Plain English with Derek Thompson - The Weight-Loss Drug Revolution, Part 1: Why These Drugs Work So Well

Episode Date: December 12, 2023

Today’s podcast is about the weight-loss drug revolution—which I believe might be one of the most important stories in the world right now. Despite all the attention weight-loss drugs are receiving, it’s possible that they might soon affect the world even more than we realize as they teach us about the science of human metabolism, decision-making, and even free will. Beverly Tchang, an endocrinologist at Weill Cornell, explains how these drugs work, what they mean for people with diabetes and obesity, and how to wrap our minds around their stranger and spookier side effects. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guest: Beverly Tchang Producer: Devon Manze Learn more about your ad choices. Visit podcastchoices.com/adchoices

What's up, everybody. It's Austin Rivers from Offguard, and I've got some exciting news. Offguard hosted by me and my guide, Pasha Gigi, is officially moving to our own podcast feed. We are now dropping two shows every week. Me and Pasha go way back and talk so much hoops already that we figured it was time to fire up the mics and let you in on these conversations. Every week, Pasha and myself will hit on the biggest stories happening around the league. Tap into the show twice a week on our new Offguard feed on Spotify or wherever you get your podcast. Today's podcast is about the weight-loss drug revolution, which I think might be one of the most important stories in the world right now. And despite all the attention that weight-loss drugs are receiving, it's possible, I think, that we might be underrating the effect that these drugs are having on our bodies, on our minds, and on our economy.

I want to begin somewhere a bit concrete, even if it's a bit fanciful. So one way we can begin to tell the story of these weight-loss drugs is for me to tell you about a lizard. called the Gila Monster. The Gila Monster is a heavy venomous lizard native to the southwest U.S. And one of the most unique traits of the Gila Monster is that the reptile only needs to eat once to survive for several months.

In fact, there's some research that suggests they can live on just five meals a year. So about 15 years ago, a small team of scientists studied the saliva of the Gila Monster to understand its metabolism. Like, how does this creature survive on five to ten dinners a year. They found this lizard saliva contained a hormone that lowered blood sugar and regulated appetite.

And when they looked at it very closely, they realized that this lizard gut hormone actually structurally resembled a human hormone, called the glucagon-like peptide 1, GLP1. Today, we are awash in GLP1 drugs, because we have figured out how to design medications that mimic the activity of this very mysterious, very special hormone. The Gila Monster discovery was not the only discovery in the history of our gut metabolism. It was just one in a long string of breakthroughs that have led to the Cambrian explosion of GLP1 weight loss drugs.

Now, you probably don't know them or most. might not know them as GLP1 weight loss drugs, you might know them by many other names. There is Samagliteide, which is sold by the Danish company Novo Nordisk under the names Ozempic or Wigovi. There's tersepetide sold by Eli Lilly under the name Mungaro. We'll talk very soon about the subtle differences between these and other weight loss drugs that are coming online, but they all basically work the same way. They all basically work like that hormone we discovered in the saliva of the Gila monster. It triggers the intestine to release hormones that stimulate insulin production,

which reduces blood sugar, and regulates what's called satiety through the nervous system, that is fullness, which makes people feel full after eating less food. Now, in a country with 40% obesity, 70% overweight,

it doesn't take much imagination to see how a relatively safe drug that reduces calorie intake could make an enormous difference in life and lifestyle and economics and commerce. But what if I told you that we haven't even begun to name the most interesting,

the most spooky benefits of these drugs on human populations. In Novo Nordisk's Wigovi trial involving 17,000 overweight and obese people without diabetes, the drug reduced incidence of heart attack, stroke, and heart-related death by 20%. There is emerging evidence that people taking GLP1 drugs slash their can, candy consumption by more than half and eat 40% more vegetables. There is survey evidence that people on these drugs increase their exercise by double-digit percentage points. For some, it reduces alcohol intake for people with drinking problems.

It reduces smoking for some smoking addicts, gambling for some gambling addicts, and even for some gets them to stop biting their nails. Now, if you are listening along and wondering to yourself, this can't be real. You can't just name a bunch of good stuff and say that this drug magically does all of them. Well, please know that when I first read all these survey results, I had the exact same idea. My first thought was, this isn't real. Someone is faking this. Someone is making this up.

