effect was that semaglutide slowed down intestinal contractions so that food passed through the digestive system more slowly, making you feel fuller for longer, and hence reducing appetite. This is why weight loss, plus the side effects of constipation and stomach pain:
"Ozempic® may cause serious side effects, including:
- inflammation of your pancreas (pancreatitis). Stop using Ozempic® and call your health care provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.
- changes in vision. Tell your health care provider if you have changes in vision during treatment with Ozempic®.
- low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Ozempic® with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include: dizziness or lightheadedness, blurred vision, anxiety, irritability or mood changes, sweating, slurred speech, hunger, confusion or drowsiness, shakiness, weakness, headache, fast heartbeat, and feeling jittery.
- kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.
- serious allergic reactions. Stop using Ozempic® and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue, or throat; problems breathing or swallowing; severe rash or itching; fainting or feeling dizzy; or very rapid heartbeat.
- gallbladder problems. Gallbladder problems have happened in some people who take Ozempic®. Tell your health care provider right away if you get symptoms which may include: pain in your upper stomach (abdomen), fever, yellowing of the skin or eyes (jaundice), or clay-colored stools.
The most common side effects of Ozempic® may include nausea, vomiting, diarrhea, stomach (abdominal) pain, and constipation."
Now you're telling me it's all in the brain? Fascinating!
I wasn't on it long enough or at high enough doses to get the good benefits; it didn't seem to affect my appetite levels at all. When I couldn't get Ozempic, my doctor put me on a different one, but the side effects were so bad I had to come off it. Now I find out it was all in my mind, eh?
I'm rather dubious about the reported fantastic benefits. I think it'll probably shake out as usual: for a small number of people, it's the most amazing thing ever. For the majority of people, it works okay. For another small number of people, it has little or no effect.
GLP-1 is a master regulator of food-related activity. It has actions in both the body (preparing for digestion) and the brain (changing the feeling of hunger). But its weight loss effects come mostly (entirely?) from the brain. Although taking artificial GLP-1 drugs does change some of the body actions, these either produce tolerance quickly, or don't cause weight loss so much as just screw with the relevant systems a bit.
Yeah, that's what I'm very eager to learn more about. If there was some Magic Bullet drug that turned off my appetite, I'd be ecstatic. There is something messed-up with signalling going on in my system, where I'm still getting "hungry, must eat" messages even when my stomach is full.
But that sounds too suspiciously like a willpower substitute drug, where (as we've seen on here in previous discussions of weight loss) us fatties get told "just power through being hungry! after 24-48 hours fasting you stop feeling hungry! it's easy, just get your willpower going and stop shoving food into your face!"
I wonder. I really do. I think right now you're correct and there is this huge, enthusiastic burst of confidence that Ozempic et al. are the new Magic Wonder Drugs that will cure everything. And I think (as with Prozac on down) eventually it'll settle down into "okay, for some it works, for some it doesn't", and we'll get a more balanced view. But that's still a few years away, and right now it's the Hot New Research Fad to see if you can use GLP-1 to cure crabgrass in the lawn and rust blotches on metal fittings.
"But that sounds too suspiciously like a willpower substitute drug, where (as we've seen on here in previous discussions of weight loss) us fatties get told 'just power through being hungry! after 24-48 hours fasting you stop feeling hungry! it's easy, just get your willpower going and stop shoving food into your face!'"
'Stop feeling hungry' is not accurate, at least not to my experience. I'd been obese for half my life when I finally decided to cut back on how many calories I ate per day, and it took a year to lose sixty pounds but something like three years to stop feeling like I was constantly starving. My realization wasn't so much that I'd stop feeling hungry if I ate less - it was that I *already* felt hungry, all the time, regardless of how much I did or didn't eat, and that not eating wouldn't actually make me any *hungrier*.
You and I know that, but the non-fat don't; they regard being hungry as "need food, body says hungry, eat food, stop being hungry" and hence "eat more food than needed, get fat - stop eating so much!" is the easy solution. "Hungry? Hunger is easy, just turn it off by ignoring it".
Like the joke (lifted from notes on the Divine Comedy) about the Cardinal who asked his servant "what do the people say about me?" and he replied "That you are always drinking, your eminence", to which the cardinal said "But that is because I am always thirsty".
Reminds me of another Catholic joke; two priests are debating whether or not it's acceptable to smoke and pray at the same time, and decide to write to the Pope to settle the matter once and for all...only to get back opposite answers. The first priest had asked if it was acceptable to smoke while praying, and the Pope had responded "No, smoking is a distraction, your mind should be focused on your prayers." But the second priest had asked if it was acceptable to pray while smoking, and the Pope had responded "Yes - it is always acceptable to pray."
I've seen that one in a version where one of the priests is a Jesuit, and he's the one who phrased the question as "Can I pray while I smoke?" in order to get a favourable answer. The idea being that the Jesuits are the ones who can logically weasel their way out of anything via loopholes 😁
The Greek poet Hipponax apparently left us part of a poem in which he offers a prayer to Hermes before stealing something. (The citation I'm looking at is to "Fr 32", which I assume is the 32nd entry in his "Fragments".)
The Hacker's Diet has a section on what the author calls "the eating switch" - he has some graphs of possible switch behavior and argues that in his case, hunger was giving him faulty signals about when to start and stop eating. His solution was to track calories ruthlessly and to drink coffee until nauseated whenever his count told him it was not time to eat more calories.
You say that as a joke, but that's close to the advice I got years back from a cardiologist.
Like a fool, my first mistake was I decided I'd answer questions honestly. So, to the usual "why aren't you on a diet?" accusation, I said I was, but I had trouble with willpower.
And then I got "Well, hunger strikers have no problem with willpower. Just don't eat".
Yeah, that was really helpful advice about dieting and what to do, doc!
> Like the joke (lifted from notes on the Divine Comedy) about the Cardinal who asked his servant "what do the people say about me?" and he replied "That you are always drinking, your eminence"
They must have had a strong relationship.
There's a great scene in the 1973 film The Three Musketeers in which Richelieu is listening to a report from his spymaster:
[𝘴𝘱𝘺𝘮𝘢𝘴𝘵𝘦𝘳]
The following conversation took place between the Queen and her dressmaker:
[...]
Constance: That nasty filthy rotten evil man, evil filthy repulsive evil man, calls himself a man of the church?
That's actually why I was able to do alternate-day fasting for awhile -- I realized I was starving all the time, so why not be starving and not eat? I am on tirzepatide now so it's moot, but I totally get your logic.
Something I've been thinking about for myself-- there are a bunch of things that drive eating for me, and I think one of them is "stomach feels bad, soothe the stomach".
Now, if I'm hungry, eating will make my stomach feel better, but I just had a few days of being overfed, and I still wanted to eat, and I think it was a confusion about whether food would make me feel better.
I have no idea whether anyone else has this problem at all, and fortunately, it went away for me.
I had it on IBS. It felt like a hunger pain but I later realized it was not. After I started taking nortriptyline for it and it went away, I stopped overeating to “soothe the pain”, and when it is occasionally back I no longer try to treat it with food.
I am curious if anorexia exists in the brain or the stomach.
I think they have ID’ed some genes in connection with it.
The other day I heard Karen Carpenter’s version of “Still Crazy After All These Years” in which as you might expect she sounded unlikely to have ever been crazy - and then I thought: but she was!
But I relayed this to my companion who said he thought the latest on anorexia was, it was not about “thinking you’re not thin enough” anymore.
Damned if I know. I think it's at least partially socially driven, but (last I heard) it's also correlated with mental problems like bipolar and OCD.
I wouldn't be surprised if there's some sort of physical vulnerability which is amplified by social weirdness about weight and food.
Of Herbs and Altars is a youtube channel by a woman who says part of what was driving her anorexia was trying to prove she was sick enough to get help. Sorry, I don't remember which video is the one where she talks about that.
You might be interested in the newest discussion of eating disorders, which I'm hoping will make it into the DSM-6.
They're trying to add a trauma-based eating disorder, ARFID (Avoidant Restrictive Food Intake Disorder), which is a pattern of disordered eating either caused by a) a physical trauma, like being really sick for a while or choking, or b) a mental trauma, like a parental divorce.
Anorexics famously tend to say something like "food was something I could control" about half the time, and that seems to map pretty well onto the "mental trauma" category of ARFID. (For another famous singer who has some horribly interesting writing on the subject, you may want to look at the story of "Melon Cake" by Demi Lovato--theirs was externally enforced eating habits not under their control.)
What makes ARFID otherwise useful as a diagnosis is that it acknowledges that disordered eating doesn't always manifest in not eating--it oftentimes looks like someone is incredibly picky about their food.
(I am interested in this as I learned about this after I had a physical and mental trauma episode (stress induced vomiting) that left me unable to eat for a month and I still sometimes have a weird relationship with food about two years later.)
It seems like no one here has ever tried or studied the carnivore diet. Im HIGHLY skeptical about Ozempic - no doubt it works - but at what cost to the individual's health through adverse side effects (and:the cost to society of funding this expensive drug?) . My son has bipolar and I have explored various diets with him. The carnivore diet beats everything in our view. Amazingly by eating just meat eggs fish cheese and butter, you not only cease to have cravings (like Ozempic) but you also lose weight rapidly (like ozempic) and the diet is so anti-inflammatory that huge wide ranging health benefits are seen - reduced anxiety, much greater mental clarity, increased discipline and drive, better sleep, indeed many patients report cures or complete remission of MS, bipolar, and Parkinsons. It hasnt cured my son's bipolar, but it has nonetheless been a game changer for him in reducing both anxiety and the weight gain caused by his meds. For me personally, I have found the carnivore diet to be extraordinary - I have never lost weight so easily before and coupled it with mental clarity and drive. So I would advise everyone to explore the carnivore diet rather than the Faustian bargain that is Ozempic.
It's important to remember that one must report all side effects that occur during a drug trial, and the percentage of people who suffered from said side effects. There is always also a built-in nocebo bias whereby a trial patient reports any and all symptoms. That's why you'll hardly find a drug e.g. that doesn't warm of possible head-aches etc. It will take the life time of the drug (society using it for an extended amount of time) to drill down as to what are true side effects of the drug and what are unrelated or partially related (i.e. interactions between said drug and the drugs of the patient's own drug regimen, the patient's disease burden, genetics, etc.).
Of all the control system responses, at least this one is where we could in principle hope for lack of negatives (at least in the majority case as there will always be minority side-effects): the big and (historically) relevant negative is losing ability to handle long-term food scarcity, but presumably semaglutide would become unavailable before food…
Because all of these diseases are the off-target effects of hyperinsulinism. Not hyperglycaemia, not some fancy neuroscience woo, just that. Our diets cause that (mainly the sugar in it, but the seed oils and matodextrin and other crap contribute), so we have this gargantuan explosion of chronic illness. Academic medicine does not get it, got a few things very wrong (saturated fat, meat, etc), and so people will keep dying as governments increasingly force the shitty academic-decreed diet on everyone.
I think that's correct. My concern with GLP-1 agonists is that some people who take these drugs will think, "I'm not that hungry this morning; I think I'll just have ONE frosted Pop-Tart."
If a person eats one frosted Pop-Tart instead of two, that's an improvement over the status quo.
If anything less than magically making people switch to a fully healthy diet is a "concern", then we can safely replace you with a rock that looks at every new drug and replies with "concern"
If somebody locked me up in a confined living environment, made me run through mazes every day, and only allowed me controlled doses of specific measures of calories chow, I'd lose weight, too.
Unhappily, that is what it *would* take for me to shift all I need to shift of this blubber.
I can very easily have *no* Pop-Tarts because they don't appeal to me. Same with Oreos. Crusty bread and butter, though? Oooooh - put down the bread knife and back away from the table, fatty!
Having NO Pop-Tarts is very easy. Billions of people are doing that every day, including me.
But Pop-Tarts are kind of like quarks, in that you can't have just one, you have to have two, or none. It's not even a matter of, say, having a single potato chip.
I did try them years back when they came onto the Irish market for the first time and was not impressed. Even now when I see the newest flavour on the supermarket shelf, I'm not one bit tempted to try them again. Same with Oreos, I had a couple when they came to Ireland (when Kraft - the owners at the time - started marketing them in the UK and Ireland) and again thought "I can't see what is so great about them".
Jaffa cakes, though - no, I can't have just one. It's the full packet, which is why I have to be ruthless about not buying them.
There's actually a way if you place a second pop-tart ingesting being close to the toaster that you may end up with only a single pop-tart that you can ingest.
Be careful with it, though. It can lead to nuclear explosions. (If you have a nuclear family)
But, more seriously, what I always used to do is just take one out of the package, then put the other back and vow that I'd have it for lunch or whatever. Then I wouldn't get to it until the next day. It is possible. The physics books are mistaken!
True, I hadn't realized you could add another person to the equation, like with enough effort you can extract a single quark, but paired with another from the energy used to extract it. Two people can indeed fully consume a single packet, with one individual Pop-Tart per person. The risk, however, is that it won't end up being satisfactory for one of the people involved, leading to consumption of an additional packet.
I'm not sure I trust your research that you can put the second one away. An experiment must be repeatable, and so far, I'm unable to replicate your results.
I think it is theoretically possible, but requires the as-yet-unobserved single slot toaster. Maybe it will show up in higher energy kitchenware collider experiments... :-)
I know of no credible theoretical framework predicting single-slot toasters. I thought we were sticking to non-crackpot theories. One may as well postulate a nutritious Pop-Tart.
I'm very weird. I've tried a poptart. I didn't like it. I mostly eat what I consider to be decent quality food-- high fat cheese and yogurt, meat, eggs, and vegetables from people who at least promise they're good. I do eat carbs, including some sugar, and I've discovered a taste for ramen.
I also never liked oreos because they taste burnt.
can't remember where I read this, but I think a large number of GLP drug users just lose some preference for sugary and fatty, generally unhealthy food. I remember reading an anecdote from someone who said all their life, they loved Doritos or Oreos or something similar, and couldn't imagine not eating them all the time, and now on a GLP-1 drug, they simply just do not think about them any more. And people simply find themselves eating less bad foods.
Just like the rats choosing to eat the normal chow rather than the more-palatable food offered.
Maybe that person would grab the banana or granola bar instead.
Speaking as a fat tub of lard, I think I tried Pop-Tarts once and heartily disliked them. My problem is "stick to just *two* slices of buttered toast" and if Ozempic or some other drug could help with that, it'd be marvellous. Carb cravings are my downfall.
Not all fat people are scoffing down Pop-Tarts, that's the problem with the general cultural view of obesity. Too much even of 'good' foods are bad for you also.
When I was 310 lbs and started calorie restriction, I was not exercising at all, and I was able to have a diet of something like "ham egg and cheese croissant at arby's for breakfast, sandwich and chips for lunch, chicken wings and roasted potatoes for dinner, ounce of cheese for a snack" and be under 1800 kcal/day and lose a ton of weight. That isn't doing it "correctly", but it lost me the first 50-60 lbs that got me back to a weight where I was comfortable bicycling again, and then as I got closer to 200 lbs I started tracking macronutrient ratios and weight lifting and all this stuff that is closer to the "right way". So never underestimate the power of ANY kind of restraint on the part of an obese person, once you start saying "no" to a few things (for whatever reason) good things can happen.
But if something is a normal part of the human condition, and there are problems when it's not there that go away when it is, then it's reasonable to say that the lack of that thing is causing the problem. We have no trouble describing thirst/dehydration as a medical problem that is caused by lack of water, as opposed to a mysterious ailment that everyone has but is miraculously cured by water.
A certain level of physical activity, even if not deliberately structured as "exercise", is a normal part of the human condition, and maybe one necessary to good physical and mental health in ways we don't entirely understand.
The problem with the human condition is that it evolved in circumstances that are ever more remote from what the modern life looks like. So, until we can finally purposefully modify humans, it looks like understanding what replacements are feasible (and why) for those evolution-approved parts is increasingly desirable.
An analogy that Steven Pinker used for this kind of 'analysis' was to point out that, if you remove a part from your car and it starts to make klunk noises, it doesn't follow that the function of the part was to suppress klunking.
When I was depressed, I didn’t have energy to exercise. And whenever I pushed myself, it took the last bit of the mental energy I had and pushed me further into the depressed mood that I subconsciously compensated for with food and overate as a result. After a year on anti depressants one of the symptoms that I was getting better was that my body started craving movement and exercise. And vice versa, when I lowered the dose of my antidepressants, it became harder for me to force myself to do the dance classes that I normally love and when there I would constantly watch the clock wishing it ended sooner.
In computing, there is a a pattern in which simple mechanisms, which were developed early in the history of computers, are gradually replaced by more complicated ones. The early mechanisms are simple but powerful, and have many side effects. The more complicated, later mechanisms are more precise in their results.
For example, in early computers, the off button switches them off by just cutting the power. The "cutting the power" mechanism has been increasingly fenced off (smartphones are almost never completely off) and the off button has grown an increasingly complicated set of behaviors. There many other examples, in from the internals of computers as well as UX.
I wonder if biochemistry has a similar progression. It won't be the same, as in computers many of the later mechanisms are targeted to specific goals for comprehensibility reasons, and comprehensibility is not a constraint on evolution. But it does seem likely that evolution could construct simple mechanisms first, and then later augment and even replace them with more complicated ones. Although I guess that evolution more frequently leaves "multiple mechanisms that do the same thing" around, for redundancy.
I mention this because reading about Ozempic's inhibiting of the hunger mechanism reminded me of the the process of "disabling a critical old mechanism" which is also found in computing, in the scenario above. So, maybe we can do this because there are also multiple other, perhaps more complicated mechanism which also support the necessary behaviors? Although, the example of haloperidol suggests that this is not always the case...
I think that your metaphor is apt. Consider the lineage of the x86 CPU architecture: you start with the 4004, a microcontroller suitable for a primitive calculator and go through the 8008, 8080 and 8086, 80x86, amd64 to modern multi-core CPUs. What you end up with is a mess of an architecture, because you are dragging around half a century of design decisions, all in the name of backwards compatibility, because you never know if someone might want to run QDOS on your ThreadRipper.
The path from prokaryote to mammal is similar. You start with something simple, and then you add features randomly for a few billion years, and out pops a human.
Worse, the shaping of these signalling pathways is not done by any intelligent design process, but by the blind idiot god of evolution. The solution preferred is not the most elegant solution, but simply the first one who popped up by chance mutations and conferred enough benefit to become universal. Asking 'why GLP-1 for that?' is like asking 'why did that neural network encode that weird subproperty in that particular neuron' -- it just was the first good enough solution the blind optimization process stumbled upon.
Poorly tested in what way? The FDA has been all over the history of GLP-1 drugs, and arguably has required excessive testing already. If there were even moderately-uncommon side-effects beyond the usuals, we would certainly know it by now.
>An unexpected side effect might take a decade to show up
Much appreciated! I was going to make the same point. I don't think that this is a solvable problem. We can't reasonably wait for decade-long or multi-decade-long safety trials.
It's clearly not a soluble problem. DES didn't show up as a problem until the daughters of the women taking it were adults and developed excessive cancer. And in principle it could take even longer.
Well, this was a problem only if DES was taken during pregnancy and we all know now to be extremely cautious with drugs when pregnant. But studies on pregnant women are tricky for obvious reasons.
The history of FDA approved medication used for off-label use, particularly high profit ones, does not give me any comfort: Vioxx, Depracote and many more.
Any medication can have side effects - primary use approvals are because the side effect negatives are outweighed by the primary effect benefits.
Ozempic use for weight control is off-label.
Your faith in the FDA is touching, but it is much less clear if you actually understand what the FDA's "all over" study of anything it approves, actually is (or is not).
There's a common media narrative about the FDA not noticing, or not talking about, or being willfully blind to, drug side effects. Like most "the-experts-didn't-notice-this" narratives, it falls apart when you look more closely.
The Vioxx affair is generally used as an example of why politicians and random civil society groups shouldn't try to disagree with the FDA's safety analysis: more recent analyses have clearly shown that Vioxx (generic name rofecoxib), a COX-2-selective NSAID, is safer than non-selective NSAIDs like Advil (generic name ibuprofen) and Aleve (generic name naproxen). I am, honestly, very unhappy that billions of people have been exposed to the risks of non-selective NSAIDs like Advil and Aleve when they could, counterfactually, have instead taken Vioxx.
I assume, with Depakote (generic name valproate, or valproic acid, or sodium valproate, or others I don't recall), that you're referring to the birth defects caused by paternal exposure? In that case,the data [1] is pretty clearly misinterpreted: one sensitivity analysis of many finds significantly increased risk, but others, and the primary analysis, don't. The apparent result in the one sensitivity analysis IMO is almost certainly caused by doing multiple comparisons - because one can't, and shouldn't, draw conclusions from sensitivity analyses (other than increasing or decreasing one's confidence in the primary analysis). (I will admit I haven't spent too much reading the report, so I could be missing something.) If it is true that there's increased risk, the absolute risk is so small that it couldn't really have been detected in pre-approval studies; nor could it have been detected in post-approval surveillance studies without many years of data.
It is reasonable to argue that more money should be spent on postmarketing surveillance - but most people wouldn't agree with that, I think, just based on cost-effectiveness.
There are many valid criticisms of the FDA, but insufficiently characterizing side effects isn't one of them. The FDA's weighing of side effects against benefits when deciding on whether to approve a drug for a particular use leaves room for disagreement, but that's not related to their characterization of side effects.
A nice writeup, but you are answering to a different subject that what I wrote about...which is that whatever the FDA's decisions made for a given drug for a given use case(s), based upon net benefit over side effects - these FDA decisions do not cover off-label use.
As for Vioxx: is it really safer? This timeline sure doesn't think so - or are there tens of thousands of heart attacks from Advil? Do tell.
My understanding was that the death rate fell significantly when vioxx was taken off the market, which would pretty much falsify the idea that it's safer than alternatives. Alternatives are what people would have been using after it was taken off the market.
Semaglutide for obesity is not off-label ever since the FDA approved it on-label for weight control under the name Wegovy. From what I can tell, it's identical to Ozempic minus some slight dosage differences.
Maybe it turns us all into p-zombies, and when an AGI figures this out, the AGI knows that it's OK to kill us all because there's no one left that experiences qualia.
I'm waiting to see Big Snack develop ozempic proof foods. I feel confident that as soon as a scientist figures out one aspect of how ozempic works, there is another scientist trying to figure out how to get something salty-sweet-and-crunchy past that mechanism.
Given that Ozempic seems to reduce general craving, and craving is a major phenomenon worked with in serious Buddhist meditation, I wonder if there are any serious meditators that are on Ozempic and if yes, what would they have to say about that.
Can you come up with an example of something that would be considered craving from the Buddhist perspective, but not from the neurobiological perspective?
I don't think traditional Buddhism distinguished much (at all?) between desire and craving in the way we do. For example, someone who wants to be wealthy wouldn't generally be described as "craving" wealth.
Fair enough. I'm not a Buddhist myself, and there's tons of scholarship exploring how to most accurately translate these concepts. I just don't recall encountering the distinction between desire and craving being very prominent in Buddhism, and it still seems like the word craving is being used differently in that Wikipedia article than to simply refer to the kinds of more hedonistic craving that we tend to associate the term with.
Anyway, serious meditators can can offer more insight, but my guess is that it's a category error trying to compare the reduction in craving by something like Ozempic to meditation.
This is right. Tanha (desire) and upadana (grasping) a subtle concept and in the doctrine of dependent origination is considered fundamental to the processes of perception that make up dualistic conscious reality.
From a dharma perspective, chemically weakening this signal could be superficially beneficial but do little to address the root form of ignorance responsible for dualistic suffering, which can only be resolved through "wisdom" from direct seeing and the eightfold path.
I started taking Wegovy about four months ago. I haven’t ramped past 1mg due to insurance bullshit, but I have lost 20 lbs. I drink a quarter of the alcohol I did before. My bloodwork went from “good for near 40” to “good for any age” and I have a better ability to sleep and handle mild sleep deprivation. I’m fairly certain that if a nasty case of tennis elbow hadn’t been keeping me out of the gym that literally every metric would have improved. As it stands, unfortunately my blood pressure is still in the new “stage 1 hypertension” range.
It’s pretty crazy, though. The data says I may be an outlier in how well I respond. But it has still been unbelievable.
Should note I have seen a significant reduction in libido since I began. However, it’s very hard to determine whether the drug is responsible due to significant stressors which have co-occurred with starting the drug. These include a death of an immediate family member and an absolutely crazy work schedule which has continued far past the expected end date and significantly reduced my ability to sleep adequately.
My libido seems to have begun improving over the past couple of weeks but I’m set to go to the high dose next week, so we’ll see.
If all those stressors hadn't lower your libido, I think that could have been taken as evidence that ozempic was increasing it, because that would have been unusual.
My blood pressure medication has been reduced by 75% since being on Mounjaro. It's shortsighted for insurance companies to keep this drug out of reach for so many people. Once they realize their profits will increase with the availability of this drug, I imagine it will be much more easily approved.
Could the point of intermittent fasting be to force the body to acknowledge fully fasting and thus stop treating the normal time between meals as if it was a fast (possibly thereby increasing GLP-1 or something else)?
Yes, it's the other way around: inflammation is metabolically costly, and starvation causes the body to turn down the inflammatory response (good for treating chronic inflammation in today's world, which is abundant in cheap food; bad in our ancestral environment, where weaker inflammatory response coupled with bad hygiene and lack of antibiotics = higher risk of death by infectious disease).
So far, the data show that weight loss reverses when people stop taking the GLP-1RA drugs. In that way, these drugs are like other weight loss interventions (calorie counting, carb restriction, intermittent fasting, etc.) They work as long as you comply, and stop working when you stop complying.
Most people eventually stop complying with the other interventions, which is why the long-term weight loss stats are so bad. Will the GLP-1RAs be the exception to the rule? I'd like to see good data, but my suspicion is that they won't be. I suspect that most people eventually find the side effects unpleasant enough that they stop taking them, and that they then regain the weight they lost.
The reams of coverage about these medications contain little discussion about long-term compliance, but that is an absolutely critical factor to consider. Wegovy was approved in 2021. What percentage of the people who started taking it for weight loss in 2021 are still taking it? Do we know?
There’s interesting research to suggest that around the 2 year mark of taking it, the appetite-suppressant effects are lost and most patients will cease losing weight. Instead, the same dosage as before now works to keep them at their appropriate ‘set point’ weight - tantalising the suggestion that the weight loss drive might be linked to BMI, and that perhaps GLP drugs given to people at a healthy weight might not have the same impact as they do on obese people.
This is a mechanism we know the body is supposed to have: to adjust hunger and appetite in response to body weight. GLP seems to restore some of this process.
This has been my experience. I lost ~50lbs over the course of a year, putting me slightly south of overweight, and then stabilized there. I also started finding junk food appealing again...but not enough to reverse the effect; I've been stable within a ~10lb range for six months or so I think.
I wonder if there is some length of time where stopping will keep the weight off in general. Like, you only gain the weight in the way someone who was never obese gains weight. It would depend how long the set point takes to stabilize and whether withdrawal will inevitably reset it higher.
It does completely change your relationship with food. You feel less hungry, but that has a flip side of you get less used to food-seeking behaviors that people tend to engage in compulsively like opening the fridge or impulse buying a donut.
Anecdotally, I'm still taking it after a couple of years. The main compliance issues have been insurance shenanigans and travel.
My intuition is the opposite of yours; I think GLP-1 compliance will be high, at least relative to dietary interventions. Dietary interventions require *continuous* compliance. It's *much* easier to comply with "spend an hour a month managing shots" than "spend 720 hours a month resisting cravings". It's a special case of it costing less average willpower to do something unpleasant (and be done with it, at least for a while) than to abstain from something pleasant (and have the option still there...waiting).
(I notice my model predicts something that's probably already been studied: I'd expect better compliance on exercise regimens than dietary.)
Also, I vaguely remember hearing of work on longer-term variants (1mo+), which I expect to help even more. Longer durations imply longer periods where people won't fall of the wagon because they can't.
This is a very good summary of the current state of play. I am indebted to the author for referencing the possible mechanism that underlie Neurodegenerative diseases (AD, PD) as it saved me from doing the literature search. For those interested, there is an ongoing trial of Semaglutide (phase 3) in early Alzheimer’s disease due to read out towards the end of next year. Given the relative lack of efficacy of current treatments, a genuine positive signal (beyond statistical significance) would be well significant.
Fun fact: Edward Drinker Cope, along with Othniel Charles Marsh, was also one of the two paleontologists involved in the Bone Wars, quite possibly the most bonkers incident in the history of science.
"So probably GLP-1 binds to neurons in the brain stem, those signal to other neurons and immune cells via alpha-adrenergic receptors and delta-opioid receptors, and then the immune cells initiate an inflammatory reaction."
Scott, do you know of any specific references that tested whether GLP-1 agonists block non-addictive rewards or cause general anhedonia? I haven't been able to find any human studies that actually quantified those effects, which is frustrating because that's pretty much the only qualm I have about what are otherwise wildly effective and apparently very tolerable medications.
'So probably GLP-1 binds to neurons in the brain stem, those signal to other neurons and immune cells via alpha-adrenergic receptors and delta-opioid receptors, and then the immune cells initiate an inflammatory reaction.'
Is that a typo or am I misunderstanding something here? Seems like it ought to be, 'initiate an ANTI-inflammatory reaction.'
Friends report Ozempic does reduce tanha/grasping/thirst; I’d predict this to ground out in reduced smooth muscle reflexes in general.
I’m also curious about Ozempic’s effects on smooth muscle latches; “stomach paralysis” is among the side effects I’d expect of a drug that hits this system
I wonder if Ozempic will continue to be the term of art for GLP-1 medicines generally - Ozempic is losing market share and the underlying molecule Semaglutide has been surpassed by several other products at this point in terms of efficacy.
Pah, those people will never get a job at the New York Post. The play you want is "Gila Saliva: Weight Loss Driver." Or perhaps "Gila Venom, Weight Loss Momentum."
Since this seems to help with so many unrelated diseases / problems: maybe the natural GLP-1 level many people have today is just suboptimal? Either because lifestyle / diet / environmental poison changes over time decreased the average GLP-1 levels or lowered its effectiveness (by introducing antagonistic effects).
If you had a hormon used in many systems (hunger/ inflammation/ rewards) and get the level slightly out of whack, you would expect these systems to all slightly degrade. Restoring the “proper” (evolutionary normal) level would then look like wonderously curing an assortment of “random” common ills that grew more common over time.
Not saying this is true … but I think it would be useful to check whether something like this could e.g. be a partial cause of the obesity epidemic (I know that people aren’t very sold on the env poison theories … but it should be easier to check this specific hormonal pathway than “all possible new chemicals introduced in the last 70 years”).
It might be simpler to come up with a test for GLP-1 levels and compare Ozempic candidates to naturally thin and non-addictive personalities. Or if anyone’s still doing whole genome studies, to look for clues there.
Furthermore: Maybe finding food, having a meal and then resting for a while, is a natural cycle that has functions akin to sleep. When you have eaten you don't need to stress as much, you can concentrate on digesting the meal and "housekeeping" in the body. When you need to find some more food you go in a different, more stressed and risky state with the immune system on its guard. GLP-1 would be the signal for switching between these states. This raises the obvious possibility that having your GLP-1-triggered mechanisms constantly activated by these drugs is also suboptimal or even bad, like being on melatonin or caffeine all the time. Maybe you need the cycling too? If this is the case, a better drug would have faster (4-6 hours?) kinetics.
I think the most likely cause of obesity is pathogenic microbiota that has evolved in modern feedlot animal husbandry: These days the majority of mammalian biomass on Earth is less mobile than the manure it produces; the gut microbes in this environment are free from considering the health and mobility of its host. An obvious way for the gut microbe to increase its own fitness would be to make the host eat more, and so produce more manure. If it made the animal bigger, the farmer would not consider it a pathology or a problem. So maybe there is some bug to be found in shit and guts, one that ruins the GLP-1-producing mechanism, or even produces its own GLP-1 antagonist. Or an analogue for the other, hunger-inducing, hormone. This would put the host in a permanent high-stress food-seeking mode.
Bad manure would explain many things, like the correlation of elevation with obesity. Americans would be fatter because of less free range cattle and more antibiotic feeding.
Forgive an underdeveloped but vexing rising thought I'd appreciate feedback on.
I've historically shared the same instinct that evolutionary biology should preclude miracle cures (wonder drugs) that solve multiple problems with minimal downsides because complex and complicated biological systems should not have naturally evolved to let such opportunity exists. Real biology is terrible tradeoffs in massively complicated intertwined feedback loops, and leaning heavily on one lever to knock a system way towards one extreme can't be expected to help systematically.
However, in the modern world, we are now introducing stressors to our existence that are radically novel, and my general instinct now is inverting. Perhaps epidemic-level human maladies are due to narrow modern stressors, these stressors don't just manifest as one "break" in our system, but as manifold, and a single point solution to that novel stressor, if back at the origin of the problem, could very well have systemic benefits with minimal downsides.
