GLP-1s: Overdosing, Side Effects & Long-Term Risks | Dr. Abud Bakri & Dr. Andrew Huberman

0:00 We're hearing that some people, I think Sam Altman actually talked about this publicly with with Kara Swisher about what he thought Yeah, where he overdosed actually a compound pharmacy issue he thought was what did it. I trust him to do the right calculation so it does sound like that was a compounding pharmacy issue. >> Could have afforded to just go to the pharmacy a great option. >> back then people were just getting them where they could get them. I don't I didn't ask him why why that happened but nonetheless get the dosage right. Make sure you're getting the right stuff clean. But he talked about the kind of lack of motivation which many people have described anecdotally like okay lowered their food drive but lowered their drive period.

0:39 >> Yep. >> Makes sense, you know, depending on which pathways are being affected but do you think that's a real effect? Is that something that people need to be concerned about? Do you think people can microdose this stuff because a lot of people are microdosing it regardless of what their source is. They're taking a lot less than the kind of standard clinical trials would be and we're leaving out retatrutide for now cuz it's so new. We're going to talk about it but I'm talking about the standard if you will.

1:01 >> and tirzepatide. So that you have your, you know, semaglutide which is Ozempic and Wegovy. The Wegovy is the FDA approved version for weight loss. For tirzepatide you have Zepbound and Mounjaro. Zepbound being the FDA approved version for weight loss that allows them to keep their patents for for longer. These medications are good trying to transforming medicine especially where where I practice, right? If you if we kind of zoom out our medical system, if we didn't have these interventions was going to collapse on itself thanks to the obesity prediabetes diabetes epidemics we don't have enough clinicians or finances to get everybody who was prediabetic in the in the last, you know, 20 years and they all transition to diabetes and ended up with, you know, diabetic medications and dialysis and eventually cardiovascular disease and all these things. We don't have the resources to take care of all these people. Like our medical system was going to collapse.

1:50 And there wasn't enough finances to take care of it. Now these GLP-1s are coming in and kind of transforming that phase of medicine because now we have a chance to dramatically change the rate of obesity, diabetes, prediabetes, and all these cardiometabolic disorders. So, where do we stand? We needed something to happen. I mean, ideally, everybody, you know, would get morning sunlight and eat only healthy foods, unprocessed foods, and have low stress, and sleep great at night, and maybe no one would develop to become obese.

2:16 But, the reality is people become overweight, obese. They get stuck in that hole. And if you just try to step out of the hole the way you came in, sometimes that doesn't work. You need a different path out of that problem. And that that's been, you know, the diet and exercise literature for the last 40 years. Millions of books have been sold on how to get people leaner. We now have interventions medically that can dramatically change people's weights for the first time. We've had drugs in the past that, you know, 5, 10% of body weight. Now, with the GLP-1s, we're getting 10, 20, even 30% of body weight being shaved off of people, especially with the new retatrutide data. Is there a free lunch? That's the the big question. Like I like we kind of talked about earlier, there's always been these medical mishaps that have happened. So far, the data is very promising when it comes to GLP-1s in that we are now reversing this rate of chronic disease. Is it going to stay that way? That's a good question. I'm cautiously optimistic when it comes to these medications.

3:10 I've been prescribing them since I was a resident in my VA clinic. I was putting all these vets that are, you know, 300 lb on GLP-1s. They were losing 50, 100 lb. Before it was an FDA-approved for weight loss, we knew that that if you put diabetics on this drug, they would lose weight. Thanks to a lot of bodybuilders that kind of pioneered that. >> When did the bodybuilders first start using GLPs? >> late 2010s. >> Wow.

