Dr. Ben Bikman: And I am— I'm worried about the long-term effects. The risk of suicidal behavior doubles and the risk of major depression triples in people who are on the drug for up to 2 years. Another paper was just published this week finding that the risk of blindness doubles, more than doubles, in people on high-dose GLP-1s. So rather than saying this is a weight loss drug, let's— what if we changed the conversation and said this is a drug that is designed to help you change your eating habits?

Dr. Rhonda Patrick: Obviously, I think right now there's a big trend in rapid weight loss and weight loss that's made very easy by taking GLP-1 agonist drugs, things like Ozempic and Wegovy. And I'd love to know what your thoughts are on— maybe first you can explain just, you know, generally how these GLP-1 agonists work.

Dr. Ben Bikman: Mm-hmm.

Dr. Rhonda Patrick: And why they're causing weight loss and how they affect metabolic health. but also whether they're addressing the underlying root cause of obesity.

Dr. Ben Bikman: Yeah.

Dr. Rhonda Patrick: And, you know, if or if there's sort of shortcutting around that.

Dr. Ben Bikman: Right. Well, there's no question it's a bit of a shortcut. And I am— I'm worried about the long-term effects. So with GLP-1, I have had my finger on the pulse of GLP-1 probably since— well, not since its inception, but since the late '90s, early 2000s. My PhD lab was one of the first labs funded in the US looking at the study of incretins by a drug company. And so I've long been familiar with GLP-1 and the other incretins, incretin being a word to describe these gut-derived hormones that have metabolic effects. But it's been interesting for me to note the evolution in their use, because originally they were only used as anti-diabetic drugs. And then the, what was considered kind of an off-target effect of controlling satiety is now the mechanism of action at these much higher doses as the dose has been multiplied up to the kind of current Wegovy weight loss dose. So it's really just been an evolution in the dose of this, of semaglutide for the most part, although there are other glutides that fit in this as well, but semaglutide's the main one. So at the lower dose, Originally used, these GLP-1 activators worked actually by inhibiting glucagon. So back to the alpha cell that I mentioned earlier, it's— we come back to them now where in type 2 diabetes, the insulin resistance of the alpha cell results in a chronic elevation of glucagon, chronically then telling the liver to be releasing glucose, leading to the hyperglycemia that defines the diabetic state. at this low dose, semaglutide inhibits the alpha cell. It inhibits glucagon. And by inhibiting glucagon, you're helping correct blood glucose. So it was an effective antidiabetic. Now, some people have the very mistaken view that semaglutide or GLP-1 activators also release insulin. That is not true. That has been shown to happen in isolated cell cultures, but in humans, there's no evidence. And the authority on the subject is a guy named Arnie. A-R-N-E. Astrup. A-S-T-R-U-P. Arne Astrup in Denmark. He's one of the absolute authorities on this topic. He's published multiple papers in humans showing that no amount of GLP-1 elicits an insulin release. So that we need to put that idea to bed. In humans, that does not happen. GLP-1 does not act as what's called an insulin secretagogue, or a hormone that— a drug that forces the beta cell to make insulin. GLP-1 inhibits glucagon, which helps correct blood glucose. Now, as the dose starts to go up higher, just, I guess, just for the sake of time, I'd mention 2 effects, which is one in the guts and then one central. Within the intestines, GLP-1 will act to delay gastric emptying and slow peristalsis. So that has the effect of a person eating and having that bulk sit in their stomach much longer, which is going to generally discourage them from wanting to eat more. At the same time, same time, it's going to take a lot longer to get through the intestines. Now, that is good for weight loss because it forces them to eat less. A consequence of that is it ranges from the uncomfortable to the problematic. So on the uncomfortable side, the person will have food that's sitting in their stomach for up to 20 hours. And so they will start burping a lot. And they will have like people who go through general surgery and have to be put under for general anesthesia, they found that normally you tell the person, don't eat for 24 hours, and their stomach's empty, so they're not going to vomit food up while they're asleep. But when they found that if people were on these— were on semaglutide, the food was still there, and they would still have food in their stomach even though they hadn't eaten for 24 hours. So this results in what people colloquially just call Ozempic burps, where they just have putrid breath and burping and just Stomach nausea. But because of the change in gastric emptying, even some medications like birth control medications don't work anymore, for example, because you've so changed how long it takes that drug to get from the stomach into the small intestine where it would've been absorbed. So it starts to change the absorption of certain compounds and drugs, as well as potentially affecting the absorption of nutrients, which may be Part of what the person is observing with regards to other changes in, say, muscle mass, maybe that's a result of just poor nutrition, because even though they're eating, they might not be getting— they might not be digesting and absorbing everything they're eating anymore because of how the rate of the peristalsis has changed so much. So anyway, numerous changes of the guts. And then there's a central nervous system effect to activate satiety centers. Now, the combination of those 2 is powerful. Where you have the, I'm full signal here, and I have a lot of stuff in my stomach here, resulting in a person who has a much better control over their appetite, I guess, to say that a polite way, or to say that another way, they just don't have as much of an interest in eating. So that's the main mechanism of action. And GLP-1 is a normal hormone. I didn't mention this. GLP-1 is a naturally produced hormone. From the gut. We have it. We know that we can change its levels based on what we eat. And that might explain why some people eat more and some people eat less.