For GLP-1, better biochemists or neuropsychiatrists than I can go pinpoint the origins here with insulin/glycemic issues or hunger/satiety issues, but if something about the modern world triggered an odd stressor that was upstream of the rest (something causes diabetes which in turn promotes obesity which promotes depression, and each of the downstream also partially promotes the others), then a pinpoint solution at that top to counteract the modern novelty seems possible.
And with many novelties in today's world emerging, many counter-solutions may thus be possible.
As much as I reflexively and skeptical of big-pharma (and big-medical-device and big-medicine...) suddenly I can become as much an optimist about their miracle cures as anyone else.
Perhaps, accordingly, there could be miracle cures (pharmacological or otherwise) for a litany of problems around (overweight) and (depressed) and (anxious) and (PTSD) and (addictions) and... if those clouds of associated maladies are being caused by some novel-stressors.
Novel-stressors could be hyper-abundance, novel-chemicals, chemical-contaminants, smart-phones, social-media, ...
Biochemical fixes like GLP-1 still seem miraculous, in that they aren't as straightforward a logical counteragent to whatever is causing (obesity) as a counter-toxin would be to a toxin, but I'm now very open to the prospect that if we look at problems as cloud of reaction to a novel stressor, perhaps miracles can exist?
The thing here is that real biology literally never had to contend with the problem glutides solve. I am confident that if you went and gave glutides to a group of medieval peasant farmers or ancestral hunter gatherers, they would die of starvation or from water-borne illnesses at a much higher rate over ten years.
Consider the effect of glutides on alcohol consumption. Now consider that almost 100% of people’s liquid intake was in the form of small beer or diluted wine because most water was poison until you boiled it. Also, a significant fraction of caloric intake came from alcohol as a result.
This is one of the only miracle cures you might expect based on what we know about evolution and the mechanisms of obesity. Obesity is an uncommon condition ancestrally, with fitness-reducing impacts that take a long time in a caloric surplus to appear and a basic mechanism that has been more likely to help than hurt for all but 100 of our 100,000 years as a species.
There is just no reason anything which meaningfully modified this mechanism for long enough to matter would have been a risk in the past, so no reason to make it super redundant. Plus there would have been zero selective pressure against it until 100 years ago. And not even that strong of a selective pressure now.
Ozempic is one of the drugs from NN, in which semaglutide is the active ingredient, but it's not the sole ingredient. I'm not privy to the specifics, but I'm almost certain they put in shelf-life extending preservatives, and things to make the injection painless and quickly dissipating.
I'd accept interchanging Ozempic with Wegovy (AFAIK, same thing, different dose) and some future hypothetical generic name, but not with semaglutide, especially not when talking about molecules, rather than drugs.
You are absolutely privy to specifics if you care to look them up. And the inactive ingredients are both unlikely to have a major effect on pharmacology or to be fundamentally different for semaglutide formulations approved in the future.
For the “I’m not privy”, here is the 5 second google to answer your question:
Ozempic
“Non-medicinal ingredients: disodium phosphate dihydrate, propylene glycol, phenol, and water for injections.”
Wegovy is the same minus propylene glycol and phenol (those are preservatives not included in wegovy because all formulations are single use autoinjector pens, which is not the case for ozempic).
For the purposes of discussing this molecule, there is no meaningful distinction. You are being a pedant, and could just admit it rather than pretending there is some unknowable distinction.
Also why would you assume they would put in anaesthetics? That’s just a weird thing to assume, especially since the pain would be over before your anesthetic could help.
He calls me a pedant, but then writes the above, and doesn't look into what those extra ingredients do. (Phenol is an anaesthetic, propylene glycol is a stabilizer.)
> Phenol was once an important antiseptic and is still used as a preservative in injectables. It also is used as an antipruritic, a cauterizing agent, a topical anesthetic, and as a chemical skin-peeler (chemexfoliant).
From NIH:
> Propylene glycol has become widely used as a solvent, extractant, and preservative in a variety of parenteral and nonparenteral pharmaceutical formulations.
Both phenol and propylene glycol are being used as preservatives.That’s why they’re not included in wegovy but are included in ozempic.
So you’re a pedant and also when you do actually google you’re bad at it.
Edit: GoodRX does say propylene glycol is not being used as a preservative, but the source is a patent about peptides injectors rather than any labeling info for ozempic. There may be a reason that you would need this in ozempic but not wegovy, but not one I can think of.
Regardless, even if I am half wrong… How does this make you not a pedant?
I am not denying the charge. I'm pointing out that you appear to be a worse pedant than me, even. Regardless, my original point stands - semaglutide is the molecule. Good day.
I think the way to understand why GLP-1 cures everything is to reason backwards: the nature of capitalism is that it will very efficiently find ways to hack our brains such that we want more of the thing people are selling. But then it makes sense that pushing us out of our evolved distribution by making us overconsume certain products would make a wide spectrum of things go wrong because that's how opaque complex systems work.
The question is why is there a common pathway that gets hacked as opposed to sugar doing one thing, fat and salt doing another, gambling a third, alcohol a 4th, etc. But that's also just kind of how biology works a lot of the time. Like intracellularly, a whole bunch of different signals go towards a few signaling pathways that activate a few important transcription factors like c-Myc or NF-kB which then have many effects. GLP-1 similarly happens to be situated at a bottleneck through which many signals must pass which is why it is so effective. Maybe post-Ozempic, businesses will route around this bottleneck by figuring out a hack for oxytocin signaling that will cause a whole new spectrum of diseases.
So in generalities, "there is bottleneck through which many existing brain hack go, and targeting it pushes humans back into distribution, which treats a crazy diverse range of diseases" is not very surprising though the specifics are of course very interesting.
You may have your agoutis mixed-up. I believe the studies on agouti-related proteins were studying agouti mice, not the South American animal https://www.nature.com/articles/ng1199_314
Thanks for the great post Scott. Any idea how long until this becomes a common drug that is prescribed freely? IIUC, and I'm not from the USA, it is still very limited in distribution, and I assume Doctor's are still hesitant on giving it to non-obese people because of possible side effects and "there is no reason to take it if your not obese/diabetic". Do we expect this to change, and if so, when?
Very natively it seems like most drugs should pull a lever with tradeoffs. If pulling a lever is always good why hasn't evolution done it already? This argument seems to hold except in cases where our current environment differs greatly from the ancestral environment we evolved for. With this in mind there is exactly one area that seems like it should have a legitimate miracle drug. A drug that tells your body you have plenty of calories spend them freely (never enter starvation mode) and don't worry much about eating more will kill you in the ancestral environment but makes you way better adapted today. Stimulants like caffeine and Adderall seems to do some of this (get you to spend calories your body would otherwise not) but they interact with the sleep system more than the food system so they seem imperfect. Ozempic strikes me as the first thing we have found that starts to fit the bill for this miracle drug. I am more willing to believe most of its side effects are positive than I am for other drugs because in the modern world we are missing the side effect of death by calorie deficit which is sufficient for evolution not to pull this lever. (The addiction stuff is still surprising to me but a lot of the other health stuff seems to vaguely fit here). If calories are always abundant and always will be it seems like your body should be able to waste energy on a lot of useful maintenance stuff, we just need a way to send this signal without getting morbidly obese which has its own health problems.
Very close to my thinking on the subject as well. A drug that acts to limit the brain's susceptibility to superstimulus (whether that be caloric or otherwise) seems like it would have a wide range of positive effects in the modern environment.
Semi-related question: what's the difference between apoptosis and autophagy? Why is the former supposedly bad (implied by the diagram in the Alzheimer's section) and the latter good. Aren't those just different mechanisms for cellular renewal in tissues?
One of the supposed benefits of fasting is increased autophagy; my fake model understanding of this is that it cleans up senescent cells more aggressively, which ends up rejuvenating your tissues by replacing those lost cells with new ones once the calories start rolling back in. I suppose keeping senescent cells around is some sort of mal-adaptive response to the calorie overabundance of the modern environment?
Apoptosis is not bad as a rule. Apoptosis of dopaminergic signaling neurons (that diagram is about Parkinson’s disease) is related to symptomatic progression in Parkinson’s. Correct me if I am wrong, experts, but apoptosis is adult central nervous cells is almost always bad unless the alternative is imminent cancer in those cells.
apoptosis = programmed cell death. The cell kills itself in response to certain signals. This can be either good (e.g., as finnydoo mentions below, when the cell was on its way to becoming a cancer cell, or when the cell was infected with viruses) or bad (pathological apoptosis of neurons in certain neurological disorders, for example). Fun fact: during embryonic development, we have webbed hands and feet at one point, and then apoptosis kills off the "webbing" resulting in normal human fingers and toes.
autophagy = literally "self-eating" - the cell eats parts of itself (intracellular organelles, protein complexes). This has two roles: remove damaged/dysfunctional organelles and provide energy for the cell (from the breakdown of the digested cell parts). It is part of the starvation response. In our energy-rich environment, autophagy is generally seen as good.
In brief: apoptosis destroys whole cells; autophagy destroys the "unhealthy" parts of cells, leaving the cells healthier/more functional overall.
Thanks, Scott: I am a semaglutide user for almost 3 years now. When I began my BMI was 40. In the first year I lost 20% of my starting weight, where I plateaued. My blood pressure which was under control but over 120 dropped into the 110 range. My mobility improved. The only noticeable side effect was an increased tendency to constipation -- yum, Miralax. Oh yes, and Medicare will not cover it; so ~$1,000/mo. But, thank God, I can afford it.
I should add that I continue to enjoy food and alcohol. I still eat sweets and have beer and wine with most of my meals. I just fill up faster and eat smaller quantities.
I hope that it prevents dementia. I am 77. My mother and my paternal grandmother were both demented in their 80s.
On price, the good news is that in the last couple of months I was able to to find it for less than $800. I am guessing that the presence of the Eli Lilly formulation (tirzepatide) in the market place has started to affect the pricing power of Novo Nordisk. That is fine. It is the way markets ought to work. In a few years there will be more compounds available from more manufacturers and the price will be more determined by the cost of the injectors than anything else.
I have no problem with the initial high price of semaglutide. Novo Nordisk was almost heroic in its efforts to develop the medicine which took 30 years and millions of dollars. Political attacks on them ("corporate greed") are contemptible. Saint Anthony Fauci and the NIH spent the time and your taxpayer dollars inventing COVID*. Socialism always fails -- catastrophically. Free men in free markets produce enormous improvements in the human condition.
The Novo Nordisk saga has been reviewed in a couple of podcasts which I heartily recommend to everyone interested:
Undoubtedly true. As the late great Senator Everett Dirksen (R. Ill. 1951-69) said "A billion here and a billion there, and pretty soon you are talking about real money."
For the record, Novo Nordisc has not double pd the economy of Denmark. Its 2024 revenue was $37b, vs Danish GDP of $400b. Its market cap exceeds Denmark’s GDP, but that’s comparing a stock to a flow.
I tried the Ozempic a few months ago. My notes from then:
I tried the Ozempic. One part "losing 10 more pounds could be nice", one part curiosity. It did very minimal weight loss. But the curiosity was satisfied. There were three possible "mechanisms" of action I had heard in the media.
1) "delayed gastric emptying" - yes. I simply could not pass food from the stomach to the intestines at a normal speed. If I ate too much, it would make me sick.
> I had to bike less because I simply couldn't eat fast enough to get calories to burn.
2) "improved willpower" - if this happens, I didn't notice it.
> well, actually, the "motivation not to eat too much" from knowing you will get sick if you eat *kind of* looks like improved willpower.
3) "metabolism changes" - once again, nothing I noticed.
For some people, this is an effective and/or necessary tool to lose weight? I don't think I need it; if I want to lose weight by not eating, I don't need the drug.
Also, I'm not convinced it's safe. I think there are going to be a lot of cases in five years of "I was on the Ozempic and now I have permanent health issues".
It was approved by FDA back in 2017, and large-scale trials have started 2+ years before that, so while _some_ new side-effects may be discovered with this recent more wide-spread use, the frequency of those is not terribly likely to be very high.
How high was your dose? If you didn’t get to 1.7 or 2.4/week you may have never noticed it. Most in trials don’t see any obvious effects beyond nausea before that.
Also, if you were taking a compounded version it will be hard to say if you should have expected anything.
> “have low energy, bad sleep, nasty menopause, poor heart health, and ugly skin”
It makes sense for the human body to have an efficiency/performance slider.
There are various things the human body can do that save valuable calories, but make you less healthy. In starvation situations, sliding that to "do whatever it takes to scrimp calories" makes evolutionary sense.
And so a drug that slams this slider hard in the opposite direction, burn as many calories as you need to for optimal health, makes sense as an omnicure in a modern calorie rich world.
There is actually some reason to expect weight-loss drugs to be able to have good side effects. Weight loss has for most of human history been a very bad thing. A chemical tradeoff that makes you either (have low energy, poor heart health, nasty menopause and gain weight) or have (high energy, good heart health, nicer menopause and lose weight) would have been a serious tradeoff for almost all of human history - but today, with infinitely-abundant food to the point where weight gain is a larger problem than weight loss, the second can be an unalloyed good.
I mean no disrespect. But obesity is not adaptive, nor was it. It does not look very appealing. And why carry that spare tire around when you can store dried meat, nuts or grain? You just expend more energy and risk getting caught and eaten yourself, if the times are that bad.
Obesity may not be adaptive (though the visual appeal is cultural, at least to a point, as most beauty standards are) but the processes which lead to obesity certainly are. There has been precisely zero selective pressure against obesity before 100 years ago. To the extent obesity existed at all before then, it was so outweighed by the fact that getting obese required lottery wins in other fitness-relevant categories that it was a non-issue. Added to the fact that most of the negative side effects of obesity only really start to be dangerous after decades.
Carrying around the spare tire is absolutely sensible if you might starve, and especially if the main negative side effect is going to be that you die earlier after your kids are having kids anyway. And especially especially if the odds of you ever getting to spare tire are close to zero anyway.
The available food, even in a Malthus world, would not have been fine-tuned enough to keep people from accumulating calories to arbitrary amounts in some good years. If there was an heritable mechanism for it, obesity would have been common enough, and the observed fertility hit alone bad enough for it to be selected against.
It would be sensible if we did some kind of hibernation like bears and hedgehogs. Fasting records are held by former big guys, but they had vitamins and medical care available.
But when rubber meets the road? Any anecdotes or folklore of the Little John who was the sole survivor of his family in the Potato Famine, Great Leap Forward, Siege of Leningrad etc?
> The available food, even in a Malthus world, would not have been fine-tuned enough to keep people from accumulating calories to arbitrary amounts in some good years
You’re resting basically your entire argument on this assumption, and it is a bad one. We know that obesity rates were low until the 1960s, and that average calories consumed have increased dramatically since then.
More, you’re talking about “some good years” as if they would be the norm within even a single human lifetime. They wouldn’t have been, for most people over most of time. And very few people would have had enough food consistently enough over their lifetime to become obese.
If you would like to debate the positive side of my argument instead (obesogenic microbes being spread around by the use of livestock manure as a fertilizer), see my reply to Stephan in this thread.
People aren't like that unless something did it to them.
I would not, because for one the assumptions here are very bad, and do not actually support the argument that you need a different mechanism for obesity.
The argument itself sounds like a very stupid one for reasons beyond your bad assumptions about obesity. But your assumptions about obesity are so ridiculously bad that there isn’t really a need to engage with the ideas that those bad assumptions are holding up.
It's not that obesity is adaptive; it's that, for the vast, vast majority of human history, obesity would have been *unattainable* for anyone except a tiny minority of aristocrats and monarchs like Henry VIII. So there was no reproductive penalty for evolution pushing in the direction of "act in a way that would cause you to become obese in an environment full of cheap, abundant food."
Silly analogy, but imagine that there's a serious psychological defect that occurs only in quadrillionaires - it's not a problem for us, because there are no quadrillionaires.
Edited to add: I see finnydoo made the same point below.
Semaglutide and tirzepatide did not seem to help significantly with slowing my rate of weight gain, and were intolerable during my fasting months (800/cal day, to counteract the weight gain from eating enough to work).
They did however produce a general reduction in motivation and energy.
So I am skeptical that they actually only address addictive motivation.
Given that you’re claiming that drugs which are widely reported to work in general did not work in you, I don’t think they affect your motivation the same way that they affect other people. Like if you’re an exception with respect to physical weight gain, it would make sense that you’re also an exception with respect to addiction
I think you should see *some* positive results on mood and general energy levels immediately, just from giving up all processed foods if nothing else, and most people seem to find that they're practically immune to sunburn after a year or so off the PUFAs.
I've no idea how long it takes to clear the PUFAs entirely, but the legendary whats_up_coconut went from utter metabolic catastrophe to apparently excellent health and a BMI of 18 in about 3 years, so it might be feasible before the end of the world.
> But also, when a meal comes in, the body diverts other resources towards the digestion process (this is why a big lunch makes you tired). Maybe some of those resources come from the immune system, so immune cells stand down while you’re digesting.
Is that why having a fever suppresses your hunger? No energy available for digestion?
This is as good a thread as any to ask something I've been curious about: Whats the difference between anti-inflammatory drugs and immunosuppressants?
Inflammation is an activity of the immune system, so it would seem like suppressing the immune system is the main way a drug can reduce inflammation. And corticosteroids are indeed described both as anti-inflammatory and immunosuppressants. However, non-steroidal anti-inflammatory drugs (NSAIDs) aren't described as immunosuppressants and don't inhibit the immune system's ability to fight infection enough for it to be generally considered a bad idea to take them to reduce fever while having an infection. And other immunosuppressants like thiopurines aren't generally described as NSAIDs, even though though they are often taken to prevent certain inflammations, particularly ones in transplant patients and autoimmune diseases.
More on topic: Are we sure that a drug that reduces inflammations (if semaglutide really does that) won't increase susceptibility to infections and cancer? I'd think there's a trade-off between good immune activity—fighting infections and (pre-)cancerous cells—and autoimmunity and other negative effects of unnecessary inflammation. Is it a good idea to move the level of inflammatory response from its natural level a good idea in healthy people? Perhaps it is, now that most infections diseases are curable or preventable.
Is that modern diet causes chronic inflammation (more so than food in general, the way discussed in this post) established science? It always sounded like woo-woo to me, but I've never looked into it.
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Was I supposed to know that eggs were healthy? The last message I got was that they were unhealthy because they were high in cholesterol.
Oh, that was *last* week! *This* week eggs are okay but only so long as you have about one a day, because ha ha it's not the cholesterol that does the damage, it's the saturated fats!
"A. Years ago, the advice was to eat no more than one or two whole eggs per week. The reason was the high amount of cholesterol in egg yolks — approximately 200 milligrams (mg) per egg. The previous cholesterol guidelines recommended no more than 300 mg of dietary cholesterol per day.
More recent research found that dietary cholesterol had little influence on blood levels of total and "bad" LDL cholesterol. Instead, it is dietary saturated fats that raise these blood levels. The reason? Most of the cholesterol in your body does not come from your diet, but is made by your liver. And saturated fat in the diet can cause your liver to make lots of cholesterol.
While recent studies still don't offer a consistent answer, the average healthy person likely suffers no harm from eating up to seven eggs per week. In fact, eggs are a nutritious food. They are relatively low in calories and saturated fat, and rich in protein, vitamins, and minerals. They also contain nutrients, such as lutein and zeaxanthin, which are good for the eyes, and choline, which helps supports the brain and nervous system."
And *next" week the advice will be that you can eat up to three eggs a day, and in fact *should* be doing so!
"Eating one to three eggs per day can have several health benefits, but this varies from person to person. At this level of consumption, people can expect minimal changes in their cholesterol levels.
It is unclear whether there is an upper limit on how many eggs a person can eat per day. More research in this area is necessary to provide clarity."
When it comes to diet and nutrition, nobody knows effin' anything.
Yes, exactly. 80% of nutrition "science" is nonsense. I love eggs and for about 2 years was eating 2-3 dozen per week (sunny side up in a pool of butter). Total cholesterol was 158, LDL at 56. Then I kind of burnt out on them and am eating more cruciferous vegetables instead and using olive oil instead of 100% butter for cooking, and my cholesterol is now higher (total 200, HDL still 56).
Many Thanks! This is beyond my expertise. We would have to track down a Vodún public health practitioner/cleric to assess the feasibility. The politics of vaccinating a single voodoo doll for a population which contains factions who oppose vaccine mandates could get interesting... :-)
1) I've been on Ozempic for six weeks. I've lost 17 pounds and feel great. I'm only taking 50% the recommended dose for this time in the process.
2) I wasn't obese before but I was putting on a sizable dad gut. I had to lie about my weight to get the drug.
3) My blood sugars (type 1 diabetic) are vastly improved.
4) It basically makes you feel slightly sick to your stomach. You can't eat much at once and often have to poop after each meal.
5) A surprising effect is that it's impossible to get drunk on Ozempic. Not that I'm trying to go on benders, but if you've ever had a glass of wine on an empty stomach versus on a full stomach, you know the difference. Ozempic is like your stomach is always full. You can never get more than a buzz.
6) I recommend it highly. You can get compounded Ozempic on Henrymeds or a bunch of other sites for $200-$300 without insurance. If like me you only need a 50% dose that cuts the cost in half.
So they do it by units because it's compounded, but its supposed to mirror the Ozempic doses. 5 units four weeks, 10 units four weeks, 15 units thereafter.
I started Jun 26th or so, so tomorrow will be the end of the seventh week I guess. I've done something like 2,2,3,4,5,5,5,7. I diving the 7 into two small injections of 4 and 3 that I give on Monday and Friday, or a unit a day. I plan on staying at this level.
The side effects were probably worse at the beginning versus now.
I would be uneasy about taking an alternative version of a med that's made by a compounding pharmacy. I think what worries me is that there is no agency making sure they really give the customer the dose they are saying that they are. I'm sure the active ingredient is the most expensive part of their preparation, so they would have a motive to give less drug than they claim they're giving. Also I wonder about sanitation, esp. for an injectable, and errors in choosing whatever else goes into the shot in addition to the drug. But I'm not sure how valid these worries are. *Is* there some process of keeping them honest, by randomly check prescription contents? Is there an agency that checks their sanitation and makes sure they're following any special requirements for sanitation of injectables (if there are any special requirements)? Are you just taking your chances, or did you find out some reassuring info about these places?
Ozempic is considered to be "in a shortage" by the FDA. This allows compounding pharmacies to purchase the raw ingredient from the manufacturer (this is why it costs $200-$300, not $5).
Why is it in a shortage? As an insider to this industry the government is going to negotiate the price of GLP-1s within the next few years. Right now the list price on Ozempic is $900-$1000, and they pay a rebate to the insurer that makes the net price much lower. They want the high list price to be the "starting point" for discount negotiations. At the same time, they know they can sell it profitably at much lower prices, they just don't want to admit it. So it's going to be "in shortage" probably until after the government negotiates the official price for Medicare in a couple of years. Even if you can get it for $200-$300 compounded, that isn't the "official price" that will be the starting point for negotiations.
If you sign up for these services you will have a consultation with a nurse most likely and they can answer any questions you have. For instance, we did discuss whether or not their product had a salt base or not and they were knowledgable of the issues.
Unfortunately not approved for Type 1 DM so will be hard to get coverage for it from insurer. Anecdotally, I know of number of IDDM patients who've done great on it, since decreased intake + weight loss is such a huge factor in controlling both types of diabetes. Also should see same (?more) reductions in MACE (major adverse CV events- heart attacks & strokes), since CV disease even higher in T1DM. If I had IDDM, I'd strongly consider it...
There are plenty of essentially free lunches, medically speaking. There just haven’t been all that many introduced since routine childhood vaccinations. We’re overdue for a new one.
Antibiotics. Aseptic surgery. Insulin for type 1 diabetes. Probably many I can’t think of for more niche uses.
All have downsides (like glp-1ra) but all have proven so effective and life-saving that it’s hard to see them not being used even if the side effects were much worse or more common. (Antibiotic resistance is kinda tricky to characterize here, but it may make them fall out of “free lunch” category.)
I’d argue that anyone who would disagree that childhood vaccination, broadly, counts as a free lunch is too stupid to talk to. They don’t have zero side effects. But they have such minimal side effects compared to the diseases they prevent that it’s a true no-brainer. There are certainly arguments that some specific ones may not be worth the cost, but as a category it probably count as the greatest medical invention of all time. Like, unless they come up with a one-shot treatment that prevents 99% of strokes or something.
GLP-1RA may not ultimately turn out to be free lunch in the way antibiotics or aseptic surgery are. They might cause 90% of patients to get medullary thyroid cancer within 20 years or something. But there is such a thing as a free lunch. Most of us are only alive because of one or more of them.
To add to the "free lunch" cases: All of the deficiency diseases (scurvy, rickets, beriberi, pellagra, ...) that were solved by micronutrients.
In public health: All of the infectious diseases that chlorination stopped. Getting further afield: There are a bunch of food processing steps, most notably pasteurization that were comparably effective.
But looking at the bigger picture, medicine and medical science has also given mankind puerperal fever (in Victorian times), aids, the opioid epidemic, contaminated blood, maybe COVID. The balance is still positive IMO but maybe that's just cos I've avoided all the problems.
How do you figure AIDS? Did medical science tell people to eat primate meat they cut with open wounds and/or fuck chimps? Or do you mean mishandling of the early pandemic made the problem worse than it might have been? Because that seemed to be largely at the intersection of politics rather than on medicine itself.
And for COVID, lab leak is at “can’t definitively prove because the lab being where zoonoses had previously occurred plus incomplete data about the early course are confounding, but probably didn’t happen”. So “maybe” is doing a lot of lifting in “maybe Covid”.
I thought I read that the human-to-human transmission of HIV developed because of an immunisation program in Africa which was reusing needles. But I read that a long time ago - about the time its origin was first tracked down (by a reporter rather than a scientist, if memory serves).
Just found this: "My central hypothesis was that the Aids pandemic was sparked by an experimental oral polio vaccine (OPV) called CHAT, which was fed to more than a million infants, children and adults in the former Belgian colonies of central Africa between 1957 and 1960. It is now accepted that the immediate ancestor of HIV-1 is the simian immunodeficiency virus (SIV) of the common chimpanzee. In the late Fifties, polio vaccines were grown in cells from monkey kidneys, but evidence suggests that some batches of the CHAT vaccine fed in Africa were, uniquely, produced in chimp cells."
The polio vaccine thing is discredited horseshit. There are some lingering questions about HIV origin, but all of them are muddied by the fact that HIV was for sure spreading for decades before it got recognized for what it was. People were definitely dying of AIDS or else dying of other shit before they could develop advanced AIDS no later than the 1950sx, as recognizable HIV has been identified in samples from 1951. I think the current best thinking is that it probably jumped into people in the 1920s or so.
There is some question of subtype origin, but it’s muddied by the fact that its origin happened very late in the period where we couldn’t identify viruses well. If I had to guess about the subtypes, lots of SIV strains jump to individual people but are not very succesful ant infecting or spreading, and don’t cause long term harm. One strain, once, developed some really good adaptations for infecting and spreading between people. And all the other circulating strains are a result of chance confections of wild strains with the human spreading strain that happened soon after it emerged. Probably as it was first spreading among the community that it emerged in as they were presumably still processing primate meat. Eventually human strains became too specialized and lost the ability to easily exchange genes.
But I have done no research about the specific origin hypotheses Besides the conspiracy theory versions of which the vaccine thing is one, and that was just the first idea off top of mind.
It seems like a lot of things cured by GLP-1 agonists are diseases of modernity. So a natural theory is that there's some kind of GLP-1 ANTagonist in our food or environment that has been causing all sorts of problems. If true, Ozempic would simply be reversing the problems caused by this mystery chemical.
I find this plausible because it's more likely for a chemical to break a bunch of things than to improve a bunch of things above the natural baseline. If the latter existed, you'd expect our bodies to evolve to produce it naturally. And if something breaks a bunch of things, counteracting that something will fix them all.
We don't have drugs that can make a healthy person live an extra fifty years, but if you just drank poison, an antidote could extend your life by that much easily.
All there needs to be is some plausible mechanism by which the goods we eat have caused glp-1 per calorie to be reduced. Probably sugar sweetened beverages or something which increase calories consumed without causing the same glp-1 release as equicaloric meals.
What do you think of the theory that the obesity epidemic, and a bunch of other common modern diseases, are caused by the accidental introduction of a GLP-1 _ant_agonist as a contaminant to our food or water? Then semaglutide doesn't actually cure everything, but a bunch of modern diseases that we didn't realize all had a single cause are all cured by the same thing. (my current belief in this theory is something like 7%—low, but above the waterline of a hypothesis that would be worth investigating)
The experience described by people on these drugs, of not wanting things, reminds me of my 1st 90 days on phentermine. Broadly across the spectrum I had a vastly diminished preference for A happening over B, which for me was a huge and very welcome change. I have a tendency to get fixated on a plan happening, sometimes to unreasonable and disruptive lengths, and often (but not solely) in connection with food or drink. For example, one Friday night I was preparing homemade pizza, a ~3 hr process, and dropped the pizza taking it out of the oven at 10pm. Rather than eat something else (or order a pizza, or make a frozen one), I pulled remainder dough from the fridge, rose it for an hour, and baked a new pizza finally eating after midnight. Similarly I might get fixated on having a certain kind of day on Saturday when the weather's good, and get irrationally too upset when some unforeseen event derails it.
While I was on phentermine that first time, my preferences that things go a very specific way vastly diminished, and almost disappeared. I stopped using negative phrases/mantras that I would repeat to myself alone in the car. Additionally, I got far less excited and showed muted responses for things that should have made me really happy, like being given first row NFL tickets or coming into a bit of extra money.
I understand these drugs don't have any chemical similarity, so I'm not sure what to take away from this. In my work with recreational drug abusers, I have encountered people who take stimulants becoming more fixated rather than less, so this isn't what I would have thought. Maybe there's just a variety of things that, as a consequence of patient feeling better about some other part of their life, or a placebo effect of some type, have some secondary effect of reducing compulsive behaviors and fixations.
The anti-addiction elements of Ozempic are interesting, but my guess is they'll take a long time to penetrate the system. I'm no doctor, but I worked for many years with our county's drug treatment court, and there are a lot of treatment standards that are set by things outside of your control. Many of the treatment centers that you can direct addicts to while in these programs are also suboxone dealers, so their incentives are to offer that, and the federal grants are conditioned now on the court going along with whatever the doctor says and never pushing somebody to wean off the suboxone. We have had experts and conference speakers advocating naltrexone and vivitrol for our program, but we had no real way to push adoption of that. At some point IF Ozempic and pals get cheaper, I could certainly see combo weight loss / addiction clinics popping up to service this profitably, but it will take awhile for the entrenched drug treatment center industry who hold all the exclusive contracts to either change or have deals expire and be replaced.
I have been on Rybelsus for six months, at the highest dose, and though my weight loss has been disappointing my impulsivity has been cut down to such a degree that I'm tempted to try it as a monotherapy for my bipolar disorder. Unfortunately the potential negative consequences of such a personal trial are too high, so I won't be doing that.
I'm curious about the GLP-1 foods. If I eat a lot more salmon, kale, lentils, etc., will that help me much with hunger or with fighting other addictive behaviors, or is the duration of natural GLP-1 so short that they're healthy foods, but unlikely to produce any noticeable effects beyond any other health food?
This seems a bit like controlling guns, when violence in general is likely a symptom of more fundamental, systemic failures. If we look for an answer to the question, Why violence? our time might be more productive. Uyghurs run people down with their cars when they want to kill them; Brits stab people with a knife. Others prefer the anonymity of explosives.
We should be more concerned with addressing conditions that move people to resort to both violence and obesity.
Why are people morbidly obese? Why do they spend hours every day scrolling tiny, hand-held computers? Why do they listen to half-wits ranting on 'social media'? Why do they insist on nutrition-poor diets, then flock to gymnasia to work off the results? Time and money might be better spent dealing with the root causes of obesity.
Pure speculation here, but perhaps some of the higher-order, indirect positive effects on overall health & well-being come from the lower levels of stress (experienced consciously or unconsciously) by those individuals with these cravings.
If everyone has low-level inflammation all the time, and if this is causing us permanent damage, does that mean we should be taking low-level anti-inflammatory drugs?
Are there drugs that treat inflammation and don't have weird side effects?
I mean, I guess the claim is that Ozempic treats inflammation somehow But surely there's a way to do that more directly?
Quote: " [...] inflammation. This is a catch-all term for the immune response to microbes [...]". Just to be picky, inflammation is also a response for a physical damage such as a frostbite, it's not only about biological threats.
I just want to chime in and say that the effects on cravings and addiction are clearly not downstream of weight loss. First, they are not seen post bariatric surgery. Secondly, the reduction in cravings for alcohol and other substances begins immediately for many people, just as the reduction in craving for food does.
