270 ‒ Journal club with Andrew Huberman: metformin, power of belief, & how to read scientific papers

1. 0:00 – 0:10

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Attia.

2. 0:10 – 6:33

   The motivation behind this journal club conversation

   1. AHAndrew Huberman0:10

      Peter, so good to have you here.

   2. PAPeter Attia0:12

      So great to be here, my friend.

   3. AHAndrew Huberman0:14

      This is something that you and I have been wanting to do for a while, and it's basically something that we do all the time, which is to peruse the literature and find papers that we are excited about for whatever reason, and oftentimes that will lead to a text dialogue or a phone call or both. But this time we've opted to try talking about these papers that we find particularly exciting in real time for the first time as this podcast format. First of all, so that people can get some sense of why we're so excited about these papers. We, we do feel that, um, people should know about these findings. And second of all, that it's an opportunity for people to learn how to dissect information and think about the papers they hear about in the news, the papers they might download from PubMed if they're inclined, but also just to start thinking like scientists and clinicians and get a better sense of what it looks like to pick through a paper, um, the good, the bad, and the ugly. So we're flying a little blind here, which is fun. Um, I'm definitely excited for all the above reasons.

   4. PAPeter Attia1:21

      Y- yeah, no, this is, uh... You and I have been talking about this for some time and, and, um, you know, actually, we used to run a journal club inside the practice where once a month one person would, um, just pick a paper and we would go through it in kind of a formal journal club presentation. We've gotten away from it for the last year just because we've been a little stretched thin. I think it's something we need to resume because it's, uh, it's a great way to learn, and it's a skill. You know, people probably ask you all the time, 'cause I know I get asked all the time, "Hey, w- w- what are the dos and don'ts of interpreting, you know, scientific papers? Is it enough to just read the abstract?" Um, and then-

   5. AHAndrew Huberman1:57

      No [laughs]

   6. PAPeter Attia1:57

      ... you know, usually the answer is, well, no. Um, but the how-to is, is tougher, and I think the two papers we've chosen today illustrate two opposite ends of the spectrum. You know, you're gonna obviously talk about something that we're gonna probably get into the technical nature of the assays, the limitations, et cetera. And the paper ultimately I've chosen to present, although I apologize I'm surprising you with this up until [chuckles] you know, a few minutes ago, is, is actually a very straightforward, simple epidemiologic paper that I think has important significance. I had originally gone down the rabbit hole on a, a much more nuanced paper about ATP binding cassettes in cholesterol absorption, but ultimately I thought this one might be more interesting to a broader audience.

   7. AHAndrew Huberman2:36

      Yeah.

   8. PAPeter Attia2:36

      By the way, I gotta tell you this funny story. So I had a dream last night about you, and, um, in this dream [chuckles] you were obsessed with making this certain drink that was like your elixir, and it had all of these crazy ingredients in it.

   9. AHAndrew Huberman2:51

      Supplements.

   10. PAPeter Attia2:52

       Sup- tons of supplements in it.

   11. AHAndrew Huberman2:53

       [laughs]

   12. PAPeter Attia2:53

       But the one thing I remembered when I woke up, 'cause I forgot most of them, I was really trying so hard to remember them, one thing that you had in it was dew. Like, you had to collect a certain amount of dew off the leaves every morning to put into this drink.

   13. AHAndrew Huberman3:07

       [laughs] Oh.

   14. PAPeter Attia3:07

       It was so-- But it was like just-

   15. AHAndrew Huberman3:09

       Sounds like something that I would do. [chuckles] Yeah

   16. PAPeter Attia3:11

       ... and, and so but here's the best part. You had, you had, like, a thermos of this stuff that had to be with you everywhere, and all of your clothing had to be tailored with a special pocket that you could put the thermos into so that you were never without the special Andrew drink. And again, you know how dreams when you're having them seem so logical and real, and then you wake up and you're like, "That doesn't even make sense. Like, why would he want the thermos in his shirt like that, that would warm it up?" Like, you know, all these... But, but boy, it was a realistic dream, and there were lots of things in it, including dew. Sp- special dew off the leaves every morning.

   17. AHAndrew Huberman3:50

       I love it. Well, it's not that far from reality. I'm a big, um, fan of yerba mate. I'm drinking it right now, in fact.

   18. PAPeter Attia3:57

       As am I.

   19. AHAndrew Huberman3:57

       Um, uh, in its many forms, usually the loose leaf. I don't tend to drink it out of the gourd. My dad's Ar- Argentine, so that's where I picked it up. I started drinking it when I was, like, five years old or younger, which I don't recommend people do. It's heavily caffeinated. Don't drink the smoked versions either, folks. I think those are potentially carcinogenic. But this thing that you describe of, of carrying around the thermos close to the body, if you are ever in Uruguay or if you ever spot grown men in a restaurant anywhere in the world carrying a thermos with them and to their meals and, and hugging it close, chances are they're Uruguayan.

   20. PAPeter Attia4:32

       Mm.

   21. AHAndrew Huberman4:33

       Uh, and they're drinking yerba mate. They drink it usually after their meals. It's supposed to be good for your digestion. So it's not that far from-

   22. PAPeter Attia4:39

       There you go

   23. AHAndrew Huberman4:39

       ... from reality. I don't carry the thermos, but I do drink mate every day and, um, I'm gonna start collecting dew off the leaves. Uh-

   24. PAPeter Attia4:47

       Just a few drops every morning.

   25. AHAndrew Huberman4:48

       [laughs]

   26. PAPeter Attia4:49

       Just, just [laughs] as you brew it. Yeah.

   27. AHAndrew Huberman4:51

       Oh, my. Um, some other time we can talk about dreams. Recently I've, I've been doing some dream exploration. I've had some absolutely transformative dreams for the first time in my life.

   28. PAPeter Attia5:01

       Mm.

   29. AHAndrew Huberman5:01

       One dream in particular that has, that allowed me to feel something I've never felt before and has catalyzed a large number of important decisions in a way that no other experience, waking or sleep, has ever impacted me. And this was drug-free, et cetera. Um-

   30. PAPeter Attia5:17

       And, and do you think you could have had that dream-- We don't have to get into it if you don't wanna talk about it now, but, uh, was there a lot of work you had to do to prepare for that dream to have taken place?
3. 6:33 – 13:45

   Why Peter chose a paper on metformin, how metformin works, and why it generated excitement as a longevity-enhancing agent

   1. AHAndrew Huberman6:33

      Yeah. Um, who should go first?

   2. PAPeter Attia6:37

      I, I'm happy to go first.

   3. AHAndrew Huberman6:38

      Great, yeah.

   4. PAPeter Attia6:38

      This one's, this one's... This is a pretty straightforward paper. So, so we're gonna talk about a, a paper titled Reassessing the Evidence of a Survival Advantage in Type 2 Diabetics Treated with Metformin Compared with Controls Without Diabetes: A Retrospective Cohort Study. This is by Matthew Thomas Keyes and colleagues. This was published, uh, last fall. Um, why is this paper important? So this paper is important because in 2014, uh, Bannister published a paper that I think in many ways kind of got the world very excited about metformin. So this is almost 10 years ago, and I'm sure many people have heard about this paper, even if they're not familiar with it, but they've heard the concept of the paper. And in many ways, it's the paper that has led to the excitement around the potential for geroprotection with metformin. And I should probably just define for the audience what geroprotection means. When we think of-

   5. AHAndrew Huberman7:34

      And probably also, sorry to interrupt, what metformin is-

   6. PAPeter Attia7:36

      Yeah

   7. AHAndrew Huberman7:36

      ... just for the uninformed.

   8. PAPeter Attia7:37

      Yeah. That, that's a great point. So I'll start with the, with the latter. So metformin is a drug that has been used for many years. Uh, depends, you know, where it was first approved, I think was in Europe. Um, but, you know, call it directionally 50-plus years of use as a first-line agent for patients with Type 2 diabetes. Uh, in the US, maybe 40-plus years. So this is a drug that's been around forever, trade name, uh, Glucophage, um, or brand name, and, uh, but, but again, it's, you know, it's a generic drug today. The mechanism by which metformin works is debated hotly. Um, but what I think is not debated is the immediate thing that metformin does, which is it inhibits complex one of the mitochondria. So a- again, maybe just taking a step back. So the mitochondria, as everybody thinks of those, is the cellular engine for making ATP. So the most efficient way that we make ATP is through oxidative phosphorylation, where we take either fatty acid pieces or a breakdown product of glucose once it's partially metabolized to pyruvate. We put that into an electron transport chain, and we basically trade chemical energy for electrons that can then be used to make phosphates onto ADP. So it's, you know, you think of everything you do. Eating is taking the chemical energy in food, taking the energy that's in those bonds, making electrical energy in the mitochondria. Those electrons pump a gradient that allow you to make ATP. To give a sense of how primal and important this is, if you block that process completely, you die. So everybody's probably heard of cyanide, right? Cyanide is something that is incredibly toxic, even at the smallest doses. Cyanide is a complete blocker of this process, and if my memory serves me correctly, I think it blocks complex four of the mitochondria. I don't know if you recall if it complex three or complex four.

   9. AHAndrew Huberman9:34

      I, I know a lot about toxins that impact the nervous system, but I don't know a lot about poisons.

   10. PAPeter Attia9:38

       The mitochondria, yeah.

   11. AHAndrew Huberman9:39

       But if ever you want to have some fun, we can talk about all the dangerous stuff that animals make and insects make and how they kill you.

   12. PAPeter Attia9:45

       Yeah, like botulotoxin-

   13. AHAndrew Huberman9:47

       That's like my favorite topic

   14. PAPeter Attia9:47

       ... and all these things that block sodium channels.

   15. AHAndrew Huberman9:48

       Uh, alpha-latrotoxin-

   16. PAPeter Attia9:49

       Yeah, yeah

   17. AHAndrew Huberman9:49

       ... bungaro- I, I really geek out on this stuff 'cause it allows me to talk about neuroscience, animals-

   18. PAPeter Attia9:54

       [laughs]

   19. AHAndrew Huberman9:55

       ... and scary stuff.

   20. PAPeter Attia9:56

       Yeah.

   21. AHAndrew Huberman9:56

       It, like, combines it. So we could do that sometime for fun, maybe at the end if we have a few moments.

   22. PAPeter Attia10:00

       So, so, you know, something like cyanide that is a very potent inhibitor of this e- electron transport chain will kill you instantly. People understand that, of course, a drop of cyanide and you would, you would be dead i- literally instantaneously. So metformin works at the first of those complexes. I believe there are four, if my memory serves correctly, four electron transport chain, uh, complexes. And, um, but of course, it's not a complete inhibition of it. It's just kind of a weak blocker of that. And the net effect of that is what? So the net effect of that is that it changes the ratio of adenosine monophosphate to adenosine diphosphate. Um, what's less clear is why does that have a benefit in diabetics? Um, because what it unambiguously does is reduces the amount of glucose that the liver puts out. So hepatic glucose output is one of the fundamental problems that's happening in Type 2 diabetes. Y- you may recall, I think we talked about this even on a previous podcast, you and I sitting here with normal blood sugar have about five grams of glucose in our total circulation. That's it. Five grams. Think about how quickly the brain will go through that.

