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

GLP-1 Dosing Safety

00:00We're hearing that some people I think Sam Alman actually talked about this publicly um overdose with with Cara Swisser 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 afford it is the buy the farmer a great option I think back then people were just getting them where they can I didn't ask him why uh why that happened but nonetheless get the dosage right make sure you're getting the right stuff clean but he talked about the kind

00:29lack of uh motivation which many people have described anecdotally um like okay lowered their food drive but lowered their drive period. Yep. Makes sense, you know, depending on which pathways are being affected. But do you think that's a real effect?

00:44Is that something that people need to be concerned about? Do you think people can micro dose this stuff? Because a lot of people are micro doing it regardless of what their source is. They're taking a lot less than the kind of standard clinical trials would be.

00:55And we're leaving out Red True Tide for now. Yep. Because it's so new. We're going to talk about it, but I'm talking about the standard if semiclutinide tepide. Yeah. I'll tell you that you have your you know semiglutide which is obey and vigov is the FDA approved version for the weight loss.

01:08For teptide you have zeppbound and monero. Zepbound being the FDA approved version for weight loss that allows them to keep their patents for longer. um these medications are good kind of transforming medicine especially where where I practice right

Fixing a Collapsing Medical System

01:21if you if we kind of zoom out our medical system if we didn't have these interventions was going to collapse on it itself thanks to the obesity pre-diabetes diabetes epidemics because we don't have enough clinicians or finances to get everybody who was pre-diabetic in the in the last you know 20 years and they all transitioned 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 and there wasn't enough

01:50finances to take care of it. Now these GLP1s are coming in and kind of transforming that phase of medicine because now we have a chance to dramatically change the rate of obesity uh diabetes pre-diabetes and all these cardio metabolic disorders.

02:02So 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.

02:15But 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.

02:31Millions 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 GLP1s we're getting 10 20 even 30% of body weight being shaved off of people especially with the new reduced data.

02:49Is there a free lunch? That's the big question. Like 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 GLP1s and that we are now reversing this rate of chronic disease.

03:03Is it going to stay that way? That's a good question. I'm I'm cautiously uh optimistic when it comes to these medications. I've been prescribing them since I was a resident. Uh in my VA clinic, I was putting all these vets that are, you know, 300 lb on GLV1s, they were losing 50, 100 lb.

03:19Before it wasn't 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 the bodybuilders. Um that kind of pioneered that. When did the bodybuilders first start using GLPS?

03:31Uh late 20110s. Wow.

Gila Monsters & Drug Origins

03:34And then the signal I don't I don't think Norvo or Lily wanted to make these for obesity. They were focused on making diabetes drugs because like if we zoom out even further, this is another animal derived compound, right? It's found in the the saliva of the Hila monsters.

03:49GLP1 was discovered. It's too um 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.

04:03So then we started noticing that diabetics like my my grandma got uh Betta which was one of these first uh GOP one 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 and more energetic.

04:20So we had seen the effects on diabetics and then you get luraglutide dlutide and then eventually semiglutide was the is the blockbuster but you get all these

Lifetime Treatment vs Weight Regain

04:30positive effects coming from these drugs on diabetics. It gets translated into obese people and overweight patients. The question is what is the long-term effect of this? Do you have to stay on this drug forever? Um can you titer it off? The the pharmaceutical companies have not given us good guidelines on that.

04:44They've shown us what happens if you stop the drug. You max out on maximum dose. Pull the brakes on. People tend to sometimes gain the weight. Some people don't, but some people will regain back to baseline. Because 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, the GIP, GLP, glucagon, insulin, testosterone, estrogen, all these things kind of modulate.

05:08And there's this thing called a set point theory or settling points and they integrate should I eat or not eat, right? So the GP1 is a giant signal to the brain of don't eat. So we're we're modulating this pathway. What happens to all these young kids that are 18 19 years old on 5 milligrams of reducide uh [snorts] that have lost 30 40 pounds?

05:27Are 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?

