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GLP-1 Dosing Safety
We're hearing that some people, I think Sam Altman actually talked about this publicly, overdosed with Kara Swisher about what he thought was... yeah, where he overdosed. Actually, a compounding 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. Can people afford it? Is buying from the farmer a great option? I think back then people were just getting them where they could. I didn't ask him why that happened, but nonetheless, get the dosage right and 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, they lowered their food drive but lowered their drive period. Yep. Makes sense, depending on which pathways are being affected. But do you think that's a real effect? Is that something people need to be concerned about? Do you think people can microdose this stuff? A lot of people are microdosing it regardless of their source. They're taking a lot less than the standard clinical trials would be. We're leaving out retatrutide for now, yep, because it's so new. We're going to talk about it, but I'm talking about the standard, semaglutide and tirzepatide.
Yeah. I'll tell you that you have semaglutide, which is Ozempic, and Wegovy is the FDA-approved version for weight loss. For tirzepatide, you have Mounjaro and Zepbound. Zepbound is the FDA-approved version for weight loss, and that allows them to keep their patents for longer. These medications are transforming medicine, especially where I practice. If we zoom out on our medical system and we didn't have these interventions, it was going to collapse on itself thanks to the obesity, prediabetes, and diabetes epidemics, because we don't have enough clinicians or finances to get everybody who was prediabetic in the last 20 years, who then transitioned to diabetes, ended up on diabetic medications and dialysis, and eventually cardiovascular disease. We don't have the resources to take care of all these people. Our medical system was going to collapse, and there wasn't enough finance to take care of it.
Fixing a Collapsing Medical System
Now these GLP-1s are coming in and 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. Ideally, everybody would get morning sunlight, eat only healthy, unprocessed foods, have low stress, sleep great at night, and maybe no one would become obese. But the reality is people become overweight and 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. That has been 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 medical interventions that can dramatically change people's weights for the first time. We've had drugs in the past that shaved off 5 to 10% of body weight. With GLP-1s we're getting 10, 20, even 30% of body weight shaved off people, especially with the newer data. Is there a free lunch? That's the big question. As we talked about earlier, there have always been medical mishaps. So far the data is very promising when it comes to GLP-1s, and we are now reversing the rate of chronic disease. Is it going to stay that way? That's a good question. I'm cautiously optimistic about these medications. I've been prescribing them since I was a resident. In my VA clinic, I was putting veterans who were 300 pounds on GLP-1s, and they were losing 50 to 100 pounds. Before it was FDA-approved for weight loss, we knew that if you put diabetics on this drug, they would lose weight, thanks in part to a lot of bodybuilders who pioneered that.
When did bodybuilders first start using GLP-1s? Late 2010s. Wow. I don't think Novo or Lilly wanted to make these for obesity initially. They were focused on making diabetes drugs. If we zoom out even further, this is another animal-derived compound, right? It's found in the saliva of the Gila monster. GLP-1 was discovered, but it was too short-acting to work on its own. Then pharmaceutical companies, and this is where you have to give pharma credit, developed these into more functional versions with longer half-lives that could stick around in the serum long enough to have a clinical effect. We started noticing that diabetics, like my grandma, who got Byetta, one of the first GLP-1 drugs about 25 years ago, were benefiting. Of all the drugs she was on, that was the one that changed her whole trajectory, which is part of why I went into medicine. She had less insulin need, she was losing weight, and she was more energetic. We had seen the effects in diabetics, then you get liraglutide, dulaglutide, and eventually semaglutide, which became the blockbuster. All these positive effects coming from these drugs in diabetics then translated to obese and overweight patients. The question is what the long-term effect is. Do you have to stay on this drug forever? Can you taper off? The pharmaceutical companies have not given us good guidelines on that. They've shown us what happens if you stop the drug at maximum dose and pull the brakes: people sometimes regain the weight. Some people don't, but some regain back to baseline.
Lifetime Treatment vs Weight Regain
Because if you think about it, the better way to think about weight loss is that it's a calculation your brain does every single day with all the different hormones and peptides made from the gut: GIP, GLP, glucagon, insulin, testosterone, estrogen. All these things modulate it. There is a concept called set point theory, or settling points, and they integrate the question of should I eat or not eat. GLP-1 is a giant signal to the brain of "don't eat." So we're modulating this pathway. What happens to all these young kids who are 18 or 19 years old on 5 milligrams of semaglutide who have lost 30 to 40 pounds? Are they going to have to be on it for life to maintain that weight? Can I ask you about that? When people say you might 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 six months off because you can't access it? There's a shortage, and maybe better drugs will come along. 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 having to constantly inject themselves with insulin. Now there are better delivery devices. I feel like eventually there'll be some slow-release polymer that will give you a microdose, and you could dial it up if you want. Those are all pills, now. Personally, I don't worry so much about "for the rest of your life." I worry more about the much shorter life if people are obese. But what about these brain effects?