This also connects to a slightly broader point, and I don't think the science is quite here yet, but it appears that there is a strong reduction in cravings with GLP-1RAs that is separate from a reduction in reward value. It may be part of the same overall 'reward system', but patient reports and small trials overwhelmingly point to a lack of craving and desire that is too rapid to be a behavior learned from failing to receive a satisfying reward (though reward reduction may also be a part of what works over time). With alcohol, for example, people will often just forget to have their nightly glass of wine; just as 'food noise' goes away, random thoughts and desires for other substances may disappear almost immediately for many people.
The assertion "None of these anti-addictive drugs affect wholesome rewards like the feeling of a job well done or a child’s smile." is interesting - is there evidence for that? There's a big gap between "safety studies didn't notice major immediately obvious side effects" and "do not affect".
>Medicine is bad at answering “why” questions. Often the answer looks like “because it modulates ABC transmission, which inhibits XYZ, which signals to MNO, and MNO is involved in the disease.” This is all very scientific-sounding but totally fails to satisfy any normal human curiosity.
Ah, but what _direction_ of curiosity? Some of us will ask - But how does it bind to the ABC receptor? What pocket? Which residues? How many kT of delta-H? Salt bridge or hydrogen bond? What are the kinetics for diffusion through the cell membrane to get to the ABC receptor?
This is awesome. It has zero effect on me. But I want to say it's a big plus point for maintaining biological diversity. (Keeping species alive.) I love Gila Monsters!
These drugs affect an already dysregulated appetite. Do they help us understand why/how the appetite gets that way and offer lines of research to prevent it?
There is some indication that part of the normal function of the glp-1 system is fermentable fibers causing release of the hormone for a long time after food intake stops. The significant reduction in dietary fiber intake which co-occurred with a significant jump in total calories probably explains much of that.
It’s just a lot harder to stick to a regimen of getting enough fiber than a once-weekly injection.
>But GLP-1 drugs also prevent dementia in non-diabetics, so there has to be more going on.
Could this finding be explained by the increase in average A1C with age? Seems like a lot of the population most likely to develop dementia, the elderly, has relatively large amounts of glucose hanging around in the blood stream all the time. Even the elderly who do not qualify as diabetic would have on average a high A1C compared to the average younger non-diabetic.. So we could think of these non-diabetic elderly people as let’s say 20 or 30 or 40% diabetic, depending on how high their A1C is. Whatever it is that high blood sugar does to increase the risk of dementia, these technically non-diabetic people have the same risk factor as diabetics, just a slightly smaller risk.
The threshold for diabetes doesn’t change as you age. And glp-1ras will only reduce blood sugar and A1C to slightly on the lower end of the normal range. Given how long they have been widely prescribed for non-diabetics (not very) it would be astounding if such a small change in average blood sugar was causing dementia and we didn’t already know about it.
>And glp-1ras will only reduce blood sugar and A1C to slightly on the lower end of the normal range.
Do you mean it reduces them to something like 20 or 30th percentile? If they start off at 80th or 90th percentile and go down to 20th or 30th, I get that that'se a small change in the actual amount of average glucose in somebody's cells over the past couple months. But given that the normal distribution of A1C is very tightly clustered around 5.0 or so, it seems that the body regulates this amt pretty rigorously. That suggests that a small deviation numerically may matter. Sort of as with body temperature -- the difference between 98.6 and 100.6 is small, but in the case of temp this small difference is significant.
Given how long they have been widely prescribed for non-diabetics (not very) it would be astounding if such a small change in average blood sugar was causing dementia and we didn’t already know about it.
I just looked up the numbers. It's not a small change in average blood sugar. The change in A1C on Ozempic averages about 2%
But that doesn’t mean the A1C measure becomes 2% smaller, i.e. becomes 98% the size it was.. In this case what the experimenters mean by going down 2% is that you subtract 2 from the pre-treatment A1C number (which itself is a percent). If a diabetic person’s A1C is 7.0, it goes down, on average, to 5.0. So the decrease is 30% plus. (See Table 14 in the linked article.) That’s a big change.
I’m just saying that by now we could not have missed such a strong association. If this were the mechanism we’d have been starting people on metformin at much lower A1Cs 20 years ago.
I suspect the research has been done. And maybe metformin didn’t adjust a1c in non-diabetic patients or maybe it did and didn’t meaningfully affect dementia risk.
But they have to have trialled it. It would cost nothing and have zero risk. And it’s kinda obvious given the association with diabetes.
And before I sleep I should note that ozempic does have a large a1c reduction in diabetics. And diabetes is associated strongly with Alzheimer’s. That linked study is of “Ozempic!”. Like super double Ozempic, used for the primary indication Ozempic (TM) is approved for.
The effect is much more modest in non-diabetics. You would hope it was. A 2% a1c reduction in a non-diabetic is something you find in bloodwork to figure out why this dude is fainting all the time. I need to also pull up the a1c data for wegovy’s phase 3 trials to say exactly how much. But I will.
You still haven't clarified what the association is that you are talking about. Do you mean an association between A1C and dementia,, even in nondiabetics? If that's what you mean yes, there is definitely an association, and research into it. For ex.: "Diabetes was associated with a 10% faster rate of memory decline (β=−0.04 per decade; 95% CI: −0.06,−0.01). A 1-unit increase in HbA1c corresponded with a 0.05 SD decrease in memory score per decade (95% CI: −0.08,−0.03). Even among individuals with HbA1c <6.5% (threshold for diabetes), higher HbA1c was associated with memory decline (β=−0.05 per decade; 95% CI: −0.08,−0.03)." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325158/
What is "Ozempic!" Are you talking about dose given? There are results for doses of both 0.5 and 1.0. Do you mean Ozempic + metformin? Virtually all the subjects were already on metformin or some other diabetic med when the study began.
I stumbled over that sentence as well. I would guess most of us are going to be affected by the modern Western diet; those who don‘t end up classified as diabetic would still be „20 or 30 or 40 percent diabetic“ as you put it.
Personal anecdote of organic Ozempic-like effects, and evolutionary speculation:
I went on a strict diet for an autoimmune condition. No grains (except white rice), legumes, cow dairy, refined seed oils, added sugar, alcohol, or eating outside of a 6-hour window. But also no caloric restrictions, so my new diet involved lots of vegetables fried in massive amounts of butter/coconut oil; or hash browns also fried in large amounts of oil, with melted cheese and two fried eggs on top; or 300+ grams of beef at a time in a high-fat curry. Everything I ate was salty, fatty, very high food reward.
After a few weeks, I stopped getting hungry. By that I mean I could forget to eat a meal and not notice. Regardless of my caloric intake, not eating required no willpower. For comparison, before the diet, I could eat 3k calories in a day and still have ravishing hunger for sugary crap into the late night.
Over ~9 months on the diet, I lost 80 pounds. No hunger. If I had to guess, the causal factors were the sugar, alcohol, and time restrictions.
Thinking about WHY it all worked... it seems there are three different metabolic modes:
1. Hunger is closely tied to caloric intake and use (normal mode)
2. Hunger is strong regardless of caloric intake (feasting mode)
3. Hunger is mostly absent regardless of caloric intake (cutting mode)
I would guess 2. is triggered by consuming lots of sugar or alcohol - its notable that the body in this condition seems to crave more sugar in particular.
3. in my experience was triggered by a high-fat, high-protein, relatively low-carb diet (I wasn't going for keto, but I tended to only have one moderate portion of carbs with only one of my two daily meals) with intermittent fasting.
What situations in the ancestral environment are similar?
There's a limited window of ripeness for many fruits, and a temporary glut of overeating may be the only way to fully take advantage of the temporary glut in available calories. If I eat 1000 calories of sugar, in ancestral conditions that's probably a good indicator to my body that I should be eating more sugar. Unfortunately for moderns, it's always oreo season.
But compare the hunter-gatherer after the fruit is all gone. He goes back to hunting and fishing, which produce irregularly spaced out meals high in fat and protein. Caloric intake may be regular on a longer timescale, but he could easily go a day without food - and in order to be successful at hunting, he needs a constant supply of energy, regardless of how well he's eaten today. Under these conditions, would it not be ideal for the body to actively draw energy from fat stores, and suppress hunger?
My hunch is that a successful diet is one which puts you into cutting mode, and the best way to do it is to trick the body into thinking you're in the ancestral state which called for cutting mode. Perhaps that's what Ozempic is doing?
> What situations in the ancestral environment are similar?
There's a limited window of ripeness for many fruits, and a temporary glut of overeating may be the only way to fully take advantage of the temporary glut in available calories. If I eat 1000 calories of sugar, in ancestral conditions that's probably a good indicator to my body that I should be eating more sugar. Unfortunately for moderns, it's always oreo season.
"By playing around with its structure, Big Pharma was eventually able to create liraglutide (twelve hours), semaglutide (one week), and cafraglutide (one month)."
A lot of talented chemists would have worked on this and I think it is a slight disservice to not mention the company at least once in the article to give credit.
(although in your annual survey you don't have chemist listed as a profession, so maybe you just don't know we exist?)
The chemists are academics. From Eric Topol Substack “Dr. Daniel Drucker from the University of Toronto, who is one of the leading endocrinologists in the world, and he along with Joel Habener and Jens Juul Holst from the University of Copenhagen and Denmark, have been credited with numerous prizes of their discovery work of glucagon-like peptide-1 (GLP-1) “.
The discovery should definitely be cited, but I'm talking about the synthetic modifications that were mentioned, which are a whole host of research in their own rights that should be credited too. All three people you mentioned are MDs and therefore probably weren't the ones "playing around with its structure."
>Why? Isn’t addiction just the extreme version of normal wanting? Apparently not. None of these anti-addictive drugs affect wholesome rewards like the feeling of a job well done or a child’s smile. Just drug addictions, and a few compulsive behaviors like porn and gambling. But why? Why did God give your brain a special lever that only porn and cocaine can pull?
Here’s some introspected data about the craving for something one’s addicted to. I was very badly addicted for years to nicotine, in the form of cigarettes, and what I observed was that wanting a cigarette was quite different from wanting the feeling of a job well done, or wanting sex, or wanting a new car, or in fact most other kinds of wanting. Many different internal states could set off the craving for a cigarette: boredom, fatigue, hunger, irritation, anxiety, perplexity, difficulty concentrating, a vague feeling I was not up to doing a good job at some task I was facing. What all these states had in common was that they were unpleasant. And when I craved a cigarette, it seemed as though it was *the* remedy for the particular form of dysphoria I was feeling. So while I knew that I was addicted, the cravings did not feel like what one would imagine addiction feels like — a powerful inexplicable desire to have a dose of whatever one’s addicted to. It felt like cigarettes were a drug I’d discovered that fixed a multitude of bad states of mind I was subject to, and I simply could not face life without the excellent aid I’d discovered. So the craving of of the addict, or at least of me as an addict, was quite different from natural cravings. It was quite unlike a craving for sex or an attractive possession. There was no object of desire -- just the illusion that cigarettes were the cure for whatever was ailing me.
By the way, I am pretty sure the when I first started smoking, cigarettes really did improve a lot of the minor dysphorias of my life. And I’m positive that by by the time I was addicted, and could not get through a day without cigarettes, they did nothing at all alleviate the minor dysphorias. And yet I still had the feeling that one would.
Your introspection is incredibly insightful and connects a lot of dots for me in understanding addiction. I’ve noticed that mild intentional discomfort- such as cold showers is powerfully effective at combating addictive behavior. It seems to me that increasing your general tolerance for mild discomfort makes addictive behavior easier to control, and less appealing.
Yes, I agree, except I'd call it increasing your tolerance for the *idea* that you are in for some discomfort. Once I was addicted to cigarettes, they really did not fix fatigue, boredom, difficulty concentrating on the paper I was writing, or whatever. And if you had asked me at the time whether my latest cigarette had in fact help me formulate the next sentence in my paper, I would have said, no, not really -- "but," I would have added, "without the cigarette I think cranking out the sentence might have been even harder. And I'm pretty sure there are times when a cigarette is a huge help with writing. Yeah, OK, I can't come up with an example, but . . . " So I wasn't avoiding discomfort with them, I was just really stuck on the idea that overall they often helped, and being me would feel a lot harder without them. So I think the usefulness of cold showers would have been a way to remind myself I could voluntarily choose discomfort, even with the knowledge that I had no little magic helpers to take the edge off.
You’re exactly right… the cold showers themselves never actually get easier either, they suck. What you get is more like a combination of accepting the fact that you will be uncomfortable, and knowing that being uncomfortable is ultimately fine- that uncomfortable isn’t intolerable.
I have been on tirzepatide approaching 4 months. As others have remarked, the effects seem near magical - weight loss is effortless, which would otherwise have only been possible with a grueling (and in practice, long-term unsustainable) keto diet. I did not see a decrease in the desire for alcohol though. I am not a problem drinker but if anything the wish to have a pint or two has become more common. Seems to also have a hedonic reset effect, which translates into higher conscientiousness.
In my experience, the decrease is less in desire for the first drink and more in the reward in general. Alcohol feels less good, particularly as you start stacking doses. The euphoria (puddly though it is) gets reduced to the point where the many unpleasant side effects outweigh it.
Also not a problem drinker, for the most part. But wegovy has absolutely deleted everything in that sentence from the comma to the fourth t.
One thing that was seen in the recent small trial of semaglutide and alcohol use disorder is that the medication strongly reduced heavy drinking but generally didn't reduce drinking to zero.
alternative prediction: someone really underestimated how corrupt the medical science was and was successful with indirect soft methods of corrupting the data all at once
My worry is that Ozempic might reduce fertility. Maybe the explanation for the Fermi Paradox is that every other intelligent species in the galaxy has discovered a wonder drug that reduces natural cravings, including the cravings involved in reproducing the species.
I don't think lack of desire for sex is the threat to fertility. We have right now plenty of fun crazy ways to have all the sex you might want, including your kinks because kinks are normal and not bad, but having babies out of that sex? No, thank you!
See the enthusiasm for Kamala which includes "and of course she and Walz are correct on reproductive justice", where that means "all abortions all the time!"
Oh, excuse me, I'm always lagging behind on what the current correct terms are: now it's "reproductive health":
"The makings of a presidential ticket began in an unusual spot six months ago: a Minnesota abortion clinic.
At the time, it was a historic visit for Vice President Kamala Harris — no president or vice president had ever made a public stop at one. But the visit laid the groundwork for Harris to connect with Minnesota Gov. Tim Walz and learn about his interest in reproductive health, an issue Harris has taken the lead on during her White House term.
At first glance, the 60-year-old governor might not seem the most likely of political surrogates to talk about abortion and pregnancy. But Harris found a partner who has a track record of increasing abortion access in his state and can speak comfortably about his own family’s struggles with infertility.
...Democrats have warned that access to birth control and fertility treatments could be on the line if Republicans win big in this election. The concern grew more frantic after an Alabama Supreme Court ruled in February that frozen embryos could be considered children, throwing fertility treatment for people in the state into question. Democrats and Republicans alike, including former President Donald Trump, condemned the ruling, although some conservatives have said they support it.
Most Americans — around 6 in 10 — favor protecting access to IVF, according to an AP-NORC poll conducted in June. However, opinion is less developed on whether the destruction of embryos created through IVF should be banned. About 4 in 10 neither favor nor oppose a ban on the destruction of embryos created through IVF, while one-third are in favor and one-quarter are opposed."
Yes, the very thought of the prospect of embryos created because couples wanted children, actually becoming children, threw everyone into a state of being "frantic".
We want sex, we don't want babies. If Ozempic means we don't want sex either, it won't be to blame for reduced fertility.
It is odd how in *certain* areas the sight of a pregnant woman, once so common, is now much more of a unicorn.
The old etiquette chestnut from Dear Abby or Miss Manners (or TV joke) about asking a woman if she's pregnant, seems quaint now.
What is interesting and under-discussed to me is the eugenic aspect of abortion. I don't mean by the government; I mean that everyday decision a girl or woman makes about the potential parentage of her child.
Not that the decision is always made wisely.
When I was a kid visiting my grandmother with my twin cousin, we would go for long walks on the summer evenings. We would walk from the nice-enough but relatively modest midcentury ranchers (hers was one, and it had not been the home in which they raised their kids but was the realization of my grandparents' dream, my mother only living in it a couple of years) in the direction of the golf course and the much-fancier section of homes (all American cities had these sorts of neighborhoods cheek by jowl; even within a couple miles, there were very ramshackle bungalows, but we didn't choose to walk that way as we liked to go barefoot and walk on the lawns).
We would walk past one house that was our favorite. It interested us because it was so marvelously Prairie Horizontal: it was low and hundreds of feet long and very cool. Rich people lived there. It held more intrinsic glamour than is now to be seen in many a more prosperous city/zip code. And my grandmother would sometimes murmur something about how this could have been my mother's house.
I wasn't quite sure what that meant, but of course later on learned that Mother had been knocked up by her junior high/high school boyfriend.
(Interestingly, she persisted in thinking this had been some sort of immaculate conception, so there may have been more at stake than just living in a fine house, near her beloved parents.)
A lot of us are here because our mothers had abortions.
We are pro-life, inevitably, all of us - as is routinely pointed out. And we must, I suppose, be selectively pro-abortion.
I should add that while I was much too little to have understood *anything* specific, yet I did intuit that my grandmother's vague remark implied my non-existence somehow. It raised my infant defenses and I thus did not press her on this subject.
Ozempic: "wouldn’t some conditions be better in the starving state?" I remember an article in Life magazine in the mid to late 1960's about chickens kept on a starvation diet that lived twice as long as normally fed chickens.
Anecdotal: 15 years ago I was two stone overweight (it snuck up on me: 1 pound per year for 28 years of marriage!). I gave myself a year to get back to the BMI line. After a few rough calculations, I adjusted my diet by reducing my lunch from 6 slices of bread to 4. A year later I hit the BMI line. I carried on with the same diet but my weight fell no further. OK, there might be other factors like my family not encouraging me to have second helpings and I may have relaxed slightly after hitting my target, but I just wonder how much effect the mind has.
I think I also reduced my 4 (plain) Digestives to 2. :)
The only other change I can think of was that it was about the same time as I started a daily walk of about 40 mins. I've checked with my wife and she says we didn't reduce portion sizes.
And I've never understood is why, once I reached my target weight, it stabilised and didn't carry on down. It wasn't asymptotic. I just stopped losing weight. Since then I've been able to adjust it (up or down) by making minor changes.
I don't like the mind-over-matter interpretation cos even if the brain controls your weight, it doesn't mean the mind has access to the levers.
Anyway, I was amazed at how easy it was to lose weight, at least for me.
I guess it falls under self-inflicted placebo effect, but if it works...
Did we see any of this hype around other indications ten years ago when the GLP-1 inhibitor saxenda (liraglutide) was approved? I know it was not quite as efficacious as wegovy in weight loss, or is it maybe attributable to the hype cycle Scott mentions?
Does the differing efficacy of liraglutide compared to semaglutide in weight loss allow for any conclusions around potential efficacy in other indications, ie does it tell us something about the MOA?
Great article! Do you think there are any large external environmental factors at play/any research suggesting the relative effectiveness of the drug varying between for instance obese individuals living in urban city areas vs rural areas?
Does this make you more inclined to believe a SMTM-style environmental contributor to obesity?
Are there any drugs or situations that invert this and make people both more susceptible to addition and overeating?
Kinda curious how this differs from the appetite suppressing effects of other drugs, like nicotine (which as far as I know does not reduce but correlates with other compulsive behaviors).
Dr. Peter Attia writes: “Over 80% of deaths in people over 50 who do not smoke can be grouped into 4 main categories, what I like to call the four horsemen of chronic disease. These are: (1) atherosclerotic disease (comprised of cardiovascular disease and cerebrovascular disease), (2) cancer, (3) neurodegenerative disease (Alzheimer’s disease being the most common), and (4) metabolic disease (a spectrum of everything from hyperinsulinemia to insulin resistance to fatty liver disease to type 2 diabetes).”
He goes on to explain that the first three “horsemen” are really standing on top of the fourth. Might this explain that cure-all effect of Ozempic and related drugs? Fix metabolic disease, and maybe you fix the others?
To expound on the ❤️, I most like the interrogative stance of the article. Many assume health and medicine practices are answers and meanwhile there’s just a sea of questions around us.
Libido is so complex. I think there are addiction like reasons people have sex, and other more wholesome reasons, as well as identity confirmation/ego stroking. I imagine these drugs rearrange the reasons for wanting sex to align with the more wholesome reasons, but i can’t know until i try it out.
> But GLP-1 drugs are starting to feel more like the magic herb. Why?
Reading through, late, haven't read comments, here's a wild guess: satiety. The feeling of relaxing after a satisfying meal, or having completed a project, or your personal equivalent of "post-nut clarity". The rest of the time, our mind is warped by hormones messing with our brain to get us to do things necessary for us to survive in the ancestral habitat, but when they're all muted out, we can think rationally. And much of modern life requires rational thought to navigate properly, while ironically much of modern life has been designed to manipulate us through overriding our rational thought.
> First, it made rats eat less. But second, when presented with very tasty food vs. normal food, it made the rats stop preferring the very tasty food.
So far so good.
> But also, when a meal comes in, the body diverts other resources towards the digestion process (this is why a big lunch makes you tired). Maybe some of those resources come from the immune system, so immune cells stand down while you’re digesting.
That's what I'd guessed. Folk wisdom is that when sick, we should only eat easy-to-digest foods, so that the body can devote energy to fighting the sickness. If this is modulated in a Rube Goldberg way (not unprecedented in evolved systems), by recognizing when we've eaten, and tuning down other systems like immune response, then I can see how this would work, although it would imply that these drugs would make recovery from actual illness harder. (Unless all the people taking these drugs also happened to have good health insurance and are thus deploying the full power of modern medicine against their diseases... But even then, if it can produce enough other healthy side effects like lower obesity and longer sleep, it might be hard to notice.)
> Lots of bodily processes change based on whether you’re starving vs. well-fed.
My impression, based on a bit of research before fasting, was that one of the side-effects was that the body started to do priority-based recycling. Breaking down old worn-out bits and reusing the parts in place of normal food. And this is why short-term fasts can seemingly improve health, even if long-term starvation is still bad. So for the drug, if people still eat a normal amount, this process might not trigger? Or maybe we'll start to see bad effects in a few more years. Or maybe this whole model is woo-woo pseudoscience. :-)
This was a fascinating deep dive into the potential future of semaglutide and its impact on healthcare economics. As a teacher trying to stay updated on topics that cross into the realms of health and public policy, I appreciate the balance you struck between optimism and skepticism. The transhumanist angle adds an intriguing layer to the discussion—especially the idea that obesity might one day become as optional as a fashion statement. It’s a thought-provoking read, and I’m curious to see how these projections play out.
By "diabetes" you mean type 2 diabetes. Language matters, not only because it's cruel to lump kids with type 1 in with the stigma associated with type 2, but also because the drug won't affect people with type 1 the way it will affect people with type 2.
I think drug companies should offer a controlled trial for opioid addicts as a first priority. Then offer to alcoholics in treatment, then nicotine addicts. This should all be paid for by the govt which failed to protect them in the first place. Maybe it would be a panacea for homelessness also. There has to be a greater good for these drugs than vanity.
"maybe the inflammatory nature of the starving state really hurts a lot of systems. " did you mean to wrrite inflammatory nature of the well-fed state?
hmm i must be misunderstanding it then. Cause doesn't he write earlier how fasting (which surely must put you into a starving state) reduces inflammation?
This is fascinating. Thank you. Unfortunately, these drugs run a grand per month so only well-off people can access them. The greatest medication in the world is useless if you can’t have it.
Tremendous breakdown here. I've personally been doing a double take lately myself on all the magics of Ozempic. Well work the read. Thank you for the great research here!
Alcohol gets processed through the liver directly -- first in priority -- without an insulin spike. It's very analogous to purse fructose in this sense. But it's not a duplicate. All carbs except fiber eventually get converted to glucose. But alcohol does not. It gets converted to acetate, which is a fatty acid, for the body to use as energy.
Thanks Scott! These drugs are definitely odd in breadth of effects, but I appreciate having such a good summary of our current state of understanding.
The biggest unusual factor I learned in your article is the change in apparent relative value between normally-extremely-desirable (but likely fatty or sugary) food, and healthy-but-mundane food. The big questions that come to mind for me based on this regard:
1 - mechanism concerning food
2 - sexual kinks/fetishes
3 - pedophilia or paraphilias
(note: I'm using 'Wegovy' specifically or 'SGLT1 inhibitor' generally as a stand-in for any of these type of drugs, but am not certain if this is quite valid as terminology or treating everything as a single class. you get the point though)
1 - mechanism regarding food
Not the physiological mechanism which you address to the extent we know, but the more conscious psychological effects.
Does cheesecake literally seem less tasty when taking Wegovy than when not?
Or does a kale salad seem more tasty?
What would the same people rank how much they enjoy desserts or other treats, vs baseline foods, when on or off of the SGLT1 inhibitor?
When on the drug, does their perceived memory of how much they enjoyed the foods also change?
It seems hard to relate to taking a drug whose mechanism is to make less enjoyable something which is currently very enjoyable, as the temptation seems to be "quit the drug so really fun thing is really fun again", so I'm very curious the rating and memory effects and whether they help explain the psychology.
(I have never tried SGLT1 inhibitors, so my closest analog would be taking Diamox for altitude sickness. I normally greatly enjoy pop/soda/'Coke' as a treat. Diamox works via affecting CO2 levels in blood, with a side effect of making carbonated beverages taste like crap (e.g. flat, and overly sour). For me, countering altitude sickness is easily worth it, but I remember pop tasting good, and look forward to having it again once off the med. Why is a Wegovy and cheesecake scenario not similar?)
2 - sexual kinks or fetishes
I love your joke about funding a study to see if SGLT1 inhibitors make people not want sex less, but maybe make them care less about whether the sex is good.
More seriously, I'd love to know what effect they have on outside-the-norm sexual cravings and behaviors. Does Wegovy or similar make vanilla sex 'good enough', such that those with strong kinks/fetishes no longer want or act toward them as much?
I don't expect we're going to get funding, IRB approval, or a RCT to come out of this either.
However, maybe there's a place for a follow-on set of questions for Aella's kink survey related to usage of SGLT1 inhibitors?
3 - pedophilia or other paraphilias
The most extreme, and possibly socially/legally valuable, case of #2 then would be whether these drugs affect cravings and likelihood of acting upon destructive/damaging paraphilias, such as pedophilia.
If SGLT1 inhibitors can dull the extreme craving and make safe, adult, consenting sex desirable enough compared to the object of the paraphilia, this seems like a huge win for treatment options.
I understand the whole area is so taboo that study may be difficult, but hope there is some move to study this, even as part of an experimental treatment/punishment in the justice system.
"There’s a pattern in fake scammy alternative medicine. People get excited about some new herb. They invent a laundry list of effects: it improves heart health, softens menopause, increases energy, deepens sleep, clears up your skin. This is how you know it’s a fraud. Real medicine works by mimicking natural biochemical signals. Why would you have a signal for “have low energy, bad sleep, nasty menopause, poor heart health, and ugly skin”? Why would all the herb’s side effects be other good things? Real medications usually shift a system along a tradeoff curve; if they hit more than one system, the extras usually just produce side effects. If you’re lucky, you can pick out a subset of patients for whom the intended effect is more beneficial than the side effects are bad. That’s how real medicine works."
From this, I take the author doesn't think that herbal medicine is "real" medicine and allopathic medicine is the real thing. Herbal medicine is the mother of all medical science and many or most drugs today are derived from it. With such a biased attitude I don't put much stock in what the author is saying and I question his motivations.
I don’t know about the author, but the marketing of “natural herbal remedies” puts me off. Natural <> good. Herbal just means it comes from plants. Remedies is an attempt to avoid the word “medicine” and FDA attention. It smacks of quackery.
In Slovakia, and probably elsewhere, there is a randomised controlled trial on ozempic-like drug orforglipron by Eli Lilly. The trial is for weight loss. It is a small molecule, does not need to be injected, just eaten, and there are hopes it will be cheaper when it is approved. I know at least one person who lost weight at the trial. So, maybe, look out for a similar trial in your country ?
I distinctly remember the early Internet, 2002-ish, when we used to make fun of prudes who are afraid that other people are having too much fun. People who call masturbation a sin etc.
Well, this didn't age well? Now dopamine desensitization is understood to be a thing, and yes too much porn / masturbation is one of the big ways how it happens. Apparently a little puritanism is a good thing... now the media is full of restoring dopamine levels by regularly abstaining from this or that, and doing painful things. Like cold showers. Lol, cold showers sound exactly like what a Scout leader in 1900 would say. (I tried it once and I felt like getting a heart attack.)
BTW I keep wondering how the old time looks-oriented body-building got replaced with the squat-and-deadlift Rippetoe thing now. Why would dudes want strong legs instead of spectacular arms? I think it is the training itself, not the results. Basically the training just sucks and they do it for exactly this reason, all that struggling resets something in the brain, maybe dopamine.
So this can be fixed with a drug and then we can go back to unashamed hedonism? Sounds too good to be true.
Strength training is rewarding because you get stronger consistently over time… and is useful because the strength generalizes. It’s mentally challenging as well and requires a lot of skill and technique. It does also make you look stronger, even on a regular diet. Bodybuilding is mostly boring repetitive movements, and you generally see little actual strength improvements- and you don’t really look different either unless coupled with strict dieting to get lean.
One thing I don't really understand: With fasting, insulin remains very low, and this is "good" because it increases insulin sensitivity and is therefore good for metabolic health. If I understand correctly, semaglutides give the body the signal to reduce blood sugar which involves *higher* insulin for longer, but this is also "good"? What am I missing? Since this treatment originated to help type 2 diabetes, it can't be bad for insulin sensitivity I guess but the high/low insulin discrepancy (compared to fasting) doesn't make sense to me.
Also, everyone here seems to go on the medication long term. What about just short term to lose some weight then stopping it? I'm not technically obese but increasingly struggling to keep weight down due to age/menopause etc. Have a very good diet overall (no junk, don't drink, low carb, fresh homemade food) but also a big appetite so probably eat more than I strictly need. Feel like I could maintain a good weight if only I could shed the extra 10-15kg that has crept up over last 5 years or so. Has anyone done short term then stopped?
Glutides only increase post-prandial insulin production. This is good because it keeps your blood sugar from spiking. It’s also optimal because it sidesteps insulin sensitivity that is the hallmark of t2d.
Since you are in a semi-fasted state (thus with low insulin levels) the rest of the time, you get best of both worlds.
Been a while since there's been one of these "More Than You Want To Know"-style posts, although this one's less long than some previous pharmaceutical epics. I've missed such content. Classic ACX, keeping the Better Living Through Science(tm) light alive in a cynical age. Can't wait to see if these drugs eventually filter down to the (non-obese/diabetic) genpop in some form...and, of course, it'll be interesting to see how addiction profiteers try to run interference. A world without whales would be better overall, but boy do some industries count on them for survival.
1. "Diabetes is a well-known risk factor for Parkinson’s, Alzheimers, and other dementias"
Eating too much sugar seems like it is really bad. It destroys your brain. Perhaps, switching all sugars to aspartame would be better.
2. Since you believe alzheimer's is partially caused by inflamatory responses perhaps we should make a clincal trial, where NASIDS are used to slow down alzihmers.
3. Why is mild inflamation bad. I though it just clears up dead cells and helps tissue regenerate. You just state, "This is bad."
4. You say some food promotes GLP-1 release, while others foods cause a light inflammation response. Which foods cause a light inflamation response? I would try to avoid them.
5. Why does food cause a light inflammation response?
My request is that you do the next article of fasting. Is it good or bad? I thought your thoughts of different bodily processes while fasting where very interesting.
The main reason I'm here is because Scott write's Bayes' theorem as the context for Astral. Bayes is a different way of thinking, and when properly constructed allows us realize that humans are pretty piss poor at thinking through a Bayes filter, which turns out to be important.
We stumble across GLP-1 (and everybody should listen to the Aquired Podcast on Novo Nordisk for more context) and we infer that the only use for this is for weight loss. In reality, our biological system is so complex that we only get generalities of how it works, then we run phase I, II, and III trials to hope that we get some type of drug that does something like what we were hoping. If we get lucky, we say "well we understand how that works." Then confirmation bias forces us to say that any new area of impact "must have something to do with our original thesis."
I think the real issue is that new data is coming in, and rather than immediately trying to make it try into our existing framework, we say "more work to be done." Hypothesizing is not bad, but perhaps GLP-1 is part of a more significant cascade of signals in the body that we are fooling round with. I am glad that the results seem positive so far, but we should be worried that we don't understand what is going on.
And Scott has done a great job of getting me thinking, which I would expect from somebody that like to think in a Bayes framework.