   23. AHAndrew Huberman11:05

       Mm-hmm.

   24. PAPeter Attia11:06

       Within minutes. So the only thing that keeps us alive is our liver's ability to titrate out glucose. And if it puts out too much, for example, if the glucose c- if the glucose level was consistently two teaspoons, you would have Type 2 diabetes. So the difference between being metabolically healthy and having, you know, profound Type 2 diabetes is one teaspoon of glucose in your bloodstream. So the ability of the liver to tamp down on high glucose output is important. Metformin seems to do that. So-

   25. AHAndrew Huberman11:37

       Can I just ask, uh, uh, one question? Is it fair, um, to provide this overly simplified summary of the biochemistry, which is that when we eat, the food is broken down, but the breaking of bonds creates energy that then our cells can use in the form of ATP, and the mitochondria are central to that process. And that metformin is partially short-circuiting the energy production process.

   26. PAPeter Attia12:01

       Yep.

   27. AHAndrew Huberman12:02

       And so even though we are eating, when we have metformin in our system, presumably there is going to be less net glucose. The bonds are gonna be broken down. We're chewing, we're digesting, but less of that is turned into blood sugar, glucose

   28. PAPeter Attia12:17

       Well, sort of. I mean, th- it, it's not, um, [tsks] it's not depriving you of ultimately storing that energy. What it's doing is changing the way the body, um, partitions fuel. That's probably a better way to think about it to be a little bit more accurate.

   29. AHAndrew Huberman12:33

       Mm-hmm.

   30. PAPeter Attia12:33

       So, um, f- for example, like it's not depriving you of the calories that are in that glucose. That would be, you know, fantastic, but that's not-
4. 13:45 – 19:28

   Defining insulin resistance and its underlying causes

   1. PAPeter Attia13:45

      So, so we've got this drug, we've got this drug metformin. It's considered a perfect first-line agent for people with type 2 diabetes. So again, what's happening when you have type 2 diabetes, uh, the primary insult probably occurs in the muscles, and it is insulin resistance. Everybody hears that term. What does it mean? Uh, insulin is a peptide. It binds to a receptor on a cell. So let's just talk about it through the lens of the muscle, 'cause the muscle is responsible for most glucose disposal. It gets glucose out of the circulation. High glucose is toxic. We have to put it away, and we want to put most of it into our muscles. That's where we store 75 to 80% of it. When insulin binds to the insulin receptor, a ki- a tyrosine kinase is triggered inside. So just ignore all that, but a chemical reaction takes place inside the cell that leads to a phosphorylation, so a ATP donates a phosphate group, and [tsks] a transporter, just think of like a little tunnel, like a little straw, goes up through the level of the cell, and now glucose can freely flow in. So I'm sure you've talked a lot about this with your audience. W- things that move against gradients need pumps to move them. Things that move with gradients don't. Glucose is moving with its gradient into the cell. It doesn't need active transport, but it does need the transporter put there. That requires the energy, and that's the job of insulin.

   2. AHAndrew Huberman15:06

      By the way, I did not know that. I, I mean, I certainly know active and, and passive transport, uh, as it relates to, like, neurotransmitter and ion flow, um, but I'd never heard that when insulin binds to a cell, that literally a little straw is placed into the-

   3. PAPeter Attia15:18

      Yeah

   4. AHAndrew Huberman15:18

      ... membrane of the cell.

   5. PAPeter Attia15:19

      Glu- glucose doesn't need a pump to move it in-

   6. AHAndrew Huberman15:21

      That is cool

   7. PAPeter Attia15:22

      ... um, because there's much more glucose outside the cell than inside, so it just [whooshes] But the energy required is to move the, the straw up to the cell. So-

   8. AHAndrew Huberman15:30

      Cell biology is so cool.

   9. PAPeter Attia15:31

      Yeah, it is. So, so what happens is as, and Gerald Shulman at Yale did the best work on elucidating this, as the m- intramuscular fat increases, and I... by intramuscular, I mean intracellular fat, uh, triacylglycerides and diacylglycerides accumulate in a muscle cell, that signal gets interrupted.

   10. AHAndrew Huberman15:53

       Hm.

   11. PAPeter Attia15:53

       And all of a sudden, I'm making these numbers up, if you used to need two units of insulin to trigger the little transporter, now you need three, and then you need four, and then you need five. You need more and more insulin to get the thing up. That is the definition of insulin resistance.

   12. AHAndrew Huberman16:11

       Hm.

   13. PAPeter Attia16:12

       The cell is becoming resistant to the effect of insulin, and therefore, the early mark of insulin resistance, the canary in the coal mine, is not an increase in glucose. It's an increase in insulin. So normal glycemia with hyperinsulinemia, especially postprandial, meaning after you eat hyperinsulinemia, is the thing that tells you, "Hey, you're, you're five, 10 years away from this being a real problem." So fast-forward many steps down the line, someone with type 2 diabetes has long passed that system. Now, not only are they insulin resistant, where they just need a boatload of insulin, which is made by the pancreas, to get glucose out of the circulation, but now that system's not even working well, and now they're not getting glucose into the cell. So now their glucose level is elevated, and even though it's continually being chewed up and used up, because again, the brain alone would account for most of that glucose disposal, the liver is now becoming insulin resistant as well, and now the liver isn't able to regulate how much glucose to put into circulation, and it's overdoing it. So now you have too much glucose being pumped into the circulation by the liver, and you have the muscles that can't dispose of it. And it's really a vicious, brutal cascade, because the same problem of fat accumulating in the muscle is now starting to happen in the pancreas, and now the relatively few cells in the pancreas, called beta cells, that make insulin are undergoing inflammation due to the fat accumulation within the pancreas itself. And so now the thing that you need to make more insulin is less effective at making insulin. So ultimately, way, way, way down the line, a person with type 2 diabetes might actually even require insulin exogenously.

   14. AHAndrew Huberman17:52

       Could you share with us a few of the causes of type 2 diabetes, of insulin resistance? I mean, one, it sounds like, is accumulating too much fat.

   15. PAPeter Attia18:00

       Yeah, so energy-

   16. AHAndrew Huberman18:00

       Yeah

   17. PAPeter Attia18:00

       ... imbalance would be an enormous one. Inactivity or insufficient activity is probably the single most important. So when Gerald Shulman, um, was running clinical trials at Yale, um, they would be recruiting undergrads to study, obviously, 'cause you're typically recruiting young people, and they would, you know, be doing these very detailed mechanistic studies where they would require actual tissue biopsies. So, you know, you're gonna biopsy somebody's quadriceps and actually look at what's happening in the muscle. Well, I remember him telling me this when I interviewed him on my podcast. He said the most important criteria of the people we interviewed is that, 'cause they were still lean, these weren't people that were overweight, but they had to be inactive You couldn't have active people in these studies. So exercising is one of the most important things you're going to do to ward off insulin resistance. But there are other things that can cause insulin resistance. Sleep deprivation has a profound impact on insulin resistance. I think we probably talked about this previously, but if you, you know, some very elegant mechanistic studies where you sleep deprive people, you know, you let them only sleep for four hours for a week, you'll reduce their glucose disposal by about half.

   18. AHAndrew Huberman19:03

       Wow.

   19. PAPeter Attia19:04

       Which is, I mean, that's a staggering amount of... Y- you're basically inducing profound insulin resistance in just a week of sleep deprivation. Hypercortisolemia is another factor, and then obviously energy imbalance. So where when you're, when you're accumulating excess energy, when you're getting fatter, if you start spilling that fat outside of the subcutaneous fat cells into the muscle, into the liver, into the pancreas, all those things are exacerbating it.

   20. AHAndrew Huberman19:27

       Got it.

5. 19:28 – 22:20

   Metformin as a first-line treatment for type 2 diabetes, and Peter’s evolving interest in metformin as a geroprotective drug

   1. PAPeter Attia19:28

      Okay. So enter metformin, first line drug. So m- most of the drug-- so every drug you give a person with type 2 diabetes is trying to address part of this chain. So some of the drugs m- tell you to make more insulin. That's, that's one of the strategies. So here are drugs like sulfonylureas, they tell the body make more insulin. Other drugs, like insulin, just give you more of the insulin thing. Metformin tackles the problem elsewhere. It tamps down glucose by addressing the glucose dispo- the, uh, hepatic glucose output channel. GLP-1 agonists are another drug. They increase insulin sensitivity, initially causing you to also make more insulin. Um, GLP-1-

   2. AHAndrew Huberman20:08

      So that's Ozempic?

   3. PAPeter Attia20:09

      Yes.

   4. AHAndrew Huberman20:10

      Yeah.

   5. PAPeter Attia20:10

      Yeah.

   6. AHAndrew Huberman20:10

      And ber- is it true that berberine is more or less the poor man's metformin?

   7. PAPeter Attia20:15

      Yeah.

   8. AHAndrew Huberman20:16

      Okay.

   9. PAPeter Attia20:16

      Yeah.

   10. AHAndrew Huberman20:16

       It's a, from a tree bark, it just happens to have the same properties of-

   11. PAPeter Attia20:19

       Yeah, and by the way, metformin-

   12. AHAndrew Huberman20:20

       ... of reducing mTOR and reducing blood glucose.

   13. PAPeter Attia20:23

       Yeah, and metformin, by the way, uh, occurs from a lilac plant in France, like that's where it was discovered. So it's also, metformin is also based on a substance found in nature.

   14. AHAndrew Huberman20:30

       So you, you need a prescription for metformin.

   15. PAPeter Attia20:33

       Yeah.

   16. AHAndrew Huberman20:33

       You don't need a prescription for berberine.

   17. PAPeter Attia20:35

       Correct.

   18. AHAndrew Huberman20:35

       But yeah, we can talk about berberine a little bit later. I had a couple great experiences with berberine and a couple bad experiences.

   19. PAPeter Attia20:41

       Interesting.

   20. AHAndrew Huberman20:41

       Berberine.

   21. PAPeter Attia20:42

       Yeah. So, um, uh, maybe taking one step back from this. In 2011, I became very interested in metformin personally, just reading about it, obsessing over it, and just somehow decided like, "I should be taking this." So I actually began taking metformin, I still remember exactly when I started. I started it in May of 2011, and I realized that because I was on a trip with a bunch of buddies. We went to the Berkshire Hathaway, uh, shareholder meeting, which is, uh, you know, the Buffett, uh, shareholder meeting and, uh, you know, it was kind of like a fun thing to do, and I remember being so sick the whole time because I didn't titrate up the dose of metformin. I just went straight to two grams a day, which is kind of like the full dose, and we went to this-

   22. AHAndrew Huberman21:26

       Is that characteristic of your approach to things?