Dr. Rhonda Patrick: But still, my concern is that the dose of GLP-1 that we're using now has gone— it's just a little too much of a good thing. What is the dose range that you were referring to?

Dr. Ben Bikman: Yeah. Talking about— yeah, yeah. So I think that the commonly used doses are going to be in the order of, actually, in this case, I know it in milligrams. I think it's about 5 milligrams or so, 2.5+ milligrams, and a once-weekly injection. And if people are thinking of that in units, I think that's going to correspond to units of about 25 to 30 units of GLP-1. So that, to me, is too high.

Dr. Rhonda Patrick: And 2.5 milligrams being the low dose?

Dr. Ben Bikman: That is the, yeah, that's the low dose of what is used now. Right.

Dr. Rhonda Patrick: And, and the underlying, the, the addressing, obviously this was, these were used for, like you mentioned, this was a, you know, diabetes drug, right? I mean, this wasn't necessarily meant to treat obesity.

Dr. Ben Bikman: Yeah. Right.

Dr. Rhonda Patrick: Um, but I guess that it all depends on, you know, the, the cause of obesity. Overeating is partly, partly a cause of obesity, so.

Dr. Ben Bikman: Oh no, for sure it is. Yeah. In fact, I am, as, as much as people will hear me describe this and think that I'm being just universally opposed, I actually do think there's a place for these GLP-1 drugs. A paper was published in 1996 that looked at the changes in GLP-1 in 2 populations. They took otherwise healthy humans and split them up in, and they noticed changes in the obese group and the lean group. So when they gave both groups a high-fat meal, they looked at the GLP-1 response and it was roughly similar in both groups that whether they were obese or lean, they ate a high-fat meal and GLP-1 was It's the same heavy overlap, suggesting that the satiety effect of that meal would be roughly equal. Now I'm speculating a little bit there. I'm adding that last part in. So if you look at the GLP-1 response, given GLP-1's effects on satiety, which is very meaningful, the high-fat meal elicited a similar response regardless of body fat mass. However, when they gave them a high-carb meal, the lean group had a huge increase in GLP-1.

Dr. Rhonda Patrick: Wow.