But according to today's guest, Beverly Chang and endocrinologist at Wild Cornell, it's all real. And she's never seen anything like it. Now, I've been accused before of hyping other technologies, say artificial. intelligence, chat CBT. But if you ask me, under oath, what technology I think might have a bigger impact over the next three years in American life, GPT or GLP, I think I might say that the weight loss drug revolution has a chance to be the more significant. That's why this week we are doing not one, but two episodes on the GLP1 drug revolution. Today on the science and Friday on the economic and commercial ripple effects.

Of course, of course, of course. There is no such thing as a miracle drug. And it is absolutely in bounds for us to be concerned about the medicalization of normal life problems. We can't take collective problems like food supply, walkability of urban areas,

pollution, metabolic health, and pretend that we can solve all of these things with one injectable or one oral. That's silly. It's wrong. It's even dangerous. But I want us to consider the possibility that the

GLP1 revolution is even more important and much stranger than most media reports are letting on. We have invented a drug of profound behavioral, even psychological

modification. And we have to talk about it. I'm Derek Thompson. This is plain English. Beverly Chang, welcome to the podcast. Hi, Derek. Thank you for having me. First off, why don't you tell us a little bit about who you are and what you do? So I am a physician and endocrinologist as well as obesity medicine specialist.

I work at Wal-Cornell in New York. And before we talk in depth about the impact of this weight loss drug revolution, I'd love to have a clearer sense of who your patients were and what their options were before anyone had ever heard the word OZempec. What kind of patients did you see and what was their menu of options? when they came to see you? So the patients I was seeing before the, quote-unquote, ozempic revolution have really been people who had both,

like obesity, diabetes. They had more complex medical issues, including high blood pressure, heart disease, et cetera. And the difference nowadays, though, is that there's a greater public awareness, I think, of obesity as a disease and all of its consequences. So now we're seeing people,

patients come in earlier, so to speak, kind of earlier in this disease process before they develop diabetes, even before they develop pre-diabetes. And that's the shift we're seeing. And how would you describe the level of enthusiasm for this new generation of weight loss drugs among your patients compared with the options they had before? Like, have you seen anything like this in your history as a clinician? Oh my gosh, it's overwhelming, really. I mean, It's exciting on one end because I think everyone is finally taking it seriously and they're looking at it as a true medical problem. It's not just a lifestyle choice. It's not something where if you diet hard enough or exercise hard enough, you'll be able to fix it. We realize now from like decades of scientific research that there's a real biology behind obesity and you can diet and exercise all you want.

but if your genetics and your hormones are not in balance, then you're going to be fighting that the whole way. And I think that's the experience of so many of my patients. Do you remember the moment when you first heard of OZempic semaglite or read the results of some of those early reports? I mean, I know that in talking to other people on this show, including Susan Yanofsky at the NIH, who we spoke to last year, her perspective was that she had for years said, if only there was some way to get bariatric surgery without the surgery,

to have some way to provide a medication that could, for the vast majority of patients, almost guarantee 15 to 20% weight loss, but without a surgery intervention, I mean, that would just be a miracle drug, she was saying. And then when she heard, and when other obesity researchers, I think she described this conference they were at,

first saw the results of semagnotide or a similar, a GLP-1, agonist, I mean, people were standing up and clapping like they were, you know, watching the end of, you know, cats, West Side Stories and Broadway show. So I wonder, like, did you have a similar moment of just stand up in your seat? Oh my God, when you began to realize what was coming down the pike? I'm not as exciting as that, Derek, I'll be honest. But I'll tell you this, like, because we've been in the space for so long, we're kind of in the weeds. We see a transition over decades, right? Before OZembek, we were treating people with obesity with like two or three

medications. They had to take multiple pills a day just to get 5% weight loss, like 10 or 20 pounds of weight loss. For someone who's 200 pounds, that's not a lot, but it's better than nothing, right? And then as we developed more and more anti-obesity medications around like the 2010s, 2014s kind of, we are accessing more weight loss. So more than 5%, we're looking at like 10%, with some of the combination medications, for example. And so we're incrementally increasing that weight loss over decades, really.