   23. PAPeter Attia21:30

       Yes, I think that's safe to say.

   24. AHAndrew Huberman21:31

       Next time I'll give you a thermos of this dew that I collect in the morning.

   25. PAPeter Attia21:34

       Oh, really?

   26. AHAndrew Huberman21:35

       Yeah. [laughs]

   27. PAPeter Attia21:38

       So I remember being so sick that the whole time we were in Nebraska or Omaha, I guess, I couldn't-- We went to Dairy Queen, 'cause you do all the Buffett things when you're there, right? Like I couldn't have an ice cream at Dairy Queen.

   28. AHAndrew Huberman21:49

       You couldn't?

   29. PAPeter Attia21:49

       I mean, I couldn't. I'm so nauseous.

   30. AHAndrew Huberman21:51

       Oh, 'cause I would say if you've got metformin in your system, you're gonna buffer glucose. You could have four ice cream cones and probably feel fine.
6. 22:20 – 23:31

   Defining the term “geroprotection”

   1. PAPeter Attia22:20

      you know, self-experimentation.

   2. AHAndrew Huberman22:21

      Do you wanna define geroprotection? I'm, uh-

   3. PAPeter Attia22:23

      Yeah, yeah. It's a good term to define.

   4. AHAndrew Huberman22:24

      Ger- geriatric, gero.

   5. PAPeter Attia22:26

      Yeah. So, so yeah, gero from, from geriatric, old, protection, so protection from aging. And when we talk about a drug like metformin or rapamycin or even NAD, NR, these things, the idea is we're talking about them as geroprotective to signal that they are drugs that are not targeting a specific disease of aging. For example, a PCSK9 inhibitor is sort of geroprotective, but it's targeting one specific pathway, which is cardiovascular disease and dyslipidemia. Whereas the idea is a geroprotective agent would target hallmarks of aging. There are nine hallmarks of aging. Please don't ask me to recite them. I've never been able to get all nine straight, but people know what we're talking about, right? So decreased autophagy, increased senescence, decreased nutrient sensing or defective nutrient sensing, uh, proteomic instability, genomic instability, uh, methylation, all of these things, epigenetic changes. Those are all the nine hallmarks of aging.

   6. AHAndrew Huberman23:23

      You got seven.

   7. PAPeter Attia23:24

      Yeah, yeah, yeah.

   8. AHAndrew Huberman23:25

      Yeah.

   9. PAPeter Attia23:25

      So a geroprotective agent would target those deep down biological marks of

7. 23:31 – 30:43

   The 2014 study that got the anti-aging community interested in metformin

   1. PAPeter Attia23:31

      aging. And in 2014, um, a paper came out by Bannister that basically got the world focused on this problem. By the world, I mean the world of, of anti-aging. So what, what Bannister and colleagues did was they took a registry from the UK, and they got a set of patients who were on metformin with type 2 diabetes, but only metformin. So these were people who had just progressed to diabetes. They were not put on any other drug, just metformin, and then they found from the same registry a group of matched controls. So this is a standard way that epidemiologic studies are done because, again, you don't have the luxury of doing the randomization, so you're trying to account for all the biases that could exist by saying, "We're gonna take people who, uh, look just like that person with diabetes, so can we match them for age, sex, socioeconomic status, um, blood pressure, BMI, everything we can, and then let's look at what happened to them over time." Now, again, this is all happening in the future, so you're looking into the past. It's retrospective in that sense. And so let me just kind of pull up the, the sort of, uh, table here so I can kind of walk through. And this is not in the paper we talked about, but I think this is an important background. So, [clears throat] they did something that at the time I didn't really notice. I didn't notice what they did. I probably did and I forgot, but I didn't notice this until about five years ago when I went back and looked at the paper. And they did something called, um, uh, informative censoring. So the way the study worked is if you were put on metformin, we're gonna follow you. If you're not on metformin, we're gonna follow you, and we're gonna track the number of deaths from any cause that occur. This is called all-cause mortality, or ACM, and it's really the gold standard in a trial of this nature, or a study of this nature, or even a clinical trial. You wanna know how much d- are people dying from anything, 'cause we're trying to prevent or delay death of all causes. Informative censoring says, "If a person who's on metformin deviates from that inclusion criteria, we will not count them in the final assessment." So how are the ways that that can happen? Well, one, the person can be lost to follow-up. Two, they can just stop taking their metformin. Three, and more commonly, they can progress to needing a more, uh, significant drug. So all of those patients were excluded from the study. So think about that for a moment. This is, in my opinion, a significant limitation of this study, because what you're basically doing is saying, "We're only gonna consider the patients who were on metformin, stayed on metformin, and never progressed through it, and we're gonna compare those to people who were not having type 2 diabetes." So an analogy here would be imagine we're gonna do a study of two groups that we think are almost identical. One of them are smokers, and the other are identical in every way, but they're not smokers, and we're gonna follow them to see which ones get lung cancer. But every time somebody dies in the smoking group, we stop counting them. When you get to the end, you're going to have a less significant view of the health status of that group.

   2. AHAndrew Huberman26:54

      Mm-hmm.

   3. PAPeter Attia26:55

      So with that caveat, the Bannister study found a very interesting result, which was the crude death rate, um, was-- And by the way, the way these are done, this is also one of the challenges of epidemiology is the math gets much more complicated. You have to normalize death rate for the amount of time you study the people. So everything is normalized to 1,000 person years. So the crude death rate in the group of people with type 2 diabetes who were on metformin, including the censoring, was 14.4. So 14.4 deaths occurred per 1,000 patient years. If you look at the control group, it was 15.2. This was a startling result, and I remember reading this in, again, 2014 and being like, "Holy crap, this is really amazing."

   4. AHAndrew Huberman27:50

      Is there, um-- Could you explain why? 'Cause I, I, I hear those numbers and they don't seem that striking. It's a difference of about a year and a half. Now, of course, um, a difference of about a year and a half in lifespan is, is-

   5. PAPeter Attia28:03

      Well, and, and-

   6. AHAndrew Huberman28:03

      ... is remarkable but-

   7. PAPeter Attia28:04

      And actually it doesn't even translate to that. So, so taking a step back, diabet- type 2 diabetes on average will shorten your life by six years.

   8. AHAndrew Huberman28:10

      I see.

   9. PAPeter Attia28:11

      So that's the actuarial difference between having type 2 diabetes and not, all comers. Uh, but you're right, this is not a huge difference. It's only a difference of a little less than one year of life per 1,000 patient years studied.

   10. AHAndrew Huberman28:22

       Okay.

   11. PAPeter Attia28:23

       But-

   12. AHAndrew Huberman28:23

       There-- And by the way, uh, Peter just pointed out my, my math was wrong when I said about a year and a half. But-

   13. PAPeter Attia28:27

       But, but the, the point here is you would expect the people in the metformin group to have a far worse outcome, i.e. to have a far worse crude death rate. And the fact that it was statistically significant in the other direction, and it turned out on the, what's called a Cox proportional hazard, which is where you actually model the difference in lifespan. The people who took metformin and had diabetes had a 15%, one five, 15% relative reduction in all-cause death over 2.8 years, which was the median duration of follow-up compared to the non-

   14. AHAndrew Huberman29:03

       Well, that seems to be the, the number that makes me go, "Wow."

   15. PAPeter Attia29:06

       Yeah.

   16. AHAndrew Huberman29:07

       Right? That, um, because... Could you repeat those numbers again?

   17. PAPeter Attia29:11

       Yep. So 15% reduction in all-cause mortality over 2.8 years.

   18. AHAndrew Huberman29:17

       That's a big deal.

   19. PAPeter Attia29:19

       It is. And again, there's no clear explanation for it unless you believe that metformin is doing something beyond helping you lower blood glucose. Because the difference in blood glucose between these two people was still in favor of the non-diabetics.

   20. AHAndrew Huberman29:39

       Mm-hmm.

   21. PAPeter Attia29:40

       So again, the proponents of metformin being a geroprotective agent, and I put myself in this category at one point. I would put myself today in the category of undecided. But at the time, I very much believed this was a very good suggestion that metformin was doing other things. You mentioned a couple already. Metformin is a weak inhibitor of mTOR. Metformin reduces inflammation. Metformin potentially tamps down on senescent cells and their secretory products. You know, there are lots of things metformin could be doing that are off target, and it might be that those things are conferring the advantage. So fast-forward until a year ago, and I think most people took the Bannister study as kind of the best evidence we have for the benefits of metformin, and I'm sure you've had lots of people come up to you and ask you, "Should I be on metformin? Should I be on metformin?" I mean, I probably get asked that question almost as much as I'm asked any question, uh, outside of dew. I mean, people definitely wanna know if you should be consuming dew, but, but after that, it's metformin.

   22. AHAndrew Huberman30:41

       Fresh off the leaves-

   23. PAPeter Attia30:42

       Has

8. 30:43 – 37:30

   Peter presents the 2022 paper that repeats the analytical approach from the 2014 Bannister study

   1. PAPeter Attia30:43

      to be

   2. AHAndrew Huberman30:43

      ... while viewing morning sunlight.

   3. PAPeter Attia30:45

      So okay. So let's, so let's kinda fast-forward to now the, the paper that I wanted to spend a few more minutes on.

   4. AHAndrew Huberman30:50

      Yeah, and thanks for that background. I, I'm still, uh, dazzled by the, uh, insertion of the straw by way of, of, uh, insulin. I, I, I don't think I've ever heard that described. I need to, I need to go get a, get Better textbook

   5. PAPeter Attia31:04

      It's a pretty short straw, in fairness

   6. AHAndrew Huberman31:06

      Okay

   7. PAPeter Attia31:06

      You know, it's just, it's just a little transport

   8. AHAndrew Huberman31:07

      Yeah, I'm just, I, uh, just, um, b- to give people a sense of why I'm so dazzled by it, I am always fascinated by how quickly, how efficiently, and, um, how specifically biology can create these little protein complexes that do something really important. I mean, you're talking about an on-demand creation of a little, of a portal, right? I mean, these are cells engineering their own machinery in real time in response to chemical signals

   9. PAPeter Attia31:34

      But, but remind me

   10. AHAndrew Huberman31:34

       I mean, that's, that's, it's great. It's, it-

   11. PAPeter Attia31:36

       Yeah, but, but, but I'm, I'm sort of rusty on my neuroscience, but an action potential works in reverse the same way. Like, you need the ATP gradient to restore the, uh, to, to restore the gradient, but once the action potential fires, it's passive outside, right?