Neurological Impact & Learning
I do worry about a brain developing in the context of a thousandfold or more increase in these GLPs. When we had Zach Knight on the podcast, he's not a clinician, he's a scientist at UCSF and a Howard Hughes investigator, which means he's a superstar and deserves that category. He described that the diabetic drugs would increase GLP-1 by double or quadruple, but the weight loss effects weren't really there. But the drugs you rattled off a few minutes ago, Mounjaro, Ozempic, and certainly retatrutide, are talking about thousandfold increases in GLP-1. We don't know the long-term effects on neuroplasticity and learning. It could be great. Yes, it could be positive. We shouldn't always assume those effects are bad. For example, for a 60-year-old prediabetic or diabetic, the effect on Alzheimer's disease seems potentially positive. The study last year didn't show a good signal for Alzheimer's prevention, but we know diabetes and cardiometabolic disease speed up that transition, so controlling insulin dynamics might be beneficial there, and obesity is not great for Alzheimer's risk. The question is, for these cognitive effects, is the effect coming from the drug itself, or from misuse of the drug, too high of a dose, not enough electrolytes, not enough micronutrients or macronutrients, or low blood sugar? A lot of these patients are approached with a training-wheels effect when it comes to GLP-1s. You come to us, you want to use GLP-1s, and we give you the lowest dose possible that has an effect, in conjunction with lifestyle modification, dietary advice, exercise programs, and so on, and then hopefully peel away those training wheels, or keep them on if you need them, until we reach the endpoint we want.
Clinical Protocols & Side Effects
When people do it that way, I don't hear a lot of the effects anecdotally from patients that we hear about online, where people say, "I'm depressed, I hate my life because of these drugs." The question is whether they're just experiencing low blood pressure from the drugs because they're not consuming enough electrolytes or enough food, period. Some people take a mega dose of these drugs and end up not eating; a day goes by and they've eaten one meal. That's not conducive to feeling good. The reason people eat in the first place is that eating is such a pleasurable experience for humans and a social one. The other thing is, if you're not eating with people at the same table, are you losing some of that socialization? A lot of times you meet up to eat or drink or whatever it may be. I'm very curious about the cognitive effects. Is it the drug directly interacting with receptors in the brain? We've seen that the right amount of dose decreases inflammation in the brain. Or is it the social aspects of the drug changing the way you behave, leading to negative outcomes? Do you think about confounding variables? It's cool that you're willing to go outside the box and say this might be due to downstream consequences of reduced appetite. The literature shows that people are now having fewer alcohol cravings from this. It might be changing the way dopaminergic signaling happens in the brain, which is concerning, because a lot of people will be stacking this with ADHD medications. They might be using peptide stimulants, SS-31 or whatever it may be. What happens is people go to these websites, buy one more peptide, get a great result, and then think, let me add three more peptides. It's an increasing average order value problem for those sites. We'll see where GLP-1s go. The reality is it's here. There is no pre-GLP-1 world for us as clinicians or health enthusiasts. We're in a post-GLP-1 world, and everything dictates downstream from that. People I know who've taken these, and I don't know exactly which, are taking much lower dosages than were prescribed, and they are indeed sharing them. People are cost-sharing now, trying to get them from other sources. Several of those people say they feel like they can think better. I told them, well, if your insulin sensitivity has improved, and you're carrying less body fat, and body fat is an endocrine organ, 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.
Dopamine Signaling and Stacking
Well, leptin sensitivity increases as you decrease body fat mass. There are GLP-1 receptors on the POMC neurons in the brain, and no one has examined what that means downstream for the leptin-melanocortin pathway and what that means for energy status, thyroid hormone production, and reproductive status. We know a lot of people have "Ozempic babies": a woman who is subfertile or infertile starts a weight loss drug and then finds out by accident she's pregnant.
Fertility & Ozempic Babies
Was she obese before? Yes, there are overweight and obese women whose fertility improves as a result of losing weight, because we know leptin status is a key driver of fertility. If you have low leptin levels, you're starving and shouldn't be fertile. If you have too much leptin and are leptin resistant, you shouldn't be having children either. Both of those are modulated by these drugs as well. There was a science paper some years ago showing that leptin reaching a certain threshold is what signals the onset of puberty in females. Is that still considered true? I think that's part of it. It makes sense: enough body fat signals that there are enough resources. That was an animal study, and the idea was that females become reproductively competent at the point where there are enough energetic resources.