Chasing Life with Dr. Sanjay Gupta

'Welcome to Chasing Life. You know, I think it's fair to say that the introduction of GLP-1s, starting with Ozempic back in 2018, have completely revolutionized healthcare. Not only do the medications help manage diabetes, which is what they were originally designed to do, but in case you've missed it, they've also helped people lose weight, sometimes transformative amounts of weight, without having to white-knuckle it. And now, we're very clear that GLPs can also affect the brain. And because of that, they can help manage addictive or compulsive behaviors, conditions for which there have been very few effective long-term treatments, and frankly a lot of stigma and shame. So we're going to talk about it today. My guest is Dr. Dhruv Kular. He's a practicing physician and associate professor of health policy at Weill Cornell Medicine in New York. He's also a writer for the New Yorker magazine. He has seen firsthand the effects GLP-1's can have on addictive behaviors. Today, we're going to talk about how GLP-1s are changing us, changing us as humans. And when the cravings go away, sort of trying to figure out, is there something else that we're losing as well? I'm Dr. Sanjay Gupta, and this is Chasing Life.

How did you get interested in in GLP specifically? What was the moment for you?

'Well, you know, I had been following the progress of GLP-1s as a diabetes medicine and then as an obesity medicine, and what became clear was that these medications affected so much more than eating. And I got fascinated by, generally I'm very skeptical of the idea of wonder drugs, but in this case, it was hard to escape kind of the mounting evidence that one thing after another they seem to be effective for. So if you think about cardiovascular risk and stroke risk. Reversal of fatty liver disease, slowing of chronic kidney disease, even osteoarthritis. And then a few years ago, there was all these anecdotes, all these stories of people saying, I don't feel like drinking as much as I used to. I don't want to smoke cigarettes anymore. And, you know, people who had cravings for opioids said that those were being diminished. And so the anecdotal evidence became overwhelming and I got interested because it seemed like GLP-1s might be doing something fundamental to our reward system, which is very interesting. We thought about these as kind of digestive medications, maybe diabetes medications, but they're actually psychoactive medications, or so it seemed. And what was so interesting about that is if you're playing with the reward system. That can have real implications for people's maladaptive behaviors, all sorts of addictions, but also a potential downside. Other kinds of rewards are what make life worth living. And so it seemed like there's a real tension between what people were calling "moderation molecules," but also potentially them being "desire dampeners."

'You're bullish on these drugs. I think the two concerns we always hear as physicians certainly, but I think just as someone who's considering these drugs, one is what are the long-term sort of concerns about this? And two is, you know, are they doing something, the mechanism that's going to cause some other downstream problem? With regard to the first question, do we have enough data to say that long-term safety is not going to be a concern?

'Well, I think one thing to point out is that the first GLP-1s came out 20 years ago. And so the first one was exenatide, it was 2005, 2006. Much smaller populations, not as powerful of a medication, something you had to take twice a day. And over the last two decades, these medications have become much more powerful, much longer acting, and have many more effects inside the body, mostly it seems for the good but potentially for the negative as well. So that gives me some confidence that we're not going to see totally new or very concerning side effects that arise. But as I said, these medications are different than the ones the first generation or the second generation medications that were around a while ago. And I think people are quite aware of some of the side effects as they relate to GI side effects. So if you think about nausea, vomiting, you know, aversion to certain types of foods. But, you know as we're learning more about the medications, there is also this potential concern around mental health side effects and so. You know, the European medicine agency and the FDA have both looked into this and it seems like at least on the score of suicidal ideation, which was a real concern because there were a lot of reports coming out about people having suicidal thoughts, and that seems to be probably not the case. You know, the best evidence suggests that people don't have an increased risk of suicidal ideation. I think the evidence on anhedonia is much more preliminary. And so we hear people not having as much interest in things that they used to have interest in. You know, I spoke to one patient who loved gardening and she bought all these Japanese maple trees and she was so excited to plant them in her garden. She started taking a GLP-1 and she totally lost interest in gardening. Her mood was really dampened. After she came off the medication, it came back again. I think that this is probably a minority case. You know, for most people, they actually report positive mental health effects. Maybe they feel better in their body. They want to do things that they weren't doing in the past. But it's really something to keep an eye on.