And then enters something like somaglotide. When we hit that 15% weight loss threshold, suddenly we're seeing the reversal of those other medical problems that we talked about, the diabetes, the high blood pressure, the high cholesterol. Whereas before, when we're losing 10 pounds, 20 pounds, we're seeing improvements. Maybe their blood pressure is getting better. Maybe they're taking one blood pressure medication instead of two now because we got them to lose 20 pounds. But as Dr. Yonovsky has alluded to, once you're getting into these thresholds of

bariatric surgery level weight losses, we're seeing reverse. of those diabetes, hypertension, high cholesterol, etc. And how would you explain to a layperson, what makes somaglite and other GLP1 agonists special? Like, why do they work so well, do you think? It's a little bit of a chicken-or-the-eye question because I think we're learning about the medication just as much as the medication is working for us,

in the sense that because the medication works so well, it tells us, oh, I think now we're really getting at the root cause of obesity. Before, I don't know if you remember, Orlastat, but it was this medication branded under the name Xenacal, but available over-the-counter as ally, and it worked by reducing our body's ability to absorb fat from our diet. It didn't work that well. It was approved back in 1999. It didn't work that well. Now that we're looking at medications that address the peptides, the proteins produced in our gut that then travel into the brain, into the areas of the brain that control appetite, and those are working super well, I think we're realizing, oh, that's really the mechanism of obesity, or at least one of the mechanisms

of obesity. So I think that's why these GLP-1s are working so well, because we, are learning more about the biology and what causes obesity. And then there's also just the convenience of it, too. A lot of these medications are available. It's once a week injections, and I think a lot of patients

really, really like that. So one level deeper on the mechanism because I am so insanely interested in why these medications seem to work and what their effectiveness is teaching us about obesity that we didn't know before. So it seems from my reading,

in research, that the GLP1 drugs do at least three things. First, they stimulate hormones and regulate blood sugar and metabolism. And in particular, these drugs, which were, of course, initially developed for diabetes, promote the production of insulin, which is the critical hormone from mopping up blood sugar. This is the function that's been most discussed in the press. Second, they seem to send some kind of signal through the nervous system that people are full, that we have what is called satiety, that we are satiated, and I really want to talk to you a lot about this. And third, they seem to delay gastric emptying, so food stays in the stomach a bit longer. That's the menu of mechanisms, as I understand them, and we're going to go deeper into that menu.

But anything you want to edit there? I would add the caveat that the slowing of gastric emptying, we think is not the primary mechanism. Yes, it's an effect that we observe, and it probably contributes to that feeling of fullness. But really, the disease of obesity, I don't think is a disease of the gastrointestinal system. We're not seeing that. The disease of obesity is rooted in probably fat metabolism. There's the propensity to store calories in your adipose tissue in the fat. There's something about people with obesity where they just store more rather than burning them.

And then the second piece of that is what you're getting at where the GLP ones really increase that satiety. And they do so through central mechanisms, we say, back to the brain, back to that master control appetite center of the brain. And we are learning more that we're learning more about these mechanisms. And with the new therapeutic agents that are coming out, it's sort of in force. forcing what we're learning, that we're definitely on the right track when we're looking at these gut peptides. Because you know already that we have somatatine, a GLP1 receptor agonist. Just recently, we had the approval of tersephatide, which is a GLP1 and GIP receptor agonist. So that's two different gut peptides. And then there's really exciting phase two clinical trial data

on another medication called Redo-Trutide, which is a triple agonist. so three gut peptides, and we're seeing even more weight loss with three peptides. So I think we're realizing that as we hone in on how the gastrointestinal system speaks to your neuroendocrine system, we're realizing, oh, this is the crux of obesity. It's so interesting. I want to talk a little bit more about exactly how this is changing the experience of and the behaviors of your patients. I want to spend a lot of time talking about the positive, but as a result, I think I actually want to begin by talking about the negatives. What are the most common negative side effects that you are seeing in your patients and that you