Why don’t Americans stop eating all this chemical crap that masquerades as so-called food and causes most of the deterioration in public health? You are merely fighting symptoms with more and more drugs, without tackling the root causes. The health of most of the population is going down the drain, and yet big pharma comes up with more and more “wonder” drugs that in the long run make matters worse.
I lived in the US for 36 years, and have been back in Germany since 2010. It’s interesting to see how the food supply chains in Europe are under attack by the chemical, agri-business, and pharmaceutical companies (all of the same ilk). They are slowly chipping away at people’s resistance to concoctions that are marketed as food. It doesn’t help when here in Germany many people want to minimize their food bill when they go to the grocery store.
I'm not being sarcastic here, if a couple problems get solved in AI, everyone could be running these kinds of labs with the right computer equipment in their own homes at exponential rates. I wonder what happens when nobody gets sick anymore. What is that to a world?
This made me think about how so many of our most useful medicines are derived from a nature source (in this case, Gila Monster venom). A doctor friend told me awhile back that most pharmaceutical companies don’t spend nearly enough time and money investigating natural sources for drugs because it’s easier to patent drugs that are completely synthetic.
This made me think about how so many of our most useful medicines are derived from a nature source (in this case, Gila Monster venom). A doctor friend told me awhile back that most pharmaceutical companies don’t spend nearly enough time and money investigating natural sources for drugs because it’s easier to patent drugs that are completely synthetic.
Did you know the AI voice that reads the article has added in some of its own flair, meaning reading text that is not present in the written version. There is a part near the end about how it’s doubled the economy of Denmark (or one of those Scand countries), I’m following along reading the text and listening and they aren’t matching. WHY IS AI NOT JUST READING WHAT IS WRITTEN? It’s really messing with my head. I’m not crazy right? Shouldn’t it just be reading what you’ve written?
I read this post about Ozempic months ago when it was first published. While I found it intriguing, I didn't give it much further thought at the time. However, a recent personal experience has compelled me to revisit the topic and share my story.
For context, I've been struggling with sex addiction for years. This isn't a self-diagnosis born from a high libido; it's a severe condition that has significantly impacted my life. Despite having a high-paying job and a supportive family, I've found myself engaging in extremely risky sexual behaviors, including seeking out sex workers in dangerous areas of town. These compulsive actions ultimately led to the dissolution of my first marriage. I've been in treatment for about a decade, and while I'm largely in recovery, the cravings have persisted.
Given that I'm not overweight enough to be prescribed Ozempic, I initially dismissed the post's relevance to my situation. However, about a month ago, I came across an advertisement for a probiotic designed to reset gut health and reduce sugar cravings. On a whim, I decided to give it a try.
Over the past month, I've traveled extensively for work. Typically, these trips would be challenging, as they presented opportunities to act out. To my astonishment, I experienced zero cravings during my travels. For someone who hasn't been able to visit a new city without fixating on the possibility of encounters with sex workers for over two decades, this was nothing short of remarkable.
It wasn't until today that the oddity of this situation truly struck me. I realized that this dramatic change coincided with starting the probiotic regimen. Intrigued, I researched the product and discovered something fascinating: it's a GLP-1 probiotic. This immediately brought to mind the Ozempic post, prompting me to revisit it.
While this is purely anecdotal, the probiotic appears to have completely eliminated my addictive cravings and poor decision-making around sex. The parallels between this GLP-1 probiotic and Ozempic's effects are striking, potentially suggesting a broader application for GLP-1 agonists in treating various forms of addiction.
I share this experience in the hope that it might contribute to the ongoing discussion about GLP-1 agonists and their potential to address a wide range of compulsive behaviors. It's possible that we're only beginning to scratch the surface of these compounds' therapeutic potential.
I started Ozempic in June. As of now, I've noticed (though correlation is not causation, or at least that's what the Tobacco Institute tells me) about twelve distinct medical problems that I've had which have cleared up. Some of these were not at all obvious, like meibomian gland dysfunction.
After reading this I'm really curious about potential of GLP-1 receptor agonist drugs (not just Ozempic) as an anti-aging intervention. If they activate signalling system that makes people feel full, it might help with maintaining caloric restriction, which is known to extend lifespan. Additionally if it indeed has strong anti-inflammatory action it would directly affect one of the hallmarks of aging, so called inflammaging
It would make evolutionary sense for there to be several separate reward systems. Just because you are satiated on food does not mean you should avoid sex, or cease to explore your environment, or whatever other reward systems there may be. We may have some overloads like generating pleasure, but if all the reward systems were in sync that would not promote survival.
Y'all who are taking that poison really need to read this article. Its long, but writes out the entire BS of this scam, starting with the sugar industry.
Mounjaro has taken the food gremlin that lives in my brain telling me to eat all the time had made it shut up. Do you have any idea what it’s like to live with that?
I thought everyone had a good gremlin whispering in their ear every waking moment and that skinny people had really amazing self control.
Now that the food gremlin is quiet, I actually have the brain space to focus on what I’m eating, when I’m eating and why. This is such a novel change and I love it.
Just to note in response to the below that this is very plausible when you consider that many people coming off an addiction appear to balloon in weight to compensate. Could the reverse be true too - could say, highly addictive things reduce hunger? Heroin, meth and smoking would seem to indicate possibly?
I am posting this right after reading this paragraph so I sure hope you don’t address this and I feel very silly…
“GLP-1 suggests maybe this was originally a food reward system. Or at least food was a big enough part of its portfolio that it was a weird but functional hack for a satiety-signaling chemical to just turn off a whole subsection of the reward system. “You’re already full and well-nourished; why would you need the ability to crave things?”
Reflecting on what is an otherwise comprehensive and fascinating review, it’s surprising that the potential interplay between GLP-1 receptor agonists and the endocannabinoid system wasn’t addressed. Emerging research suggests that the therapeutic effects of GLP-1 receptor agonists, such as Ozempic (semaglutide), may involve interactions with the endocannabinoid system. For instance, a study published in Diabetes demonstrated that coadministration of a peripheral CB1 receptor inhibitor with a GLP-1 receptor agonist led to greater reductions in body weight and fat mass in diet-induced obese mice compared to monotherapies, indicating a functional interplay between these systems.  Additionally, research in the Journal of Endocrinological Investigation found that levels of certain endocannabinoid-related molecules could predict the metabolic efficacy of GLP-1 receptor agonist treatment in humans with obesity, further supporting the notion of cross-talk between the GLP-1 and endocannabinoid systems.  These findings imply that the endocannabinoid system may play a role in mediating some of the diverse effects observed with GLP-1 receptor agonist therapies.
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.
Addiction can be cured by fasting?
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/
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?
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.
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.
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.
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. :-(
I held a water fast for a week and my libido turned to zero.
That's more likely because starvation is associated with a decrease in testosterone.
You mean seminar, not seminary.
works differently for me i think. Weekdays I follow caloric deficit with heavy weight training.
My sex drive is thru the roof. Happy gf.
Some addicts lose interest in food. This doesn't seem to help the addiction.
Any information about a relationship between anorexia and addiction?
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.
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
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.)
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.
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.
Well yes, addiction can be cured by abstaining from the substance you are addicted to, in this case simple carbs. Who would have thought?!?
> 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.
Drug or behavioral. It's not implausible, but I don't know if I think it probable.
This sarcasm seems neither necessary nor accurately aimed given that you missed Robertas's point, no?
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.
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.
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.
How long have you fasted?
"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.
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"
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.
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.
Ditto.
I also found I missed the act of eating, both somehow as a physical activity, but also as a social ritual.
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.
Have you tried very high fat diets?
Nope.
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.
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.
Well, it worked for smoking. But it took several years for a real cure.
After 46 years smoking abstinence i still get occasional urges. I sometimes miss it.
Amphetamine addiction would be impossible...
Though you can have a habit.
Amphetamine (NOT methamphetamine!) addiction is actually quite hard to achieve, regardless whether its Methylphenidate salts, or street amphetamines.
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.
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.
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.
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.
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?).
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...
"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!
bad reasoning
https://en.wikipedia.org/wiki/Obesity_paradox
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.
Not a chance
"[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.
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)
I know a woman who quit drugs and she restricts food to feel high.
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).
Can confirm. Lost desire for everything and anything and was put in a gray haze of borderline emotional anhedonia (and enhanced depression).
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/
Think he was talking about the drug
Yes, I was.
Did you at least feel good about losing weight?
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.
"Did not lose weight"?
Come on bro, that's absurd
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?
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".
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.
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.
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.
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.
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.
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.
that sounds suspiciously similar to the side effects of ADHD medication (amphetamine salts)
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.
Lithium, huh ? Interesting angle, I'll check it out
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.
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
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.
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.
I have no dog in this fight, but I suspect you'd need to control for reduced smoking, among other things.
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
It might depend on which lithium salt it used. (Nobody consumes elemental lithium!) IIRC, Lithium was once used to treat depression.
Oh thank you, those were the replies I was thinking about!
>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). )
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.
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!
> 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.
"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.
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.
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.
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
Really interesting, thanks. Worth a write up
Much appreciated, glad you found this worthwhile.
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.
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.
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.
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.
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.
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.
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.
My impression is that smoking only affects weight by about 15 pounds. Am I mistaken?
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.
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.
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.
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.
Check out Bart Kay's work. He disproves CICO. Those who believe in CICO don't understand the first law of thermodynamics.
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.
Professor Bart Kay has disproven CICO.
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.
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..
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.
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?
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.
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...
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.
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.
"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.
"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.
Yeah, for sure it works. The problem is that people are unable to maintain it for the long term.
Yes, if you don't consume calories, you will eventually waste away. But there is much, much more to the system of metabolic health and weight loss than CICO.
https://www.youtube.com/watch?v=QAr506gUYYQ
I agree with you on that point for sure! I am not going to analyze this guy's video (which I watched about half of) but he seems like he'd make a formidable ally (or foe) for the Debate Team...
It’s not. At least for the immune effects.
I started on tirzepatide while barely 15lbs overweight. I have two pretty bad immune issues. Both are, completely miraculously, cured by it. I’ve gone off and now now numerous times even at perfect weight and it still has effects. Even when I eat normal calories and am not fasting on it.
> But when he dies, the coroner discovers that his head has a rock saying “[CALORIES IN CALORIES OUT]” where his brain should be.
What you’re saying is intuitive: ozempic makes users eat less. This skips all the annoying confounders when studying diets, and goes straight to the part where they really don’t take in as many calories. It’s not hard to believe that this reduces weight in most cases.
But what about the weird stuff? What does fasting have to do with Alzheimer’s? Is there stronger evidence for that than for, say, aducanumab?
I don’t know if anyone’s managed a study on heroin or amphetamine use and Alzheimer’s risk. It seems very unlikely that those drugs, which also reduce caloric intake, demonstrate any of the other benefits suggested for ozempic.
Obesity is a risk factor for Alzheimer's.
The issue with amphetamine use is that it's correlated with various mental abnormalities and also seems to cause cognitive decline in its own right.
I suspect "you don't want to" is the crucial part. This article argues against calorie restriction saying it's no use if you don't "treat" you brain since the satiation feeling is some kind of guess of your hypotholamus (?) on how nutritive what you just ate was based on prior experience (which is why the hunger system can apparently be tuned) :
https://aeon.co/essays/hunger-is-psychological-and-dieting-only-makes-it-worse
Funny because the article is from 2016 and Ozempic just proved it right IIUC
Really interesting pivot here into what may be the real issue. Is there any research you know of though that speaks to the ideal "happy medium" so to speak. For instance, restricting calories too much and you are unhealthy and don't get enough nutrition, but obviously an abundance of processed junk (or really any) is bad on the other end of the spectrum.
I think there's a typo after the agouti, it should say "Each of these populations is UPSTREAM of some slightly less masterful master regulators"
I think it might be both downstream and upstream, in the sense that other regulators (eg hormones) tell it what to do, and then it tells other things (eg the body) what to do. Maybe "center" is a better descriptor than "master".
I found myself thinking this as well. I see Scott’s explanation but I think the way he has worded the “slightly less masterful” phrasing makes downstream a more natural choice here.
The other little lesson from the SSRI experience is that in addition to benefits being overestimated, negative side effects tend to get overlooked. Just had a friend who had to get off Ozempic after developing a nasty case of pancreatitis…I’m guardedly optimistic about these drugs but reluctant to get on them until the smoke from the hype cycle has cleared a bit.
Pancreatitis as a side effect has not been ignored. It’s one of the main side effects on the label. But it happened in less than 1% of cases in clinical trials. It also was much more common if you already had risk factors for pancreatitis.
If the real world incidence of pancreatitis was over 1%, I’m confident there would be plenty of media doom cycles over it. Especially given how much they are charging for this shit. Hell, they tried to do that with suicidal ideation until further research made fairly clear that the opposite relationship is actually more likely.
Are there very common side effects besides nausea that have been shown in trials that I am unaware of? Or other side effects requiring discontinuation?
Stomach paralysis happens, and can last for long enough to be a serious problem. I'm not sure how common this is.
https://www.webmd.com/obesity/ozempic-and-stomach-paralysis
It’s 5% according to the article. Though the actual term for this symptom is gastroparesis, which is less scary sounding. I’m thinking webmd calls is “stomach paralysis” because it’s more accessible as a term.
It’s pretty treatable, though unpleasant. A friend of mine has chronic idiopathic gastroparesis, and has medication that helps. But it makes her chronically malnourished.
I only skimmed the article, but would be surprised if the symptom didn’t clear up for almost everyone within a couple of weeks. This is likely one of the symptoms that requires such a slow ramp up of your dose, so they catch it with the quickest turnaround on having it resolved.
It’s one to keep an eye on, though. And hopefully they figure out a way to get the benefits without this symptom. Because “5% of people just can’t take this drug ever” is not a good thing for such an otherwise beneficial treatment.
I'm surprised you find the term "gastroparesis" less scary given that it's literally a neo-Latin mishmash of Greek words for "stomach paralysis"!
Yeah, but it doesn’t contain the English word “paralysis” which most people associate with a wheelchair and a permanent condition. Gastroparesis is usually incomplete and reversible, particularly when drug induced.
“Stomach paralysis” sounds complete and permanent because of the association with the English word that is most often used to describe the consequences of a spinal cord break.
Even rational people are influenced by the context of language.
The link between suicide and SSRIs has not been disproved. A characteristic of SSRIs was that the side effects frequency were at first considered rare/low but were continually adjusted upward with post-market surveillance and patient reports. The initial trials used to get approval for a drug are often not perfect guides to what the drug effects will turn out to be when used on a mass scale.
Suicide and GLP-1RA. Sorry if I was unclear. Suicide and ssris is a black box warning still, particularly in adolescents.
Also, the initial trials of SSRIs did not actually include the population most affected by that side effect. (Adolescents). And only a few of them ever went through the process of doing trials in that population to get approval. The black box was added because the risk was identified as a risk of all antidepressants in pediatric populations during a metaanalysis of small RCTs of something like nine drugs (4, to my knowledge, are actually approved for pediatric use). The increased risk of suicidality at start of treatment for antidepressants is not significant in adult populations, to my recollection. (This is Scott’s wheelhouse, though, so if there is a deep dive on it from him I don’t remember please refer me.)
So, I think what we can take from that is that we should be extremely careful about off-label prescribing in populations not included in the trials. For instance, it’s probably irresponsible to start prescribing glp-1ra in non-diabetic pediatric patients until each is explicitly approved for the indication. And if they are being prescribed off-label, it should be by specialists in pediatric obesity with extra checks for weird side effects.
There's also many cases of paralyzing the stomach, class action lawsuits and most people gain all of the weight back when stopping, in some cases more. There are always negatives with prescription drugs and the FDA always winds up being wrong, zantsc just another example.
I agree, the effects of Ozempic don't seem too dissimilar from the effects of long-term, severe caloric restriction (not just casual fasting) across many animal species. Many scientists see it as a slowing of the aging process (hence the reduction of age-related diseases). There seems to be a deep evolutionary connection between energy consumption and aging, and this is one way that it manifests.
When we determine the exact mechanisms by which Ozempic prevents these diseases, we'll also understand exactly why exercise and varied, colorful vegetables (and their pigment molecules) help prevent these diseases.
Doubled the economy of Denmark? That’s ridiculous, and not mentioned in the linked article. The GDP of Denmark is $410B (yearly production), the market cap of Nova Nordisk is $560B (total value of future earnings).
Yeah, that jumped out at me, too. The closest thing that I could find (in a separate article) is:
> Danish GDP will grow by 2.7pc this year, the Ministry of Economic Affairs said – far faster than the 1.4pc it had expected in December.
> This revision has been driven in part by the runaway success of pharmaceutical company Novo Nordisk’s hit drug Ozempic, while the reopening of the Tyra gas field will also boost GDP by reducing energy imports and boosting exports.
Source: https://finance.yahoo.com/news/ozempic-drives-economic-boom-denmark-153814923.html
So Ozempic is *partly* driving a doubling of the economic *growth rate* (not a doubling of the economy).
Thanks, you're right, I've removed that claim.
It IS ridiculous, but it's actually a pretty widespread and oft-repeated claim. People seem to just see the two numbers, GDP and market cap, be approximately equal, and be inexorably jump to the "doubling Denmark's economy" conclusion.
A more reasonable comparison would be to the total market capitalization of Denmark's STOCK MARKET, and … huh, Nova Nordisk might about 3/4 of that.
Thanks for the article. What's behind the misleading "doubling" claim is that the market cap of Nova Nordisk, about $450bn, is bigger than the annual GDP of Denmark (about $400bn). But of course the market cap is just the value of the shares, and is not itself part of the economy. The revenue of Novo Nordisk is about $34bn which is less than 10% of the economy of Denmark, and presumably a lot of it is earned outside of Denmark. Still damn impressive that their market cap is bigger than the entire annual GDP.
Better compare something like citrus to citrus. I'll use that mkt cap compared to Denmark total wealth rather than gdp. Total wealth is 1.9 trillion. Still impressive.
Total wealth is a bit hard to calculate. Eg do you count everyone's kidneys, because they theoretically could have a (black) market value?
It's easier to compare GDP to eg company revenue.
I include all my organs when calculating my (personal) net worth. They are critical assets! It's part of the GAAAP (Generally Accepted Anatomic Accounting Principles).
It's impressive, but not unbelievable. Apple, Microsoft, and Nvidia each have higher GDP than the northern half of California.
> But of course the market cap is just the value of the shares
Well, more accurately it's the value of one share multiplied by the number of outstanding shares. It isn't clear how this figure relates to the value of the shares. If you want to buy all of the shares, you'll pay quite a bit more than the market cap; if you want to sell all of the shares, you'll get a lot less than the market cap.
I've been taking Ozempic and my personal theory on the addiction stuff is. Lose weight -> improved feelings of self esteem and self control (even if the self control came from a drug, you still feel good about it!) -> able to overcome other addictions.
But I don't know if that makes sense in rats! Very interesting article thank you.
That would be plausible if reduction in addiction happened only after some significant weight loss; if it happens more or less immediately, it has to be a direct effect of the drug.
Related question: Why does semaglutide, at the lowest possible start tapering upward from this dose, give me such crippling brain fog that after 3 weeks of it I was unable to think clearly enough to effectively do my job, my depressive spirals had doubled in both frequency and severity, and focusing on anything felt like dragging my brain kicking and screaming through a field of broken glass?
It also made me feel too sick to eat most of the time, which I suspect is the primary weight loss mechanism.
Anyone else experience these mental effects? Did they ever go away? I discontinued before upping the dose. Some anecdata suggests tirzepatide is less likely to do this, so that's next on the list.
interesting - while i don't have an answer i'm curious if there's other things that give you this same type of brain fog, or is it only semaglutide?
I've never felt anything like this from anything else. The enhanced depression, especially, was honestly kind of terrifying, at least before I recognized that it was the drug. After a couple nights where the occasional evening self-loathing/self-worth spirals I sometimes have were set off by absolutely nothing and dropped me twice as low as usual, I Googled around some, and saw others on a few Reddit threads reporting similar mental side effects. Before that I'd been worried something was becoming dramatically worse in my brain chemistry. That went away as soon as I was off semaglutide, so I guess in a way something was.
It was kind of like having a really bad bout of Covid, for a month, with none of the physical effects of Covid (well, aside from "too sick to eat" and actually maybe some muscle fatigue now that I think of it), just the mental "I feel like I have been hit by a truck and haven't slept for days" ones.
If it lowers all reward signals somewhat, maybe your reward signals are especially weak or you are especially sensitive, such that it basically turned them all off?
It might be as simple as "your blood sugar was too low". Were you tracking that?
Oh that makes sense. My own initial reaction wasn’t so helpful: “sounds like anti-adderall”
Sometimes the dumb obvious answer is the one 😀
Interestingly, I was and am on adderall at the same time. Semaglutide negated most of the mental effects of it completely.
I wasn't, but my blood sugar is normally far too high, which is why I was on the drug in the first place - A1C peaked over 10 and my doctor decided it was worth trying at that point (vs the 8ish I'd maintained in less stressful years). So I'm not sure I could possibly have gotten hypoglycemic enough to cause those effects, especially on the lowest dose (1/3 of what I was eventually supposed to titrate up to).
[very late reply] A1C is a summary statistic of the last 90 days of blood glucose, but there's also an instantaneous glucose test you can do at any time. You can get a take home finger prick kit.
In my case, I've had great fasting glucose (at 80) but have observed high A1C levels when tested.
If I were in this position I'd try testing my glucose a few times a day to see if it ever plummeted too low.
Sounds like my experience on liraglutide, only in my case it was more subtle. I had more trouble focusing, increased anhedonia, my ADHD got way worse, and I was sick to my stomach all the time.
I'm kind of bummed by your comment, because I had previously heard that semaglutide had a much better side effect profile than liraglutide.
FWIW, my (former) boss reported the same issues you do with liraglutide (only he was weaker or more sensitive or something, because with the exception of the ADHD, he made the symptoms sound way worse than that)...
...but when he tried semaglutide, he said it was like night & day; loved it. He got switched to tirzepatide, I think due to supply issues more than anything to do with the substance itself, and said it was even better (somehow)!
He's been going around telling everyone to get on one or the other for a good nine months+ at this point, heh. But if he couldn't handle liraglutide but got almost-no-to-no side effects with these newer suckers, might still be worth a try for you too.
I've heard that too, and that tirzepatide is milder still. I'll see how that goes for me.
My friend had a wonderful experience on Wegovy (almost sounded like she had an antidepressant effect on it too), but once her insurance company forced her doctor to switch to mounjaro, she started experiencing migraines, irritation, anxiety. She is waiting to get back on semaglutide bow, but perhaps it’s just person-dependent?
The other bit she mentioned is her Stanford doctor said they are seeing more side effects in women who get injections in their belly. It’s not playing well with our hormones, supposedly. Upper arm or leg is a better area to choose for injections.
Did the brain fog come after about a week of feeling sick? Because starving will definitely give you brain fog, exhaustion, and mood symptoms.
Shockingly, we do have to thank the FDA for this.
When it comes to diabetes, they got all kinds of egg on face back in the TZD era, due to their myopic focus on drugs only improving surrogate markers (in the case of diabetes, it was A1c) rather than hard outcomes (mortality; or in the cardiology case, CV death and non-fatal MI).
After that embarrassing lesson, they mandated new diabetes drugs to show cardiovascular safety via clinical outcome studies, prior to receiving regulatory approval.
So earlier, agents in the SGLT-2 inhibitor class; and now agents in the GLP-1 agonist class, have had to provide trial evidence of CV safety. It is in the course of that work that signals were seen that agents in these 2 classes were not only “safe” (ie. no increase in CV outcomes) but were in fact protective (ie. fewer CV events than placebo). And it is subsequent studies powered to show CV endpoint reductions (in CAD, HFrEF, and HFpEF for SGLT; and more recently in CAD…even without diabetes….and HFpEF for Ozempic) that have propelled both these classes into the realm of cardiac meds (even in those without diabetes, in certain indications).
But as you’ve summarized here, we still don’t know how they truly work. It remains to be seen if and when we can elucidate the mechanisms responsible to account for the observed CV outcome benefits, among others.
Nonetheless, the FDA deserves some credit, even if they stumbled into it by happenstance.
Wow, a nice story of the benefits of improved regulation.
Request: Please write “cardiovascular” if that’s what you mean. Acronyms are a negative externality - similar to pollution - of a writer saving a few keystrokes, offloading the work to everyone who needs to parse your intention.
I'm not sure I understand what we have the FDA to thank for. Is your claim that, if the FDA hadn't discovered protection against cardiac events, we would never have learned of that protection?
When you’re trying to praise the FDA you have to take what you can get
There's also baclofen, a muscle relaxant that might help against addiction.
https://en.wikipedia.org/wiki/Olivier_Ameisen
He wrote a book about baclofen ending his craving for alcohol-- he considered the craving to be a problem, not just the drinking. He also found, to his surprise, that he wasn't shopping compulsively any more.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328471/
I tried it, in smaller doses first than he recommended, the result was "OK not taking it today, I actually want to drink, not just crave to" and then it was the result every day. It did not fix the underlying issues, boredom, anhedonia, finding it hard to kill time.
I think it is safe to say that addictions tend to come from self-medication of issues and thus I believe it is mistake to look at the addiction only and not the cause the substance use is trying to address.
This is so obvious to me I wonder why docs, even Scott, see addiction as a thing on its own. Obviously someone starts drinking or snorting because they feel shitty, you get them to stop, they feel shitty again, so they will start again. It is really not just cravings but underlying issues of why was it even started back then when there were not yet cravings.
I don't think that's universally true - my husband had a serious drinking problem that he was only able to defeat with the help of naltrexone. He started drinking in college because that's just a common thing to do socially, and soon found that his brain chemistry *really loved alcohol* and he suffered terrible cravings whenever he tried to quit. His life post-naltrexone wasn't any different than his life pre-naltrexone, but it's been several years and he hasn't been tempted to start drinking again.
I think you're both right, and that people start addictions for a lot of reasons, often as self-medication, but many people are stuck with the addiction even after the original problem has resolved. I certainly feel like that's the case in my own life with some bad habits I find extremely difficult to shake.
Great post - GLP1s continue to be one of the most exciting areas of pharmacokinetics!
Re: second footnote on GLP-1s and libido: I did an analysis of a few hundred reddit comments from various ozempic/semaglutide communities and found that a reduction in libido was a commonly reported side-effect, but interestingly enough a large increase in libido was also reported almost as frequently. Increases were reported slightly more often by women than men, but I didn't have the statistical power one would desire here.
I think many people probably have suboptimal dosing schedules; I use custom software which roughly tracks my own blood level of it, but for mass market pharmaceuticals the one-size-fits all of "X or 2X or 4X once a week" provides for much less fine-grained control of optimizing for fewer negative side-effects.
Main complaint of the study from the article is i'm not sure if four weeks is enough: https://www.endocrine-abstracts.org/ea/0090/ea0090p69
Can you say specifically how you’re using ozempic and what you’re testing and how your software works?
better eating/drinking habits and such. just intakes variables and does basic stats
I think it's worth noting that semaglutide and tirzepatide are much stronger than previous gen GLP-1s and may have effects that didn't show up in earlier studies of exenatide and dulaglutide.
Yes they're stronger but they don't cross the BBB (see: https://www.tandfonline.com/doi/full/10.1080/21688370.2023.2292461 ). Exenatide and dulaglutide are the best in terms of brain uptake. Liraglutide also has limited BBB crossing and a recent small trial did not meet its primary endpoint ( https://www.theguardian.com/society/article/2024/jul/30/liraglutide-alzheimers-cognitive-decline ). On the other hand, trials of exenatide and lixisenatide for Parkinson's were successful ( https://www.nejm.org/doi/full/10.1056/NEJMoa2312323 ). There's an ongoing phase 2 trial of semaglutide for PD in Japan ( https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2051230090 ) and three phase 3 trials in AD (sponsored by Novo Nordisk). These trials will tell us whether brain uptake matters or not. Semaglutide users report psychological improvements (e.g. in terms of addiction) so it's well possible that semaglutide is neuroprotective via non brain mechanism such as cardiovascular protection or the gut-brain axis.
I think that restoration of the vasculature of the BBB has also been shown with GLP-1s and perhaps that is reducing inflammation indirectly.
Also, this study might suggest that overall blood sugar management helps the brain:
https://www.medicalnewstoday.com/articles/stable-a1c-levels-may-be-linked-lower-dementia-risk-type-2-diabetes
We'll know more when the sema phase 3 has results!
Blood sugar management lowers the risk of dementia but when you compare people who take GLP-1RAs or SGLT2 inhibitors they have half the rate of PD & AD compared to other diabetes drugs (cf. https://diabetesjournals.org/diabetes/article/72/Supplement_1/484-P/150550 & https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.15331 ). So GLP-1RAs or SGLT2is most likely have off-target effects beyond blood sugar control. Improvement of the BBB could be one thing as the BBB is more porous in neurodegenerative diseases (NDDs). Which by the way might be good for semaglutide: it's possible that semaglutide does not cross the BBB in healthy individuals but can do it in NDD patients. We'll only get the results of the semaglutide trials for AD in 2026/2027 unfortunately. The most informative will be the results of the phase 3 exenatide trial in PD (NCT04232969) that will be published in 6 months. If negative: we need to understand why it failed in phase 3 but succeeded in phase 2 (together with lixisenatide). If positive: it will make A LOT of noise and you can expect that many PD patients in existing trials will drop out and start taking exenatide off-label...
There seems to be evidence that they are inducing effects mediated by GLP-1 in the brain. Likely through the mechanism natural GLP-1 does (activating peripheral receptors that then begin telling the brain to release its own). Regular GLP-1 crosses the barrier, but it has a lot more trouble crossing the “blood” part than newer drugs do.
And not for nothing, its effects on weight loss are stronger and seemingly centrally mediated in spite of lacking BBB penetration.
How amd how frequently do you sample your blood?
i don't need to test semaglutide levels but i test other levels once every few months
So you manage to reduce the sideffects by tracking how semaglutide tracks other biomarkers? Which biomarkers are they?
And could you share more about your setup?
I don't necessarily calibrate with other biomarkers as I'm not sure there's much to read into aside from hba1c (if you feel low energy or slightly nauseous, it's best to just note this down instead of find a blood test to prove it)
but it's useful for dosage calibration, e.g. deciding you want to take it two days later than usual, or reduce the dosage by just 15%, etc
Ah, I see. So for dosage calibration you just use hba1c levels?
Amazing that you did that analysis! I can imagine two opposing effects: 1/ increased libido due to increased self-confidence after weight loss and better mental health while 2/ decreased libido due to sex addiction or just sex as a coping mechanism like binge eating, drinking, smoking, etc. It would be interesting to know the baseline. I would not be surprised if semaglutide "regresses to the mean", for instance: the sex addict ends up having a lower libido (but still "normal" range) while the obese person "single for life" now has a higher libido (still in the "normal" range again).
What about erectile dysfunction? See the recent: https://academic.oup.com/jsm/article/21/Supplement_1/qdae001.148/7600659
The RR is massive. I wonder if something can happen like "Weight loss => More attractive + increased self confidence => Start dating again => Realize that they have ED => Get a prescription". Ideally we'd like to adjust by the number of sexual partners/intercourse. Alternatively, do the same study in non-obese/overweight diabetics (who don't lose that much weight: https://x.com/EricTopol/status/1776732406340325869 ) comparing GLP1-RAs users to metformin, SGLT2i, DPP4 users.
Good point - the baselines might have a strong effect here. I also found it interesting noting a very small percentage of users who basically got full anhedonia or depression from some GLP-1s, and it seems like maybe an even smaller amount got something like a minor version of the opposite. Fascinating compounds
Fantastic post, thank you. Saved for reference.
Given natural variability in GLP-1 production, have any in-vivo studies been done in humans comparing GLP-1 production in response to food and likelihood of addictive behaviours and/or obesity?
I have significantly higher-than-average 'willpower' for stopping/reducing bad things, like overeating or addictive behaviours or drugs. I can't help but wonder if I just make a bit more GLP-1 than the average Joe or Jane.
I have, quite literally, the least self-control of anyone I've ever met, bar *maybe* a few low-IQ ex-&-future felons.
No one who knows me has ever been able to understand it, and neither have I; parents, (ex-)wife, professors, psychiatrists — hell, even my last two GPs, for some reason — have all tried to keep in touch... despite my not having enough self-discipline to sit down and write them anything back (or, in wife's case, despite the fact I cheated on her out of the blue & without being the least bit discontent 🤷♂️); and at least a couple times a year, I get several emails asking if I've finally [done the things].
I always have to say no, BUT: I'm going to tomorrow!... right after I get just one more day of slavishly adhering to all my base desires...
[*pops some pills, hits the vape, makes booty call, eats red meat (even though I think vegetarianism is the correct way to go) & entire pint of ice cream; oh look the day's over darn it–*]
It has effectively ruined my life — at least, in comparison to what it could've been — and the only reason I'm not fat is that I just (thank God) don't really care that much about food.