   12. AHAndrew Huberman31:50

       Yeah, so what Peter's referring to is, um, the way that neurons become electrically active is by the flow of ions across the cell, that from the outside of the cell to the inside of the cell, and they're, we have both active conductances, meaning they're triggered by electrical changes in the gradients, uh, via, uh, changes in electrical potential. Um, and then there are passive gradients where things can just flow back and forth until there's a balance equal inside and outside the cell. I think what's, um, what's different is that there's some movement of a lot of stuff inside of neurons when neurotransmitters like dopamine binds to its receptor and then a bunch of, you know, it's like a bucket brigade that gets kicked off internally. But it's not often that you hear about receptors getting inserted into cells very quickly

   13. PAPeter Attia32:30

       Yeah, I see your point

   14. AHAndrew Huberman32:30

       Normally you have to go through a process of, of, you know, uh, transcribing genes and making sure that the specific proteins are made, and then it, those are long, slow things that take place over the course of many hours or days. What you're talking about is a real on-demand insertion of a-

   15. PAPeter Attia32:43

       Yeah, it works in minutes

   16. AHAndrew Huberman32:43

       ... of a channel

   17. PAPeter Attia32:44

       Yeah

   18. AHAndrew Huberman32:44

       And it makes sense as to why that would, uh, be required, but it's just, oh, so very cool.

   19. PAPeter Attia32:49

       It's cool, yeah. So Keys and colleagues came along and said, "We would like to redo the entire Bannister analysis." Um, and I, I think their motivation for it was the interest in this topic is through the roof. There is a clinical trial called the TAME trial that is, I think, pretty much funded now and may be getting underway soon. The TAME trial, which is an important trial, is going to try to ask this question prospectively and through random assignment. So-

   20. AHAndrew Huberman33:18

       So this is the Targeting Aging with Metformin trial, TAME

   21. PAPeter Attia33:21

       That's correct

   22. AHAndrew Huberman33:22

       Okay

   23. PAPeter Attia33:22

       Nir Barzilai, uh, is probably the senior PI on that. Um, and I think in many ways, the Bannister study, along with some other studies, um, but of lesser significance, probably provided some of the motivation for the TAME trial. So they said, "Okay, look, we're gonna do this. We're gonna use a different cohort of people." Um, so the first study that we just talked about, the Bannister study, used, uh, I believe it was, like roughly they sampled like 95,000 subjects from a UK biobank. Here, they used a larger sample. They did about half a million people sampled from a, a, a Danish health registry, and they did something pretty elegant. They created two groups to study. So the first was just a standard replication of what Bannister did, which, uh, was just a group of people with and without diabetic that they tried to match as perfectly as possible. But then they did a second analysis in parallel with discordant twins, so same-sex twins that only differed in that one had diabetes and one didn't. I thought this was very elegant because here you have a degree of genetic similarity, and you have similar environmental, uh, uh, factors during childhood that might give you, you know, allow you to see if there's any sort of difference in signal. So now turning this back into a little bit of a journal club, virtually any clinical paper you're gonna read, table one is the characteristics of the people in the study. You always want to take a look at that. So when I look at table one here, you can see it's-- And by the way, just for people watching this, we're gonna make all these papers and figures available, so if you're, you know, don't, don't, you know, we'll have nice show notes that'll make all this clear. So table one in the Keys paper shows the baseline characteristics, and again, it's almost always gonna be the first table in a paper. Usually, the first figure in the paper is a study design. It's usually a flow chart that says, "These were the inclusion criteria. These were all the people that got excluded. This is how we randomized," et cetera. And you can see here that there are four columns. So the c- the first two are the singletons. These are people who are not related, and then the second two are the twins who are matched. And you can see, remember how I said they sampled about 500,000 people? You can see the numbers. So they got, you know, 7,842 singletons on metformin, the same number then they pulled out matched without diabetes. On the twins, they got 976 on metformin with diabetes, and then by definition, 976 co-twins without them. And you look at all these characteristics. What was their age upon entry? How many were men? What was the year of indexing when we got them? What medications were they on? What was their highest level of education, marital status, et cetera? The one thing I want to call out here that really cannot be matched in a study like this, so this is a very important limitation, is the medication. So look at, look at that column, Andrew. Notice how pretty much everything else is perfectly matched until you get to the medication list.

   24. AHAndrew Huberman36:23

       Yeah, it's all over the place.

   25. PAPeter Attia36:24

       Yeah, it's just, you, it's not even close. They're nowhere, they're nowhere near matched, right? In other words, just to give you a couple of examples, right? On the, and, uh, let's just talk about the singletons 'cause it's basically the same story on the twins. If you look at what fraction of the people with type 2 diabetes are on lipid-lowering medication, it's 45.6% versus 15.4% in the matched without diabetes. It's a three-x difference. What about antiplatelet therapy? That's 30% versus 14%. Antihypertensives, 65% vers, 63% versus 31%.

   26. AHAndrew Huberman36:56

       Right. Because people who have one health issue and are taking metformin are likely to have other health issues.

   27. PAPeter Attia37:01

       Exactly. So this is, again, a fundamental flaw of epidemiology. You can never remove all the confounders.

   28. AHAndrew Huberman37:09

       Ugh. This is why I became an experimental scientist

   29. PAPeter Attia37:12

       Yeah

   30. AHAndrew Huberman37:12

       So that we could control variables
9. 37:30 – 49:20

   Greater mortality in the metformin group: how results differed between the 2022 paper and the 2014 paper

   1. PAPeter Attia37:30

      the two big things that were done in this experiment or in this survey or, you know, study to differentiate it from Bannister was one, the twin trick, which I think is pretty cool. The second thing that they did was they did a sensitivity analysis with and without informative censoring. So one of the other things they wanted to know was, hey, does it really matter if we don't count the metformin patients who progress? So, um, so let's see kind of what, what transcribed. So the next figure, figure two-- uh, pardon me, the next table, table two, walks you through the crude, uh, mortality rate in each of the groups. So the most important row, I think, in this table is the one that says crude mortality per thousand person years. Now y- you recall that in the previous study, in the Bannister study, those were on the ballpark of about 15 per. Okay, so let's look at each of these. So in the, um, single, the singletons with- without-- so the non-twins who were not diabetic, it was 16.86.

   2. AHAndrew Huberman38:41

      And could you put a little more contour on what this thousand person years-

   3. PAPeter Attia38:46

      What, what it is?

   4. AHAndrew Huberman38:46

      Are you talking about pooling the lifespans of a, of, of a bunch of different people until you get to the number 1,000?

   5. PAPeter Attia38:53

      Yeah. Because this-

   6. AHAndrew Huberman38:53

      So you're normalizing not-- so it's not who's gonna live 1,000 years 'cause no-

   7. PAPeter Attia38:57

      Right, right, right

   8. AHAndrew Huberman38:57

      ... one's expecting that. Um, you're essentially taking-- so you've got some people that are gonna live, um, 76 years, 52 years, 91 years, and you're pooling all of those until you hit 1,000. And then that becomes kind of a, a, a, a, it's like a normalized division. You're basically like, so let's say the, the control group, um, you're asking if there were 1,000 person years available to live, how likely is it that this person would live another 15?

   9. PAPeter Attia39:26

      Yeah. So a couple ways to think about it. A sim- so taking a step back, we always have to have some way of normalizing. So when we talk about the mortality from a disease like cancer in the population, we would, we report it as what's the mortality rate per, and it's typically per 100,000 persons.

   10. AHAndrew Huberman39:43

       Okay.

   11. PAPeter Attia39:44

       So-

   12. AHAndrew Huberman39:44

       That's a much more intuitive way to express it

   13. PAPeter Attia39:46

       It is. But the reason we can do it that way is because we're literally looking at how many people died this calendar year, and we divide it by the number of people in that age group. So it's typically what you're doing when you look at aged groups in buckets of like decades. So that's why we can say the highest mortality is like people 90 and up. Even though the absolute number of deaths is small, it's because there's not that many people there, right? The majority of deaths in absolute terms probably occur in the seventh decade. But as you go up, because the denominator is shrinking, you have to normalize to it. So we just normalize to the number of people. Here are all the people that started the year, here are all the people that ended the year. What's the death rate? Why are these done in a slightly more complicated way? Because we, we, we don't follow these people for their whole lives. We're only following them for a period of observation. In this case, roughly three years. So to say something like, you know, we have a crude death rate of five deaths per thousand person years, one way to think about that is if you had 1,000 people and you followed them for one year, you'd expect five to die. If you had 500 people and you followed them for two years, you expect five to die. If you have 1,000 people and you follow them for one year, you expect five to die. Those would all be considered equivalent mortalities.

   14. AHAndrew Huberman41:13

       Great. Thank you for clarifying that.

   15. PAPeter Attia41:14

       Yeah, yeah. No, no, this, this stuff is-- I mean, like I find, I find epidemiology when you get in the weeds is way more complicated than following the basics of, um, experimental stuff where you just, you get to push all this stuff into the garbage bin and just say, "We're gonna take this number of people, we're gonna exclude this group, we're gonna randomize, and we're gonna see what happens."

   16. AHAndrew Huberman41:35

       Yeah, that's what like the paper we'll talk about next.

   17. PAPeter Attia41:37

       Yep, yep.

   18. AHAndrew Huberman41:38

       [chuckles]

   19. PAPeter Attia41:39

       So when you adjust for age, and they don't show it in this table, it's only in the text, when you adjust for age, a very important check to do is what is the crude death rate of the people on metformin who are not twins versus who are twins. Now, in this table, they look different because it's 24.93 for the metformin group and 21.68 for the twin group in-- that's on metformin. When you adjust for age, they're almost identical. It's, it goes from 29 point-- 24.93 to 24.7. One other point I'll make here for people who are gonna be looking at this table is, um, you'll notice there are parentheses after every one of these numbers. What does that, what does that offer in there? Those parentheses are offering the 95% confidence interval. So for example, to take the number, you know, 24.93 is the crude death rate of how many people are dying who take metformin, what it's telling you is we're 95% confident that the actual number is between 23.23 and 26.64. If a 95% confidence interval does not cross the number zero, it's statistically significant. Okay, so the first thing that just jumps out at you, I think when you look at this, is there's clearly a difference here between the people who have diabetes and those who don't. It complicates the study a little bit 'cause it's basically two studies in one, but you're comparing, um, 95-- pardon me Uh, 24.93 to 16.86, which by the way remains after age adjustment. When you go to the twin group, it's 24.73 to 12.94

   20. AHAndrew Huberman43:24

       So maybe just to zoom out for that, what you're describing, if I understand correctly, is this, um, uh, crude deaths per 1,000 person years. Let's just talk about the singletons, the non-twins.

   21. PAPeter Attia43:35

       Yeah, yeah.

   22. AHAndrew Huberman43:36

       Is 16.86. So 16.86 people die, and some people are probably thinking, "How can .86 of a person die?" Well, it's not always whole numbers, but, um, there's a, there's a bad joke to be made here. But, um-

   23. PAPeter Attia43:49

       Uh, yeah, just call it 17 versus 25

   24. AHAndrew Huberman43:51

       ... 17, right, 17 deaths per 1,000 versus 25 deaths.

   25. PAPeter Attia43:55

       Yep.