Dr. Ben Bikman: The obese group had no statistically significant response whatsoever. There was a little noise, but the error bars were big enough that there was no statistical difference. It again, it wiggled around a little bit, but at no point did it reach a significant increase, suggesting that you may now have two people who sit down to eat a meal. One person eats that carbohydrate-heavy meal, and they have a big GLP-1 response. They pat their tummy and slide the plate away. The other person eats that same amount and asks for seconds or even thirds because they aren't getting that GLP-1 response. So to me, the best use of these drugs in the context of weight loss isn't for weight loss per se, but it's rather to acknowledge some people aren't going to get that off switch when they eat carbs in particular, that apparently people responded the same way to fat. But they are not. There are differences in how people respond to carbohydrates with GLP-1. This study made it very, very clear. It was published in the journal Gut in 1996. To me, that's the best use of the drug, to say the physician or the clinician, the expert would be talking with the overweight patient and they would say, you know what, you need to control carbs, these refined sugars and starches, you got to eat less of them. Then the person says, yeah, but that's the problem. I can't eat less of them. I'm addicted to them. All right, let's use a low dose. And this gets into that range of, you know, 5 to 10 units, or 0.05 to 1 gram—

Dr. Rhonda Patrick: Milligram.

Dr. Ben Bikman: Milligram, yeah, milligram per week. That is going to be like kind of a microdose level. To me, that's the best use, where the physician, the expert, the clinician is saying, let's just give you a low, low dose of this drug, and it's going to— and I want you to Think of it as helping you control your cravings. Because what do people crave? People don't crave a plate of bacon and eggs. They don't crave a handful of walnuts. They crave something sweet and gooey or salty and crunchy. And usually it's going to be potato chips, crackers, cereal, ice cream. And that's what we want to help them control. So rather than saying this is a weight loss drug, let's— what if we changed the conversation and said this is a drug that is designed to help you change your eating habits? While you're on this low dose, we're going to put you on this low dose for 3 months, and I'm going to see you again in 3 months. I want you to be thinking about your evening cravings and these refined foods that you're always eating. And then you get them back 3 months later. Ideally, they say, boy, for the first time I can control my cravings and I'm doing better and I'm losing weight. Then I would say, let's see what happens when you cycle them off. And say, all right, you've learned what it looks like and what it feels like to eat differently. Let's see whether you need to still be on this microdose. Maybe they need, maybe they're done. I know people who've done this and they say, it changed me and it's been a year and I've not gone back to my old habits.

Dr. Ben Bikman: It just helps them rewire their habits. And 90 days is a good length of time to change your habits. So at 90 days, let's do a check-in. How are you doing? Oh, it's not really working. All right, well, let's keep it going. Maybe we increase it from 0.05 to 1 or something. But basically, my view, without having it outlined as a specific protocol, would be microdose and cycling. Let's put you on it with the intention of helping you change your habits. Let's take you off it to see whether the habits have stuck. If they haven't, let's cycle you back on, but always using these very, very low doses, not for weight loss, but for changing habits.

Dr. Rhonda Patrick: That's interesting that in your experience, people can do this microdose and after about 90 days, they can keep the appetite regulation under control. Because when you look at studies with people using, you know, the clinically relevant doses that they're using now of these different GLP-1 agonists, a lot of— most of the people end up gaining weight back because, you know, they go back to their old habits.

Dr. Ben Bikman: Yeah, and I think that's because they're not framing— I think a part of it's the narrative or the story. Which is, let's frame the conversation in the context of helping you change your dietary habits, rather than this is just a magic bullet and you're going to lose weight. I think in that instance, the person's changed the way they're eating, but maybe they're not— this is, I know, kind of getting into this hokey pseudo area of science perhaps, but when the conversation is focused on the habit, I think it helps change habits.

Dr. Rhonda Patrick: Oh, I mean, absolutely. The way you're thinking about something can change the outcome, for sure. I want to kind of go back to something that you mentioned that was very interesting to me, and it has to do with the way, you know, this food is sitting in your gut and the way digestion's kind of changed, and perhaps, you know, nutrient absorption.

Dr. Ben Bikman: Mm-hmm.