(Diet's shit; just go long periods of time with no food also.)
I wonder if this could be (part of) the explanation.
....wonder if I should try tirzepatide...
I assume you tried stuff like Vyvanse and maybe meditation (though that might be difficult for you to do at high doses.
I appreciate the advice! I probably didn't write the above with the correct tone, wanting it to be amusing or at least not "weak"-sounding, but in truth I'm at the end of my rope and will probably end up dead within a year or two if I can't manage to make myself DO the things I want to do (instead of the things I compulsively do, if you know what I mean).
I haven't been able to stick with meditation, very much — though I managed to for a brief while, in the past, and it did seem to help a bit; keep meaning to get back into it...
I have indeed tried amphetamine & co., and in fact, I'm trying them again right now: just took my dose, and we'll see if I manage anything. One thing I've noticed is that if I let myself do something pleasurable, I become "stuck" worse than ever when on amphetamine — need someone to watch me and smack me every time I focus on the wrong thing, heh.
Hang in there. And yeah, try this stuff, it sounds like it might have a chance of helping.
I didn't use to be like that, but then shit happened, and all the advanced coping skills utterly failed to work, and now I've got a lot of bad habits...
I appreciate that, amigo. 👊 Same to you — hey, if we developed bad habits, that's actually just proof we're good at developing habits, I say! Good ones will be a cinch!
(I know what you mean, too... it's like every attempt at — and then failure at — improving has actually just made me much, much worse. A sort of hopelessness has set in. If you feel like telling your story, I'm interested to hear it; if it's the sort that's actually unhelpful to you to vent/re-tell, of course, then never mind about that!)
You could try beeminder, boss as a service, or stickk. Also, if you can manage it, a large dose of meditation (concentration meditation like breath watching or Vipassana or noting, not the more mental types like looking for the self) (an hour a day, in one sitting, for 2-3 months). Medication in conjunction with meditation might make it more bearable. For me the effects last around a year. Or get a dominatrix that beat you if you eat a pint of ice cream?
Thanks for the tips & things to check out!
I remember when Beeminder first came out (or first entered my awareness, maybe) some years ago, but IIRC I concluded that probably I'd just fail to meet the goals I set a bunch & then stop using it, rather than actually modify my behavior to avoid the fines (if I'm thinking of the right app here—the one that fines you for not meeting deadlines right)...
...but I've never heard of the other two. Since I'm extremely diligent at work, somehow — don't even ask me why it becomes easy in that context, heh — BaaS sounds very promising...
I appreciate it, mi amigo! 🫡
.
.
(...and, uh, hey, if anyone knows of some dominatrices in Texas, I... my friend, that is, would be interested for sure—)
And after you have some general coping strategies or confidence, you could start on strategies for specific circumstances. Atomic Habits is also a useful book, probably the only useful book I've encountered.
Red meat has gotten a bad rap. I'd try a low to zero carb diet. Beef, butter, bacon, eggs, fish, fowl. Fruits & vegetables are overrated; but if you do them make sure they are low glycemic.
Here is the hack: You can't cheat. If you have urges, just eat more of the above until you are satiated.
But yeah, I understand a life without pizza and french fries, to say nothing about buns for your burgers and sandwiches, just isn't worth living to some/many folks.
Hmm, interesting to hear this — my buddy is trying this sort of diet, and claims it has made him feel better than ever; he's certainly fitter than ever, so I guess it's working...
...but I feel bad about killing all the innocent animals...
...just not enough, apparently, to stop eating meat anyway, heh.
Low carb/keto/carnivore diets work. Even its skeptics and detractors are starting to admit they do in the short term (weight loss and reversal of chronic diseases). Though, they then focus on the unknown long term effects, about which I'm still agnostic.
I too sympathize with the ethics of eating animals. There are three separate issues involved. Carbon footprint is another. And nutrition science is the third. I focus mainly on the third.
The Alzheimer's liraglutide trial was not a success: https://www.alzforum.org/news/conference-coverage/liraglutide-trial-was-negative-four-years-ago-still-negative-today
Such a long article to say "Because ozempic makes people not fat and all those diseases are the result of being fat".
Ok maybe throw in there some "insulin resistance" and "too much carbs" but jeesus dude, don't you get carpal tunnel syndrome?
That's not what this article says, and it's not true. Obesity isn't a risk factor for addiction, and is only a very weak risk factor for things like Parkinson's. Most of the people in these studies are probably diabetics taking it for diabetes and may not have even been obese to begin with.
Is obesity not an outcome of addiction in a way?
Not if you're on heroin.
Or cigarettes, so they say. But I've hated smoking all my life, never tried it, never wanted to, so I can't speak as to weight loss effects.
I meant addiction to food
That sounds like the opposite mechanism. This reduces addiction, and obesity is an outcome of a particular addiction, so this reduces obesity. Rather than the hypothesis upthread, which says that the obesity effect was mediating the addiction effect.
Is that true though ? IIRC something like 70% of Americans are obese, why would these people be any different ?
40%, actually. And many of them would be considered just chubby.
Most probably a troll job by the tone of the writing, but anyway: The connection between GLP-1 agonists and Parkinson's is "modulation of dopamine" if anything - nothing to do with obesity, as Scott already pipped me to say obesity was never found to be a risk factor, and most Parkinson's patient I've met tend to decline in weight on their own as the disease progresses. Also, while obesity in younger years increases the risk of dementia, if a 5-year trial alleviates symptoms of patients already experiencing Alzheimer's, it can't possibly be because the drug affected them aged 35-65, when the drug and the trial weren't in existence...
There are metagenomic studies on Parkinson's that have found an association with an altered gut microbiome. Of course, it could well be that Parkinson affects gastrointestinal mobility and that changes the biome.
But if it goes the other way, there could be a causal chain something like constant feeding -> dysbiosis -> Parkinson. Ozempic would act on the first, and the causative pathogen would be s.t. it would not thrive with less food or longer breaks between meals.
Always a possibility - but constant feeding that doesn't cause a caloric surplus and so isn't represented as obesity? In that case the Vagal hypothesis makes more sense, Occam's Razor-wise. Gut microbiome is currently in the "over-saturated as an explanation for everything, because we don't understand it at all" phase. Not saying it's not possible, mind you.
What an incredibly annoying comment. If you think a post is too long, feel free to stop reading it!
It's effects certainly are not just from fasting/obesity. I took it at a healthy weight and it entirely cured some very nasty immune system issues I've dealt with my whole life (Ehlers Danlos + Familial Mediterranean Fever).
That is very much not the conclusion of the article lol. The interesting thing about the article is that this is unexpectedly *not* the case. Did you *read* the article?
So I've been thinking about taking Ozempic, but now I'm scared that I do I'll lose interest and joy in all my hobbies and not accomplish anything anymore. Or that I'll no longer care if whatever I'm entertaining myself with is good or bad.
Is this a rational fear or is it my anxiety projecting nightmare scenarios from a few studies?
As far as I know, zero people have ever reported that on this med. As I said above, it's mysterious that the reward circuitry seems to separate out "addictive" reward from "wholesome" reward, but it sure does seem to do this.
Could it have something to do with the difference in "wanting" vs "liking" circuits in the brain? I vaguely remember reading something along the lines that both are parts of the dopaminergic system, but are nonetheless separate. Anecdotally, advanced meditators often report that decreasing "wanting" not only does not inhibit "liking" but actually boosts it.
See my comments above. I experienced more or less precisely what Ghatanathoah is afraid of - "lost interest and joy in all my hobbies" is the least of it, "not accomplishing anything anymore" (due to horrible brain fog/low energy) was what made me discontinue. It seems to be somewhat rare, but it is a possibility.
Scott will continue to claim "zero people have ever reported that on this med," despite your comment.
No, I don't know why. But it's a pattern.
Maybe it just prevents some kind of runaway loop in reward circuitry. Sweetness is a good way to think about it. Sweet things are enjoyable, but they don’t induce compulsive seeking behavior for sweetness. A behavior that is well-established and I argue analogous to addiction just at lower intensity.
As I said, I wasn't on it long enough or at high enough doses, so I didn't get the "wow, suddenly I don't want to eat the tasty food I usually crave!" effects.
So I imagine you won't get the effects you fear. But if you only want 'quick easy way to lose a few excess pounds', I'd avoid Ozempic. Why take it unless you really need it? On the other hand, if you're extremely overweight/diabetic and nothing else has worked, take it.
N=1, obviously, but this didn't happen to me at all. I still enjoy all kinds of things. Actually I still enjoy food, I just feel full faster so I stop eating.
Same here.
I find that food is equally rewarding at the beginning but less so very quickly. Same with alcohol. The third drink is usually just not pleasant.
This could be me not realizing “full” is a metaphor and people don’t always mean they feel physically as if they have no space.
If you die from obesity, you'll also prematurely lose interest and joy from all your hobbies and not accomplish anything anymore.
Like anything else, it's a risk-benefit calculation. Good for some and better avoided for others.
Maybe you could pre-commit to doing it for a month (or whatever a couple of administrations is), and then stopping for a month (ditto), and taking notes along the way? That way you'd have your subjective memory of the time on the drug, and your records from the time, and you could compare the two to see if they match up.
(I suppose that wouldn't tell you whether the drug turned you into a homo economicus p-zombie, but I don't know that anything would work for that...)
I might have to do that involuntarily. I just found out my insurance will stop covering all weight loss drugs starting January.
Oh, ugh, I'm sorry.
"The results were unequivocal: Ozempic and its relatives work in the brain. Although they have some effects in the body, these are short-lived and not really relevant to their mechanism of action for weight loss."
Interesting, I thought the effect was that semaglutide slowed down intestinal contractions so that food passed through the digestive system more slowly, making you feel fuller for longer, and hence reducing appetite. This is why weight loss, plus the side effects of constipation and stomach pain:
"Ozempic® may cause serious side effects, including:
- inflammation of your pancreas (pancreatitis). Stop using Ozempic® and call your health care provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.
- changes in vision. Tell your health care provider if you have changes in vision during treatment with Ozempic®.
- low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Ozempic® with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include: dizziness or lightheadedness, blurred vision, anxiety, irritability or mood changes, sweating, slurred speech, hunger, confusion or drowsiness, shakiness, weakness, headache, fast heartbeat, and feeling jittery.
- kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration), which may cause kidney problems to get worse. It is important for you to drink fluids to help reduce your chance of dehydration.
- serious allergic reactions. Stop using Ozempic® and get medical help right away if you have any symptoms of a serious allergic reaction, including swelling of your face, lips, tongue, or throat; problems breathing or swallowing; severe rash or itching; fainting or feeling dizzy; or very rapid heartbeat.
- gallbladder problems. Gallbladder problems have happened in some people who take Ozempic®. Tell your health care provider right away if you get symptoms which may include: pain in your upper stomach (abdomen), fever, yellowing of the skin or eyes (jaundice), or clay-colored stools.
The most common side effects of Ozempic® may include nausea, vomiting, diarrhea, stomach (abdominal) pain, and constipation."
Now you're telling me it's all in the brain? Fascinating!
I wasn't on it long enough or at high enough doses to get the good benefits; it didn't seem to affect my appetite levels at all. When I couldn't get Ozempic, my doctor put me on a different one, but the side effects were so bad I had to come off it. Now I find out it was all in my mind, eh?
I'm rather dubious about the reported fantastic benefits. I think it'll probably shake out as usual: for a small number of people, it's the most amazing thing ever. For the majority of people, it works okay. For another small number of people, it has little or no effect.
Sorry, I tried to explain this in the post.
GLP-1 is a master regulator of food-related activity. It has actions in both the body (preparing for digestion) and the brain (changing the feeling of hunger). But its weight loss effects come mostly (entirely?) from the brain. Although taking artificial GLP-1 drugs does change some of the body actions, these either produce tolerance quickly, or don't cause weight loss so much as just screw with the relevant systems a bit.
Yeah, that's what I'm very eager to learn more about. If there was some Magic Bullet drug that turned off my appetite, I'd be ecstatic. There is something messed-up with signalling going on in my system, where I'm still getting "hungry, must eat" messages even when my stomach is full.
But that sounds too suspiciously like a willpower substitute drug, where (as we've seen on here in previous discussions of weight loss) us fatties get told "just power through being hungry! after 24-48 hours fasting you stop feeling hungry! it's easy, just get your willpower going and stop shoving food into your face!"
I wonder. I really do. I think right now you're correct and there is this huge, enthusiastic burst of confidence that Ozempic et al. are the new Magic Wonder Drugs that will cure everything. And I think (as with Prozac on down) eventually it'll settle down into "okay, for some it works, for some it doesn't", and we'll get a more balanced view. But that's still a few years away, and right now it's the Hot New Research Fad to see if you can use GLP-1 to cure crabgrass in the lawn and rust blotches on metal fittings.
"But that sounds too suspiciously like a willpower substitute drug, where (as we've seen on here in previous discussions of weight loss) us fatties get told 'just power through being hungry! after 24-48 hours fasting you stop feeling hungry! it's easy, just get your willpower going and stop shoving food into your face!'"
'Stop feeling hungry' is not accurate, at least not to my experience. I'd been obese for half my life when I finally decided to cut back on how many calories I ate per day, and it took a year to lose sixty pounds but something like three years to stop feeling like I was constantly starving. My realization wasn't so much that I'd stop feeling hungry if I ate less - it was that I *already* felt hungry, all the time, regardless of how much I did or didn't eat, and that not eating wouldn't actually make me any *hungrier*.
You and I know that, but the non-fat don't; they regard being hungry as "need food, body says hungry, eat food, stop being hungry" and hence "eat more food than needed, get fat - stop eating so much!" is the easy solution. "Hungry? Hunger is easy, just turn it off by ignoring it".
Like the joke (lifted from notes on the Divine Comedy) about the Cardinal who asked his servant "what do the people say about me?" and he replied "That you are always drinking, your eminence", to which the cardinal said "But that is because I am always thirsty".
Reminds me of another Catholic joke; two priests are debating whether or not it's acceptable to smoke and pray at the same time, and decide to write to the Pope to settle the matter once and for all...only to get back opposite answers. The first priest had asked if it was acceptable to smoke while praying, and the Pope had responded "No, smoking is a distraction, your mind should be focused on your prayers." But the second priest had asked if it was acceptable to pray while smoking, and the Pope had responded "Yes - it is always acceptable to pray."
I've seen that one in a version where one of the priests is a Jesuit, and he's the one who phrased the question as "Can I pray while I smoke?" in order to get a favourable answer. The idea being that the Jesuits are the ones who can logically weasel their way out of anything via loopholes 😁
The Greek poet Hipponax apparently left us part of a poem in which he offers a prayer to Hermes before stealing something. (The citation I'm looking at is to "Fr 32", which I assume is the 32nd entry in his "Fragments".)
The Hacker's Diet has a section on what the author calls "the eating switch" - he has some graphs of possible switch behavior and argues that in his case, hunger was giving him faulty signals about when to start and stop eating. His solution was to track calories ruthlessly and to drink coffee until nauseated whenever his count told him it was not time to eat more calories.
Reminds me of the joke that goes:
I went to the doctor and asked for help losing weight. He said "Don't eat anything fatty".
"Oh, so just stick to salads and fruits and things like that?" I said.
"No, fatty, don't eat anything."
You say that as a joke, but that's close to the advice I got years back from a cardiologist.
Like a fool, my first mistake was I decided I'd answer questions honestly. So, to the usual "why aren't you on a diet?" accusation, I said I was, but I had trouble with willpower.
And then I got "Well, hunger strikers have no problem with willpower. Just don't eat".
Yeah, that was really helpful advice about dieting and what to do, doc!
> Like the joke (lifted from notes on the Divine Comedy) about the Cardinal who asked his servant "what do the people say about me?" and he replied "That you are always drinking, your eminence"
They must have had a strong relationship.
There's a great scene in the 1973 film The Three Musketeers in which Richelieu is listening to a report from his spymaster:
[𝘴𝘱𝘺𝘮𝘢𝘴𝘵𝘦𝘳]
The following conversation took place between the Queen and her dressmaker:
[...]
Constance: That nasty filthy rotten evil man, evil filthy repulsive evil man, calls himself a man of the church?
[𝘙𝘪𝘤𝘩𝘦𝘭𝘪𝘦𝘶, 𝘴𝘦𝘢𝘵𝘦𝘥, 𝘴𝘭𝘢𝘮𝘴 𝘩𝘪𝘴 𝘩𝘢𝘯𝘥 𝘥𝘰𝘸𝘯 𝘰𝘯 𝘩𝘪𝘴 𝘬𝘯𝘦𝘦.]
[𝘛𝘩𝘦 𝘴𝘱𝘺𝘮𝘢𝘴𝘵𝘦𝘳 𝘤𝘭𝘦𝘢𝘳𝘴 𝘩𝘪𝘴 𝘵𝘩𝘳𝘰𝘢𝘵.]
AHEM. Accor—according to this.
That's actually why I was able to do alternate-day fasting for awhile -- I realized I was starving all the time, so why not be starving and not eat? I am on tirzepatide now so it's moot, but I totally get your logic.
Something I've been thinking about for myself-- there are a bunch of things that drive eating for me, and I think one of them is "stomach feels bad, soothe the stomach".
Now, if I'm hungry, eating will make my stomach feel better, but I just had a few days of being overfed, and I still wanted to eat, and I think it was a confusion about whether food would make me feel better.
I have no idea whether anyone else has this problem at all, and fortunately, it went away for me.
I had it on IBS. It felt like a hunger pain but I later realized it was not. After I started taking nortriptyline for it and it went away, I stopped overeating to “soothe the pain”, and when it is occasionally back I no longer try to treat it with food.
I am curious if anorexia exists in the brain or the stomach.
I think they have ID’ed some genes in connection with it.
The other day I heard Karen Carpenter’s version of “Still Crazy After All These Years” in which as you might expect she sounded unlikely to have ever been crazy - and then I thought: but she was!
But I relayed this to my companion who said he thought the latest on anorexia was, it was not about “thinking you’re not thin enough” anymore.
Anorexia is a contagious social disease related to dismorphia, so probably in the brain
I know there *is* that - but I don’t think that’s necessarily what Karen Carpenter had.
Damned if I know. I think it's at least partially socially driven, but (last I heard) it's also correlated with mental problems like bipolar and OCD.
I wouldn't be surprised if there's some sort of physical vulnerability which is amplified by social weirdness about weight and food.
Of Herbs and Altars is a youtube channel by a woman who says part of what was driving her anorexia was trying to prove she was sick enough to get help. Sorry, I don't remember which video is the one where she talks about that.
https://www.youtube.com/user/ofherbsandaltars
You might be interested in the newest discussion of eating disorders, which I'm hoping will make it into the DSM-6.
They're trying to add a trauma-based eating disorder, ARFID (Avoidant Restrictive Food Intake Disorder), which is a pattern of disordered eating either caused by a) a physical trauma, like being really sick for a while or choking, or b) a mental trauma, like a parental divorce.
Anorexics famously tend to say something like "food was something I could control" about half the time, and that seems to map pretty well onto the "mental trauma" category of ARFID. (For another famous singer who has some horribly interesting writing on the subject, you may want to look at the story of "Melon Cake" by Demi Lovato--theirs was externally enforced eating habits not under their control.)
What makes ARFID otherwise useful as a diagnosis is that it acknowledges that disordered eating doesn't always manifest in not eating--it oftentimes looks like someone is incredibly picky about their food.
(I am interested in this as I learned about this after I had a physical and mental trauma episode (stress induced vomiting) that left me unable to eat for a month and I still sometimes have a weird relationship with food about two years later.)
It seems like no one here has ever tried or studied the carnivore diet. Im HIGHLY skeptical about Ozempic - no doubt it works - but at what cost to the individual's health through adverse side effects (and:the cost to society of funding this expensive drug?) . My son has bipolar and I have explored various diets with him. The carnivore diet beats everything in our view. Amazingly by eating just meat eggs fish cheese and butter, you not only cease to have cravings (like Ozempic) but you also lose weight rapidly (like ozempic) and the diet is so anti-inflammatory that huge wide ranging health benefits are seen - reduced anxiety, much greater mental clarity, increased discipline and drive, better sleep, indeed many patients report cures or complete remission of MS, bipolar, and Parkinsons. It hasnt cured my son's bipolar, but it has nonetheless been a game changer for him in reducing both anxiety and the weight gain caused by his meds. For me personally, I have found the carnivore diet to be extraordinary - I have never lost weight so easily before and coupled it with mental clarity and drive. So I would advise everyone to explore the carnivore diet rather than the Faustian bargain that is Ozempic.
It's important to remember that one must report all side effects that occur during a drug trial, and the percentage of people who suffered from said side effects. There is always also a built-in nocebo bias whereby a trial patient reports any and all symptoms. That's why you'll hardly find a drug e.g. that doesn't warm of possible head-aches etc. It will take the life time of the drug (society using it for an extended amount of time) to drill down as to what are true side effects of the drug and what are unrelated or partially related (i.e. interactions between said drug and the drugs of the patient's own drug regimen, the patient's disease burden, genetics, etc.).
if a stuff works a 1000 places - it's not specific
Of all the control system responses, at least this one is where we could in principle hope for lack of negatives (at least in the majority case as there will always be minority side-effects): the big and (historically) relevant negative is losing ability to handle long-term food scarcity, but presumably semaglutide would become unavailable before food…
Because all of these diseases are the off-target effects of hyperinsulinism. Not hyperglycaemia, not some fancy neuroscience woo, just that. Our diets cause that (mainly the sugar in it, but the seed oils and matodextrin and other crap contribute), so we have this gargantuan explosion of chronic illness. Academic medicine does not get it, got a few things very wrong (saturated fat, meat, etc), and so people will keep dying as governments increasingly force the shitty academic-decreed diet on everyone.
I think that's correct. My concern with GLP-1 agonists is that some people who take these drugs will think, "I'm not that hungry this morning; I think I'll just have ONE frosted Pop-Tart."
How is that a valid concern?
If a person eats one frosted Pop-Tart instead of two, that's an improvement over the status quo.
If anything less than magically making people switch to a fully healthy diet is a "concern", then we can safely replace you with a rock that looks at every new drug and replies with "concern"
The article mentions that ozempic makes people (or was it rats?) prefer normal food to hyper palatable food. So that doesn’t seem to be a concern.
That was rats. It's much easier to do a controlled study on rats.
If somebody locked me up in a confined living environment, made me run through mazes every day, and only allowed me controlled doses of specific measures of calories chow, I'd lose weight, too.
Unhappily, that is what it *would* take for me to shift all I need to shift of this blubber.
I've seen people say that on Ozempic, they had little desire for carbs and fat.
This is unthinkable, that someone can open a packet and have just one Pop-Tart. Hunger has nothing to do with it.
I can very easily have *no* Pop-Tarts because they don't appeal to me. Same with Oreos. Crusty bread and butter, though? Oooooh - put down the bread knife and back away from the table, fatty!
Having NO Pop-Tarts is very easy. Billions of people are doing that every day, including me.
But Pop-Tarts are kind of like quarks, in that you can't have just one, you have to have two, or none. It's not even a matter of, say, having a single potato chip.
I did try them years back when they came onto the Irish market for the first time and was not impressed. Even now when I see the newest flavour on the supermarket shelf, I'm not one bit tempted to try them again. Same with Oreos, I had a couple when they came to Ireland (when Kraft - the owners at the time - started marketing them in the UK and Ireland) and again thought "I can't see what is so great about them".
Jaffa cakes, though - no, I can't have just one. It's the full packet, which is why I have to be ruthless about not buying them.
What's so great about Oreo cookies is dipping them in milk, as every American kid knows 😊
Double-stuf Oreos are the finest American product, but you have to pull them apart, some disassembly required.
Also: vegan.
There's actually a way if you place a second pop-tart ingesting being close to the toaster that you may end up with only a single pop-tart that you can ingest.
Be careful with it, though. It can lead to nuclear explosions. (If you have a nuclear family)
But, more seriously, what I always used to do is just take one out of the package, then put the other back and vow that I'd have it for lunch or whatever. Then I wouldn't get to it until the next day. It is possible. The physics books are mistaken!
True, I hadn't realized you could add another person to the equation, like with enough effort you can extract a single quark, but paired with another from the energy used to extract it. Two people can indeed fully consume a single packet, with one individual Pop-Tart per person. The risk, however, is that it won't end up being satisfactory for one of the people involved, leading to consumption of an additional packet.
I'm not sure I trust your research that you can put the second one away. An experiment must be repeatable, and so far, I'm unable to replicate your results.
I think it is theoretically possible, but requires the as-yet-unobserved single slot toaster. Maybe it will show up in higher energy kitchenware collider experiments... :-)
I know of no credible theoretical framework predicting single-slot toasters. I thought we were sticking to non-crackpot theories. One may as well postulate a nutritious Pop-Tart.
One of my favorite party tricks is to ostentatiously say "I just want one" and eat just a single potato chip.
Pop tarts are objectively yucky but I’ve noticed they give you a surprising staying power eaten in the AM on a camping trip.
They have a lot of energy content.
Peanut M&Ms would probably be even better.
Yes, an excellent snack and much better than regular M&Ms though nothing beats Hot Tamales!
I'm very weird. I've tried a poptart. I didn't like it. I mostly eat what I consider to be decent quality food-- high fat cheese and yogurt, meat, eggs, and vegetables from people who at least promise they're good. I do eat carbs, including some sugar, and I've discovered a taste for ramen.
I also never liked oreos because they taste burnt.
can't remember where I read this, but I think a large number of GLP drug users just lose some preference for sugary and fatty, generally unhealthy food. I remember reading an anecdote from someone who said all their life, they loved Doritos or Oreos or something similar, and couldn't imagine not eating them all the time, and now on a GLP-1 drug, they simply just do not think about them any more. And people simply find themselves eating less bad foods.
Just like the rats choosing to eat the normal chow rather than the more-palatable food offered.
Maybe that person would grab the banana or granola bar instead.
Speaking as a fat tub of lard, I think I tried Pop-Tarts once and heartily disliked them. My problem is "stick to just *two* slices of buttered toast" and if Ozempic or some other drug could help with that, it'd be marvellous. Carb cravings are my downfall.
Not all fat people are scoffing down Pop-Tarts, that's the problem with the general cultural view of obesity. Too much even of 'good' foods are bad for you also.
Oh, I would one hundred percent stuff myself on buttered toast too! French bread was my addiction as a kid.
It was just a point about Pop-Tarts being kind of an overly-processed food without a lot of nutritional value.
When I was 310 lbs and started calorie restriction, I was not exercising at all, and I was able to have a diet of something like "ham egg and cheese croissant at arby's for breakfast, sandwich and chips for lunch, chicken wings and roasted potatoes for dinner, ounce of cheese for a snack" and be under 1800 kcal/day and lose a ton of weight. That isn't doing it "correctly", but it lost me the first 50-60 lbs that got me back to a weight where I was comfortable bicycling again, and then as I got closer to 200 lbs I started tracking macronutrient ratios and weight lifting and all this stuff that is closer to the "right way". So never underestimate the power of ANY kind of restraint on the part of an obese person, once you start saying "no" to a few things (for whatever reason) good things can happen.
You think huperinsulinism causes alcoholism, rather than both being side effects of craving?
Yeah, I think hyperinsulinism causes craving.
>Medicine is bad at answering “why” questions.
Can't we just reverse the causality? If exercise often helps with depression, then one of the causes of depression is lack of exercise.
It is possible that our screwed up dietary habits make us vulnerable to addictions of many kinds.
I don't think this always works - the cause of bacterial infections is not the lack of antibiotics! But sometimes it is worth thinking this way.
"Can't we just reverse the causality? If exercise often helps with depression, then one of the causes of depression is lack of exercise. "
No, because if Prozac helps with depression, we don't want to argue that one of the causes of depression is lack of Prozac.
(or if medications are cheating, substitute "getting a puppy")
We clearly need a U.S. RDA for "getting puppies."
But if something is a normal part of the human condition, and there are problems when it's not there that go away when it is, then it's reasonable to say that the lack of that thing is causing the problem. We have no trouble describing thirst/dehydration as a medical problem that is caused by lack of water, as opposed to a mysterious ailment that everyone has but is miraculously cured by water.
A certain level of physical activity, even if not deliberately structured as "exercise", is a normal part of the human condition, and maybe one necessary to good physical and mental health in ways we don't entirely understand.
The problem with the human condition is that it evolved in circumstances that are ever more remote from what the modern life looks like. So, until we can finally purposefully modify humans, it looks like understanding what replacements are feasible (and why) for those evolution-approved parts is increasingly desirable.
An analogy that Steven Pinker used for this kind of 'analysis' was to point out that, if you remove a part from your car and it starts to make klunk noises, it doesn't follow that the function of the part was to suppress klunking.
When I was depressed, I didn’t have energy to exercise. And whenever I pushed myself, it took the last bit of the mental energy I had and pushed me further into the depressed mood that I subconsciously compensated for with food and overate as a result. After a year on anti depressants one of the symptoms that I was getting better was that my body started craving movement and exercise. And vice versa, when I lowered the dose of my antidepressants, it became harder for me to force myself to do the dance classes that I normally love and when there I would constantly watch the clock wishing it ended sooner.
In computing, there is a a pattern in which simple mechanisms, which were developed early in the history of computers, are gradually replaced by more complicated ones. The early mechanisms are simple but powerful, and have many side effects. The more complicated, later mechanisms are more precise in their results.
For example, in early computers, the off button switches them off by just cutting the power. The "cutting the power" mechanism has been increasingly fenced off (smartphones are almost never completely off) and the off button has grown an increasingly complicated set of behaviors. There many other examples, in from the internals of computers as well as UX.
I wonder if biochemistry has a similar progression. It won't be the same, as in computers many of the later mechanisms are targeted to specific goals for comprehensibility reasons, and comprehensibility is not a constraint on evolution. But it does seem likely that evolution could construct simple mechanisms first, and then later augment and even replace them with more complicated ones. Although I guess that evolution more frequently leaves "multiple mechanisms that do the same thing" around, for redundancy.
I mention this because reading about Ozempic's inhibiting of the hunger mechanism reminded me of the the process of "disabling a critical old mechanism" which is also found in computing, in the scenario above. So, maybe we can do this because there are also multiple other, perhaps more complicated mechanism which also support the necessary behaviors? Although, the example of haloperidol suggests that this is not always the case...
I think that your metaphor is apt. Consider the lineage of the x86 CPU architecture: you start with the 4004, a microcontroller suitable for a primitive calculator and go through the 8008, 8080 and 8086, 80x86, amd64 to modern multi-core CPUs. What you end up with is a mess of an architecture, because you are dragging around half a century of design decisions, all in the name of backwards compatibility, because you never know if someone might want to run QDOS on your ThreadRipper.
The path from prokaryote to mammal is similar. You start with something simple, and then you add features randomly for a few billion years, and out pops a human.
Worse, the shaping of these signalling pathways is not done by any intelligent design process, but by the blind idiot god of evolution. The solution preferred is not the most elegant solution, but simply the first one who popped up by chance mutations and conferred enough benefit to become universal. Asking 'why GLP-1 for that?' is like asking 'why did that neural network encode that weird subproperty in that particular neuron' -- it just was the first good enough solution the blind optimization process stumbled upon.
I wish I could upvote this a thousand times.
If Ozempic is causing effects via brain modification - this to me seems like at least a yellow flag if not a red one.
Poorly understood, poorly tested and completely novel molecule prescribed widely - aren't we already in an ongoing experiment with one such?
It would be ironic indeed if the massive Ozempic profiteering winds up actually being a net good by limiting usage.
Poorly tested in what way? The FDA has been all over the history of GLP-1 drugs, and arguably has required excessive testing already. If there were even moderately-uncommon side-effects beyond the usuals, we would certainly know it by now.
That's not guaranteed. An unexpected side effect might take a decade to show up, or increase extremely slowly.
It *is* the way to bet, but remember that you don't really know what the odds or the stakes are.
>An unexpected side effect might take a decade to show up
Much appreciated! I was going to make the same point. I don't think that this is a solvable problem. We can't reasonably wait for decade-long or multi-decade-long safety trials.
It's clearly not a soluble problem. DES didn't show up as a problem until the daughters of the women taking it were adults and developed excessive cancer. And in principle it could take even longer.
Many Thanks! Excellent point about DES!
Well, this was a problem only if DES was taken during pregnancy and we all know now to be extremely cautious with drugs when pregnant. But studies on pregnant women are tricky for obvious reasons.
The history of FDA approved medication used for off-label use, particularly high profit ones, does not give me any comfort: Vioxx, Depracote and many more.
Any medication can have side effects - primary use approvals are because the side effect negatives are outweighed by the primary effect benefits.
Ozempic use for weight control is off-label.