are hearing about? I mean, the most common side effects are the ones that the manufacturer reports as well. It's just nausea, reflux, some constipation. I think what's interesting is as these medications become more and more utilized by patients who need them, as well as patients who may not be needing them but are getting them anyway through all these different avenues, whether it's telemedicine or compounding pharmacies. We're discovering perhaps other concerning red flags, but we don't know if those red flags are coming because the medications are just being used in a broader population, or if they're being used inappropriately in the wrong population, we just don't know. Can you tell me what those red flags are? So, I mean, I'm sure many people

have heard of these concerns, like one of them, people talk about stomach paralysis. In the medical world, we call that gastroporesis. And it's really a label for what you described earlier, which is the slowing down of gastric emptying. While we know that that is an effect of the medication, in some people that may cause too much slowing, right? For some people who have diabetes, for example, they already have a slow gut at baseline from the diabetes disease itself. Maybe this medication is too strong for them, for example. Are there concerns, again, on the negative side,

about the intersection between this drug's mechanism and the culture of weight loss. I mean, we know from decades and decades of American and really Western culture that anorexia exists and bulimia exists and there is a fixation with thinness that, of course, can tip into unhealthiness. And here we have a drug that through these various mechanisms,

the insulin mechanism and the central nervous system mechanism and maybe also the gastric emptying mechanism is incredibly effective at helping people lose weight. I mean, how do you, I suppose, as a doctor, as a clinician, think about this drug that can help people with type 2 diabetes, can help people with obesity, but can, of course also, like any other drug, be abused by people in a way that can hurt them, just because the way in which it can hurt people seems to fit very much into this vein of American culture. Yeah, I think that the problem is obesity in if itself is not just a medical disease, but it has so many. psychiatric and psychological consequences to it. If you speak to any patient with obesity, they can tell you how it affects their lives physically, medically, but most importantly, mentally and socially. And so when we see such a great pickup of these medications that cause

15, 20% weight loss on average, you're seeing downstream consequences in every part of their life. In some cases, it's good. In some cases, it becomes tricky because they may be using the medication to enable a maladaptive food relationship. Maybe they're trying to overly restrict themselves. Or it may be another unintended social consequence. I know a lot of patients who have lost weight, they go home for the holidays, they're seeing people who hasn't seen. them for a long time. And then they're faced with all of these questions and judgments, and it's a new area for them to navigate.

This is a tough issue that I'm not sure I have the perfect language for, but we're talking about weight loss drugs and their success and popularity. And I think we have to point out that there is a broader conversation happening here about weight and health. We are hearing that, yes, obesity almost certainly drives unhealthy outcomes for many. obese people, but some people with a high body mass index are metabolically healthy. And it's very nuanced because we don't want to necessarily stigmatize and medicalize every single healthy, heavy person. How do you think about that? I know on a broader scale, you know, people talk about how obesity is, or like the medicalization

of obesity is a problem, right? That this is, we talk about. about it as a disease because there's a very clear hormonal and biological driver. But then there's, it's also true that there are people who have higher weights, who have a bit larger body, and they don't actually have any medical problems. And maybe they're even fitter than you or me, right? And so this, this movement they call health at every size, I think, has been given a counter-narrative to obesity as a medical disease, whereas I think it needs to be much more nuanced than that. I know people of the Hays movement says that we don't, we shouldn't treat obesity, right? That we can be healthy at any level of our

weight. And it's interesting because recently there was a Nature article that was published following individuals at different weights over the course of decades of their life to see who actually developed a medical problem, who actually developed diabetes or who developed consequences of that weight. And 20% of people with excess weight still didn't develop any consequences of it. So I actually suspect that as we progress in the true, treatment of obesity, we're going to get better at distinguishing people with obesity versus people who just have higher weights. People who have higher weight, carrying more fat, larger bodies,