   26. AHAndrew Huberman43:56

       And the 25 is in the folks that took metformin. Now, that to the naive listener, and to me, means, oh, you know, metformin basically kills you, [laughs] right? Um, not, uh, faster, or y- you know, you're more likely to die. But we have to remember that these people have another... They have a major health issue that the other group does not have.

   27. PAPeter Attia44:17

       That's right.

   28. AHAndrew Huberman44:17

       Because people weren't assigned drug or not assigned drug. It wasn't placebo drug. It's let's look at people taking this drug for a bad health issue and compare to everyone else.

   29. PAPeter Attia44:28

       That's right. So now you have to go into, and, and I'll just sort of skip the next figure, but the next figure is a Kaplan-Meier curve. I, I, I think it's actually worth looking at it 'cause they show up in all sorts of studies. So if you look at figure one, it's a Kaplan-Meier curve, which is a mortality curve. So you'll see these in any study that is looking at death, and this can be prospective randomized, this can be retrospective, but these are always gonna show up, and I think it's really worth understanding what a Kaplan-Meier curve shows you. So on the x-axis is always time, and on the y-axis is always the cumulative survival. So it's a curve that always goes from zero to one, 1% or 100%, and it's always decreasing monotonically, meaning it can only go down or stay flat. It can never go back up. So that's what a cumulative, uh, mortality curve looks like.

   30. AHAndrew Huberman45:24

       Now we're looking at you're starting at alive, and you're looking at how many people die for every year that passes.
10. 49:20 – 54:18

    Understanding statistical significance, statistical power, sample size, and why epidemiology uses enormous cohorts

    1. PAPeter Attia49:20

       one is different from the other.

    2. AHAndrew Huberman49:21

       Yeah, that's actually a good opportunity to, um, to, uh, raise a common myth, which is a lot of people when they look at a paper, let's say it's a bar graph, you know

    3. PAPeter Attia49:32

       Yes. Yeah

    4. AHAndrew Huberman49:32

       Um, and they see these error bars, and they will s- say, people often think, "Oh, if the error bars overlap, it's not a significant difference. But if the error bars don't overlap, meaning there's enough separation, then that's a real and meaningful difference." And that's not always the case. It depends a lot on the form of the experiment. Um, I often see some of the, the more robust Twitter battles over, you know, how people are reading graphs, and I think it's important to remember that, um, you run the statistics, uh, hopefully the correct statistics for the, for the sample. Um, but determining significance, whether or not the, the result could be due to something other than chance, of course, your confidence in that increases as it becomes typically p values, P less than .00001 per- percent chance that it's due, um, to chance, right? So very low probability. P less than .05 tends to be the kind of gold standard cutoff. Um, but when you're talking about data like these, which are repeated measures over time, people are dropping out literally, um, over time, you're saying they've modeled it to make predictions as to what would happen. We're not necessarily looking at, you know, raw data points here.

    5. PAPeter Attia50:39

       Yeah, the raw data was in the previous table. That's now taken and run through this Cox model, and it's smoothed out.

    6. AHAndrew Huberman50:47

       Got it.

    7. PAPeter Attia50:48

       And, uh, to your point about the bar graphs, yeah, I think the other thing you always wanna understand is just because something doesn't achieve statistical significance, the only way you can say it's not significant is you have to know what it was powered to detect. Um, and statistical power is, uh, a very important concept that probably doesn't get discussed enough. Uh, but before you do an experiment, you have to have an expectation of what you believe the difference is between the groups, and you have to determine the number of samples you will need to assess whether or not that difference is there or not. So you use something, uh, it's, it's called a power table, and you, you would go to the power table. So if you, if you're doing treatment A versus treatment B, and you say, "Well, look, I think treatment A is going to have a 50% response, and I think treatment B will have a 65% response," you literally go to a power table that says 50% response, 15% difference. That gives you a place on the grid, and I wanna be 90% sure that I'm right, so 90% power. I'm being a little bit-- So there's gonna be a statistician listening to this who's gonna wanna kill me, but this is directionally the way we would describe it. And that tells you this is how many animals or people you would need in this study. You're gonna need 147 in each group. And by the way, if you now do the experiment with 147, and you fail to find significance, you can comfortably say there is no statistical difference, at least up to that 15%. There may be a difference at 10%.

    8. AHAndrew Huberman52:23

       Mm-hmm.

    9. PAPeter Attia52:23

       But you weren't powered to look at 10%.

    10. AHAndrew Huberman52:26

        Yeah. And, um, very important point that you're making. Another point that's just a more general one about statistics, in general, the way to reduce variability in a data set is to increase sample size. And that kinda makes sense, right? If you, if I just walk into a 10th grade class and I go, "Yeah, I'm gonna measure height," and I look, uh, by the first three kids that I see, and I happen to look over there and it's the three that all play on the volleyball team together, I, my sample size is small, and I'm likely to get a skewed representation, in this case, taller than average. So increasing sample size tends to decrease variation. So the, that's why when you hear about a study from the UK Biobank or from, you know, um, half a million Danish citizens, like for instance in this study, that's, those are enormous sample sizes. So even though this is, uh, not an experimental study, it's an epidemiological observational study, um, there's tremendous power by way of the enormous number of subjects in the, in the study.

    11. PAPeter Attia53:22

        And that's the way that epidemiology will make up for its deficit. So you could never do a randomized assignment study on half a million people. Um, you'd have, you know... So, so epidemiology makes up for its biggest limitation, which is it can never compensate for inherent biases by saying, "We can do infinite duration if we want. Like, we could, we could survey people over the course of their lives, and we can have the biggest sample size possible," 'cause this is relatively cheap. The cost of actually doing an experiment where you have tens of thousands of people is prohibitive. I mean, if you look at the Women's Health Initiative, which was a five-year study on, I don't know, what was it? 50,000 women. I mean, that was a billion-dollar study.

    12. AHAndrew Huberman54:05

        Phew.

    13. PAPeter Attia54:06

        So this is w- this is the balancing act between epidemiology and randomized prospective experiments. And, uh, they, so they both offer something, but you just have to know the blind spots of each

11. 54:18 – 1:06:10

    Interpreting the hazard ratios from the 2022 metformin study, and the notable takeaways from the study

    1. PAPeter Attia54:18

       one. Um, so let's just kinda wrap this up. I mean, I think, uh, let's just go to table four, which I think is the most important table, um, in, in here, which now lays out the, the, the final results in terms of the hazard ratio. So this is, this is the way we wanna really be thinking about this. So again, hazard ratios, um, these are important things to understand. A hazard ratio is a number, and you always subtract one from the hazard ratio, and that tells you if it's a positive number, if it's a number-- Sorry, if it's a number greater than one, you subtract one, and that tells you the relative harm. So if the hazard ratio is 1.5, you subtract one. .5 is a 50% increase in risk. Um, if the number is negative, you may recall on the Bannister paper, the hazard ratio was .85. So if it's less than, so that means it's a 15% reduction in relative risk. And here you can see all the hazard ratios are positive. So what it's telling you here is, and I'm gonna walk through this 'cause it's, there's a lot of information packed here. You've got singletons, you've got twins. They're showing you three different ways that they do it. They do an unadjusted model If you just look at the singletons with and without metformin and you make no adjustments, the hazard ratio is 1.48, meaning the people on metformin had a 48% greater chance of dying in any given year than their non-diabetic counterpart.

    2. AHAndrew Huberman55:41

       The only reason I'm smiling is not 'cause I enjoy people dying, quite, uh, quite to the contrary, is that, um, this is novel for me in that I've read some epidemiological studies before, but it's not normally where I spend the majority of my time. But up until now, I was thinking, "Okay, people taking metformin are, are dying more than those that aren't." I just... And I am just relieved to know that I wasn't, um, looking at all this backwards.

    3. PAPeter Attia56:03

       Hear hear.

    4. AHAndrew Huberman56:04

       Okay. So they're dying more, but of course, we don't have a group that's taking metformin who doesn't have diabetes, and we don't have a group, um, who, uh, has diabetes and, uh, you know, is taking metformin plus something else. So again, we're, we're only dealing with these constrained-

    5. PAPeter Attia56:20

       Yeah, now there's-

    6. AHAndrew Huberman56:20

       ... populations

    7. PAPeter Attia56:21

       ... another arm to this study that I'm not getting into 'cause it adds more complexity, which is they also have another group that's got diabetes, takes metformin, and takes sulfonylureas, which is a, a bigger drug, and those people die even more.

    8. AHAndrew Huberman56:35

       Whoa. So [laughs] okay.

    9. PAPeter Attia56:36

       Which again speaks to the point, right?

    10. AHAndrew Huberman56:39

        Right.

    11. PAPeter Attia56:39

        The more you need these medications, they're never able to erase the effect of diabetes.

    12. AHAndrew Huberman56:45

        But in this case, it seems that they might be accelerating, possibly accelerating death due to diabetes. Possibly.

    13. PAPeter Attia56:52

        We, we could never know that from this because we're, we don't see... We would need to see diabetics who don't take metformin-

    14. AHAndrew Huberman56:58

        Right

    15. PAPeter Attia56:58

        ... who take nothing, and I would bet that they would do even worse.

    16. AHAndrew Huberman57:02

        Mm-hmm.

    17. PAPeter Attia57:02

        So my, my intuition is that the metformin is helping, but not helping nearly as much as we thought before. So my point is they make another set of adjustments. They say, "Okay. Well, look, in the first one, in the unadjusted model, we only matched for age and gender." Okay, that's pretty crude. What if we adjust for the medications they're on, the cardiovascular, psychiatric, pulmonary, dementia meds, and marital status? I don't know why they threw marital status in there, but they did.

    18. AHAndrew Huberman57:30

        I don't know. Maybe being married or unmarried can accelerate-

    19. PAPeter Attia57:32

        I'm sure it can

    20. AHAndrew Huberman57:33

        ... can impact you.

    21. PAPeter Attia57:33

        But it just seems like a random thing to throw in with all their meds. I would have personally done that adjustment higher up. But nevertheless, if you do that, all of a sudden the, uh, hazard ratio drops from 1.48 to 1.32, which means, yep, you still have a 32% greater chance of dying in any given year. All right. What if we also adjust for the highest level of, um, education along with any of the other covariates? Well, that doesn't really change it at all. It ends up at 1.33 or a 33% chance increase in death. Okay.

    22. AHAndrew Huberman58:04

        I always knew that more school wasn't gonna save me.

    23. PAPeter Attia58:06

        Was, it's not doing jack. So now [laughs] let's do it for the twins. If you do the twin study, which you could argue is a slightly purer study because you at least have one genetic and environmental thing that you've attached, the unadjusted model is brutal, 2.15. That's 115%. Think about this. These are twins who in theory are the same in every way except one has diabetes and one doesn't, and the one with diabetes on metformin still has 115% greater chance of dying than the non-diabetic co-twin.