Dr. Rhonda Patrick: I hadn't really thought about it in that way, because what I'm sort of alluding to is, you know, the— I guess it's pretty well known now is that when people are rapidly losing weight, whether it's on a GLP-1 agonist or it's from caloric restriction, they can lose a lot of muscle along with the fat.

Dr. Ben Bikman: Yeah.

Dr. Rhonda Patrick: It's not just all fat, particularly if people are not getting enough dietary protein, which is a big signal for muscle protein synthesis, and if they're not engaging in resistance training, which is the other very important signal for growing muscle mass. Yeah. So, my question to you was going to be, you know, Is there a kind of a way around this muscle loss by increasing dietary protein? Obviously, the resistance training would be key, perhaps even more key now, because, you know, for one, if people aren't eating, I mean, I don't know how many meals a day people are eating. It probably varies depending on the person and what their side effects and stuff are, but eating the protein, and then, like, are they absorbing all the protein? I don't know if anyone's even looked at that, but that's interesting.

Dr. Ben Bikman: Yeah, I haven't seen it either. Yeah, but it does beg the question, is it, is the use of semaglutide, so it's very real. The evidence is very real showing One of the best papers in the New England Journal of Medicine about 2, 3 years ago found that about almost 40% of the weight loss that the person was losing was fat-free mass. Now, that is itself a big pool, but some of it would be muscle and bone mass. But I have not seen data that has determined whether it is a direct effect of the semaglutide. In other words, is the drug actually harming muscle and bone, or is it just an artifact of the poor nutrition? It might be a little bit of both, but it also might matter in the dose where I've heard reports. In fact, my lab is doing a muscle cell culture now looking at varying doses of the drug where it's possible at a lower dose it's facilitative, and at a higher dose it may be more catabolic when it comes to muscle mass and the dynamics of muscle protein synthesis. But even still, as far as I'm aware, it's unknown. Is it a direct effect of the drug, or is it an artifact of just poor nutrition because the person's not eating, and what they are eating, they're not absorbing very well? They're certainly not eating enough protein.

Dr. Rhonda Patrick: Yeah. This kind of— there's another interesting point here, and that is, like, GLP-1 receptors, and, I mean, they're all over many different organs.

Dr. Ben Bikman: Yeah, the muscle has them, and so does bone.

Dr. Rhonda Patrick: Bone, right.

Dr. Ben Bikman: Yeah, so that is an interesting point. Neurons do.

Dr. Rhonda Patrick: Yeah, I mean, and it also starts to touch on the broader use of GLP-1 drugs where you and I both know people are using them well beyond the— as much as I bemoan the fact that it's now an obesity drug where it was once just a diabetic drug, now people are saying, well, it's a blood pressure drug, it's an Alzheimer's drug, it's a fertility drug. I just don't know. In fact, as far as I am aware, there's very few studies to touch on that broader

Dr. Ben Bikman: On the mechanism. And even all of that could simply be an outcome of improving metabolic health, because back to the origins or the beginning of our conversation, because metabolic health is so foundational to chronic disease, all of this could just be a consequence of improving metabolic health.

Dr. Rhonda Patrick: But it still is worth the pursuit of determining, well, maybe it is a direct effect. Maybe there is the direct effect of the drug at the neuron, or at the muscle cell, et cetera. As far as I'm aware, that's not been elucidated yet. Yeah, that was my next question for you. I mean, we do have these observational studies that have looked at, you know, people on, you know, various forms of the GLP-1 agonists.

Dr. Ben Bikman: Yeah.

Dr. Rhonda Patrick: And a reduced incidence of cardiovascular disease, obviously type 2 diabetes, Alzheimer's disease now. And you have to wonder, like, is Is there a direct effect of, you know, agonizing these GLP-1 receptors on different tissues, or is this just an indirect effect of weight loss and improved metabolic health, right?

Dr. Ben Bikman: Yeah, yeah, yeah.