whatever it may be, whatever people are comfortable with that description may be, may not be a medical disease. And they're not the people we're trying to target. But right now, the way we define obesity as this like physical characteristic doesn't serve that purpose just yet. So we do need to do better as a medical community. It's really interesting to think about the idea that, you know, I presented you a question that said, you know, how is this drug going to negatively affect America's relationship with weight? And you're saying, yeah, it could absolutely and may already in many ways for many people be negatively affecting Americans' relationship with weight. But also, we don't understand the science of obesity yet. And this drug is in many,

many ways helping us to understand the science of obesity. And if we did somehow, in some near future, get a perfect understanding of the science of obesity, there might be less shame about certain kinds of weights because we could see exactly what kind of obesity or for which people excess weight was leading to bad health. And for which people, they were simply, you know, they simply had a higher BMI. But at the level of blood chemistry and, you know, LDLs and blood pressure, they were actually just as healthy as someone with a BMI that was like half of that. And so that's a really interesting answer, that the science might be following the technology and making us all smarter about weight and health. Let's move to some of the positive

and sometimes surprisingly positive aspects of this drug. I'll sort us off with a very general question. What's the most significant way that you've seen patients change their life for the better? Is it mostly reduced calorie intake leads to weight loss, leads to better feelings about weight loss and better health? Is it sort of that linear or there are other significant ways that you've seen patients change their life in response to these drugs? It's a hard question to answer because when you speak to a patient with obesity, it really does affect all aspects of their lives. The clothes they wear, the job that they interview for, the people they hang out with, what their, weekends look like. Of course, food choices and physical activity is all rolled into that.

It's, in a way, it's linear because there's a bit of a snowball effect. Once they start losing weight, or rather, once they, their brain has a handle, has control again over when they feel full, when they feel hungry, then everything's starts to fall into lime, right? You'll hear people talk about food noise, the absence of food noise, where once they start taking a GLP1, they realize that they were thinking about food all the time. They're eating breakfast and they're thinking about what to do for lunch. And once they're on a GLP1, all of that goes away. And then they have this sort of new mental clarity to be focusing on anything else.

That could be, you know, whatever their next work task might be or that might be planning a vacation or anything else. So I think for my patients, when they start on the medication, number one, there's a mental change.

There's that hormonal change where they feel, a difference in their fullness and hunger levels and then a mental change where their relationship to food becomes so that they see it as just sustenance, their brain sees it as only sustenance and not a source of comfort. And then everything downstream of that is what we've discussed before, just relationships with people, activities,

they feel more energy to be going out and exercising, perhaps, all of that. And this is where, to me, the effects of these drugs is so mysterious and almost wondrous. And I'm always cautious when I talk about, you know, the effects of a new technology being wondrous, because there is no miracle drug. And yet at the same time, I was just reading a Morgan Stanley research paper on this new class of GLP-1s. And this is just sort of my paraphrasing of their research. the highest share of respondents to Morgan Stanley surveys report eating fewer snacks, baked goods,

and salty snacks. One study found they reduced alcohol and candy consumption by 60% and increased fruits and vegetable consumption by 40%. Another survey found a 40% reduction in snacks and a 36% increase in exercise. Can I just admit, that doesn't seem real. Like if you came to me and you said, hey, we invented an injection or a pill, and it makes you eat less candy and eat more vegetables. It makes you eat fewer snacks and increase your exercise. I would say, you can't just list a bunch of healthy habits and say we invented a medication that magically makes all those things happen. And yet here I am, like reading the results of a Morgan Stanley survey on GLP-1s, and Morgan Stanley's job is not to bump up the stock of Novo Nordisk, it's to help their investors

figure out, should I put money in Eli Lilly in Nova Nordisk, or should I put money anywhere else in the economy? And here they're saying, this is what we think these drugs seem to do. Is this serious? Like, help me make sense of this. It just, it does, I have to be honest, as someone who, as a journalist, is paid to be skeptical, even as I want to be a techno-positive person, it doesn't seem real, and yet I'm reading it right here in a report. I think everyone believes it to be real. This is why people in like the food industry are panicking in some respect because they're like, oh, how do we get people to still eat highly processed foods, highly palatable, rewarding foods if so many of them are going to be on these medications that fight that feeling?