    24. AHAndrew Huberman58:38

        Brutal.

    25. PAPeter Attia58:39

        When you make that first adjustment of all the meds and marital status, you bring it down to a 70% increase in risk, and when you throw education in, it goes up to an 80% chance of risk. Now, they did this really cool thing, which was they did the analysis on with and without censoring. So everything I just said here was based on no censoring.

    26. AHAndrew Huberman59:01

        Tell me about censoring.

    27. PAPeter Attia59:02

        Censoring is when you stop counting the metformin people who have died.

    28. AHAndrew Huberman59:06

        Mm.

    29. PAPeter Attia59:06

        Okay. So in the singleton group, when you unadjust it, and the reason I'm doing the unadjusted is that's where they did the sensitivity analysis. I don't think it really matters that much. It's, you just have to draw a line in the sand somewhere. You'll recall that that was a 48% chance of increased mortality, all-cause mortality, if you stop counting, if you, if you, pardon me, if you don't censor, meaning if you include everybody, including when people on metformin with diabetes die. If you censor them, it comes down to 1.39. In other words, this is a very important finding, it did not undo the benefits that we saw in the Bannister study. Bannister saw a 15% reduction in mortality when they censored. When Keyes censored, it got better, but not that much better. It went from 48 to 39%. In the twins, it went from 115% down to only 97%. So in some ways, this presents a little bit of an enigma because it's not entirely clear to me, having read these papers many times, exactly why Bannister found such an outlined, like s- such a different response. There's another res- there's another technical detail of this paper, which is they, you can see on the right side of table four, they did something called a nested case control. But you'll see, and I was gonna go into a long explanation of what nested case controls are. It's another pretty elegant way to do case control studies where you sample by year and you, you, you sort of normalize. You, you don't count all the cases at the end. You count them one by one. I don't think it's worth getting into, Andrew, 'cause it doesn't change the answer. You can see it changes it just slightly, but it doesn't change the point. The point here is the Keyes paper makes it und- undeniably clear that in that population, there was no advantage offered by metformin that undid the disadvantage of having type 2 diabetes. This does not mean that metformin wasn't helping them, because we don't know what these people would have been like without metformin. It could be that this bought them a 50% reduction in relative mortality to where they'd been. But what it says is In a way, this is what you would have expected. This is what you would have expected 10 years ago before the Bannister paper came out

    30. AHAndrew Huberman1:01:31

        Or maybe even before metformin was used, because in some ways it's saying, um, what is the likelihood that sick people who are on a lot of medication are gonna die compared to not sick people who aren't on a lot of medication?
12. 1:06:10 – 1:18:29

    Drugs that may extend lifespan, why Peter stopped taking metformin, and a discussion of caloric restriction

    1. PAPeter Attia1:06:10

       So the, the-- there have not been that many drugs that have worked in the ITP. The ITP is very rigorous, right? V- It's a, it doesn't use an inbred strain of mice. It is done concurrently in three labs with very large sample sizing. And so when something works in the ITP, it's pretty exciting. Rapamycin has been studied several times. It's always worked. Another one we should talk about at a subsequent time is 17 alpha-estradiol. This continues to work in male mice, and it produces comparable effects to rapamycin.

    2. AHAndrew Huberman1:06:43

       Estrogen.

    3. PAPeter Attia1:06:43

       Doesn't work in female mice.

    4. AHAndrew Huberman1:06:45

       Makes male, makes-

    5. PAPeter Attia1:06:45

       But, but this is alpha, not beta. So this is 17 alpha-estradiol, not beta-estradiol, which is the estradiol that we all-- that, that is bioavailable in all of us.

    6. AHAndrew Huberman1:06:54

       And, and, uh, just as a brief aside, um, I think you and I basically agree that, um, unless it's a problem, h- males, we're talking post-puberty, um, should try and have their estrogen as high as possible without having negative symptomology because of the importance of estrogen for libido, for brain function, tissue-

    7. PAPeter Attia1:07:14

       Bone health

    8. AHAndrew Huberman1:07:15

       ... health, bone health.

    9. PAPeter Attia1:07:16

       Yeah. Body composition maybe.

    10. AHAndrew Huberman1:07:16

        That this idea of crushing estrogen and raising testosterone is just silly, right? There's not-- And let's just leave raising testosterone out of it. But many of the approaches to raising testosterone that are pharmacologic in nature also raise estrogen. A lot of people try and push down on estrogen, and that is Just again, unless people are getting, um, hyperestrogenic effects like gynecomastia or other issues, s- is the exact wrong direction to go. You want estrogen high

    11. PAPeter Attia1:07:42

        Estro- estrogen is a very important hormone for men and women.

    12. AHAndrew Huberman1:07:46

        Yeah, that's it.

    13. PAPeter Attia1:07:47

        Um, canagliflozin, an SGLT2 inhibitor, also very successful in the ITP. But again, interestingly, rapomy- um, um, metformin not. So metformin has failed in the ITP.

    14. AHAndrew Huberman1:07:58

        So you no longer take metformin?

    15. PAPeter Attia1:07:59

        I stopped five years ago at-

    16. AHAndrew Huberman1:08:00

        I mean, you're not a diabetic, so presumably you were taking it to bu-

    17. PAPeter Attia1:08:03

        I was taking it for geroprotection

    18. AHAndrew Huberman1:08:04

        ... to, to buffer blood glucose-

    19. PAPeter Attia1:08:05

        Y- yeah, in order to potentially-

    20. AHAndrew Huberman1:08:06

        ... in order to potentially live longer

    21. PAPeter Attia1:08:07

        ... yes, exactly. And the reason I stopped, and this will be the last thing before we move on-

    22. AHAndrew Huberman1:08:11

        Well, 'cause you couldn't go to the Dairy Queen at the buffet event.

    23. PAPeter Attia1:08:14

        [laughs] No.

    24. AHAndrew Huberman1:08:14

        I understand.

    25. PAPeter Attia1:08:14

        Finally, the nausea went away after a few weeks-

    26. AHAndrew Huberman1:08:17

        Oh

    27. PAPeter Attia1:08:17

        ... or a month maybe. Um, but once I got really into lactate testing, I noticed how high my lactate was, uh, at rest. So a resting fasted lactate should be, in a healthy person, should be below one, like somewhere between .3, .6 millimole. And only when you start to exercise should lactate go up. And in 2018 was when I started blood testing for my zone two. So previously, when I was doing zone two testing, I was just going off my power meter and heart rate. But this is when... Uh, this is after I'd met Inigo San Millan, and I started, like, wanting to use the lactate threshold of two millimole as my, as my determinant of where to put my wattage on the bike. And I'm, like, doing finger pricks before I start, and I'm like 1.6 millimole, and I'm like, "What the hell is going on? I can't be 1.6" bu-

    28. AHAndrew Huberman1:09:07

        This is if you ran the, a flight of stairs up the back of the Empire State Building.

    29. PAPeter Attia1:09:10

        Well, no, that would put me a lot higher, right? But, but, and, and, and I-

    30. AHAndrew Huberman1:09:14

        I was being generous to your fitness.
13. 1:18:29 – 1:20:05

    Current thoughts on the use of metformin for longevity

    1. AHAndrew Huberman1:18:29

       Um, this is an amazing paper, um, for the simple reason that it provides a wonderful tutorial of the benefits and drawbacks of this type of work, and I think it's also wonderful because we hear a lot about metformin, rapamycin, and, um, these anti-aging approaches, but I, uh, was not aware that there was any study of such a large population of people, so it's pr- pretty interesting.

    2. PAPeter Attia1:18:56

       Yeah. So I think it remains to be seen if, uh... And my patients often ask me, "Hey, should I be on metformin?" And I give them a much, much, much, much shorter version of what we just talked about, and I say, "Look, if the TAME study," which should answer this question more definitively, right? This is taking a group of non-diabetics and randomizing them to placebo versus metformin and studying for specific disease outcomes. If the TAME study ends up demonstrating that there is, uh, a geroprotective benefit of metformin, I, I'll reconsider everything, right? So I think that's, you know, we just have to, I think, all walk around with a, an appropriate degree of humility around what we know and what we don't know. But, but I would say right now, the epidemiology, the animal data My own personal experience with its impact on my lactate production and exercise performance, uh, we could... There's a whole other rabbit hole we could go down another time, which is the impact on hypertrophy and strength, which appears to be attenuated as well by metformin. Um, you know, I'll, I'll, I'll... I still prescribe it to patients all the time if they're insulin resistant, for sure. It's still a valuable drug, but I don't think of it as a great tool for the person who's insulin sensitive and exercising a

14. 1:20:05 – 1:23:53

    Could there be any longevity benefit to short periods of caloric restriction?

    1. PAPeter Attia1:20:05

       lot.

    2. AHAndrew Huberman1:20:06

       I can't help but ask this question. Do you think there's any longevity benefit to short periods of caloric restriction? Um, you know, so for instance, I decide to... By the way, I haven't done this, but let's say I were to decide to, you know, fast and do a one meal a day type thing where I'm going to be in a slight caloric deficit, you know, 500 to 1,000 calories for a couple of days, and then go back to eating, um, the way that I ate before, uh, that short caloric restriction/fast. Is there any benefit to it in terms of cellular health? Can you, you know, sort of reset the system? Is there any idea that the, the changes, the clearing of senescent cells that we hear about autophagy, that we... You know, that y- in the short term, you can glean a lot of benefits and then go back to, to your regular pattern of eating and then periodically, you know, once every couple of weeks or once a month, just, you know, fast for a day or two. Is there any benefit to that that's, that's purely in the domain of longevity? Not l- c- because there's all discipline function there, there's a flexibility function, there's probably an insulin sensitivity function, but is there any evidence that it can help us live longer?

    3. PAPeter Attia1:21:17

       I think the short answer is no, um, uh, for two reasons. One, I don't think that that duration would be sufficient if, if one is gonna take that approach. But two, um, even if you went with something longer, like what I used to do, right? I used to do seven days of water only per quarter, three days per month. So I was... But I was basically always, like it would be three-day fast, three-day fast, seven-day fast. Just imagine doing that all year, rotating, rotating, rotating. For many years, I did that. Um, now I certainly believed, and to this day, I would say I have no idea if that provided a benefit. Um, but my thesis was, uh, the downside of this is relatively circumscribed, which is profound misery for a few days, and, um, what I didn't appreciate at the time, which I obviously now look back at and realize, is muscle mass lost. You're just-- It's very difficult to gain back the muscle cumulatively after all of that loss. Um, but my thought was exactly as you said, like there's got to be a resetting of the system here. This must be sufficiently long enough to trigger all of those systems. But you're getting at a bigger problem with geroscience, which I'm really hoping the epigenetic field comes to the rescue on. It has not come close to it to date, which is we don't have biomarkers around true metrics of aging. Everything we have to date stinks. So we're really good at using molecules or interventions for which we have biomarkers, right? Like when you lift weights, you can look at how much weight you're lifting. You can look at your DEXA scan and see how much muscle mass you're generating. Like th- those are biomarkers. Those are giving you outputs that say, "My input is good," or, "My input needs to be modified." Um, when you take a sleep supplement, you can look at your Eight Sleep and go, "Oh, my sleep is getting better." Like there's a biomarker. Um, when you take metformin, when you take rapamycin, when you fast, we don't have a biomarker that gives us any insight into whether [chuckles] or not we're moving in the right direction, and if we are, are we taking enough? We just don't know. So I, I, I often get asked like what's the single most important topic you would want to see more research dollars put to in terms of this space? And it's unquestionably this, as unsexy as it is. Like who cares about biomarkers? But like without them, I don't think we're going to get great answers 'cause you can't do most of the experiments you and I would dream up.