Dr. Ben Bikman: So I don't know, but what I can speak to is our unpublished results right now in muscle cells. We're treating them with varying doses of semaglutide. At the higher doses, there is catabolism of the muscle, and they're far less resilient and far more fragile. So we challenge the muscle with a chemical challenge, and they die way more readily. at doses used now at the level in which you see the dose in the drug in the plasma. So it's a physiological dose.

Dr. Rhonda Patrick: Okay, well then this gets back to the microdosing, and this is kind of, you know, I feel like you were talking about microdosing GLP-1 agonists for a very different reason than I'm going to ask you about now, and you're talking about appetite regulation.

Dr. Ben Bikman: Yeah.

Dr. Rhonda Patrick: And I think that's super interesting, particularly for people who don't have, real good control of their appetite, or perhaps their— I mean, who knows, their hormones are out of whack, right? But there is now this sort of growing budding interest amongst, you know, many people about this potential GLP-1 agonist being a longevity drug because of these different, you know, outcome studies that have been observational in nature, right?

Dr. Ben Bikman: Yeah. We're looking at correlation here, but the question is, well, like, Some people are now sort of starting to whisper about, we think, we think now maybe these drugs are actually affecting, they're actually pro-longevity.

Dr. Rhonda Patrick: And so microdosing, you know, these drugs in the, in the, in the ranges that you've been discussing earlier might be a way of getting the benefits. And you're also getting the side effect benefit of appetite regulation.

Dr. Ben Bikman: Yeah.

Dr. Rhonda Patrick: So maybe you're not going to be eating as much as well. Maybe it's just easier. to not eat as much.

Dr. Ben Bikman: Right. Yeah, yeah. So I, I appreciate the way you framed that, which is you mentioned a word that for a basic scientist is a dreaded word: correlation. I don't look favorably on correlation because I'm a basic scientist. I want to do one thing and observe a direct effect from that one thing. So one reason I am extremely cautious and even a little chagrined with the entire realm of longevity is that it's— it's not to disparage it necessarily, but it's entirely based on correlation when it comes to humans. We can only speculate and predict and model these sorts of things. Now, I'm not saying there's no utility to that, but I also think it behooves us to be mindful of the limitation that comes with that. So with GLP-1, in fact, it's worth noting another paper was just published this week finding that the risk of blindness doubles, more than doubles in people on high-dose GLP-1s. A paper was just published. So you look at the degree of blindness that occurs in adults. And those using the drug, it was more than twice the risk of developing blindness. Now, that's correlational. We don't know what else they may be doing. And so I don't mean to suggest that— I truly don't mean to suggest the drug is causing blindness, no more than someone could say the drug is promoting longevity. Although you actually can do a hard outcome with blindness, you can't really do the hard outcome with when does the person die very well. But there's so many variables that get worked in here that I cannot say it's because of the drug. But it is Another reason to have some caution that what's the point? So maybe we just come back to the dose, that maybe that's where we can find a common ground for all the enthusiasts and those who are enthusiastic but also a little skeptical. On my end, where I am enthusiastic, but I also just want to bring in a note of caution, maybe where we do have that common ground is the dose. So with regards to GLP-1, At the risk of seeing everything through a singular lens, one of the most common variables that predicts longevity within families— there's one paper that actually mentions the word of familial longevity— and then the longevity studies like the Amoris study in Sweden or the Honolulu Aging Study or the Shanghai Aging Study, some of the most consistent variables is metabolic health. Um, optimal glucose levels and insulin sensitivity. In fact, that one study, I think it was in the Mediterranean, that looked at families where you have a high number of centenarians, they found that the most common theme was that they were all very insulin sensitive. And as much as people have a— over the years, there's been an ideology of villainizing protein as, as a villain of aging because protein activates mTOR, and when mTOR is too activated, it promotes aging. I find that view unfortunate because for reasons you and I've mentioned, like muscle and bone mass, you have to have mTOR turned on. You have to, or you can't have any anabolic, no retention of lean mass, let alone building it. But when you vilify protein because of mTOR, you ought to vilify insulin because insulin activates mTOR much higher than even the most anabolic amino acids like leucine does, and it keeps it active. One dose of insulin can activate mTOR for up to 24 hours. Whereas leucine, the most anabolic of the amino acids, will only activate mTOR for about an hour or 2. And so if mTOR matters for longevity, and I know I've sort of contorted the whole thing about longevity here, all the more reason to come back to these kinds of metabolic first principles. And so looking at insulin sensitivity and glucose control, and I would just say the same thing with GLP-1.