Or maybe we're just all anhedonic at baseline.

That could be.

And so we're just sad.

That's right, in this environment. I can't be on that.

If you were an alcoholic, would you consider using this for your alcoholism?

I think so. So, I will say that I don't think the evidence is 100% there yet, but it is getting there, getting more and more impressive month over month. And so, one thing to point out is that the last time we had any medication that was approved for alcohol use disorder was 20 years ago. And that was an injectable version of naltrexone, which itself was first approved in the 1980s. So we have not had a lot of new options for people with alcohol use disorder. And first, there was, you know, the anecdotal reports, and then there was observational studies. You know, people who happened to have been taking these medications seem to have, you know, less bad things happen in terms of their alcohol use. And now there's a series of randomized control trials that are pretty clearly showing that people want to drink less on these medications. So that's both people who have a serious alcohol problem but also people who just enjoy alcohol socially and don't consider themselves to have a problem. What's super interesting to me is that it doesn't seem like it's making people abstinent from alcohol, it's not like they stopped drinking alcohol altogether. In most cases, what's happening is people's heavy drinking days or those excessive days where they're drinking five, six, seven, eight drinks in a sitting, that's what really diminishes. Now, there are two or three randomized control trials that have showed this, so I would not be surprised if these medications get an indication from the FDA or other regulatory bodies that they should be and could be used for alcohol use disorder in the near future.

'That is interesting. This idea of moderation versus thinking about something as binary. Because when we talk about addiction, whether it be alcohol or other things, it's usually referred to in a binary way. You've got to completely go cold turkey. And I think the point that you make in the New Yorker article is this idea that it can keep you sort of more level as opposed- so people may still be able to drink alcohol, just like they're still able to eat food, obviously, but just do it more moderately.

It seems that way. It seems to diminish some of the excesses or extremes. Of course, some people, just like some people basically stop eating almost anything and lose too much weight and aren't able to maintain their level of energy on these medications, some will totally come off alcohol or cigarettes or opioids. And that might be great. A lot of people, I mean, alcohol is such a part of our culture and so many social gatherings involve alcohol. And a lot of the people really do want to cut back on the excessive drinking, but not become totally abstinent. And for some people, this might be a path to getting there.

Tell me about Mary. This is the person you profiled in the New Yorker article.

'Sure, so Mary, she's a woman who lives in Denmark, which of course is the home of Novo Nordisk and the producer of semaglutide or Ozempic. And she's the woman that had struggled with alcohol use disorder for her entire life. Basically, since she was a teenager, she was drinking pretty heavily, as you mentioned, sometimes 12, 15, 18 beers. And her tolerance was so high that she no longer even seemed buzzed around her friends, but she knew that it was really ruining her life. And she tried everything. She tried alcohol rehab. She tried Alcoholics Anonymous. She tried medications like Antabuse, where if you drink on that medication, it makes you feel violently ill. And none of it really worked for her. Every time, she would come back and she would continue to have an unhealthy relationship with alcohol. And almost by happenstance, she was at a bar and she was having drinks with one of her friends who also drank a lot. And her friend wasn't drinking almost at all that evening. And so Mary was kind of perplexed. She was like, what's going on here? You know, usually we're throwing back a number of beverages. And what her friend said was that she'd started taking Ozempic for weight loss, and now she couldn't bring herself to drink more than two beers at a time. She basically had to go outside and barf, she said, if she drank more than 2 beers at time. And Mary was kind of really interested in this. She looked it up on the internet and ended up getting a Facebook ad that directed her to a clinical trial, though studying Ozempic for alcohol use disorder right near her. And she enrolled in this trial, and she had a really interesting experience. As she got on the medication, first she switched from beer, which is what she always drank, to white wine, and then she stopped drinking altogether. And she noticed that a number of other things started to happen. So people have probably heard about food noise that GLP-1 started to diminish. For her, it diminished alcohol noise, so those kind of intrusive, unwanted, repetitive thoughts about drinking. When am I going to drink? How much am I going to drink? How do I not drink too much right now? All these things really quieted down. And what was so interesting to me is that, you know, that's kind of a immediate desire or change in her behavior, but there was this higher level behavioral changes that she also experienced. So she got really interested in exercise. She started exercising more. She now had the mental space to think about her diet. She had been struggling with her partner for many years, but never been able to completely detach or break up with her her partner. And now, She ended up doing that. And I thought that was so interesting, in part because it seemed like, on the one hand, she had the mental space to do that, but on the other hand, it raised the question of, you know, is this medication, is the drug, changing our preferences and our behaviors to extent that you might actually break up with your long-term partner?