    4. AHAndrew Huberman1:23:52

       Got it.

15. 1:23:53 – 1:30:05

    Peter and Andrew’s process for reading scientific papers

    1. AHAndrew Huberman1:23:53

       Well, I'm grateful that you're sitting across the table from me telling me all this and that, um, everyone can hear this. Uh, but again, we will put a link to the papers, plural, that, uh, Peter just described. And for those of you that are listening and not watching, um, hopefully you were able to track the, the general, um, themes and takeaways. And, um, it is fun to go to these papers. You see these big stacks of numbers and, and it can be a little bit overwhelming, but, um, my, uh, additional suggestion on parsing papers is y- notice that Peter said that he spent, you know, he's read it several times. Y- unlike a newspaper article or, or a, a Instagram post, with a paper, you're not necessarily going to get it the first time. You certainly won't get everything. So the-- I, I think spending some time with papers for me means reading it and then reading it again a little bit later or, you know-

    2. PAPeter Attia1:24:42

       And, and tell me what-

    3. AHAndrew Huberman1:24:43

       One figure at a time.

    4. PAPeter Attia1:24:44

       Yeah, I was just about to say, what's your... 'Cause, 'cause I kind of have a way that I do it, but I'm curious as to how you do it. Like if you're-

    5. AHAndrew Huberman1:24:49

       Mm-hmm

    6. PAPeter Attia1:24:49

       ... if you're encountering a paper for the first time, what-- do you have an order in which you like to go through the... Do, do you want-- do you read it sequentially or do you look at the figures first? I mean, how do you, how do you go through it?

    7. AHAndrew Huberman1:24:58

       Yeah. Unless it's an area that I know very, very well where I can, you know, skip to some things, um, before reading it the whole way through, um, my process is always the same. And actually, this is fun because I used to teach a class when I was a professor at UC San Diego, um, called Neural Circuits in Health and Disease, and it was an evening course that grew very quickly from 50 students to 400 plus students, and we would do exactly this.

    8. PAPeter Attia1:25:22

       Mm.

    9. AHAndrew Huberman1:25:22

       We would parse papers. And, um, and I had everyone ask what I called the four questions. Um, and it wasn't exactly four questions, but I have a, a little three by five card next to me or a piece of, uh, maybe an app by 11 paper typically, and when I sit down with a paper, I want to figure out What is the question they're asking?

    10. PAPeter Attia1:25:41

        Mm-hmm.

    11. AHAndrew Huberman1:25:41

        What's the general question? What's the specific question? And I write down the question.

    12. PAPeter Attia1:25:45

        Mm.

    13. AHAndrew Huberman1:25:46

        Then what was the approach? You know, how did they test that question? And sometimes that can get a bit detailed. You can get into, you know, immunohistochemistry, and they did a, you know, PCR for this. It, it's not so important, uh, for most people that they understand every method, but it is worthwhile that if you encounter a method like PCR or, um, you know, chromatography or fMRI, that you at least look up on the internet what its purpose is. Okay? That will help a lot. And then it was what they found. And there, um, you can usually figure out what they believe they found anyway by reading the figure headers, right? What are... You know, figure one, here's the header. They-- typically, if it's a, an experimental paper, it will tell you what they want you to think they found.

    14. PAPeter Attia1:26:28

        Mm.

    15. AHAndrew Huberman1:26:28

        And then I tend to wanna know the conclusion of the study. And then this is really the key one, and this is the one that, um, would really distinguish the high-performing students from the others. You have to go back at the end and ask whether or not the conclusions, the major conclusions drawn in the paper, are really substantiated by what they found and what they did, and that involves some thinking. It involves really, you know, spending some time thinking about what, what they identified. Now, this isn't something that anyone can do straight off the bat. It's a skill that you develop over time, and different papers require different formats. But those four questions really form the cornerstone of, uh, of teaching undergraduates, and I think graduate students as well, of how to read a paper. And, um, again, it's something that can be cultivated. Um, a-and it's still how I approach papers. So what I do typically is I'll read title, abstract. I s- usually then will skip to the figures and see how much of it I can digest without reading the text, and then go back and read the text. But in fairness, journals, great journals like Science, like Nature, oftentimes will pack so much information, and the Cell Press journals too, into each figure, and it's coded with no definition of the acronyms that almost always I'm into the introduction and results within a couple of minutes wondering what the hell this acronym is or that acronym is. And it's, um, it's just-- Yeah, it's just wild h-how much, um, how much nomenclature there really is. I can't remember, was it you or was it our friend Paul Conti when he was here, um, who said that... Oh, no, I'm sorry. It was neither. It was chair of ophthalmology at Stanford, uh, Dr. Geoffrey Goldberg, who was a guest on the podcast recently, who off camera, I think it was, told us that if you look at the total number of words and terms that a physician leaving medical school owns in their mind and their vocabulary, it's the equivalent of, like, two additional full languages of fluency beyond their native language.

    16. PAPeter Attia1:28:23

        Yeah.

    17. AHAndrew Huberman1:28:23

        So you're trilingual at least. Now, I wonder, do you speak a language other than English?

    18. PAPeter Attia1:28:27

        Poorly.

    19. AHAndrew Huberman1:28:27

        Okay. So you're, you're, you're, you're at least trilingual and [chuckles] probably more. So the-- No one is expected to be able to parse these papers the first time through without, you know, substantial training.

    20. PAPeter Attia1:28:38

        Yeah. No, I, I, I, I think that's a, that's a great format. And you're absolutely right. I have a different way that I do it when I'm familiar with the subject matter versus when I'm not.

    21. AHAndrew Huberman1:28:47

        Yeah, how do you do it?

    22. PAPeter Attia1:28:48

        Uh, well, again, if I'm reading papers that are something that I know really well, I can basically glean everything I need to know from the figures. Um, and then sometimes I'll just do a quick skim on methods. Uh, but I don't need to read the discussion. I don't need to read the intro. I don't need to read anything else. Uh, if it's something that I know less about, then I usually do exactly what you say. I try to start with the figures. I usually end up generating more questions, like what, what, what do you mean? What i-- How-- What is this? How did they do that? Ugh. And then I gotta go back and read methods typically. And one of the other things that's probably worth mentioning is a lot of papers these days have supplemental information that are not attached to the paper. So, um, you're amazed at how much stuff gets put in the supplemental section, and the reason for that, of course, is that the journals are very, uh, specific on the format and length of a paper. So a lot of the times when you're submitting something, you know, like if you wanna put any additional information in there, it can't go in the main article. It has to go in the supplemental figure. So even for this paper, there were a couple of the numbers I spouted off that I had to pull out of the supplemental paper. For example, when they did the sensitivity analysis on the, um, censoring versus non-censoring, that, that was in the supplemental figure. That was actually not even in the paper we

16. 1:30:05 – 1:37:19

    The biological effects of belief, and how “belief effects” differ from placebo effects

    1. PAPeter Attia1:30:05

       presented.

    2. AHAndrew Huberman1:30:06

       Well, should we pivot-

    3. PAPeter Attia1:30:08

       Change gears

    4. AHAndrew Huberman1:30:08

       ... to this other paper?

    5. PAPeter Attia1:30:09

       Yeah.

    6. AHAndrew Huberman1:30:10

       It's a very different sort of paper. It's an experimental paper where there's a manipulation. I must say, I love, love, love this paper, and I don't often say that about papers. I'm so excited about this paper for so many reasons, but I wanna give a couple of caveats up front. First of all, the paper is not published yet. The only reason I was able to get this paper is because it's on BioRxiv. There's a new trend over the last, I would say, five, six years of people posting the papers that they've submitted to journals for peer review online so that people can look at them prior to those papers being peer reviewed. So there is a strong possibility that the final version of this paper, which again we will provide a link to, is going to look different, maybe even quite a bit different than the one that we're going to discuss. Nonetheless, there are a couple of things that make me confident in the data that we're about to talk about. First of all, the group that published this paper is really playing in their wheelhouse. This is what they do, and they publish a lot of really nice papers in this area. Um, I'm n- going to mispronounce, um, her first name, but I think it's Chao-Hsi Wu at, um, who's at the Icahn School of Medicine at Mount Sinai, runs a laboratory there studying addiction in humans, and, um, the first auth-author of the paper is Ofer Perl. Um, this paper is wild, and I'll just give you a couple of the takeaways first as a bit of a hook to hopefully, uh, entice people into listening further, 'cause this is an important paper. This paper basically addresses how our beliefs about the drugs we take impacts how they affect us at a real level, not just at a subjective level, but at a biological level. So just to back up a little bit, um, a former guest on this podcast, Dr. Alia Crum, um, whose name is actually Alia Crum, but she goes by Alia Crum, talked about belief effects. Belief effects are different than placebo effects. Placebo effects are really just category effects. It's, "Okay, I'm gonna give you this pill, Peter, and I'm gonna tell you that this pill is molecule X5952 and that it's going to make your memory better," and then I give you a memory test, right? And your group performs better than the people in the control group who I give a pill to and I say, "This is just a placebo." Or there are other variants on this where, um, people will get a drug and you tell them it's placebo. They'll get a placebo, you tell them it's drug. It's, it's a binary thing. It's an on or an off thing. You're either in the drug group or the placebo group and you're either told that you're getting drug or placebo. And we know that placebo effects exist. In fact, one of the crueler ones, I was never the subject of this, but there was kind of lore in high school that, you know, like kids would do this mean thing. It's a form of bullying, I really don't like it, where, you know, they'd get some kid at a party to drink, um, alcohol-free beer, and then that kid would start acting drunk, and then they'd go, "Gotcha. You know, it doesn't even have alcohol in it." Now, that's a mean joke, um, and just reminds me of some of the, the, uh, the horrors of high school. Maybe that's why I didn't go very often, which I also don't suggest. But no, it, um, it's a mean joke, but it speaks to the placebo effect, right? And there's also a social context effect. So placebo effects are real. Um, we know this. Belief effects are different. Belief effects are not A or B, placebo or non-placebo. Belief effects have a lot of knowledge to enrich one's belief about a, a certain something that can shift their psychology and physiology one way or the other. And I think the best examples of these really, of these belief effects really do come from Alia Crum's lab in the psychology department at Stanford, although some of this work she did prior to getting to Stanford. For instance, if people are put into a group where they watch a brief video, just a few minutes of video about how stress really limits our performance, let's say at archery or at mathematics or at music or at public speaking, and then you test them in any of those domains or other domains in a stressful circumstance, they perform less well, okay? And we know they perform less well because we're me- by virtue of a heightened stress response. You can measure heart rate. You can measure stroke volume of the heart. You can measure, um, peripheral blood flow, which goes down when people are stressed, narrowing of vision, et cetera. You take a different group of people and randomly assign them to another group where now they're being told that stress enhances performance. It mobilizes resources. It narrows your vision such that you can perform tasks better, et cetera, et cetera, and their performance increases above a control group that receives just useless information.