3:33 >> Early And then the signal I don't I don't think Novo or Lilly wanted to make these for obesity. They were focused on making diabetes drugs. Cuz like if we zoom out even further, this is another animal-derived compound, right? It's found in the the saliva of the Gila monsters. GLP-1 was discovered. It's too short-acting to have worked on its own. Then pharmaceutical companies, this is where you got to give pharma their credit, they developed these drugs into more functioning versions that had, you know, longer half-lives and could stick around in the serum for longer to have the clinical effect. So then we started noticing that diabetics, like my my grandma got Byetta, which was one of these first GLP-1 drugs like 25 years ago. It was the out of all the drugs she was on, the reason I went into medicine, that was the drug that changed her her whole trajectory because she had less insulin needs and she was losing weight, more energetic. So we had seen the effects on diabetics and then you get liraglutide, dulaglutide, and then eventually semaglutide is the is the blockbuster. But you get all these positive effects coming from these drugs on diabetics, it gets translated into obese people and overweight patients.

4:35 The question is what is the long-term effect of this? Do you have to stay on this drug forever? Can you titrate it off? The pharmaceutical companies have not given us good guidance on that. They've shown us what happens if you stop the drug. You max out on maximum dose of tirzepatide, pull the brakes on, people tend to sometimes gain the weight, some people don't, but some people will regain back to baseline. Cuz if you think about it, the better way to think about weight loss, it's a calculation your brain does every single day with all the different hormones and and peptides that are made from the gut, GIP, GLP, glucagon, insulin, testosterone, estrogen, all these things going to modulate and there's this thing called a set point theory or settling points, and they integrate, should I eat or not eat, right? So the GLP-1 is a giant signal to the brain of don't eat.

5:19 So we're we're modulating this pathway. What happens to all these young kids that are 18, 19 years old on 5 mg of retatrutide that have lost 30, 40 lbs, are they going to have to be on that for life now to maintain that weight? >> Can I ask you about that because when people say perhaps you have to be on a drug for the rest of your life, I think, okay, what's the availability, what's the cost, what's the real-world cost of taking 6 months off cuz you can't access it, there's a shortage, and maybe better drugs will come on. Like I don't necessarily have a problem with it, although if you talk to type 1 diabetics, in the old days they weren't crazy about the idea that they had to constantly inject themselves with insulin. Now there are better better delivery devices. I kind of feel like eventually there'll be some slow release polymer that will just kind of give you a microdose of it. You could dial it up if you want.

6:04 >> Like there's there's oral pills now. >> Personally, I don't worry so much about like oh for the rest of your life. I worry more about the much shorter life if if people are obese. But what about these brain effects? >> Like I I get >> worry about a brain that's developing in the context of of a you know, thousandfold or more increase in these GLP-1s because when we had Zach and I on the podcast, he's not a clinician, he's a scientist up at UCSF, Howard Hughes investigator, which means he's like a superstar and deserves to be in that category. As he described it, the diabetic drugs would increase GLP-1 by like like double, quadruple, but the weight loss effects weren't really there. But the drugs that you rattled off a few minutes ago, Mounjaro and Ozempic etc. and and certainly Rybelsus and Trulicity, we're talking about thousandfold increases in GLP-1s. We don't know what the long-term effects of those are on like neural plasticity and learning. Could be great. Could be positive. We shouldn't always assume those effects are bad.

6:55 >> Yeah, like the effects for like let's say a 60-year-old pre-diabetic diabetic on Alzheimer's disease seems to be potentially positive. I think the that's the study last year didn't show a good signal on our Alzheimer's prevention, but we know diabetes and cardiometabolic disease speeds up that transition. So controlling insulin dynamics might be beneficial there and the obesity is not great for for Alzheimer's risk. The question is what about for like these cognitive effects? Is the effect happening from the drug itself? Is it from misuse of the drug? Too too high of a dose? You're not getting enough electrolytes, you're not getting enough micronutrients, macronutrients, you know, your blood sugar is low. Cuz a lot of these patients, the way we we approach it is training wheel effect when it comes to GLP-1s. Okay, you come to us, you're a patient, you want to use GLP-1s, we'll give you a lowest dose as possible that has an effect for you GLP-1 in conjunction with lifestyle modification, dietary advice, exercise programs, etc., etc., etc. And then hopefully peel away those those training wheels or keep them on if you need them until we get to the end point that we want. Now, when people do it that way, I don't hear a lot of these effects anecdotally from from Berkeley patients that we hear about online where people are like, "Oh, I'm depressed. I hate my life." from from these drugs. And the question is are they just, you know, a lot of people have low blood pressure from from these drugs cuz they're not, you know, consuming enough electrolytes or enough food period? Cuz like some people will take a mega dose of these drugs and end up not eating like a day goes by, they've eaten one meal.