Your faith in the FDA is touching, but it is much less clear if you actually understand what the FDA's "all over" study of anything it approves, actually is (or is not).
There's a common media narrative about the FDA not noticing, or not talking about, or being willfully blind to, drug side effects. Like most "the-experts-didn't-notice-this" narratives, it falls apart when you look more closely.
The Vioxx affair is generally used as an example of why politicians and random civil society groups shouldn't try to disagree with the FDA's safety analysis: more recent analyses have clearly shown that Vioxx (generic name rofecoxib), a COX-2-selective NSAID, is safer than non-selective NSAIDs like Advil (generic name ibuprofen) and Aleve (generic name naproxen). I am, honestly, very unhappy that billions of people have been exposed to the risks of non-selective NSAIDs like Advil and Aleve when they could, counterfactually, have instead taken Vioxx.
I assume, with Depakote (generic name valproate, or valproic acid, or sodium valproate, or others I don't recall), that you're referring to the birth defects caused by paternal exposure? In that case,the data [1] is pretty clearly misinterpreted: one sensitivity analysis of many finds significantly increased risk, but others, and the primary analysis, don't. The apparent result in the one sensitivity analysis IMO is almost certainly caused by doing multiple comparisons - because one can't, and shouldn't, draw conclusions from sensitivity analyses (other than increasing or decreasing one's confidence in the primary analysis). (I will admit I haven't spent too much reading the report, so I could be missing something.) If it is true that there's increased risk, the absolute risk is so small that it couldn't really have been detected in pre-approval studies; nor could it have been detected in post-approval surveillance studies without many years of data.
It is reasonable to argue that more money should be spent on postmarketing surveillance - but most people wouldn't agree with that, I think, just based on cost-effectiveness.
There are many valid criticisms of the FDA, but insufficiently characterizing side effects isn't one of them. The FDA's weighing of side effects against benefits when deciding on whether to approve a drug for a particular use leaves room for disagreement, but that's not related to their characterization of side effects.
[1] https://www.ema.europa.eu/en/documents/other/valproate-prac-non-interventional-imposed-pass-final-study-report-assessment-report-emea-h-n-psr-j-0043_en.pdf
A nice writeup, but you are answering to a different subject that what I wrote about...which is that whatever the FDA's decisions made for a given drug for a given use case(s), based upon net benefit over side effects - these FDA decisions do not cover off-label use.
As for Vioxx: is it really safer? This timeline sure doesn't think so - or are there tens of thousands of heart attacks from Advil? Do tell.
https://www.npr.org/2007/11/10/5470430/timeline-the-rise-and-fall-of-vioxx
My understanding was that the death rate fell significantly when vioxx was taken off the market, which would pretty much falsify the idea that it's safer than alternatives. Alternatives are what people would have been using after it was taken off the market.
Semaglutide for obesity is not off-label ever since the FDA approved it on-label for weight control under the name Wegovy. From what I can tell, it's identical to Ozempic minus some slight dosage differences.
Maybe it turns us all into p-zombies, and when an AGI figures this out, the AGI knows that it's OK to kill us all because there's no one left that experiences qualia.
I saw that movie already - the AGI decided that regardless of Ozempic intake...
Fortunately, that is a fantasy movie.
Great article. Thank you.
I'm waiting to see Big Snack develop ozempic proof foods. I feel confident that as soon as a scientist figures out one aspect of how ozempic works, there is another scientist trying to figure out how to get something salty-sweet-and-crunchy past that mechanism.
Ugh. The arms race is definitely on.
Given that Ozempic seems to reduce general craving, and craving is a major phenomenon worked with in serious Buddhist meditation, I wonder if there are any serious meditators that are on Ozempic and if yes, what would they have to say about that.
I think the Buddhist concept of craving is far broader than the way in which is used in this article.
Can you come up with an example of something that would be considered craving from the Buddhist perspective, but not from the neurobiological perspective?
I don't think traditional Buddhism distinguished much (at all?) between desire and craving in the way we do. For example, someone who wants to be wealthy wouldn't generally be described as "craving" wealth.
https://en.m.wikipedia.org/wiki/Taṇhā
From your link: Buddhism categorizes desires as either taṇhā or chanda.[22] Chanda literally means "impulse, excitement, will, desire for".
So there does seem to be some destinction.
Fair enough. I'm not a Buddhist myself, and there's tons of scholarship exploring how to most accurately translate these concepts. I just don't recall encountering the distinction between desire and craving being very prominent in Buddhism, and it still seems like the word craving is being used differently in that Wikipedia article than to simply refer to the kinds of more hedonistic craving that we tend to associate the term with.
Anyway, serious meditators can can offer more insight, but my guess is that it's a category error trying to compare the reduction in craving by something like Ozempic to meditation.
This is right. Tanha (desire) and upadana (grasping) a subtle concept and in the doctrine of dependent origination is considered fundamental to the processes of perception that make up dualistic conscious reality.
From a dharma perspective, chemically weakening this signal could be superficially beneficial but do little to address the root form of ignorance responsible for dualistic suffering, which can only be resolved through "wisdom" from direct seeing and the eightfold path.
I’m pretty close to just trying this stuff. I workout all the time but also fully addicted to food. Been too fat for too long.
>all results related to curcumin are false until proven otherwise
For those who don't know: https://www.science.org/content/blog-post/curcumin-will-waste-your-time
>Nobody knows what caused the Big Bang, but cosmologists are increasingly convinced that GLP-1 might have been involved!
Are you sure these weren't cosmetologists?
Good luck finding a cosmetologist who has heard of both the Big Bang and GLP-1.
I started taking Wegovy about four months ago. I haven’t ramped past 1mg due to insurance bullshit, but I have lost 20 lbs. I drink a quarter of the alcohol I did before. My bloodwork went from “good for near 40” to “good for any age” and I have a better ability to sleep and handle mild sleep deprivation. I’m fairly certain that if a nasty case of tennis elbow hadn’t been keeping me out of the gym that literally every metric would have improved. As it stands, unfortunately my blood pressure is still in the new “stage 1 hypertension” range.
It’s pretty crazy, though. The data says I may be an outlier in how well I respond. But it has still been unbelievable.
Should note I have seen a significant reduction in libido since I began. However, it’s very hard to determine whether the drug is responsible due to significant stressors which have co-occurred with starting the drug. These include a death of an immediate family member and an absolutely crazy work schedule which has continued far past the expected end date and significantly reduced my ability to sleep adequately.
My libido seems to have begun improving over the past couple of weeks but I’m set to go to the high dose next week, so we’ll see.
If all those stressors hadn't lower your libido, I think that could have been taken as evidence that ozempic was increasing it, because that would have been unusual.
My blood pressure medication has been reduced by 75% since being on Mounjaro. It's shortsighted for insurance companies to keep this drug out of reach for so many people. Once they realize their profits will increase with the availability of this drug, I imagine it will be much more easily approved.
“In particular, maybe the inflammatory nature of the starving state really hurts a lot of systems.”
How is this true? Seems to contradict the advice on intermittent fasting https://www.medicalnewstoday.com/articles/how-fasting-can-reduce-disease-risk-by-lowering-inflammation#:~:text=Now%2C%20the%20authors%20of%20the,%2C%20heart%20disease%2C%20and%20obesity.
Maybe that’s different than the “starving” mode?
I was also confused by this.
Could the point of intermittent fasting be to force the body to acknowledge fully fasting and thus stop treating the normal time between meals as if it was a fast (possibly thereby increasing GLP-1 or something else)?
Yes, it's the other way around: inflammation is metabolically costly, and starvation causes the body to turn down the inflammatory response (good for treating chronic inflammation in today's world, which is abundant in cheap food; bad in our ancestral environment, where weaker inflammatory response coupled with bad hygiene and lack of antibiotics = higher risk of death by infectious disease).
So far, the data show that weight loss reverses when people stop taking the GLP-1RA drugs. In that way, these drugs are like other weight loss interventions (calorie counting, carb restriction, intermittent fasting, etc.) They work as long as you comply, and stop working when you stop complying.
Most people eventually stop complying with the other interventions, which is why the long-term weight loss stats are so bad. Will the GLP-1RAs be the exception to the rule? I'd like to see good data, but my suspicion is that they won't be. I suspect that most people eventually find the side effects unpleasant enough that they stop taking them, and that they then regain the weight they lost.
The reams of coverage about these medications contain little discussion about long-term compliance, but that is an absolutely critical factor to consider. Wegovy was approved in 2021. What percentage of the people who started taking it for weight loss in 2021 are still taking it? Do we know?
There’s interesting research to suggest that around the 2 year mark of taking it, the appetite-suppressant effects are lost and most patients will cease losing weight. Instead, the same dosage as before now works to keep them at their appropriate ‘set point’ weight - tantalising the suggestion that the weight loss drive might be linked to BMI, and that perhaps GLP drugs given to people at a healthy weight might not have the same impact as they do on obese people.
This is a mechanism we know the body is supposed to have: to adjust hunger and appetite in response to body weight. GLP seems to restore some of this process.
This has been my experience. I lost ~50lbs over the course of a year, putting me slightly south of overweight, and then stabilized there. I also started finding junk food appealing again...but not enough to reverse the effect; I've been stable within a ~10lb range for six months or so I think.
I wonder if there is some length of time where stopping will keep the weight off in general. Like, you only gain the weight in the way someone who was never obese gains weight. It would depend how long the set point takes to stabilize and whether withdrawal will inevitably reset it higher.
It does completely change your relationship with food. You feel less hungry, but that has a flip side of you get less used to food-seeking behaviors that people tend to engage in compulsively like opening the fridge or impulse buying a donut.
Anecdotally, I'm still taking it after a couple of years. The main compliance issues have been insurance shenanigans and travel.
My intuition is the opposite of yours; I think GLP-1 compliance will be high, at least relative to dietary interventions. Dietary interventions require *continuous* compliance. It's *much* easier to comply with "spend an hour a month managing shots" than "spend 720 hours a month resisting cravings". It's a special case of it costing less average willpower to do something unpleasant (and be done with it, at least for a while) than to abstain from something pleasant (and have the option still there...waiting).
(I notice my model predicts something that's probably already been studied: I'd expect better compliance on exercise regimens than dietary.)
Also, I vaguely remember hearing of work on longer-term variants (1mo+), which I expect to help even more. Longer durations imply longer periods where people won't fall of the wagon because they can't.
This is a very good summary of the current state of play. I am indebted to the author for referencing the possible mechanism that underlie Neurodegenerative diseases (AD, PD) as it saved me from doing the literature search. For those interested, there is an ongoing trial of Semaglutide (phase 3) in early Alzheimer’s disease due to read out towards the end of next year. Given the relative lack of efficacy of current treatments, a genuine positive signal (beyond statistical significance) would be well significant.
Fun fact: Edward Drinker Cope, along with Othniel Charles Marsh, was also one of the two paleontologists involved in the Bone Wars, quite possibly the most bonkers incident in the history of science.
I wonder if Ozempic can now be considered a Coping mechanism.
"By the end of the Bone Wars, both men had exhausted their funds in the pursuit of paleontological supremacy."
https://en.m.wikipedia.org/wiki/Bone_Wars
Mind-boggling.
Here, though,
"So probably GLP-1 binds to neurons in the brain stem, those signal to other neurons and immune cells via alpha-adrenergic receptors and delta-opioid receptors, and then the immune cells initiate an inflammatory reaction."
—don't you men "an anti-inflammatory reaction"?
Scott, do you know of any specific references that tested whether GLP-1 agonists block non-addictive rewards or cause general anhedonia? I haven't been able to find any human studies that actually quantified those effects, which is frustrating because that's pretty much the only qualm I have about what are otherwise wildly effective and apparently very tolerable medications.
'So probably GLP-1 binds to neurons in the brain stem, those signal to other neurons and immune cells via alpha-adrenergic receptors and delta-opioid receptors, and then the immune cells initiate an inflammatory reaction.'
Is that a typo or am I misunderstanding something here? Seems like it ought to be, 'initiate an ANTI-inflammatory reaction.'
Friends report Ozempic does reduce tanha/grasping/thirst; I’d predict this to ground out in reduced smooth muscle reflexes in general.
I’m also curious about Ozempic’s effects on smooth muscle latches; “stomach paralysis” is among the side effects I’d expect of a drug that hits this system
I wonder if Ozempic will continue to be the term of art for GLP-1 medicines generally - Ozempic is losing market share and the underlying molecule Semaglutide has been surpassed by several other products at this point in terms of efficacy.
Pah, those people will never get a job at the New York Post. The play you want is "Gila Saliva: Weight Loss Driver." Or perhaps "Gila Venom, Weight Loss Momentum."
Gila Spit To Get You Fit.
Reptile Drool To Look Good at the Pool.
Lizard Secretion For Weight Loss Accretion.
Gilas suffer
To make you buffer
********
Swallow that venom
To look good in denim
********
Gila monsters so you don't have to.
Since this seems to help with so many unrelated diseases / problems: maybe the natural GLP-1 level many people have today is just suboptimal? Either because lifestyle / diet / environmental poison changes over time decreased the average GLP-1 levels or lowered its effectiveness (by introducing antagonistic effects).
If you had a hormon used in many systems (hunger/ inflammation/ rewards) and get the level slightly out of whack, you would expect these systems to all slightly degrade. Restoring the “proper” (evolutionary normal) level would then look like wonderously curing an assortment of “random” common ills that grew more common over time.
Not saying this is true … but I think it would be useful to check whether something like this could e.g. be a partial cause of the obesity epidemic (I know that people aren’t very sold on the env poison theories … but it should be easier to check this specific hormonal pathway than “all possible new chemicals introduced in the last 70 years”).
It might be simpler to come up with a test for GLP-1 levels and compare Ozempic candidates to naturally thin and non-addictive personalities. Or if anyone’s still doing whole genome studies, to look for clues there.
So the Japanese all just have "naturally thin and non-addictive personalities"?
This seems unlikely to me given the bajillion pachinko parlors and smoking and gatcha games that the place has.
If they’re thin but addictive, they’ll provide a useful data point.
Furthermore: Maybe finding food, having a meal and then resting for a while, is a natural cycle that has functions akin to sleep. When you have eaten you don't need to stress as much, you can concentrate on digesting the meal and "housekeeping" in the body. When you need to find some more food you go in a different, more stressed and risky state with the immune system on its guard. GLP-1 would be the signal for switching between these states. This raises the obvious possibility that having your GLP-1-triggered mechanisms constantly activated by these drugs is also suboptimal or even bad, like being on melatonin or caffeine all the time. Maybe you need the cycling too? If this is the case, a better drug would have faster (4-6 hours?) kinetics.
I think the most likely cause of obesity is pathogenic microbiota that has evolved in modern feedlot animal husbandry: These days the majority of mammalian biomass on Earth is less mobile than the manure it produces; the gut microbes in this environment are free from considering the health and mobility of its host. An obvious way for the gut microbe to increase its own fitness would be to make the host eat more, and so produce more manure. If it made the animal bigger, the farmer would not consider it a pathology or a problem. So maybe there is some bug to be found in shit and guts, one that ruins the GLP-1-producing mechanism, or even produces its own GLP-1 antagonist. Or an analogue for the other, hunger-inducing, hormone. This would put the host in a permanent high-stress food-seeking mode.
Bad manure would explain many things, like the correlation of elevation with obesity. Americans would be fatter because of less free range cattle and more antibiotic feeding.
>These days the majority of mammalian biomass on Earth is less mobile than the manure it produces;
True! And quite an image, and quite a comparison!
Forgive an underdeveloped but vexing rising thought I'd appreciate feedback on.
I've historically shared the same instinct that evolutionary biology should preclude miracle cures (wonder drugs) that solve multiple problems with minimal downsides because complex and complicated biological systems should not have naturally evolved to let such opportunity exists. Real biology is terrible tradeoffs in massively complicated intertwined feedback loops, and leaning heavily on one lever to knock a system way towards one extreme can't be expected to help systematically.
However, in the modern world, we are now introducing stressors to our existence that are radically novel, and my general instinct now is inverting. Perhaps epidemic-level human maladies are due to narrow modern stressors, these stressors don't just manifest as one "break" in our system, but as manifold, and a single point solution to that novel stressor, if back at the origin of the problem, could very well have systemic benefits with minimal downsides.
For GLP-1, better biochemists or neuropsychiatrists than I can go pinpoint the origins here with insulin/glycemic issues or hunger/satiety issues, but if something about the modern world triggered an odd stressor that was upstream of the rest (something causes diabetes which in turn promotes obesity which promotes depression, and each of the downstream also partially promotes the others), then a pinpoint solution at that top to counteract the modern novelty seems possible.
And with many novelties in today's world emerging, many counter-solutions may thus be possible.
As much as I reflexively and skeptical of big-pharma (and big-medical-device and big-medicine...) suddenly I can become as much an optimist about their miracle cures as anyone else.
Perhaps, accordingly, there could be miracle cures (pharmacological or otherwise) for a litany of problems around (overweight) and (depressed) and (anxious) and (PTSD) and (addictions) and... if those clouds of associated maladies are being caused by some novel-stressors.
Novel-stressors could be hyper-abundance, novel-chemicals, chemical-contaminants, smart-phones, social-media, ...
Biochemical fixes like GLP-1 still seem miraculous, in that they aren't as straightforward a logical counteragent to whatever is causing (obesity) as a counter-toxin would be to a toxin, but I'm now very open to the prospect that if we look at problems as cloud of reaction to a novel stressor, perhaps miracles can exist?
The thing here is that real biology literally never had to contend with the problem glutides solve. I am confident that if you went and gave glutides to a group of medieval peasant farmers or ancestral hunter gatherers, they would die of starvation or from water-borne illnesses at a much higher rate over ten years.
Consider the effect of glutides on alcohol consumption. Now consider that almost 100% of people’s liquid intake was in the form of small beer or diluted wine because most water was poison until you boiled it. Also, a significant fraction of caloric intake came from alcohol as a result.
This is one of the only miracle cures you might expect based on what we know about evolution and the mechanisms of obesity. Obesity is an uncommon condition ancestrally, with fitness-reducing impacts that take a long time in a caloric surplus to appear and a basic mechanism that has been more likely to help than hurt for all but 100 of our 100,000 years as a species.
There is just no reason anything which meaningfully modified this mechanism for long enough to matter would have been a risk in the past, so no reason to make it super redundant. Plus there would have been zero selective pressure against it until 100 years ago. And not even that strong of a selective pressure now.
"Ozempic is a large molecule"
*Semaglutide* is a large molecule.
Yeah and Kleenex is a facial tissue. Come off it, Mosby.
And orange juice is a small molecule.
Ozempic is one of the drugs from NN, in which semaglutide is the active ingredient, but it's not the sole ingredient. I'm not privy to the specifics, but I'm almost certain they put in shelf-life extending preservatives, and things to make the injection painless and quickly dissipating.
I'd accept interchanging Ozempic with Wegovy (AFAIK, same thing, different dose) and some future hypothetical generic name, but not with semaglutide, especially not when talking about molecules, rather than drugs.
You are absolutely privy to specifics if you care to look them up. And the inactive ingredients are both unlikely to have a major effect on pharmacology or to be fundamentally different for semaglutide formulations approved in the future.
For the “I’m not privy”, here is the 5 second google to answer your question:
Ozempic
“Non-medicinal ingredients: disodium phosphate dihydrate, propylene glycol, phenol, and water for injections.”
Wegovy is the same minus propylene glycol and phenol (those are preservatives not included in wegovy because all formulations are single use autoinjector pens, which is not the case for ozempic).
For the purposes of discussing this molecule, there is no meaningful distinction. You are being a pedant, and could just admit it rather than pretending there is some unknowable distinction.
Also why would you assume they would put in anaesthetics? That’s just a weird thing to assume, especially since the pain would be over before your anesthetic could help.
He calls me a pedant, but then writes the above, and doesn't look into what those extra ingredients do. (Phenol is an anaesthetic, propylene glycol is a stabilizer.)
From CDC:
> Phenol was once an important antiseptic and is still used as a preservative in injectables. It also is used as an antipruritic, a cauterizing agent, a topical anesthetic, and as a chemical skin-peeler (chemexfoliant).
From NIH:
> Propylene glycol has become widely used as a solvent, extractant, and preservative in a variety of parenteral and nonparenteral pharmaceutical formulations.
Both phenol and propylene glycol are being used as preservatives.That’s why they’re not included in wegovy but are included in ozempic.
So you’re a pedant and also when you do actually google you’re bad at it.
Edit: GoodRX does say propylene glycol is not being used as a preservative, but the source is a patent about peptides injectors rather than any labeling info for ozempic. There may be a reason that you would need this in ozempic but not wegovy, but not one I can think of.
Regardless, even if I am half wrong… How does this make you not a pedant?
I am not denying the charge. I'm pointing out that you appear to be a worse pedant than me, even. Regardless, my original point stands - semaglutide is the molecule. Good day.
The real question is: why didn't they bother giving natural human GLP-1 a single-word name ending with "-aglutide"?
Because that is a drug naming convention and natural glp-1 has not been marketed as a drug due to its poor pharmacokinetics.
Marketed or seriously pursued, even.
Because gila monsters! C'mon, gila monsters are cool.
I think the way to understand why GLP-1 cures everything is to reason backwards: the nature of capitalism is that it will very efficiently find ways to hack our brains such that we want more of the thing people are selling. But then it makes sense that pushing us out of our evolved distribution by making us overconsume certain products would make a wide spectrum of things go wrong because that's how opaque complex systems work.
The question is why is there a common pathway that gets hacked as opposed to sugar doing one thing, fat and salt doing another, gambling a third, alcohol a 4th, etc. But that's also just kind of how biology works a lot of the time. Like intracellularly, a whole bunch of different signals go towards a few signaling pathways that activate a few important transcription factors like c-Myc or NF-kB which then have many effects. GLP-1 similarly happens to be situated at a bottleneck through which many signals must pass which is why it is so effective. Maybe post-Ozempic, businesses will route around this bottleneck by figuring out a hack for oxytocin signaling that will cause a whole new spectrum of diseases.
So in generalities, "there is bottleneck through which many existing brain hack go, and targeting it pushes humans back into distribution, which treats a crazy diverse range of diseases" is not very surprising though the specifics are of course very interesting.
You may have your agoutis mixed-up. I believe the studies on agouti-related proteins were studying agouti mice, not the South American animal https://www.nature.com/articles/ng1199_314
Thanks for the great post Scott. Any idea how long until this becomes a common drug that is prescribed freely? IIUC, and I'm not from the USA, it is still very limited in distribution, and I assume Doctor's are still hesitant on giving it to non-obese people because of possible side effects and "there is no reason to take it if your not obese/diabetic". Do we expect this to change, and if so, when?
Very natively it seems like most drugs should pull a lever with tradeoffs. If pulling a lever is always good why hasn't evolution done it already? This argument seems to hold except in cases where our current environment differs greatly from the ancestral environment we evolved for. With this in mind there is exactly one area that seems like it should have a legitimate miracle drug. A drug that tells your body you have plenty of calories spend them freely (never enter starvation mode) and don't worry much about eating more will kill you in the ancestral environment but makes you way better adapted today. Stimulants like caffeine and Adderall seems to do some of this (get you to spend calories your body would otherwise not) but they interact with the sleep system more than the food system so they seem imperfect. Ozempic strikes me as the first thing we have found that starts to fit the bill for this miracle drug. I am more willing to believe most of its side effects are positive than I am for other drugs because in the modern world we are missing the side effect of death by calorie deficit which is sufficient for evolution not to pull this lever. (The addiction stuff is still surprising to me but a lot of the other health stuff seems to vaguely fit here). If calories are always abundant and always will be it seems like your body should be able to waste energy on a lot of useful maintenance stuff, we just need a way to send this signal without getting morbidly obese which has its own health problems.
Very close to my thinking on the subject as well. A drug that acts to limit the brain's susceptibility to superstimulus (whether that be caloric or otherwise) seems like it would have a wide range of positive effects in the modern environment.
Semi-related question: what's the difference between apoptosis and autophagy? Why is the former supposedly bad (implied by the diagram in the Alzheimer's section) and the latter good. Aren't those just different mechanisms for cellular renewal in tissues?
One of the supposed benefits of fasting is increased autophagy; my fake model understanding of this is that it cleans up senescent cells more aggressively, which ends up rejuvenating your tissues by replacing those lost cells with new ones once the calories start rolling back in. I suppose keeping senescent cells around is some sort of mal-adaptive response to the calorie overabundance of the modern environment?
Apoptosis is not bad as a rule. Apoptosis of dopaminergic signaling neurons (that diagram is about Parkinson’s disease) is related to symptomatic progression in Parkinson’s. Correct me if I am wrong, experts, but apoptosis is adult central nervous cells is almost always bad unless the alternative is imminent cancer in those cells.
apoptosis = programmed cell death. The cell kills itself in response to certain signals. This can be either good (e.g., as finnydoo mentions below, when the cell was on its way to becoming a cancer cell, or when the cell was infected with viruses) or bad (pathological apoptosis of neurons in certain neurological disorders, for example). Fun fact: during embryonic development, we have webbed hands and feet at one point, and then apoptosis kills off the "webbing" resulting in normal human fingers and toes.
autophagy = literally "self-eating" - the cell eats parts of itself (intracellular organelles, protein complexes). This has two roles: remove damaged/dysfunctional organelles and provide energy for the cell (from the breakdown of the digested cell parts). It is part of the starvation response. In our energy-rich environment, autophagy is generally seen as good.
In brief: apoptosis destroys whole cells; autophagy destroys the "unhealthy" parts of cells, leaving the cells healthier/more functional overall.
Thanks, Scott: I am a semaglutide user for almost 3 years now. When I began my BMI was 40. In the first year I lost 20% of my starting weight, where I plateaued. My blood pressure which was under control but over 120 dropped into the 110 range. My mobility improved. The only noticeable side effect was an increased tendency to constipation -- yum, Miralax. Oh yes, and Medicare will not cover it; so ~$1,000/mo. But, thank God, I can afford it.
I should add that I continue to enjoy food and alcohol. I still eat sweets and have beer and wine with most of my meals. I just fill up faster and eat smaller quantities.
I hope that it prevents dementia. I am 77. My mother and my paternal grandmother were both demented in their 80s.
On price, the good news is that in the last couple of months I was able to to find it for less than $800. I am guessing that the presence of the Eli Lilly formulation (tirzepatide) in the market place has started to affect the pricing power of Novo Nordisk. That is fine. It is the way markets ought to work. In a few years there will be more compounds available from more manufacturers and the price will be more determined by the cost of the injectors than anything else.
I have no problem with the initial high price of semaglutide. Novo Nordisk was almost heroic in its efforts to develop the medicine which took 30 years and millions of dollars. Political attacks on them ("corporate greed") are contemptible. Saint Anthony Fauci and the NIH spent the time and your taxpayer dollars inventing COVID*. Socialism always fails -- catastrophically. Free men in free markets produce enormous improvements in the human condition.
The Novo Nordisk saga has been reviewed in a couple of podcasts which I heartily recommend to everyone interested:
https://www.acquired.fm/episodes/novo-nordisk-ozempic
https://www.acquired.fm/episodes/the-scientific-journey-behind-ozempic-with-lotte-bjerre-knudsen-novo-nordisks-chief-scientific-advisor
* No Scott, I don't agree. I think the science is with Alex Washburn and Nick Patterson and the geopolitics confirm their conclusions.
>Novo Nordisk was almost heroic in its efforts to develop the medicine which took 30 years and millions of dollars
Millions is probably an underestimate. Novo Nordisk spends billions of dollars a year on R & D.
They're also spending around 7 billion dollars a year on production of Semaglutide.
Undoubtedly true. As the late great Senator Everett Dirksen (R. Ill. 1951-69) said "A billion here and a billion there, and pretty soon you are talking about real money."
Maybe try himandhair. I’m not sure where you are, but they were able to offer the same drug for cheaper
I care a lot less about the money than I do my health. The FDA has issued a warning on semaglutide formulations:
Accept no substitute:
"FDA has received adverse event reports after patients used compounded semaglutide."
https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/medications-containing-semaglutide-marketed-type-2-diabetes-or-weight-loss
"Mother told me, yes, she told me, I'd meet girls like you.
She also told me, "Stay away, You'll never know what you'll catch".
Just the other day I heard of a soldier's falling off.
Some Indonesian junk that's going 'round"
"Surrender" by Cheap Trick https://www.youtube.com/watch?v=T_Km11HNzUY
>GLP-1 receptor agonist medications like Ozempic are already FDA-approved to treat diabetes and obesity
And heart disease for overweight patients! https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-reduce-risk-serious-heart-problems-specifically-adults-obesity-or
For the record, Novo Nordisc has not double pd the economy of Denmark. Its 2024 revenue was $37b, vs Danish GDP of $400b. Its market cap exceeds Denmark’s GDP, but that’s comparing a stock to a flow.
I tried the Ozempic a few months ago. My notes from then:
I tried the Ozempic. One part "losing 10 more pounds could be nice", one part curiosity. It did very minimal weight loss. But the curiosity was satisfied. There were three possible "mechanisms" of action I had heard in the media.
1) "delayed gastric emptying" - yes. I simply could not pass food from the stomach to the intestines at a normal speed. If I ate too much, it would make me sick.
> I had to bike less because I simply couldn't eat fast enough to get calories to burn.
2) "improved willpower" - if this happens, I didn't notice it.
> well, actually, the "motivation not to eat too much" from knowing you will get sick if you eat *kind of* looks like improved willpower.
3) "metabolism changes" - once again, nothing I noticed.
For some people, this is an effective and/or necessary tool to lose weight? I don't think I need it; if I want to lose weight by not eating, I don't need the drug.
Also, I'm not convinced it's safe. I think there are going to be a lot of cases in five years of "I was on the Ozempic and now I have permanent health issues".
It was approved by FDA back in 2017, and large-scale trials have started 2+ years before that, so while _some_ new side-effects may be discovered with this recent more wide-spread use, the frequency of those is not terribly likely to be very high.
How high was your dose? If you didn’t get to 1.7 or 2.4/week you may have never noticed it. Most in trials don’t see any obvious effects beyond nausea before that.
Also, if you were taking a compounded version it will be hard to say if you should have expected anything.
> “have low energy, bad sleep, nasty menopause, poor heart health, and ugly skin”
It makes sense for the human body to have an efficiency/performance slider.
There are various things the human body can do that save valuable calories, but make you less healthy. In starvation situations, sliding that to "do whatever it takes to scrimp calories" makes evolutionary sense.
And so a drug that slams this slider hard in the opposite direction, burn as many calories as you need to for optimal health, makes sense as an omnicure in a modern calorie rich world.
(Amateur biology, almost certainly wrong).
There is actually some reason to expect weight-loss drugs to be able to have good side effects. Weight loss has for most of human history been a very bad thing. A chemical tradeoff that makes you either (have low energy, poor heart health, nasty menopause and gain weight) or have (high energy, good heart health, nicer menopause and lose weight) would have been a serious tradeoff for almost all of human history - but today, with infinitely-abundant food to the point where weight gain is a larger problem than weight loss, the second can be an unalloyed good.
I mean no disrespect. But obesity is not adaptive, nor was it. It does not look very appealing. And why carry that spare tire around when you can store dried meat, nuts or grain? You just expend more energy and risk getting caught and eaten yourself, if the times are that bad.
Obesity may not be adaptive (though the visual appeal is cultural, at least to a point, as most beauty standards are) but the processes which lead to obesity certainly are. There has been precisely zero selective pressure against obesity before 100 years ago. To the extent obesity existed at all before then, it was so outweighed by the fact that getting obese required lottery wins in other fitness-relevant categories that it was a non-issue. Added to the fact that most of the negative side effects of obesity only really start to be dangerous after decades.
Carrying around the spare tire is absolutely sensible if you might starve, and especially if the main negative side effect is going to be that you die earlier after your kids are having kids anyway. And especially especially if the odds of you ever getting to spare tire are close to zero anyway.
The available food, even in a Malthus world, would not have been fine-tuned enough to keep people from accumulating calories to arbitrary amounts in some good years. If there was an heritable mechanism for it, obesity would have been common enough, and the observed fertility hit alone bad enough for it to be selected against.
It would be sensible if we did some kind of hibernation like bears and hedgehogs. Fasting records are held by former big guys, but they had vitamins and medical care available.
But when rubber meets the road? Any anecdotes or folklore of the Little John who was the sole survivor of his family in the Potato Famine, Great Leap Forward, Siege of Leningrad etc?
> The available food, even in a Malthus world, would not have been fine-tuned enough to keep people from accumulating calories to arbitrary amounts in some good years
You’re resting basically your entire argument on this assumption, and it is a bad one. We know that obesity rates were low until the 1960s, and that average calories consumed have increased dramatically since then.
More, you’re talking about “some good years” as if they would be the norm within even a single human lifetime. They wouldn’t have been, for most people over most of time. And very few people would have had enough food consistently enough over their lifetime to become obese.