You know, we've known for decades that the food industry has thrown in so much time and energy into the science of food and taste buds, finding that quote unquote bliss point, right, where a food needs to feel rewarding, but not satisfying in a way. It shouldn't make you feel full, but it makes you want to eat more, that kind of hack.

And it really is a way that, in a way, their food industry science has hacked into our brains to take advantage of those appetite and reward pathways. On the obesity medicine side, I think we're finally catching up to that science and realizing, oh, why don't we let's, why don't, can we find pathways to fight that? And we have. And I think the research that you're seeing has shown exactly that. It's almost like you're saying GLP-1s are like an anti-snack drug.

And not just an anti-obesity medication, but an anti-snack drug, an anti-candy drug, an anti-salty snack drug. You're the scientist here. Explain to me a plausible mechanism by which a drug that simulates a peptide, a hormone, would make a person eat fewer snacks. and eat more fruits and vegetables and go to the gym more. I understand that we're dealing with a little bit of a nebulous territory here. It's terra incognita.

We don't know exactly what's happening. But explain to me a plausible mechanism that would explain these survey results. Well, we do know that the GLP1 peptide goes to a lot of different areas of the brain. And there are some areas of the brain that control specifically those appetite thresholds. That's in our hypothalamus,

which is what controls is the master regulator of a lot of things. Like our body temperature, our circadian rhythms are controlled by the hypothalamus. And so the point at which we feel full and hungry, which we throw into the category of homeostasis, GLP-1s act there. We also know that GLP-1s can travel to our rewarding areas of the brain, the dopamine, the serotonin, things that make us feel good. We know that GLP-1s act there too.

So it changes the what we call hedonic relationship to food, where we're just looking at food for comfort or we engage in emotional eating behaviors. The change in preference for taste is still very mysterious, I would say. And I don't know how many of those pathways overlap. certainly it's an area of a lot of research. I'm sure the food industry is looking into it and how to work around it as well. But I think kind of hearkening back to one of your earlier questions, one of the reasons why the GOP ones are so effective is because they have these multimodal effects.

It's not just, okay, food for sustenance. It's also emotional eating. And some of these newer agents which have GIP and glucagon, other peptides, also have what we call peripheral effects on the actual adipose tissue or the fat metabolism. As remarkable as I think I've already made these drugs seem, there is a possibility that there's actually one step further in terms of the remarkableness. Sarah Zhang, a writer for The Atlantic, wrote an article, this past May called,

did scientists accidentally invent an anti-addiction drug? People taking a Zempeg for weight loss say they've also stopped drinking, smoking, shopping, and even nail biting. This is where things go from, all right,

we're talking about a miracle drug here to, this is actually like a little bit spooky. A drug that again discovered as a diabetes drug to resemble a certain peptide hormone might also have this side effect of getting people to reduce their compulsive behavior, reduce their addictions.

I was reading Sarah's really excellent piece again yesterday, and I have a sort of bastardized theory of what might be going on here, and it relates to what you just said. So I wonder if maybe I can just sort of tell you my just-so story here, and you tell me just like how absolutely crazy it is. So I was thinking about compulsions and about the difference between my compulsions and my wife's compulsions. So my wife loves shopping, and I don't. And I love looking up sports stats when I feel bored at work, and she does not. Now, let's say that it's, you know, 1 p.m. on a Tuesday, and we're both supposed to be working, but we're both underslept.

We're both new parents. Our kid has been crying. We have low willpower. and so as a result, my wife, when she wants to procrastinate, she wants to, like, you know, go shopping on her computer. To me, the concept of shopping has no dopamine reward. It's very easy for me to resist the compulsion of shopping because shopping holds no dopamine promise for me. The same way that, like, looking up sports stats, holds no dopamine promise for her. And it's sort of like, what if you created a drug that made my wife feel about shopping, the way I feel about shopping? What does it reduce the dopamine signal for her when she just thought about the concept

of buying a new necklace or a new shirt or new blouse? That she would suddenly lose the compulsion to shop when she had sort of a dip in willpower the same way that I might lose the compulsion to like, you know, I don't know, look up fancy wines when I feel a moment of low willpower. You know, one of my vices, my sins. It seems to me conceivable