Boy, that's not going to be part of their ad campaign, is my guess.

Well, for her, you know, it seemed like it was a good thing. Like, it was something, at least the way she presented it to me, it was a bad, difficult relationship. And she wanted to get out of it, but just, like, couldn't do it.

'Let me ask a fundamental question about these impacts of GLP-1 drugs and, by the way, GLP, the audience knows this but "glucagon-like peptides." There's a lot of a lot sort of stories about peptides lately, this is one of them. Insulin is another peptide, just to sort of give that context. But was the expectation that these medications were going to affect the brain or was this sort of happenstance? Just because patients started saying, by the way, this is also something that's happening to me.

'Well, classically, we've thought about these GLP-1 medications, as you said, glucagon-like peptide-1, as digestive tract medication. So GLP-1 attaches to receptors in the pancreas, in the gastrointestinal tract, in the brain. It stimulates the release of insulin. So your blood sugar goes down. It slows the passage of food through the stomach. It signals to our brains that we're full. And so, that was kind of the canonical understanding of GLP-1 medications. What has become increasingly clear, and we're still figuring some of this out, is that it probably acts on the reward system, what's called the mesolimbic pathway in the brain. And that is partly what drives changes in certain addictive behaviors and desire to take certain addictive substances. So the mesolymbic pathway is a little bit complicated, but the basic idea is that there's a release of dopamine in this pathway and. That leads you to kind of get that quick hit. And it stimulates certain types of behaviors that are associated with, you know, things that are pleasurable in the moment. So that might be cocaine, that might alcohol, that might social media, that may be gambling, but it's less associated with longer term desire. So if you want to be a good, I want to a good father, you know, I want do well at work, I want spend time with my friends, those are less affected by mesolimbic, quick-hit kind of pathway. And at least in animal studies, what seems to be happening is that the dopamine spikes in that pathway are diminished on GLP-1 medications, but the baseline levels are not really affected. And so it's not like you don't want to do anything, you've lost motivation to do everything, at least for most people, it's that those quick hit spikes are diminished to the extent that you might not feel as excited or feel as much pleasure when you take a drug or make a big purchase or are gambling.

It's not just, I mean, we often think about those as sort of the bad behaviors, right? Gambling or making a big purchase, but other things as well that are necessary for human life, right? I mean the types of food you choose, having sex, going for a long run, things like that in part what motivates us is that dopamine hit.

'That's right. And that's what I think is what still needs to be worked out. Because as you said, the same mechanistic pathway that might be leading you to do less of the maladaptive behaviors might actually be adaptive in some way. And maybe you diminish people's desire to have sex, to go for runs, to do other things that we would like people to be doing. I think this is potentially- I mean, psychology is complex. And so this is one pathway. But it might be counterbalanced by this idea that when people lose weight, their libido tends to increase. You know, like having a lot of excess weight is associated with decreased libido. Maybe you want to work out more because you feel better about your body. And so, this is one potential mechanism through which people might not get that quick hit of the same amount of pleasure from doing those activities. But it's put in this larger context, of course, you know, there's many other centers in the brain. We talk about the prefrontal cortex, which kind of is involved with higher level reasoning about some of these things. And so I think we're still seeing how all of this will shake out, but I really think that this is an area that needs a lot more study, and all of the experts that I spoke to as well felt like we just don't have a complete understanding of what's happening with the reward system.