05:39What's the real world cost of taking six months off because you can't access it? Y there's a shortage and maybe better drugs will come along. 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.

05:54Now there are better better delivery devices. I kind of feel like eventually there'll be some slowrelease um polymer that will just kind of give you a micro dose of it. You could dial it up if you want. Those are all pills. Now personally I don't worry so much about like for the rest of your life.

06:07I worry

Neurological Impact & Learning

06:09more about the much shorter life if people are obese. But what about these brain effects? I I do worry about a brain that's developing in the context of of a you know thousandfold or more increase in these GLPs because when we had um Zach Knight 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.

06:30He described that the diabetic drugs would increase GLP 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, Monaro, Zmpic, etc. And certainly Redat True Tide.

06:45We're talking about thousandfold increases in GPS, we don't know what the long-term effects of those are on like neuroplasticity and learning. Could be great. Yes. Could be positive. We shouldn't always assume those effects are bad. 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.

07:01I think the the study last year didn't show a good signal on our Alzheimer's prevention, but we know diabetes and cardio metabolic disease speeds up that transition. So controlling insulin dynamics might be beneficial there and the obesity is not great for for Alzheimer's risk.

07:15The 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.

07:28Because a lot of these patients, the way we we approach it is training wheel effect when it comes to GLP-p1s. Like, hey, you come to us,

Clinical Protocols & Side Effects

07:35you're a patient, you want to use GLP1s, 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., 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.

07:51Now, when people do it that way, I don't hear a lot of these effects anecdotally from from work [clears throat] 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 because they're not, you know, consuming enough electrolytes or enough food period?

08:11Cuz 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. That's not conducive to to good feeling good. everyone, you know, the reason people are eating in the first place is because eating is is such a pleasurable experience for humans and a social experience, etc., etc.

08:25The other thing is if you're not eating with people on the same table, are you having less of that socialization aspect? A lot of times 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 out?

08:48dare you think of confounding variables. [laughter] 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 um downstream consequences of of reduced appetite. Yeah. And we know the literature shows that people now are having less alcohol cravings from this.

09:04It might be changing

Dopamine Signaling and Stacking

09:06the way the dopanergic signaling is happening in the brain, which is concerning, right? Because a lot of people will be stacking this with, you know, ADHD medications. Uh they might be using some of these peptide stimulants, um smack link, whatever it may be.

09:16So the question because what happens is people go to these websites, they they buy one more peptide and they got a great result and they'll be like, you know, let me add three more peptides on peptides. Yes, it's a increasing AOV problem. So the average sale value goes up from these sites.

09:32We'll see where where GLP ones go. The the the reality is it's here. There there is no pre GLP1 world for us as clinicians, as health enthusiasts. We're in a postGP1 world and everything kind of dictates downstream from that. The people I know who've taken um these and I don't know exactly which are taking much lower dosages than were prescribed to them and they are indeed sharing them with getting the prescription than people are sharing them.

09:54People are cost sharing now people are trying to get them from other sources. 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.

10:07It'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, I mean, leptin sensitivity

Fertility & Ozempic Babies

10:16increases as you decrease the body fat mass. There's there's GP1 receptors on the pomcy neurons in the brain and no one's kind of examined what that means downstream for the leptin melano leptin melanoin pathway and what that means for energy status, you know, thyroid hormone production, reproductive status.

10:29We know a lot of people are oyic 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. Was she obese before? Yeah, there's these you're overweight, obese women that are having um their fertility improve as a result of losing the weight because we know uh your leptin status is a key driver of fertility because if if you're having low leptin levels, you're starving.

10:52You shouldn't be fertile. If you have too much leptin and you're leptin resistant, you shouldn't be having kids either. So, both of those those things kind of get modulated by these drugs as well. There was a science paper some years ago that leptin hitting a certain threshold is actually what signals the onset of puberty in females.

11:08Is 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 um animals or that was an animal study or the idea was that people perhaps also become females become reproductively competent at the point where there's enough energetic resources that interesting [music]