that you've mentioned that the GLP-1s interact with the brain, the hypothalamus, that they're also acting or interacting with the dopamine cycle and in some way reducing the dopamine hit that patients have historically received from vices. And so when they think about biting their nails,

when they think about smoking, when they think about that fifth drink, they don't get the dopamine reward that they've historically gotten, and as a result, this past compulsion no longer holds future promise. Does that make any sense? Is that a plausible mechanism

for why? these GLP-1s turn out to also be on top of everything else an anti-compulsion drug? 100%. I mean, there's a lot of research into that nowadays, too. But if you, again, talking to people with obesity who are on these medications, I mean, before the medications, they'll talk about the relationship to food like an addiction or the relationship to sugar or highly palatable foods, takeout, things like that, and they feel an addiction in a sense of, As soon as they start thinking about ordering food, ordering takeout, they already have that tingle of reward. And once they're on a GLP1, they come back and tell me, I'm just not interested in

alcohol anymore. Before I could easily finish a bottle of wine with dinner every night. And now my brain just doesn't go there anymore. It's funny, Derek, that you mentioned willpower too, because when we talk about where these GLP wants work and how they inform us of the biology of obesity, one area of research is also kind of getting at that willpower question. You know, we talked about the hypothalamus, we talked about your dopamine reward systems, but what we don't talk about a lot is the frontal lobe.

So our frontal lobe of the brain is really, responsible for executive functioning, right? It keeps us from saying something offensive at our next party. In the same way, it actually is responsible for helping people stop a meal, physically put down a fork or recognize that they're full and that they stop eating. And we've actually observed in some studies that there is a difference between people with obesity or without obesity in that stopping signal, that people with obesity have a weaker signal. So if people like to talk about willpower, which I find to be a useless construct,

because for me, willpower is more philosophical. But if you wanted to distill willpower into neurobiological mechanisms, then it probably goes back to the frontal lobe. And the fact that the GLP ones are helping globally with so many type of addictive behaviors tells me that, oh, maybe there is that frontal lobe mechanism that also drives obesity. And certainly there are people looking into that, too. You mentioned that it gets people to drink less alcohol. I've heard from some people on Ozenbek that the disinclination to drink alcohol isn't just about willpower.

It's about physical nausea. Sometimes there are foods, alcohol, other sugary foods, that people feel nauseous about. So that's another mechanism by which they might be regulating their consumption. We're talking about bad habits here, like biting nails, eating potato chips, drinking too much tequila. Why wouldn't these drugs also reduce the affinity for or the dopamine hit from good habits? Does that make sense? Like, why don't we get stories about how Zempec hurts people's ability to fall in love or

the ability to enjoy a beautiful sunrise or sunset? Do you see where I'm headed here? I see what you're getting at. in a way it may just be how we're categorizing things vice hobby or you know whatever we feel gives us that dopamine hit um i would say i mean there are some people who come back and they're a little bit sad because what would what used to be a source of comfort for them no longer gives them that feeling of reward and now they have to go find a different source of dopamine. So, I mean, usually it does relate to food and they feel, some people feel relief that they

don't feel emotionally, so, such emotional connection to food, but they also feel a little bit sad that they've lost that. I think, and I'm not a neurobiologist, but I think there is also a difference between that hit, so to speak, that dopamine hit that we might get from scrolling at night and watching videos that just sort of make us laugh or whatever, versus a bonded relationship with another person or with a specific interest of ours, walking in the woods, whatever it may be. I think what your question also gets at is this neurochemical difference between like short-term reward and long-term bonding, right? Short-term rewards is what we get

from scrolling through videos and watching cat or baby videos or whatever that may be, something that just sparks a feeling of happiness in a very short period of time. And that may be more related to your dopamine hit, really that hit. Whereas when we have a longer commitment or a bonded relationship, to a partner or a child or a hobby or whatever it may be, I think it's a different set of hormones that's involved, such as oxytocin in addition to dopamine and all of that. Yeah, it's really interesting.