Average calories is not a perfect measure, but it is useful. That’s before considering how the distribution has flattened considerably.
And not for nothing. It’s not just “fewer people avoiding famine” but many, many more people having access to significant excess calories.
If you would like to debate the positive side of my argument instead (obesogenic microbes being spread around by the use of livestock manure as a fertilizer), see my reply to Stephan in this thread.
People aren't like that unless something did it to them.
I would not, because for one the assumptions here are very bad, and do not actually support the argument that you need a different mechanism for obesity.
The argument itself sounds like a very stupid one for reasons beyond your bad assumptions about obesity. But your assumptions about obesity are so ridiculously bad that there isn’t really a need to engage with the ideas that those bad assumptions are holding up.
It's not that obesity is adaptive; it's that, for the vast, vast majority of human history, obesity would have been *unattainable* for anyone except a tiny minority of aristocrats and monarchs like Henry VIII. So there was no reproductive penalty for evolution pushing in the direction of "act in a way that would cause you to become obese in an environment full of cheap, abundant food."
Silly analogy, but imagine that there's a serious psychological defect that occurs only in quadrillionaires - it's not a problem for us, because there are no quadrillionaires.
Edited to add: I see finnydoo made the same point below.
Semaglutide and tirzepatide did not seem to help significantly with slowing my rate of weight gain, and were intolerable during my fasting months (800/cal day, to counteract the weight gain from eating enough to work).
They did however produce a general reduction in motivation and energy.
So I am skeptical that they actually only address addictive motivation.
Why were they intolerable?
Given that you’re claiming that drugs which are widely reported to work in general did not work in you, I don’t think they affect your motivation the same way that they affect other people. Like if you’re an exception with respect to physical weight gain, it would make sense that you’re also an exception with respect to addiction
Have you tried giving up polyunsaturated fats? Seems to fix all sorts of things, very slowly.
I've tried going very-low-linoleic. But if it takes seven years to work, I'm around 5% of the way in. No positive results as yet.
I think you should see *some* positive results on mood and general energy levels immediately, just from giving up all processed foods if nothing else, and most people seem to find that they're practically immune to sunburn after a year or so off the PUFAs.
I've no idea how long it takes to clear the PUFAs entirely, but the legendary whats_up_coconut went from utter metabolic catastrophe to apparently excellent health and a BMI of 18 in about 3 years, so it might be feasible before the end of the world.
My latest hand-wavy model is here:
https://theheartattackdiet.substack.com/p/what-im-currently-thinking
And I would very much appreciate you ripping it to shreds if you have the time. I don't like to believe things that aren't true.
Best of luck Eliezer.
“Why did God give your brain a special lever that only porn and cocaine can pull?”
Because God works hard and plays harder.
If God didn't want us to eat babies, why would he make them out of meat?
> But also, when a meal comes in, the body diverts other resources towards the digestion process (this is why a big lunch makes you tired). Maybe some of those resources come from the immune system, so immune cells stand down while you’re digesting.
Is that why having a fever suppresses your hunger? No energy available for digestion?
This is as good a thread as any to ask something I've been curious about: Whats the difference between anti-inflammatory drugs and immunosuppressants?
Inflammation is an activity of the immune system, so it would seem like suppressing the immune system is the main way a drug can reduce inflammation. And corticosteroids are indeed described both as anti-inflammatory and immunosuppressants. However, non-steroidal anti-inflammatory drugs (NSAIDs) aren't described as immunosuppressants and don't inhibit the immune system's ability to fight infection enough for it to be generally considered a bad idea to take them to reduce fever while having an infection. And other immunosuppressants like thiopurines aren't generally described as NSAIDs, even though though they are often taken to prevent certain inflammations, particularly ones in transplant patients and autoimmune diseases.
More on topic: Are we sure that a drug that reduces inflammations (if semaglutide really does that) won't increase susceptibility to infections and cancer? I'd think there's a trade-off between good immune activity—fighting infections and (pre-)cancerous cells—and autoimmunity and other negative effects of unnecessary inflammation. Is it a good idea to move the level of inflammatory response from its natural level a good idea in healthy people? Perhaps it is, now that most infections diseases are curable or preventable.
| So far nobody has managed to get that study premise past an IRB, sorry.
Experimental psychologist: "Hold my beer!"
Is that modern diet causes chronic inflammation (more so than food in general, the way discussed in this post) established science? It always sounded like woo-woo to me, but I've never looked into it.
----
Was I supposed to know that eggs were healthy? The last message I got was that they were unhealthy because they were high in cholesterol.
Oh, that was *last* week! *This* week eggs are okay but only so long as you have about one a day, because ha ha it's not the cholesterol that does the damage, it's the saturated fats!
https://www.health.harvard.edu/newsletter_article/how-many-eggs-can-i-safely-eat
"A. Years ago, the advice was to eat no more than one or two whole eggs per week. The reason was the high amount of cholesterol in egg yolks — approximately 200 milligrams (mg) per egg. The previous cholesterol guidelines recommended no more than 300 mg of dietary cholesterol per day.
More recent research found that dietary cholesterol had little influence on blood levels of total and "bad" LDL cholesterol. Instead, it is dietary saturated fats that raise these blood levels. The reason? Most of the cholesterol in your body does not come from your diet, but is made by your liver. And saturated fat in the diet can cause your liver to make lots of cholesterol.
While recent studies still don't offer a consistent answer, the average healthy person likely suffers no harm from eating up to seven eggs per week. In fact, eggs are a nutritious food. They are relatively low in calories and saturated fat, and rich in protein, vitamins, and minerals. They also contain nutrients, such as lutein and zeaxanthin, which are good for the eyes, and choline, which helps supports the brain and nervous system."
And *next" week the advice will be that you can eat up to three eggs a day, and in fact *should* be doing so!
https://www.medicalnewstoday.com/articles/323001#benefits-of-eggs
"Eating one to three eggs per day can have several health benefits, but this varies from person to person. At this level of consumption, people can expect minimal changes in their cholesterol levels.
It is unclear whether there is an upper limit on how many eggs a person can eat per day. More research in this area is necessary to provide clarity."
When it comes to diet and nutrition, nobody knows effin' anything.
Yes, exactly. 80% of nutrition "science" is nonsense. I love eggs and for about 2 years was eating 2-3 dozen per week (sunny side up in a pool of butter). Total cholesterol was 158, LDL at 56. Then I kind of burnt out on them and am eating more cruciferous vegetables instead and using olive oil instead of 100% butter for cooking, and my cholesterol is now higher (total 200, HDL still 56).
>When it comes to diet and nutrition, nobody knows effin' anything.
All of the studies with voodoo doll gavage do cast some doubt over the field. :-)
Is it possible to construct a single voodoo doll for an entire population?
Many Thanks! This is beyond my expertise. We would have to track down a Vodún public health practitioner/cleric to assess the feasibility. The politics of vaccinating a single voodoo doll for a population which contains factions who oppose vaccine mandates could get interesting... :-)
1) I've been on Ozempic for six weeks. I've lost 17 pounds and feel great. I'm only taking 50% the recommended dose for this time in the process.
2) I wasn't obese before but I was putting on a sizable dad gut. I had to lie about my weight to get the drug.
3) My blood sugars (type 1 diabetic) are vastly improved.
4) It basically makes you feel slightly sick to your stomach. You can't eat much at once and often have to poop after each meal.
5) A surprising effect is that it's impossible to get drunk on Ozempic. Not that I'm trying to go on benders, but if you've ever had a glass of wine on an empty stomach versus on a full stomach, you know the difference. Ozempic is like your stomach is always full. You can never get more than a buzz.
6) I recommend it highly. You can get compounded Ozempic on Henrymeds or a bunch of other sites for $200-$300 without insurance. If like me you only need a 50% dose that cuts the cost in half.
What is your actual dose?
So they do it by units because it's compounded, but its supposed to mirror the Ozempic doses. 5 units four weeks, 10 units four weeks, 15 units thereafter.
I started Jun 26th or so, so tomorrow will be the end of the seventh week I guess. I've done something like 2,2,3,4,5,5,5,7. I diving the 7 into two small injections of 4 and 3 that I give on Monday and Friday, or a unit a day. I plan on staying at this level.
The side effects were probably worse at the beginning versus now.
Interesting
What led you to take half a dose?
I was worried about side effects. Since I got results with lower doses I just stuck to it.
I would be uneasy about taking an alternative version of a med that's made by a compounding pharmacy. I think what worries me is that there is no agency making sure they really give the customer the dose they are saying that they are. I'm sure the active ingredient is the most expensive part of their preparation, so they would have a motive to give less drug than they claim they're giving. Also I wonder about sanitation, esp. for an injectable, and errors in choosing whatever else goes into the shot in addition to the drug. But I'm not sure how valid these worries are. *Is* there some process of keeping them honest, by randomly check prescription contents? Is there an agency that checks their sanitation and makes sure they're following any special requirements for sanitation of injectables (if there are any special requirements)? Are you just taking your chances, or did you find out some reassuring info about these places?
Compounding pharmacies are regulated, though of course its possible to have fly by night businesses like any industry.
https://www.fda.gov/media/98964/download
https://www.mcguirewoods.com/client-resources/alerts/2023/7/critical-ozempic-shortages-compounding-pharmacies/
Ozempic is considered to be "in a shortage" by the FDA. This allows compounding pharmacies to purchase the raw ingredient from the manufacturer (this is why it costs $200-$300, not $5).
Why is it in a shortage? As an insider to this industry the government is going to negotiate the price of GLP-1s within the next few years. Right now the list price on Ozempic is $900-$1000, and they pay a rebate to the insurer that makes the net price much lower. They want the high list price to be the "starting point" for discount negotiations. At the same time, they know they can sell it profitably at much lower prices, they just don't want to admit it. So it's going to be "in shortage" probably until after the government negotiates the official price for Medicare in a couple of years. Even if you can get it for $200-$300 compounded, that isn't the "official price" that will be the starting point for negotiations.
If you sign up for these services you will have a consultation with a nurse most likely and they can answer any questions you have. For instance, we did discuss whether or not their product had a salt base or not and they were knowledgable of the issues.
Type 1 diabetic? Fascinating. My husband is Type 1 (LADA, technically) and uses insulin. I wonder if he's be helped.
My A1C is starting to crater. I wear a Dexcom and I basically never get high anymore.
Wow. Thanks for your response.
Unfortunately not approved for Type 1 DM so will be hard to get coverage for it from insurer. Anecdotally, I know of number of IDDM patients who've done great on it, since decreased intake + weight loss is such a huge factor in controlling both types of diabetes. Also should see same (?more) reductions in MACE (major adverse CV events- heart attacks & strokes), since CV disease even higher in T1DM. If I had IDDM, I'd strongly consider it...
"it's different this time"
Versus
"There is no such thing as a free lunch"
There are plenty of essentially free lunches, medically speaking. There just haven’t been all that many introduced since routine childhood vaccinations. We’re overdue for a new one.
plenty? you name childhood vaccinations. Some would disagree . (I am in agreement largely).
Antibiotics. Aseptic surgery. Insulin for type 1 diabetes. Probably many I can’t think of for more niche uses.
All have downsides (like glp-1ra) but all have proven so effective and life-saving that it’s hard to see them not being used even if the side effects were much worse or more common. (Antibiotic resistance is kinda tricky to characterize here, but it may make them fall out of “free lunch” category.)
I’d argue that anyone who would disagree that childhood vaccination, broadly, counts as a free lunch is too stupid to talk to. They don’t have zero side effects. But they have such minimal side effects compared to the diseases they prevent that it’s a true no-brainer. There are certainly arguments that some specific ones may not be worth the cost, but as a category it probably count as the greatest medical invention of all time. Like, unless they come up with a one-shot treatment that prevents 99% of strokes or something.
GLP-1RA may not ultimately turn out to be free lunch in the way antibiotics or aseptic surgery are. They might cause 90% of patients to get medullary thyroid cancer within 20 years or something. But there is such a thing as a free lunch. Most of us are only alive because of one or more of them.
>I’d argue that anyone who would disagree that childhood vaccination, broadly, counts as a free lunch is too stupid to talk to.
I'd argue that anyone who says stuff like this is too narcissistic to listen to.
See? Point proven.
To add to the "free lunch" cases: All of the deficiency diseases (scurvy, rickets, beriberi, pellagra, ...) that were solved by micronutrients.
In public health: All of the infectious diseases that chlorination stopped. Getting further afield: There are a bunch of food processing steps, most notably pasteurization that were comparably effective.
I almost put in water chlorination but figured it was going too far afield.
Many Thanks!
But looking at the bigger picture, medicine and medical science has also given mankind puerperal fever (in Victorian times), aids, the opioid epidemic, contaminated blood, maybe COVID. The balance is still positive IMO but maybe that's just cos I've avoided all the problems.
How do you figure AIDS? Did medical science tell people to eat primate meat they cut with open wounds and/or fuck chimps? Or do you mean mishandling of the early pandemic made the problem worse than it might have been? Because that seemed to be largely at the intersection of politics rather than on medicine itself.
And for COVID, lab leak is at “can’t definitively prove because the lab being where zoonoses had previously occurred plus incomplete data about the early course are confounding, but probably didn’t happen”. So “maybe” is doing a lot of lifting in “maybe Covid”.
I thought I read that the human-to-human transmission of HIV developed because of an immunisation program in Africa which was reusing needles. But I read that a long time ago - about the time its origin was first tracked down (by a reporter rather than a scientist, if memory serves).
Also, about the same time I read that there were two different AIDs: one from chimps and one from gorillas - I see it's now 4 different AIDs origin viruses: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935100/#:~:text=Phylogenetic%20analyses%20have%20revealed%20the,may%20have%20been%20via%20gorillas.
Just found this: "My central hypothesis was that the Aids pandemic was sparked by an experimental oral polio vaccine (OPV) called CHAT, which was fed to more than a million infants, children and adults in the former Belgian colonies of central Africa between 1957 and 1960. It is now accepted that the immediate ancestor of HIV-1 is the simian immunodeficiency virus (SIV) of the common chimpanzee. In the late Fifties, polio vaccines were grown in cells from monkey kidneys, but evidence suggests that some batches of the CHAT vaccine fed in Africa were, uniquely, produced in chimp cells."
Guess we'll never really know - like COVID.
The polio vaccine thing is discredited horseshit. There are some lingering questions about HIV origin, but all of them are muddied by the fact that HIV was for sure spreading for decades before it got recognized for what it was. People were definitely dying of AIDS or else dying of other shit before they could develop advanced AIDS no later than the 1950sx, as recognizable HIV has been identified in samples from 1951. I think the current best thinking is that it probably jumped into people in the 1920s or so.
There is some question of subtype origin, but it’s muddied by the fact that its origin happened very late in the period where we couldn’t identify viruses well. If I had to guess about the subtypes, lots of SIV strains jump to individual people but are not very succesful ant infecting or spreading, and don’t cause long term harm. One strain, once, developed some really good adaptations for infecting and spreading between people. And all the other circulating strains are a result of chance confections of wild strains with the human spreading strain that happened soon after it emerged. Probably as it was first spreading among the community that it emerged in as they were presumably still processing primate meat. Eventually human strains became too specialized and lost the ability to easily exchange genes.
But I have done no research about the specific origin hypotheses Besides the conspiracy theory versions of which the vaccine thing is one, and that was just the first idea off top of mind.
That all makes sense. Thanks.
It seems like a lot of things cured by GLP-1 agonists are diseases of modernity. So a natural theory is that there's some kind of GLP-1 ANTagonist in our food or environment that has been causing all sorts of problems. If true, Ozempic would simply be reversing the problems caused by this mystery chemical.
I find this plausible because it's more likely for a chemical to break a bunch of things than to improve a bunch of things above the natural baseline. If the latter existed, you'd expect our bodies to evolve to produce it naturally. And if something breaks a bunch of things, counteracting that something will fix them all.
We don't have drugs that can make a healthy person live an extra fifty years, but if you just drank poison, an antidote could extend your life by that much easily.
All there needs to be is some plausible mechanism by which the goods we eat have caused glp-1 per calorie to be reduced. Probably sugar sweetened beverages or something which increase calories consumed without causing the same glp-1 release as equicaloric meals.
If I’m stewing together modernity explanations, microplastics naturally get flushed out by Ozempic
.... how? what? ... I cant even imagine what mechanism you could believe.
What do you think of the theory that the obesity epidemic, and a bunch of other common modern diseases, are caused by the accidental introduction of a GLP-1 _ant_agonist as a contaminant to our food or water? Then semaglutide doesn't actually cure everything, but a bunch of modern diseases that we didn't realize all had a single cause are all cured by the same thing. (my current belief in this theory is something like 7%—low, but above the waterline of a hypothesis that would be worth investigating)
Pretty interesting theory
Fascinating. I read it while I was eating some ice cream.
The experience described by people on these drugs, of not wanting things, reminds me of my 1st 90 days on phentermine. Broadly across the spectrum I had a vastly diminished preference for A happening over B, which for me was a huge and very welcome change. I have a tendency to get fixated on a plan happening, sometimes to unreasonable and disruptive lengths, and often (but not solely) in connection with food or drink. For example, one Friday night I was preparing homemade pizza, a ~3 hr process, and dropped the pizza taking it out of the oven at 10pm. Rather than eat something else (or order a pizza, or make a frozen one), I pulled remainder dough from the fridge, rose it for an hour, and baked a new pizza finally eating after midnight. Similarly I might get fixated on having a certain kind of day on Saturday when the weather's good, and get irrationally too upset when some unforeseen event derails it.
While I was on phentermine that first time, my preferences that things go a very specific way vastly diminished, and almost disappeared. I stopped using negative phrases/mantras that I would repeat to myself alone in the car. Additionally, I got far less excited and showed muted responses for things that should have made me really happy, like being given first row NFL tickets or coming into a bit of extra money.
I understand these drugs don't have any chemical similarity, so I'm not sure what to take away from this. In my work with recreational drug abusers, I have encountered people who take stimulants becoming more fixated rather than less, so this isn't what I would have thought. Maybe there's just a variety of things that, as a consequence of patient feeling better about some other part of their life, or a placebo effect of some type, have some secondary effect of reducing compulsive behaviors and fixations.
The anti-addiction elements of Ozempic are interesting, but my guess is they'll take a long time to penetrate the system. I'm no doctor, but I worked for many years with our county's drug treatment court, and there are a lot of treatment standards that are set by things outside of your control. Many of the treatment centers that you can direct addicts to while in these programs are also suboxone dealers, so their incentives are to offer that, and the federal grants are conditioned now on the court going along with whatever the doctor says and never pushing somebody to wean off the suboxone. We have had experts and conference speakers advocating naltrexone and vivitrol for our program, but we had no real way to push adoption of that. At some point IF Ozempic and pals get cheaper, I could certainly see combo weight loss / addiction clinics popping up to service this profitably, but it will take awhile for the entrenched drug treatment center industry who hold all the exclusive contracts to either change or have deals expire and be replaced.
Vivitrol works great for stimulant as well as opiate addiction, including meth, for which there’s no equivalent to Suboxone
I have been on Rybelsus for six months, at the highest dose, and though my weight loss has been disappointing my impulsivity has been cut down to such a degree that I'm tempted to try it as a monotherapy for my bipolar disorder. Unfortunately the potential negative consequences of such a personal trial are too high, so I won't be doing that.
I was wondering how your GLP-1 therapy was going. Sorry the weight loss is disappointing, but that's great about the impulsivity.
Why not the shot? It’s really no big deal to give a sub-Q injection once a week.
I'm curious about the GLP-1 foods. If I eat a lot more salmon, kale, lentils, etc., will that help me much with hunger or with fighting other addictive behaviors, or is the duration of natural GLP-1 so short that they're healthy foods, but unlikely to produce any noticeable effects beyond any other health food?
"In chronic inflammation, ie the thing most of us with modern diets have all the time,"
Wait. Stop. Go back. You can't drop a fucking bomb like that in the middle of an article and then just move on.
Yes, I for two would be interested in an in-depth look at "inflammation".
This seems a bit like controlling guns, when violence in general is likely a symptom of more fundamental, systemic failures. If we look for an answer to the question, Why violence? our time might be more productive. Uyghurs run people down with their cars when they want to kill them; Brits stab people with a knife. Others prefer the anonymity of explosives.
We should be more concerned with addressing conditions that move people to resort to both violence and obesity.
Why are people morbidly obese? Why do they spend hours every day scrolling tiny, hand-held computers? Why do they listen to half-wits ranting on 'social media'? Why do they insist on nutrition-poor diets, then flock to gymnasia to work off the results? Time and money might be better spent dealing with the root causes of obesity.
Pure speculation here, but perhaps some of the higher-order, indirect positive effects on overall health & well-being come from the lower levels of stress (experienced consciously or unconsciously) by those individuals with these cravings.
If everyone has low-level inflammation all the time, and if this is causing us permanent damage, does that mean we should be taking low-level anti-inflammatory drugs?
Are there drugs that treat inflammation and don't have weird side effects?
I mean, I guess the claim is that Ozempic treats inflammation somehow But surely there's a way to do that more directly?
Quote: " [...] inflammation. This is a catch-all term for the immune response to microbes [...]". Just to be picky, inflammation is also a response for a physical damage such as a frostbite, it's not only about biological threats.
I just want to chime in and say that the effects on cravings and addiction are clearly not downstream of weight loss. First, they are not seen post bariatric surgery. Secondly, the reduction in cravings for alcohol and other substances begins immediately for many people, just as the reduction in craving for food does.
This also connects to a slightly broader point, and I don't think the science is quite here yet, but it appears that there is a strong reduction in cravings with GLP-1RAs that is separate from a reduction in reward value. It may be part of the same overall 'reward system', but patient reports and small trials overwhelmingly point to a lack of craving and desire that is too rapid to be a behavior learned from failing to receive a satisfying reward (though reward reduction may also be a part of what works over time). With alcohol, for example, people will often just forget to have their nightly glass of wine; just as 'food noise' goes away, random thoughts and desires for other substances may disappear almost immediately for many people.
And thanks for linking to Recursive Adaptation!
What about chronic pain and chronic fatigue conditions?
It's another huge burden on society and it seems strongly related to the broad cluster of processes we refer to as "inflammation"
https://www.painscience.com/articles/why-does-pain-hurt-so-much.php
Do we know if these meds could help with that?
The assertion "None of these anti-addictive drugs affect wholesome rewards like the feeling of a job well done or a child’s smile." is interesting - is there evidence for that? There's a big gap between "safety studies didn't notice major immediately obvious side effects" and "do not affect".
>Medicine is bad at answering “why” questions. Often the answer looks like “because it modulates ABC transmission, which inhibits XYZ, which signals to MNO, and MNO is involved in the disease.” This is all very scientific-sounding but totally fails to satisfy any normal human curiosity.
Ah, but what _direction_ of curiosity? Some of us will ask - But how does it bind to the ABC receptor? What pocket? Which residues? How many kT of delta-H? Salt bridge or hydrogen bond? What are the kinetics for diffusion through the cell membrane to get to the ABC receptor?
I think we here are not normal. Perhaps even "abby" normal. One might even say "weird", if that word hasn't been politicized by now.
LOL! Many Thanks!
>(all results related to curcumin are false until proven otherwise)
I've heard a rumor that it can be used as a yellowish food coloring. :-)
I like the cut of your mustard.
:-) LOL Many Thanks!
So he's saying that it *wasn't* Colonel Mustard?
Much appreciated! Well, advice on plant-based stuff ebbs and flows. I think Professor Plum is a leading candidate at the moment... :-)
This is awesome. It has zero effect on me. But I want to say it's a big plus point for maintaining biological diversity. (Keeping species alive.) I love Gila Monsters!
>here’s skibika toilet (2013)
These drugs affect an already dysregulated appetite. Do they help us understand why/how the appetite gets that way and offer lines of research to prevent it?
There is some indication that part of the normal function of the glp-1 system is fermentable fibers causing release of the hormone for a long time after food intake stops. The significant reduction in dietary fiber intake which co-occurred with a significant jump in total calories probably explains much of that.
It’s just a lot harder to stick to a regimen of getting enough fiber than a once-weekly injection.
>But GLP-1 drugs also prevent dementia in non-diabetics, so there has to be more going on.
Could this finding be explained by the increase in average A1C with age? Seems like a lot of the population most likely to develop dementia, the elderly, has relatively large amounts of glucose hanging around in the blood stream all the time. Even the elderly who do not qualify as diabetic would have on average a high A1C compared to the average younger non-diabetic.. So we could think of these non-diabetic elderly people as let’s say 20 or 30 or 40% diabetic, depending on how high their A1C is. Whatever it is that high blood sugar does to increase the risk of dementia, these technically non-diabetic people have the same risk factor as diabetics, just a slightly smaller risk.
The threshold for diabetes doesn’t change as you age. And glp-1ras will only reduce blood sugar and A1C to slightly on the lower end of the normal range. Given how long they have been widely prescribed for non-diabetics (not very) it would be astounding if such a small change in average blood sugar was causing dementia and we didn’t already know about it.
>The threshold for diabetes doesn’t change as you age.
No, it does:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715934/
https://bmcendocrdisord.biomedcentral.com/articles/10.1186/s12902-019-0338-7
>And glp-1ras will only reduce blood sugar and A1C to slightly on the lower end of the normal range.
Do you mean it reduces them to something like 20 or 30th percentile? If they start off at 80th or 90th percentile and go down to 20th or 30th, I get that that'se a small change in the actual amount of average glucose in somebody's cells over the past couple months. But given that the normal distribution of A1C is very tightly clustered around 5.0 or so, it seems that the body regulates this amt pretty rigorously. That suggests that a small deviation numerically may matter. Sort of as with body temperature -- the difference between 98.6 and 100.6 is small, but in the case of temp this small difference is significant.
Given how long they have been widely prescribed for non-diabetics (not very) it would be astounding if such a small change in average blood sugar was causing dementia and we didn’t already know about it.
I just looked up the numbers. It's not a small change in average blood sugar. The change in A1C on Ozempic averages about 2%
https://www.ncbi.nlm.nih.gov/books/NBK544016/ (see table 14)
But that doesn’t mean the A1C measure becomes 2% smaller, i.e. becomes 98% the size it was.. In this case what the experimenters mean by going down 2% is that you subtract 2 from the pre-treatment A1C number (which itself is a percent). If a diabetic person’s A1C is 7.0, it goes down, on average, to 5.0. So the decrease is 30% plus. (See Table 14 in the linked article.) That’s a big change.
I’m just saying that by now we could not have missed such a strong association. If this were the mechanism we’d have been starting people on metformin at much lower A1Cs 20 years ago.
I suspect the research has been done. And maybe metformin didn’t adjust a1c in non-diabetic patients or maybe it did and didn’t meaningfully affect dementia risk.
But they have to have trialled it. It would cost nothing and have zero risk. And it’s kinda obvious given the association with diabetes.
What association do you mean? Association between A1C and dementia? Something else?
And before I sleep I should note that ozempic does have a large a1c reduction in diabetics. And diabetes is associated strongly with Alzheimer’s. That linked study is of “Ozempic!”. Like super double Ozempic, used for the primary indication Ozempic (TM) is approved for.
The effect is much more modest in non-diabetics. You would hope it was. A 2% a1c reduction in a non-diabetic is something you find in bloodwork to figure out why this dude is fainting all the time. I need to also pull up the a1c data for wegovy’s phase 3 trials to say exactly how much. But I will.
You still haven't clarified what the association is that you are talking about. Do you mean an association between A1C and dementia,, even in nondiabetics? If that's what you mean yes, there is definitely an association, and research into it. For ex.: "Diabetes was associated with a 10% faster rate of memory decline (β=−0.04 per decade; 95% CI: −0.06,−0.01). A 1-unit increase in HbA1c corresponded with a 0.05 SD decrease in memory score per decade (95% CI: −0.08,−0.03). Even among individuals with HbA1c <6.5% (threshold for diabetes), higher HbA1c was associated with memory decline (β=−0.05 per decade; 95% CI: −0.08,−0.03)." https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5325158/
What is "Ozempic!" Are you talking about dose given? There are results for doses of both 0.5 and 1.0. Do you mean Ozempic + metformin? Virtually all the subjects were already on metformin or some other diabetic med when the study began.
I stumbled over that sentence as well. I would guess most of us are going to be affected by the modern Western diet; those who don‘t end up classified as diabetic would still be „20 or 30 or 40 percent diabetic“ as you put it.
Personal anecdote of organic Ozempic-like effects, and evolutionary speculation:
I went on a strict diet for an autoimmune condition. No grains (except white rice), legumes, cow dairy, refined seed oils, added sugar, alcohol, or eating outside of a 6-hour window. But also no caloric restrictions, so my new diet involved lots of vegetables fried in massive amounts of butter/coconut oil; or hash browns also fried in large amounts of oil, with melted cheese and two fried eggs on top; or 300+ grams of beef at a time in a high-fat curry. Everything I ate was salty, fatty, very high food reward.
After a few weeks, I stopped getting hungry. By that I mean I could forget to eat a meal and not notice. Regardless of my caloric intake, not eating required no willpower. For comparison, before the diet, I could eat 3k calories in a day and still have ravishing hunger for sugary crap into the late night.
Over ~9 months on the diet, I lost 80 pounds. No hunger. If I had to guess, the causal factors were the sugar, alcohol, and time restrictions.
Thinking about WHY it all worked... it seems there are three different metabolic modes:
1. Hunger is closely tied to caloric intake and use (normal mode)
2. Hunger is strong regardless of caloric intake (feasting mode)
3. Hunger is mostly absent regardless of caloric intake (cutting mode)
I would guess 2. is triggered by consuming lots of sugar or alcohol - its notable that the body in this condition seems to crave more sugar in particular.
3. in my experience was triggered by a high-fat, high-protein, relatively low-carb diet (I wasn't going for keto, but I tended to only have one moderate portion of carbs with only one of my two daily meals) with intermittent fasting.
What situations in the ancestral environment are similar?
There's a limited window of ripeness for many fruits, and a temporary glut of overeating may be the only way to fully take advantage of the temporary glut in available calories. If I eat 1000 calories of sugar, in ancestral conditions that's probably a good indicator to my body that I should be eating more sugar. Unfortunately for moderns, it's always oreo season.
But compare the hunter-gatherer after the fruit is all gone. He goes back to hunting and fishing, which produce irregularly spaced out meals high in fat and protein. Caloric intake may be regular on a longer timescale, but he could easily go a day without food - and in order to be successful at hunting, he needs a constant supply of energy, regardless of how well he's eaten today. Under these conditions, would it not be ideal for the body to actively draw energy from fat stores, and suppress hunger?
My hunch is that a successful diet is one which puts you into cutting mode, and the best way to do it is to trick the body into thinking you're in the ancestral state which called for cutting mode. Perhaps that's what Ozempic is doing?
> What situations in the ancestral environment are similar?
There's a limited window of ripeness for many fruits, and a temporary glut of overeating may be the only way to fully take advantage of the temporary glut in available calories. If I eat 1000 calories of sugar, in ancestral conditions that's probably a good indicator to my body that I should be eating more sugar. Unfortunately for moderns, it's always oreo season.
It may be a just-so story, but I like this.
In other news, it's peach season.
"By playing around with its structure, Big Pharma was eventually able to create liraglutide (twelve hours), semaglutide (one week), and cafraglutide (one month)."
A lot of talented chemists would have worked on this and I think it is a slight disservice to not mention the company at least once in the article to give credit.
(although in your annual survey you don't have chemist listed as a profession, so maybe you just don't know we exist?)
The chemists are academics. From Eric Topol Substack “Dr. Daniel Drucker from the University of Toronto, who is one of the leading endocrinologists in the world, and he along with Joel Habener and Jens Juul Holst from the University of Copenhagen and Denmark, have been credited with numerous prizes of their discovery work of glucagon-like peptide-1 (GLP-1) “.
The discovery should definitely be cited, but I'm talking about the synthetic modifications that were mentioned, which are a whole host of research in their own rights that should be credited too. All three people you mentioned are MDs and therefore probably weren't the ones "playing around with its structure."
Jeffrey Soreff, who posts a lot here, is a chemist.
>Why? Isn’t addiction just the extreme version of normal wanting? Apparently not. None of these anti-addictive drugs affect wholesome rewards like the feeling of a job well done or a child’s smile. Just drug addictions, and a few compulsive behaviors like porn and gambling. But why? Why did God give your brain a special lever that only porn and cocaine can pull?