'When we come back, we're going to discuss the possible dark effects of GLP-1s on the brain. Stay with us.

I think one of the things I worry about then is this idea that we may be creating a population of people who are skinnier, less likely to have diabetes, but have just kind of lost the joy. I think this is the point we're sort of revolving around. With all the research you've done, all the clinical trials you've seen, how worried are you about that?

I think it's a serious worry. I mean, one thing to note is that something like one out of every eight Americans has now been on this class of medications, and that is tens of millions of people and that number is only going to go up. And so, we are basically in the midst of a vast social experiment where we are not only tinkering with people's metabolism, but also potentially with their psychology. And so, I think that's a real concern and there's only so much information that you can glean out of a clinical trial where there's a several dozen people or several hundred people. Of course, the general population is going to be much more diverse, so I think it is a significant concern. If you read things like Reddit or you read some books of people who have been on these medications, some people do report a blunting of mood. And so, I think it's a real thing that we need to be aware of. I think there are some things that we're starting to potentially learn. And then there's all sorts of other outstanding questions, even if these medications are very effective for treating addiction. You know, what is the treatment model? Are these a bridge to sobriety or will people need to be taking them indefinitely? How do we get people to stay on these medications? I mean, drugs only work if you take them. And in some studies, something like half of people come off these medications within a year of taking them, whether that's because of side effects, or because of cost, or because of access. And so, there's all sorts of outstanding questions. And I think we just don't have the totality of evidence that we would want to have to make strong conclusions about how this is going to play out.

For Mary, she had a significant benefit from this.

She did, although she had to come off the medication because she lost 55 pounds in five months and basically was eating several hundred calories a day. And it was enough to jumpstart that path to sobriety for her, so she was able to maintain that afterwards. But, you know, it's kind of a mixed story in that it both helped her get sober and lose a lot of weight, but also she wasn't able to stay on it because she loss so much weight.

'But it is worth pointing out that she, the benefits of this for her in terms of her addiction to alcohol seem to have persisted, even though she came off the medications. Because I think one of the things you hear about GLP-1 drugs, especially when it comes to weight, is that once you stop the medications, a significant percentage of people will regain that weight. In terms of the long-term impact on the brain, is it sort of the same thinking there?

The short answer is that we don't know. I think for some people, what they need is a break from the status quo and these medications might give them that break where they can jump start changes in their life to get on a healthier path. For other people, they may need to stay on it for the duration. I mean, addiction is a chronic disease. It's something that people struggle with for years and decades, potentially their entire life. What I think is important to point out is that a lot of these trials study people for you know, four weeks, six weeks, six months, not much longer than that. And so, as these things become more available and more used for addiction in the real world, that's where a lot this real world observational study will become really important.

'When you started digging into this, Dhruv, thinking about addiction, thinking about GLP-1s, did this change how you think about addiction at all?

You know, I had already thought about addiction as a biological disease moreso than a moral failing. And I think we are all making that transition over the past few decades. You know, if this were back in the middle of last century, people basically thought that you should exert your willpower to overcome whatever addiction you have. And it's not to say that our behaviors don't matter, our decisions don't matter, but it drove home to me just how much of addiction is a neurobiological process. As part of my reporting, I went to undergo an MRI in one of the studies that I was reporting on. And they showed us, basically, they slid me into an MRI machine, showed me photographs of alcohol, like wine and beer and bourbon, but also showed me pictures of Big Macs and mountains and rivers and all sorts of stuff. And they were looking at how does my brain process these images. And for me, when I saw a picture of alcohol, there was a little bit of activity, but nothing really significant. Then they put up a brain of someone who was struggling with alcohol use disorder, and these areas just lit up. You know, the ventral striatum in an area where the mesolimbic pathway we're talking about deposits its dopamine and you get that hit. Another area called the medial prefrontal cortex where you're making these higher order decisions about what rewards are worth pursuing, lit up again. And so, you know, these things are happening even before we have any conscious realization that there's something, a decision even to be made. And so again, for me, it drove home the idea that it's not going to be effective to shame people for having these impulses or cravings or urges and that these medications, you now, they may come with some side effects but they may be able to blunt the response that the brain is having in these particular areas.