You talked about the hypothalamus and the frontal cortex, and I'm definitely the furthest thing from a neuroscientist, but I'm imagining that in my head, a kind of tug of war between appetite and judgment, and this is wildly oversimplified. But if you imagine a kind of of war between appetite and judgment in all sorts of decisions we make throughout the day, right? Should I have that third scoop of ice cream? Well, appetite sometimes wins that over judgment.

Should I have that next cocktail? And it's a Thursday. Well, sometimes appetite wins out over judgment. But if you somehow develop a technology for turning down the volume of appetite, it would allow judgment to be heard over appetite more easily. And as a result, you might cash out in making decisions that are less compulsive because appetite has been somewhat muted. This is another possible just-so story that I'm telling about brain chemistry, which I only partly understand. But it seems to interestingly connect a lot of pieces that you're putting on the table here of why might this drug be useful at reducing compulsions, but not destroy patient's ability

to soak joy out of the rest of life that isn't a compulsion, maybe has to do with this tug-of-war between appetite and judgment. That's true. I think for a lot of people, it helps achieve that, quote-unquote, moderation that people have been touting forever, whether that be moderation in terms of food or alcohol or other vices. It helps, as you say, strike that better balance. Last point, you mentioned willpower.

And I am so interested in this topic. I do think that in the space of diet and exercise and weight and health, there's sometimes this perspective that says everything is downstream of willpower. We can make ourselves do and be anything that we want if we just try hard enough. But the story that you're telling me is that Ozympics, amagletide, and these other GLP1 drugs suggest that what we call willpower might actually be. be downstream of our blood chemistry. Like we are taking a drug that is changing our hormones,

changing the messages sent between ourselves, and that is changing our ability to accomplish what we want to accomplish. Philosophically, this is very rich to me. Philosophically, I find it a little bit dangerous because I don't want to feel, or I don't want people to feel like they are a slave to their brain in a weird way or just a slave to their hormones

and all of these brain chemicals that they don't quote unquote have control over. That's why I try to keep those conversations separate. Willpower is very philosophical. The mechanism of willpower can probably be distilled into executive functioning, your frontal lobe. What gets lit up when you are trying to start? stop yourself or prevent yourself from doing or engaging in a vice.

And so it's an interesting question. I think that as the research of obesity moves forward, we're going to be able to piece that apart more and hopefully help people realize that, practically speaking, there are just, you know, things under their control, under their willpower, so to speak, and that may very well be, you know, lifestyle, diet, exercise to the degree that their environment allows them to do that. And then there are pieces that are less under their control, less under willpower control, which are literally hormones and definitely their genetics. And that's kind of the separation I like to, place out for my patients so that they realize it's really an interplay between both. No one's trying to say that you have no control over your life or your health, but it's really a matter of acknowledging what is under your control and what isn't. What you just said made me think that the word willpower actually has two very different

components, which are right there in the name, will and power, will, meaning, choice or desire and power, which I'll define as the ability to achieve what we want, what we desire. These drugs seem to give people more power to shape their appetites and their weight as they wish. And yet, the mechanism that allows them to do that calls into question for me the very concept of free will, because it shows that by changing blood chemistry, we can change people's desires, right? These drugs are behavioral modifiers. They modify behavior. They change what we want. And I guess I just want to put a pin in this for a future podcast. If we can inject ourselves in the thigh once a week or take a pill once a day, and that can change what we want

and our ability to will ourselves, to accomplish what we want, that to me raises just incredibly, immensely interesting questions about exactly how free our will is. Anyway, maybe that's for another podcast that you can come back and wrap with me about. Thank you so much for this. This was so much fun. I really appreciate you helping me understand all these wondrous things about these drugs. Thank you again. Thank you so much for listening. Plain English is hosted by me, Derek Thompson, and produced by Devin Manzi. Some great news for you all. As you probably know, we are returning, have returned back to our normal schedule of two pods a week. So be on the lookout for new episodes every Tuesday and Friday. If you like our podcast, please rate.

five stars, subscribe wherever you listen, and I'll see you later.