Here’s some introspected data about the craving for something one’s addicted to. I was very badly addicted for years to nicotine, in the form of cigarettes, and what I observed was that wanting a cigarette was quite different from wanting the feeling of a job well done, or wanting sex, or wanting a new car, or in fact most other kinds of wanting. Many different internal states could set off the craving for a cigarette: boredom, fatigue, hunger, irritation, anxiety, perplexity, difficulty concentrating, a vague feeling I was not up to doing a good job at some task I was facing. What all these states had in common was that they were unpleasant. And when I craved a cigarette, it seemed as though it was *the* remedy for the particular form of dysphoria I was feeling. So while I knew that I was addicted, the cravings did not feel like what one would imagine addiction feels like — a powerful inexplicable desire to have a dose of whatever one’s addicted to. It felt like cigarettes were a drug I’d discovered that fixed a multitude of bad states of mind I was subject to, and I simply could not face life without the excellent aid I’d discovered. So the craving of of the addict, or at least of me as an addict, was quite different from natural cravings. It was quite unlike a craving for sex or an attractive possession. There was no object of desire -- just the illusion that cigarettes were the cure for whatever was ailing me.
By the way, I am pretty sure the when I first started smoking, cigarettes really did improve a lot of the minor dysphorias of my life. And I’m positive that by by the time I was addicted, and could not get through a day without cigarettes, they did nothing at all alleviate the minor dysphorias. And yet I still had the feeling that one would.
Your introspection is incredibly insightful and connects a lot of dots for me in understanding addiction. I’ve noticed that mild intentional discomfort- such as cold showers is powerfully effective at combating addictive behavior. It seems to me that increasing your general tolerance for mild discomfort makes addictive behavior easier to control, and less appealing.
Yes, I agree, except I'd call it increasing your tolerance for the *idea* that you are in for some discomfort. Once I was addicted to cigarettes, they really did not fix fatigue, boredom, difficulty concentrating on the paper I was writing, or whatever. And if you had asked me at the time whether my latest cigarette had in fact help me formulate the next sentence in my paper, I would have said, no, not really -- "but," I would have added, "without the cigarette I think cranking out the sentence might have been even harder. And I'm pretty sure there are times when a cigarette is a huge help with writing. Yeah, OK, I can't come up with an example, but . . . " So I wasn't avoiding discomfort with them, I was just really stuck on the idea that overall they often helped, and being me would feel a lot harder without them. So I think the usefulness of cold showers would have been a way to remind myself I could voluntarily choose discomfort, even with the knowledge that I had no little magic helpers to take the edge off.
You’re exactly right… the cold showers themselves never actually get easier either, they suck. What you get is more like a combination of accepting the fact that you will be uncomfortable, and knowing that being uncomfortable is ultimately fine- that uncomfortable isn’t intolerable.
This is a very interesting thread!
Yes, I agree with this.
I have been on tirzepatide approaching 4 months. As others have remarked, the effects seem near magical - weight loss is effortless, which would otherwise have only been possible with a grueling (and in practice, long-term unsustainable) keto diet. I did not see a decrease in the desire for alcohol though. I am not a problem drinker but if anything the wish to have a pint or two has become more common. Seems to also have a hedonic reset effect, which translates into higher conscientiousness.
In my experience, the decrease is less in desire for the first drink and more in the reward in general. Alcohol feels less good, particularly as you start stacking doses. The euphoria (puddly though it is) gets reduced to the point where the many unpleasant side effects outweigh it.
Also not a problem drinker, for the most part. But wegovy has absolutely deleted everything in that sentence from the comma to the fourth t.
One thing that was seen in the recent small trial of semaglutide and alcohol use disorder is that the medication strongly reduced heavy drinking but generally didn't reduce drinking to zero.
From my organizations substack:
https://recursiveadaptation.com/p/first-ever-randomized-trial-of-ozempic
"I asked Claude. It had some surprisingly clever guesses."
How many seconds to midnight?
alternative prediction: someone really underestimated how corrupt the medical science was and was successful with indirect soft methods of corrupting the data all at once
My worry is that Ozempic might reduce fertility. Maybe the explanation for the Fermi Paradox is that every other intelligent species in the galaxy has discovered a wonder drug that reduces natural cravings, including the cravings involved in reproducing the species.
I don't think lack of desire for sex is the threat to fertility. We have right now plenty of fun crazy ways to have all the sex you might want, including your kinks because kinks are normal and not bad, but having babies out of that sex? No, thank you!
See the enthusiasm for Kamala which includes "and of course she and Walz are correct on reproductive justice", where that means "all abortions all the time!"
Oh, excuse me, I'm always lagging behind on what the current correct terms are: now it's "reproductive health":
https://apnews.com/article/walz-harris-ivf-abortion-reproductive-rights-55cb772464c99ba9c2b4c2043cb87560
"The makings of a presidential ticket began in an unusual spot six months ago: a Minnesota abortion clinic.
At the time, it was a historic visit for Vice President Kamala Harris — no president or vice president had ever made a public stop at one. But the visit laid the groundwork for Harris to connect with Minnesota Gov. Tim Walz and learn about his interest in reproductive health, an issue Harris has taken the lead on during her White House term.
At first glance, the 60-year-old governor might not seem the most likely of political surrogates to talk about abortion and pregnancy. But Harris found a partner who has a track record of increasing abortion access in his state and can speak comfortably about his own family’s struggles with infertility.
...Democrats have warned that access to birth control and fertility treatments could be on the line if Republicans win big in this election. The concern grew more frantic after an Alabama Supreme Court ruled in February that frozen embryos could be considered children, throwing fertility treatment for people in the state into question. Democrats and Republicans alike, including former President Donald Trump, condemned the ruling, although some conservatives have said they support it.
Most Americans — around 6 in 10 — favor protecting access to IVF, according to an AP-NORC poll conducted in June. However, opinion is less developed on whether the destruction of embryos created through IVF should be banned. About 4 in 10 neither favor nor oppose a ban on the destruction of embryos created through IVF, while one-third are in favor and one-quarter are opposed."
Yes, the very thought of the prospect of embryos created because couples wanted children, actually becoming children, threw everyone into a state of being "frantic".
We want sex, we don't want babies. If Ozempic means we don't want sex either, it won't be to blame for reduced fertility.
It is odd how in *certain* areas the sight of a pregnant woman, once so common, is now much more of a unicorn.
The old etiquette chestnut from Dear Abby or Miss Manners (or TV joke) about asking a woman if she's pregnant, seems quaint now.
What is interesting and under-discussed to me is the eugenic aspect of abortion. I don't mean by the government; I mean that everyday decision a girl or woman makes about the potential parentage of her child.
Not that the decision is always made wisely.
When I was a kid visiting my grandmother with my twin cousin, we would go for long walks on the summer evenings. We would walk from the nice-enough but relatively modest midcentury ranchers (hers was one, and it had not been the home in which they raised their kids but was the realization of my grandparents' dream, my mother only living in it a couple of years) in the direction of the golf course and the much-fancier section of homes (all American cities had these sorts of neighborhoods cheek by jowl; even within a couple miles, there were very ramshackle bungalows, but we didn't choose to walk that way as we liked to go barefoot and walk on the lawns).
We would walk past one house that was our favorite. It interested us because it was so marvelously Prairie Horizontal: it was low and hundreds of feet long and very cool. Rich people lived there. It held more intrinsic glamour than is now to be seen in many a more prosperous city/zip code. And my grandmother would sometimes murmur something about how this could have been my mother's house.
I wasn't quite sure what that meant, but of course later on learned that Mother had been knocked up by her junior high/high school boyfriend.
(Interestingly, she persisted in thinking this had been some sort of immaculate conception, so there may have been more at stake than just living in a fine house, near her beloved parents.)
A lot of us are here because our mothers had abortions.
We are pro-life, inevitably, all of us - as is routinely pointed out. And we must, I suppose, be selectively pro-abortion.
Discrimination is all.
I should add that while I was much too little to have understood *anything* specific, yet I did intuit that my grandmother's vague remark implied my non-existence somehow. It raised my infant defenses and I thus did not press her on this subject.
Great article!
"Diabetes is a well-known risk factor for Parkinson’s, Alzheimers, and other dementias.": actually diabetes is probably protective from Parkinson's disease (like obesity): https://pubmed.ncbi.nlm.nih.gov/38113326 (we see that in animal models as well, although these animal models are pretty bad for neurodegenerative diseases: https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-023-01733-9 )
Ozempic: "wouldn’t some conditions be better in the starving state?" I remember an article in Life magazine in the mid to late 1960's about chickens kept on a starvation diet that lived twice as long as normally fed chickens.
Well, it does sound like Huxley’s Soma.
Beware.
Anecdotal: 15 years ago I was two stone overweight (it snuck up on me: 1 pound per year for 28 years of marriage!). I gave myself a year to get back to the BMI line. After a few rough calculations, I adjusted my diet by reducing my lunch from 6 slices of bread to 4. A year later I hit the BMI line. I carried on with the same diet but my weight fell no further. OK, there might be other factors like my family not encouraging me to have second helpings and I may have relaxed slightly after hitting my target, but I just wonder how much effect the mind has.
Must close - 4 slices of bread are waiting.
I think I also reduced my 4 (plain) Digestives to 2. :)
The only other change I can think of was that it was about the same time as I started a daily walk of about 40 mins. I've checked with my wife and she says we didn't reduce portion sizes.
And I've never understood is why, once I reached my target weight, it stabilised and didn't carry on down. It wasn't asymptotic. I just stopped losing weight. Since then I've been able to adjust it (up or down) by making minor changes.
I don't like the mind-over-matter interpretation cos even if the brain controls your weight, it doesn't mean the mind has access to the levers.
Anyway, I was amazed at how easy it was to lose weight, at least for me.
I guess it falls under self-inflicted placebo effect, but if it works...
Did we see any of this hype around other indications ten years ago when the GLP-1 inhibitor saxenda (liraglutide) was approved? I know it was not quite as efficacious as wegovy in weight loss, or is it maybe attributable to the hype cycle Scott mentions?
Does the differing efficacy of liraglutide compared to semaglutide in weight loss allow for any conclusions around potential efficacy in other indications, ie does it tell us something about the MOA?
Great article! Do you think there are any large external environmental factors at play/any research suggesting the relative effectiveness of the drug varying between for instance obese individuals living in urban city areas vs rural areas?
If it's an effective treatment for dementia related diseases, profits will be astronomical.
Great writeup, fascinating.
Does this make you more inclined to believe a SMTM-style environmental contributor to obesity?
Are there any drugs or situations that invert this and make people both more susceptible to addition and overeating?
Kinda curious how this differs from the appetite suppressing effects of other drugs, like nicotine (which as far as I know does not reduce but correlates with other compulsive behaviors).
EDIT: Ok now I'm reading "Nicotinic Receptor-Mediated Effects on Appetite and Food Intake" https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2367209/ thanks for sending me down this rabbit hole :D
If anyone wants a rant ~arguing from the meta level that we should expect this to all be publication bias https://open.substack.com/pub/mackgallagher/p/glp-1-agonists-are-as-expected-an?r=2bgcsx&utm_medium=ios
Dr. Peter Attia writes: “Over 80% of deaths in people over 50 who do not smoke can be grouped into 4 main categories, what I like to call the four horsemen of chronic disease. These are: (1) atherosclerotic disease (comprised of cardiovascular disease and cerebrovascular disease), (2) cancer, (3) neurodegenerative disease (Alzheimer’s disease being the most common), and (4) metabolic disease (a spectrum of everything from hyperinsulinemia to insulin resistance to fatty liver disease to type 2 diabetes).”
He goes on to explain that the first three “horsemen” are really standing on top of the fourth. Might this explain that cure-all effect of Ozempic and related drugs? Fix metabolic disease, and maybe you fix the others?
To expound on the ❤️, I most like the interrogative stance of the article. Many assume health and medicine practices are answers and meanwhile there’s just a sea of questions around us.
Libido is so complex. I think there are addiction like reasons people have sex, and other more wholesome reasons, as well as identity confirmation/ego stroking. I imagine these drugs rearrange the reasons for wanting sex to align with the more wholesome reasons, but i can’t know until i try it out.
Great read and exciting and fun! Thank you!
> But GLP-1 drugs are starting to feel more like the magic herb. Why?
Reading through, late, haven't read comments, here's a wild guess: satiety. The feeling of relaxing after a satisfying meal, or having completed a project, or your personal equivalent of "post-nut clarity". The rest of the time, our mind is warped by hormones messing with our brain to get us to do things necessary for us to survive in the ancestral habitat, but when they're all muted out, we can think rationally. And much of modern life requires rational thought to navigate properly, while ironically much of modern life has been designed to manipulate us through overriding our rational thought.
> First, it made rats eat less. But second, when presented with very tasty food vs. normal food, it made the rats stop preferring the very tasty food.
So far so good.
> But also, when a meal comes in, the body diverts other resources towards the digestion process (this is why a big lunch makes you tired). Maybe some of those resources come from the immune system, so immune cells stand down while you’re digesting.
That's what I'd guessed. Folk wisdom is that when sick, we should only eat easy-to-digest foods, so that the body can devote energy to fighting the sickness. If this is modulated in a Rube Goldberg way (not unprecedented in evolved systems), by recognizing when we've eaten, and tuning down other systems like immune response, then I can see how this would work, although it would imply that these drugs would make recovery from actual illness harder. (Unless all the people taking these drugs also happened to have good health insurance and are thus deploying the full power of modern medicine against their diseases... But even then, if it can produce enough other healthy side effects like lower obesity and longer sleep, it might be hard to notice.)
> Lots of bodily processes change based on whether you’re starving vs. well-fed.
My impression, based on a bit of research before fasting, was that one of the side-effects was that the body started to do priority-based recycling. Breaking down old worn-out bits and reusing the parts in place of normal food. And this is why short-term fasts can seemingly improve health, even if long-term starvation is still bad. So for the drug, if people still eat a normal amount, this process might not trigger? Or maybe we'll start to see bad effects in a few more years. Or maybe this whole model is woo-woo pseudoscience. :-)
This was a fascinating deep dive into the potential future of semaglutide and its impact on healthcare economics. As a teacher trying to stay updated on topics that cross into the realms of health and public policy, I appreciate the balance you struck between optimism and skepticism. The transhumanist angle adds an intriguing layer to the discussion—especially the idea that obesity might one day become as optional as a fashion statement. It’s a thought-provoking read, and I’m curious to see how these projections play out.
By "diabetes" you mean type 2 diabetes. Language matters, not only because it's cruel to lump kids with type 1 in with the stigma associated with type 2, but also because the drug won't affect people with type 1 the way it will affect people with type 2.
I think drug companies should offer a controlled trial for opioid addicts as a first priority. Then offer to alcoholics in treatment, then nicotine addicts. This should all be paid for by the govt which failed to protect them in the first place. Maybe it would be a panacea for homelessness also. There has to be a greater good for these drugs than vanity.
"If you want to learn more about GLP-1 receptor agonists and addiction, including the application to public policy"
Misread as
"If you want to learn more about GLP-1 receptor agonists and addiction, including the *addiction* to public policy"
... Some people are definitely addicted to public policy!
"maybe the inflammatory nature of the starving state really hurts a lot of systems. " did you mean to wrrite inflammatory nature of the well-fed state?
hmm i must be misunderstanding it then. Cause doesn't he write earlier how fasting (which surely must put you into a starving state) reduces inflammation?
This is fascinating. Thank you. Unfortunately, these drugs run a grand per month so only well-off people can access them. The greatest medication in the world is useless if you can’t have it.
"softens menopause"
Tremendous breakdown here. I've personally been doing a double take lately myself on all the magics of Ozempic. Well work the read. Thank you for the great research here!
Alcohol gets processed through the liver directly -- first in priority -- without an insulin spike. It's very analogous to purse fructose in this sense. But it's not a duplicate. All carbs except fiber eventually get converted to glucose. But alcohol does not. It gets converted to acetate, which is a fatty acid, for the body to use as energy.
Alcohol is a 4th and separate macro.
Thanks Scott! These drugs are definitely odd in breadth of effects, but I appreciate having such a good summary of our current state of understanding.
The biggest unusual factor I learned in your article is the change in apparent relative value between normally-extremely-desirable (but likely fatty or sugary) food, and healthy-but-mundane food. The big questions that come to mind for me based on this regard:
1 - mechanism concerning food
2 - sexual kinks/fetishes
3 - pedophilia or paraphilias
(note: I'm using 'Wegovy' specifically or 'SGLT1 inhibitor' generally as a stand-in for any of these type of drugs, but am not certain if this is quite valid as terminology or treating everything as a single class. you get the point though)
1 - mechanism regarding food
Not the physiological mechanism which you address to the extent we know, but the more conscious psychological effects.
Does cheesecake literally seem less tasty when taking Wegovy than when not?
Or does a kale salad seem more tasty?
What would the same people rank how much they enjoy desserts or other treats, vs baseline foods, when on or off of the SGLT1 inhibitor?
When on the drug, does their perceived memory of how much they enjoyed the foods also change?
It seems hard to relate to taking a drug whose mechanism is to make less enjoyable something which is currently very enjoyable, as the temptation seems to be "quit the drug so really fun thing is really fun again", so I'm very curious the rating and memory effects and whether they help explain the psychology.
(I have never tried SGLT1 inhibitors, so my closest analog would be taking Diamox for altitude sickness. I normally greatly enjoy pop/soda/'Coke' as a treat. Diamox works via affecting CO2 levels in blood, with a side effect of making carbonated beverages taste like crap (e.g. flat, and overly sour). For me, countering altitude sickness is easily worth it, but I remember pop tasting good, and look forward to having it again once off the med. Why is a Wegovy and cheesecake scenario not similar?)
2 - sexual kinks or fetishes
I love your joke about funding a study to see if SGLT1 inhibitors make people not want sex less, but maybe make them care less about whether the sex is good.
More seriously, I'd love to know what effect they have on outside-the-norm sexual cravings and behaviors. Does Wegovy or similar make vanilla sex 'good enough', such that those with strong kinks/fetishes no longer want or act toward them as much?
I don't expect we're going to get funding, IRB approval, or a RCT to come out of this either.
However, maybe there's a place for a follow-on set of questions for Aella's kink survey related to usage of SGLT1 inhibitors?
3 - pedophilia or other paraphilias
The most extreme, and possibly socially/legally valuable, case of #2 then would be whether these drugs affect cravings and likelihood of acting upon destructive/damaging paraphilias, such as pedophilia.
If SGLT1 inhibitors can dull the extreme craving and make safe, adult, consenting sex desirable enough compared to the object of the paraphilia, this seems like a huge win for treatment options.
I understand the whole area is so taboo that study may be difficult, but hope there is some move to study this, even as part of an experimental treatment/punishment in the justice system.
"There’s a pattern in fake scammy alternative medicine. People get excited about some new herb. They invent a laundry list of effects: it improves heart health, softens menopause, increases energy, deepens sleep, clears up your skin. This is how you know it’s a fraud. Real medicine works by mimicking natural biochemical signals. Why would you have a signal for “have low energy, bad sleep, nasty menopause, poor heart health, and ugly skin”? Why would all the herb’s side effects be other good things? Real medications usually shift a system along a tradeoff curve; if they hit more than one system, the extras usually just produce side effects. If you’re lucky, you can pick out a subset of patients for whom the intended effect is more beneficial than the side effects are bad. That’s how real medicine works."
From this, I take the author doesn't think that herbal medicine is "real" medicine and allopathic medicine is the real thing. Herbal medicine is the mother of all medical science and many or most drugs today are derived from it. With such a biased attitude I don't put much stock in what the author is saying and I question his motivations.
I don’t know about the author, but the marketing of “natural herbal remedies” puts me off. Natural <> good. Herbal just means it comes from plants. Remedies is an attempt to avoid the word “medicine” and FDA attention. It smacks of quackery.
Two questions: Should I take Aspirin on a regular basis? Should I take Ozempic on a regular basis?
Take a pill of healthy living on a daily basis and you’ll be fine
I exercise daily and watch my diet. Still, I want every advantage I can get.
Cool
... so how *do* you get Ozempic?
(sorry if this is an overly stupid question)
Be fat or diabetic, have good insurance, and go to the doctor.
In Slovakia, and probably elsewhere, there is a randomised controlled trial on ozempic-like drug orforglipron by Eli Lilly. The trial is for weight loss. It is a small molecule, does not need to be injected, just eaten, and there are hopes it will be cheaper when it is approved. I know at least one person who lost weight at the trial. So, maybe, look out for a similar trial in your country ?
I distinctly remember the early Internet, 2002-ish, when we used to make fun of prudes who are afraid that other people are having too much fun. People who call masturbation a sin etc.
Well, this didn't age well? Now dopamine desensitization is understood to be a thing, and yes too much porn / masturbation is one of the big ways how it happens. Apparently a little puritanism is a good thing... now the media is full of restoring dopamine levels by regularly abstaining from this or that, and doing painful things. Like cold showers. Lol, cold showers sound exactly like what a Scout leader in 1900 would say. (I tried it once and I felt like getting a heart attack.)
BTW I keep wondering how the old time looks-oriented body-building got replaced with the squat-and-deadlift Rippetoe thing now. Why would dudes want strong legs instead of spectacular arms? I think it is the training itself, not the results. Basically the training just sucks and they do it for exactly this reason, all that struggling resets something in the brain, maybe dopamine.
So this can be fixed with a drug and then we can go back to unashamed hedonism? Sounds too good to be true.
Strength training is rewarding because you get stronger consistently over time… and is useful because the strength generalizes. It’s mentally challenging as well and requires a lot of skill and technique. It does also make you look stronger, even on a regular diet. Bodybuilding is mostly boring repetitive movements, and you generally see little actual strength improvements- and you don’t really look different either unless coupled with strict dieting to get lean.
Cure all but one disease? https://www.msn.com/en-us/health/other/ozempic-is-changing-people-s-skin-say-plastic-surgeons/ar-AA1oF5t4
If a quarter of the money spent on these drugs was used to get people walking 10 min after every meal, we wouldn’t be reading this article
One thing I don't really understand: With fasting, insulin remains very low, and this is "good" because it increases insulin sensitivity and is therefore good for metabolic health. If I understand correctly, semaglutides give the body the signal to reduce blood sugar which involves *higher* insulin for longer, but this is also "good"? What am I missing? Since this treatment originated to help type 2 diabetes, it can't be bad for insulin sensitivity I guess but the high/low insulin discrepancy (compared to fasting) doesn't make sense to me.
Also, everyone here seems to go on the medication long term. What about just short term to lose some weight then stopping it? I'm not technically obese but increasingly struggling to keep weight down due to age/menopause etc. Have a very good diet overall (no junk, don't drink, low carb, fresh homemade food) but also a big appetite so probably eat more than I strictly need. Feel like I could maintain a good weight if only I could shed the extra 10-15kg that has crept up over last 5 years or so. Has anyone done short term then stopped?
Glutides only increase post-prandial insulin production. This is good because it keeps your blood sugar from spiking. It’s also optimal because it sidesteps insulin sensitivity that is the hallmark of t2d.
Since you are in a semi-fasted state (thus with low insulin levels) the rest of the time, you get best of both worlds.
"wouldn’t some conditions be better in the starving state?" - maybe autoimmune conditions (https://pubmed.ncbi.nlm.nih.gov/37572827/), but evidence is mixed. Especially strong in murine models of lupus (https://pubmed.ncbi.nlm.nih.gov/?term=lupus+calorie+restriction), except when the effect unexpectedly reverses (https://pubmed.ncbi.nlm.nih.gov/33187196/). Some evidence fats matter (https://pubmed.ncbi.nlm.nih.gov/?term=lupus+omega+3). This is all generally consistent with Scott's argument that eating creates low-level inflammation, which is elevated in autoimmune diseases.
also, there is a case report of "Semaglutide-Induced Lupus": https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10981839.
Love pet pet
Anytime I hear the word “miracle drug” two things occur. 1, it’s not. And 2, pharma propaganda ignores #1.
Should have titled it "Why did God give your brain a special lever that only porn and cocaine can pull?" but, yeah - fantastic. Illuminating!
Been a while since there's been one of these "More Than You Want To Know"-style posts, although this one's less long than some previous pharmaceutical epics. I've missed such content. Classic ACX, keeping the Better Living Through Science(tm) light alive in a cynical age. Can't wait to see if these drugs eventually filter down to the (non-obese/diabetic) genpop in some form...and, of course, it'll be interesting to see how addiction profiteers try to run interference. A world without whales would be better overall, but boy do some industries count on them for survival.
I take GABA and has no effect on food intake. Just makes me sleepy after 2 hours
1. "Diabetes is a well-known risk factor for Parkinson’s, Alzheimers, and other dementias"
Eating too much sugar seems like it is really bad. It destroys your brain. Perhaps, switching all sugars to aspartame would be better.
2. Since you believe alzheimer's is partially caused by inflamatory responses perhaps we should make a clincal trial, where NASIDS are used to slow down alzihmers.
3. Why is mild inflamation bad. I though it just clears up dead cells and helps tissue regenerate. You just state, "This is bad."
4. You say some food promotes GLP-1 release, while others foods cause a light inflammation response. Which foods cause a light inflamation response? I would try to avoid them.
5. Why does food cause a light inflammation response?
My request is that you do the next article of fasting. Is it good or bad? I thought your thoughts of different bodily processes while fasting where very interesting.
The main reason I'm here is because Scott write's Bayes' theorem as the context for Astral. Bayes is a different way of thinking, and when properly constructed allows us realize that humans are pretty piss poor at thinking through a Bayes filter, which turns out to be important.
We stumble across GLP-1 (and everybody should listen to the Aquired Podcast on Novo Nordisk for more context) and we infer that the only use for this is for weight loss. In reality, our biological system is so complex that we only get generalities of how it works, then we run phase I, II, and III trials to hope that we get some type of drug that does something like what we were hoping. If we get lucky, we say "well we understand how that works." Then confirmation bias forces us to say that any new area of impact "must have something to do with our original thesis."
I think the real issue is that new data is coming in, and rather than immediately trying to make it try into our existing framework, we say "more work to be done." Hypothesizing is not bad, but perhaps GLP-1 is part of a more significant cascade of signals in the body that we are fooling round with. I am glad that the results seem positive so far, but we should be worried that we don't understand what is going on.
And Scott has done a great job of getting me thinking, which I would expect from somebody that like to think in a Bayes framework.
Why don’t Americans stop eating all this chemical crap that masquerades as so-called food and causes most of the deterioration in public health? You are merely fighting symptoms with more and more drugs, without tackling the root causes. The health of most of the population is going down the drain, and yet big pharma comes up with more and more “wonder” drugs that in the long run make matters worse.
Hallelujah, someone with common sense! As a non-American living in the US I look around me in total astonishment at this utter insanity.
I lived in the US for 36 years, and have been back in Germany since 2010. It’s interesting to see how the food supply chains in Europe are under attack by the chemical, agri-business, and pharmaceutical companies (all of the same ilk). They are slowly chipping away at people’s resistance to concoctions that are marketed as food. It doesn’t help when here in Germany many people want to minimize their food bill when they go to the grocery store.
I’m not surprised to hear that. Big pharma and big ag are slowly getting a stranglehold on the whole world 😕
I'm not being sarcastic here, if a couple problems get solved in AI, everyone could be running these kinds of labs with the right computer equipment in their own homes at exponential rates. I wonder what happens when nobody gets sick anymore. What is that to a world?
This made me think about how so many of our most useful medicines are derived from a nature source (in this case, Gila Monster venom). A doctor friend told me awhile back that most pharmaceutical companies don’t spend nearly enough time and money investigating natural sources for drugs because it’s easier to patent drugs that are completely synthetic.
This made me think about how so many of our most useful medicines are derived from a nature source (in this case, Gila Monster venom). A doctor friend told me awhile back that most pharmaceutical companies don’t spend nearly enough time and money investigating natural sources for drugs because it’s easier to patent drugs that are completely synthetic.
Did you know the AI voice that reads the article has added in some of its own flair, meaning reading text that is not present in the written version. There is a part near the end about how it’s doubled the economy of Denmark (or one of those Scand countries), I’m following along reading the text and listening and they aren’t matching. WHY IS AI NOT JUST READING WHAT IS WRITTEN? It’s really messing with my head. I’m not crazy right? Shouldn’t it just be reading what you’ve written?
It was in the original version of the post, then Scott edited it out
I read this post about Ozempic months ago when it was first published. While I found it intriguing, I didn't give it much further thought at the time. However, a recent personal experience has compelled me to revisit the topic and share my story.
For context, I've been struggling with sex addiction for years. This isn't a self-diagnosis born from a high libido; it's a severe condition that has significantly impacted my life. Despite having a high-paying job and a supportive family, I've found myself engaging in extremely risky sexual behaviors, including seeking out sex workers in dangerous areas of town. These compulsive actions ultimately led to the dissolution of my first marriage. I've been in treatment for about a decade, and while I'm largely in recovery, the cravings have persisted.
Given that I'm not overweight enough to be prescribed Ozempic, I initially dismissed the post's relevance to my situation. However, about a month ago, I came across an advertisement for a probiotic designed to reset gut health and reduce sugar cravings. On a whim, I decided to give it a try.
Over the past month, I've traveled extensively for work. Typically, these trips would be challenging, as they presented opportunities to act out. To my astonishment, I experienced zero cravings during my travels. For someone who hasn't been able to visit a new city without fixating on the possibility of encounters with sex workers for over two decades, this was nothing short of remarkable.
It wasn't until today that the oddity of this situation truly struck me. I realized that this dramatic change coincided with starting the probiotic regimen. Intrigued, I researched the product and discovered something fascinating: it's a GLP-1 probiotic. This immediately brought to mind the Ozempic post, prompting me to revisit it.
While this is purely anecdotal, the probiotic appears to have completely eliminated my addictive cravings and poor decision-making around sex. The parallels between this GLP-1 probiotic and Ozempic's effects are striking, potentially suggesting a broader application for GLP-1 agonists in treating various forms of addiction.
I share this experience in the hope that it might contribute to the ongoing discussion about GLP-1 agonists and their potential to address a wide range of compulsive behaviors. It's possible that we're only beginning to scratch the surface of these compounds' therapeutic potential.
What was the name of the GLP-1 probiotic?
I started Ozempic in June. As of now, I've noticed (though correlation is not causation, or at least that's what the Tobacco Institute tells me) about twelve distinct medical problems that I've had which have cleared up. Some of these were not at all obvious, like meibomian gland dysfunction.
After reading this I'm really curious about potential of GLP-1 receptor agonist drugs (not just Ozempic) as an anti-aging intervention. If they activate signalling system that makes people feel full, it might help with maintaining caloric restriction, which is known to extend lifespan. Additionally if it indeed has strong anti-inflammatory action it would directly affect one of the hallmarks of aging, so called inflammaging
It would make evolutionary sense for there to be several separate reward systems. Just because you are satiated on food does not mean you should avoid sex, or cease to explore your environment, or whatever other reward systems there may be. We may have some overloads like generating pleasure, but if all the reward systems were in sync that would not promote survival.
Great to see the Australian Bluetounge lizard get some love.
No thanks
Y'all who are taking that poison really need to read this article. Its long, but writes out the entire BS of this scam, starting with the sugar industry.
https://open.substack.com/pub/conspiracysarah/p/sugar-and-ozempic-the-long-game-of?utm_source=share&utm_medium=android&r=p6r68
And they don’t cause atrophied heart muscle?
Mounjaro has taken the food gremlin that lives in my brain telling me to eat all the time had made it shut up. Do you have any idea what it’s like to live with that?
I thought everyone had a good gremlin whispering in their ear every waking moment and that skinny people had really amazing self control.
Now that the food gremlin is quiet, I actually have the brain space to focus on what I’m eating, when I’m eating and why. This is such a novel change and I love it.
Just to note in response to the below that this is very plausible when you consider that many people coming off an addiction appear to balloon in weight to compensate. Could the reverse be true too - could say, highly addictive things reduce hunger? Heroin, meth and smoking would seem to indicate possibly?
I am posting this right after reading this paragraph so I sure hope you don’t address this and I feel very silly…
“GLP-1 suggests maybe this was originally a food reward system. Or at least food was a big enough part of its portfolio that it was a weird but functional hack for a satiety-signaling chemical to just turn off a whole subsection of the reward system. “You’re already full and well-nourished; why would you need the ability to crave things?”
Reflecting on what is an otherwise comprehensive and fascinating review, it’s surprising that the potential interplay between GLP-1 receptor agonists and the endocannabinoid system wasn’t addressed. Emerging research suggests that the therapeutic effects of GLP-1 receptor agonists, such as Ozempic (semaglutide), may involve interactions with the endocannabinoid system. For instance, a study published in Diabetes demonstrated that coadministration of a peripheral CB1 receptor inhibitor with a GLP-1 receptor agonist led to greater reductions in body weight and fat mass in diet-induced obese mice compared to monotherapies, indicating a functional interplay between these systems.  Additionally, research in the Journal of Endocrinological Investigation found that levels of certain endocannabinoid-related molecules could predict the metabolic efficacy of GLP-1 receptor agonist treatment in humans with obesity, further supporting the notion of cross-talk between the GLP-1 and endocannabinoid systems.  These findings imply that the endocannabinoid system may play a role in mediating some of the diverse effects observed with GLP-1 receptor agonist therapies.