Dr. Rhonda Patrick: While we may find that GLP-1 has a direct effect of, say, activating autophagy, Maybe it could, and that could be a mechanism whereby it promotes longevity. At the same time, I don't have to go that far, 'cause I could just say, does it improve insulin sensitivity? Okay, good. Then it's probably gonna correlate and predict and even cause improved longevity because of the evidence we have in that realm. So yeah, what you're saying essentially is that the improved metabolic health is probably what's driving the longevity benefits. And I would—

Dr. Ben Bikman: It's at least low-hanging fruit.

Dr. Rhonda Patrick: Yeah, I, I would agree. That makes the most sense. Yeah. You know, and it is, it is important to obviously keep everything in context as well. Obviously, there's people that are obese and metabolically unhealthy that have really just changed. It's changed their lives, right?

Dr. Ben Bikman: Yep.

Dr. Rhonda Patrick: But the question is, do they have to keep taking it?

Dr. Ben Bikman: Yeah. And in fact, 70% in the US, 70% of Americans get off the drug at 2 years, either because of cost or nausea or whatever. 70% stop taking it. And like you said, when they stop taking it, if habits haven't changed, maybe that's an important caveat, they gain it all back. Not to mention those who stay on the drug. A paper was published within the past 6 months. I think it was within the past 6 months, definitely within the past year. The risk of suicidal behavior doubles and the risk of major depression triples in people who are on the drug for up to 2 years.

Dr. Rhonda Patrick: On any dose of it or the high dose?

Dr. Ben Bikman: On the currently used um, Wegovy dose, which is the higher dose, which is common. Um,

Dr. Rhonda Patrick: so not a microdose, right?

Dr. Ben Bikman: Yeah. Yes. Well, my view of this is I don't know the mechanism. I don't know what the central effect is of this drug. But as much one way, and this is my own kind of philosophical view, we, we rejoice in the fact that this drug has helped me. It's reduced my cravings for junk food, let's say. And we would say that's a wonderful outcome. What if in the midst of reducing the cravings for junk food, it reduces their cravings for everything they enjoyed. Where you hear— this is anecdotal now— people lose interest in their old habits. A gal, the gal who used to like walking around the block with her girlfriends, doesn't really want to go anymore.

Dr. Ben Bikman: The guy who used to like getting on and playing video games, he doesn't want to do that anymore. They don't want to— a couple, they don't go play pickleball with their friends anymore, whatever. Maybe what we describe as improved eating control is actually just a reduced joy for life in general. But regardless of the mechanism or the philosophy behind it, the evidence is extremely clear. The major depression risk— people were 3 times more likely to have clinically diagnosed major depression, and again, twice more likely for suicidal behavior, and twice as likely— it was like 106% increased risk of anxiety.

Dr. Rhonda Patrick: And this is after the weight loss and after being on the drug?

Dr. Ben Bikman: And yeah, that's right. It was 2 years on the drug. So this is, this is part of why I'm cautious, where I respect the power of this tool. It is extremely powerful. Because it's so powerful, I think we, we should be mindful of going too far with it, which is why I am such an advocate. If it's going to be used at all, let's use it in a very specific context, at a very specific dosing regimen, with a cycling protocol where we want them to have in their mind, we don't want you on this drug indefinitely. This is not a lifetime solution. It is a crutch until you've learned how to walk on your own, if you will, and change your habits. That to me is— so microdose cycling with the conversation surrounding eating habits.