8:19 That's not conducive to to good feeling good. Everyone, you know, the reason people are losing in the first place is cuz eating is is such a pleasurable experience for humans and a social experience, etc., etc. The other thing is if you're not eating with people at the same table, are you having less of that socialization aspect? A lot of times you you meet up to eat or drink or whatever it may be. So, I'm very curious when it comes to the cognitive effects, is it from the drug directly interacting with receptors in the brain? When we we've seen that the right amount of dose decreases inflammation in the brain. Or is it because of the social aspects of the drug changing the way you behave and therefore leading to negative outcomes?

8:49 >> I admire you think of confounding variables. >> >> It's like, "No, it's so cool cuz you're willing to go outside the box and say, 'Hey, listen, this might be due to some of the downstream consequences of of reduced appetite.'" >> Yeah, and we know the literature shows that people now are having less alcohol cravings from from this. It might be changing the way the dopaminergic signaling is happening in the brain, which is concerning, right? Cuz a lot of people will be stacking this with, you know, ADHD medications. They might be using some of these peptide stimulants, semaxanide, whatever it may be. So, the question cuz what happens is people go to these websites, they they buy one of the peptides and they're like, "Oh, that's a great result." And they'll be like, "You know, let me add three more peptides on."

9:24 >> Accessory peptides. >> Yes. It's a increasing AOV problem. So, the average sale value goes up from these research sites. We'll see where where GLP-1s go. The the the reality is it's here. There is there is no pre-GLP-1 world for us as clinicians, as health enthusiasts. We're in a post-GLP-1 world and everything kind of dictates downstream from that. >> The people I know who've taken these, and I don't know exactly which they're taking, much lower dosages than what was prescribed to them, and they are indeed sharing them with getting the prescription and then people are sharing them, people are cost sharing. Now people are trying to get them from other sources.

9:59 >> Several of those people say they they feel like they can think better, but I told them, "Well, yeah, if your insulin sensitivity is improved, if you're carrying less body fat, body fat's an endocrine organ, it's you know, you need some body fat, but there could be a number of reasons for that. I don't know if these are direct effects on the brain." >> Yeah, well, leptin sensitivity increases as you decrease the body fat mass. There's there's GLP-1 receptors on the POMC neurons in the brain. And no one's kind of examined what that means downstream for the leptin melanocortin leptin melanocortin pathway and what that means for energy status, you know, thyroid hormone production, reproductive status. We know a lot of people are Ozempic babies in that a lady will will be subfertile or infertile, start a weight loss drug, and then find out by accident she's pregnant.

10:41 >> Was she obese before? >> Yeah, there there these are overweight obese women that are having their fertility improve as a result of losing the weight because we know your leptin status is a key driver of fertility because if you're having low leptin levels, you're starving, you shouldn't be fertile. If you have too much leptin and you're at leptin resistant, you shouldn't be having kids either. So, both of those things kind of get modulated by these drugs as well.

11:02 >> There was a science paper some years ago that leptin hitting a certain threshold is actually what signals the onset of puberty in females. Is that still considered true? >> I think that's that's that's part of it. >> Makes sense. Like enough body fat to signal that there are enough resources and then animals were that was an animal study where the idea was that people perhaps also become females become reproductively competent at the point where there's enough energetic resources that Interesting.

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