'So, for the lay public though, what we've seen with GLP-1 drugs and their impact on addiction should probably reframe I think how society thinks about addiction. Because I think you're quite right, I think a lot of people still think of this as a moral failure or a lack of willpower. Just stop drinking, just stop using those drugs, whatever. But the fact that you see fundamental changes in the brain in someone who just looks at a picture of alcohol. I think that that's a pretty important story.

It should be out there and it should be something that people are considering as they have a loved one or a family member or someone else who is struggling with an addiction. But in a way, what we talked about earlier, where tens of millions of people are on these medications, helps in this process. Because the same story is being told about obesity. In the past, people saw that primarily as a lack of willpower. And now, we know it's so much more than that. There are genetics predispositions, there are environmental factors, all these things that make it difficult for people to make other food choices and for their body to process food in the way that people without obesity do. And so, I think a lot of people are having this experience that, hey, the food noise inside my head is suddenly diminished, and millions of people are potentially having that experience. And I think it's a short leap then to think, for other people, it might not be food, it might be that donut, it might now be pizza, but it might be, you know, a Negroni, it might be a cocaine, it might be oxycodone, whatever it might be.

This all sounds good, right? I mean, if you're somebody who's listening and you have struggled with addiction or you know someone who's struggling with addiction, the idea that this substance could potentially reduce the reward that you feel from that substance and also reduce the pain that you might feel from stopping the substance, I'm trying to find the criticism here of this. And you dug into it, how do you come down on it?

'I think, for the most part, for most people, this is a good thing. The challenge that I see is that the same processes that make you less interested in drugs, food, or alcohol potentially bleed over to other things, other parts of your life that we may not want to discourage. Again, we talked about things like spending time with friends, having sex, going for a run, really being motivated to do anything that you were previously interested in. Again, I think for most people, this bleed-over effect is probably not bad enough or maybe not even present at all in the way that would lead us to want us to, you know, maybe take them off that drug, but for some people, for a minority of people, that is the big concern. And as you mentioned, there are a number of anecdotal reports, including from some of the people who helped develop these medications that are pretty skeptical. I looked up the Danish scientist who helped discover GLP-1s and he said that maybe life on GLP-1s will be so miserably boring that you can't stand it any longer and you have to go back to your old life. I don't think that's most people's experience, but he's someone who discovered GLP-1 and he has this concern, and so that would also be my big concern. Like, are there enough people that are having these negative consequences, in terms of their motivation and their pleasure for other parts of their life, that really they have to come off the medication?

You know what it strikes me as? It strikes me like what you heard about social media earlier when a lot of the people who developed a lot these social media platforms are like, this is this amazing thing, we're putting it out there for society, by the way, we don't let our kids use it.

Right.

You know? It kind of smacks of those same notes a little bit. Like, I think we should be paying attention to what some of these early scientists around GLP are saying. I think that they've put this amazing substance into the world, but they're clearly raising some flags of concern.

'I think it's totally the right question to be asking. And if this was just about maybe the aesthetics of obesity and people wanting to get skinnier and look better, I would say that concern is probably large enough that I would most people should not be eager to start these medications. But we have seen so many important positive health effects for people who have high levels of obesity. We've talked about cardiovascular disease and fatty liver disease and kidney disease and obstructive sleep apnea. And so that concern really just needs to be weighed against. I mean, medicine is basically all about trade-offs, right? I mean, everything we do is a risk-benefit calculation and right now the benefits seem pretty large. That's not to say that the risks aren't there and maybe they'll become more apparent over time, but I am pretty bullish on these medications because every study that comes out seems to have a positive finding on a really important measure or marker of people's health.

That was Dr. Dhruv Kular, and you can read his story, "Can Ozempic Cure Addiction?" It's in the New Yorker Magazine. Thanks for joining us, and hope to see you next week.