    7. PAPeter Attia1:34:44

       Mm-hmm.

    8. AHAndrew Huberman1:34:44

       Or at least useless as it relates to the task. So in both cases, by the way, the groups are being told the truth. Stress can be depleting or it can enhance performance. But this is different than placebo because now it's scaling according to the amount and the type of information that they're getting.

    9. PAPeter Attia1:35:00

       And, and can you give me a sense of magnitude of benefit or detriment that one could experience in a situation like the one you just described?

    10. AHAndrew Huberman1:35:07

        Yeah. So it's, it's striking. They're opposite in direction.

    11. PAPeter Attia1:35:10

        Yep.

    12. AHAndrew Huberman1:35:10

        So the stress gets us worse, makes you, um... Let's say, I think that if we were to just put a rough percentage on this, it would be somewhere between 10% and 30% worse at performance-

    13. PAPeter Attia1:35:20

        Wow

    14. AHAndrew Huberman1:35:20

        ... than the control group. And stress as enhancing is a- approximately equivalent improvement. So they're in opposite directions. Even more striking is the, the studies that, um, Alia's lab did, um, and others looking at, for instance, you give people a milkshake. You tell them it's a high-calorie milkshake, has a lot of nutrients, and then you measure ghrelin secretion in the blood. And ghrelin is a marker of hunger that increases the longer it's been since you've eaten. And what you notice is that it suppresses ghrelin to a great degree and for a long period of time. You give another group a shake. You tell them it's a low-calorie shake, that it's got some nutrients in it but that it doesn't have much fat, not much sugar, et cetera. They drink the shake. Less ghrelin s- suppression.

    15. PAPeter Attia1:36:00

        And it's the same shake.

    16. AHAndrew Huberman1:36:01

        And it's the same shake. And satiety lines up with that also in that study. And then the third one, which is also pretty striking, is they took hotel workers. They gave them a short tutorial or not informing them that moving around during the day and vacuuming and doing all that kind of thing is great. It helps you l- lower your BMI, which is great for your health. You give-- You incentivize them, and then you let them out into the wild of their everyday job. You measure their activity levels. The two groups don't differ. They're doing roughly the same task, leaning down, cleaning out trash cans, et cetera. Guess what? The group that was informed about the health benefits of exercise lose 12% more weight compared to the other group.

    17. PAPeter Attia1:36:38

        And no difference in actual movement?

    18. AHAndrew Huberman1:36:40

        Apparently not. Now, how could that be? I mean, literally, this was sparked by, in Alia's words, you know, this was sparked by her graduate advisor saying, "What if all the effects of exercise are placebo?"

    19. PAPeter Attia1:36:53

        [laughs]

    20. AHAndrew Huberman1:36:54

        Right? Like, which is, which is not what anyone really believes, but it's just such a... You know, I, I love that anecdote, uh, that Alia told us because it just really speaks to how, like, really smart people think. They sit back and they go, "Yeah, like exercise obviously has benefits," but, like, what if a lot of the benefits are that you tell yourself it's good for you and the brain can actually activate these, these mechanisms in the body? And why wouldn't that be the case? 'Cause the nervous system extends through both. So-

    21. PAPeter Attia1:37:17

        So interesting

    22. AHAndrew Huberman1:37:17

        ... so interesting. Okay,

17. 1:37:19 – 1:43:00

    The neurobiology of nicotine: a precursor conversation before delving into the paper Andrew chose

    1. AHAndrew Huberman1:37:19

       so fast-forward to this study, which is really about belief effects, not placebo effects. And to make a long story short, we know that nicotine, vaped, smoked, dipped, or snuffed, or these little ZYN pouches, or taken in capsule form, does improve cognitive performance. I'm not suggesting people run out and start doing any of those things. I did a whole episode on nicotine. The delivery device often will kill you some other way or is bad for you. But it causes vasoconstriction, which is also not good for certain people, but nicotine is cognitive enhancing. Why? Well, you have a couple sites in the brain, namely In the basal forebrain, nucleus basalis, in the back of the brain, structures like locus coeruleus, but also this what's called, it's got a funny name, the pedunculopontine nucleus, which is this nucleus in the, in, in the, the pons in the back of the brain, in the brain stem, that sends those little axon wires into the thalamus. The thalamus is a gateway for sensory information. And in the thalamus, the visual information, the auditory information, it has nicotinic receptors, and when the pedunculopontine nucleus releases nicotine or when you ingest nicotine, what it does is it increases the signal-to-noise of information coming in through your senses. So the fidelity of the signal that gets up to your cortex, which is your conscious perception of those senses, is increased.

    2. PAPeter Attia1:38:37

       And how much endogenous nicotine do we produce?

    3. AHAndrew Huberman1:38:40

       Ooh, um, well it's going to be acetylcholine binding to nicotinic receptors.

    4. PAPeter Attia1:38:44

       I see. We're not making nicotine.

    5. AHAndrew Huberman1:38:45

       Right. We're not making nicotine.

    6. PAPeter Attia1:38:45

       We're just binding... So this is a-

    7. AHAndrew Huberman1:38:47

       Yeah

    8. PAPeter Attia1:38:47

       ... this is a nicotinic acetylcholine receptor.

    9. AHAndrew Huberman1:38:49

       Right, of which there are at least seven and probably, like, 14 subtypes. But-

    10. PAPeter Attia1:38:54

        Okay

    11. AHAndrew Huberman1:38:54

        ... um, so y- right. They're called nicotinic receptors in an annoying way, in the same way that cannabinoid receptors are called cannabinoid receptors, but then everyone thinks, oh, you know, those receptors are there f- so because we're supposed to smoke pot, or those receptors are there 'cause we're supposed to ingest nicotine. No. The drugs that we use to study-

    12. PAPeter Attia1:39:10

        The drug is named after the receptor

    13. AHAndrew Huberman1:39:11

        ... those, that's right.

    14. PAPeter Attia1:39:12

        Yeah. Yeah.

    15. AHAndrew Huberman1:39:12

        Right. Exactly. Receptor is named after the drug. And so the important thing to know is that whether or not it's basal forebrain or pedunculopontine nucleus or locus coeruleus, that at least in the brain, 'cause we're not talking about muscle where acetylcholine does something else via nicotinic receptors, there... in general, it just tends to be a signal-to-noise enhancer. And so for the non-engineering types out there, no problem. Signal-to-noise, just imagine I'm talking right now and there's a lot of static in the background. There are two ways for you to be able to hear me more clearly. W- we can reduce the static, or I can increase the fidelity, the, the, um, volume and the clarity of what I'm saying, okay? Um, for instance, and that's really what acetylcholine does. That's why when people smoke a cigarette, they get that boost of nicotine, and they just feel clearer. It really works. The other thing that happens is the thalamus sends information to a couple of places. First of all, it sends information to the reward centers of the brain, the mesolimbic reward pathway that releases dopamine, and typically when nicotine is increased in our system, dopamine goes up. That's one of the reasons why nicotine is reinforcing. We just like it. It's a, we seek it out. They've done beautiful experiments with honeybees even, where, you know, you put nicotine on certain plants or it comes from certain plants, and they'll forage there more. You get, you know, them kind of like buzzed. That was a pun. Bad pun.

    16. PAPeter Attia1:40:26

        [laughs]

    17. AHAndrew Huberman1:40:26

        Um, in any event, there's also an output from this thing, the thalamus, to the ventromedial prefrontal cortex, which is an area of the forebrain that really allows us to limit our focus and our attention for sake of learning. It's allows us to pay attention. This is the circuit-

    18. PAPeter Attia1:40:41

        You talked about this in your gr- fantastic podcast on stimulants.

    19. AHAndrew Huberman1:40:47

        Yeah. Yeah, on ADH-

    20. PAPeter Attia1:40:48

        Yeah

    21. AHAndrew Huberman1:40:48

        ... uh, so ADHD, typically ADHD drugs, so things like Adderall, Vyvanse, methamphetamine for that matter, um, Ritalin.

    22. PAPeter Attia1:40:55

        Yeah, why it's counterintuitive that a stimulant would be a treatment for someone with difficulty focusing.

    23. AHAndrew Huberman1:41:02

        Yeah. In young kids who have difficulty focusing, if you give them something they love, they're like a laser, and the reason is that ventromedial prefrontal cortex circuit can r- engages when the kid is interested and engaged. But kids with ADD, ADHD tend to have a hard time engaging their mind for other types of tasks, and other types of tasks are important for getting through life, and it turns out that giving those stimulant drugs, in many cases, can enhance the function of that circuit, and it can strengthen so that ideally the kids don't need the drugs in the long run, although that's not often the way that it plays out.

    24. PAPeter Attia1:41:37

        Mm.

    25. AHAndrew Huberman1:41:38

        And there are other ways to get at this. You know, there's now a big battle out there, you know, is ADHD real? Is it not real? Of course, it's real. Does every kid need ADHD meds? No. Are there other things like nutrition, more playtime outside, et cetera, that can help improve their symptoms without drugs? Yes. Is the combination of all those things together known to be most beneficial? Yes. Are the dosages given too high and generally should be, you know, titrated down? Maybe. Some kids need a lot. Some n- kids need a little. I probably just, you know, uh, gained and lost a few enemies there. So, um, the point is that, um, these circuits are hardwired circuits.

    26. PAPeter Attia1:42:14

        Sorry, one other question, Andrew. Um, i- if my r- memory serves correctly, doesn't nicotine potentially have a calming effect as well?

    27. AHAndrew Huberman1:42:23

        Mm.

    28. PAPeter Attia1:42:23

        And that seems a bit counterintuitive to the focusing one. Are they, is it a dose effect or a timing effect? H- how does that work?

    29. AHAndrew Huberman1:42:29

        Yeah, it's a dosing effect. So the interesting thing about nicotine is that it can enhance focus in the brain, but in the periphery, it actually provides some muscle relaxation.

    30. PAPeter Attia1:42:38

        Mm.
18. 1:43:00 – 1:52:02

    Andrew presents a paper that demonstrates the impact of belief

    1. AHAndrew Huberman1:43:00

       So, um, hence its reinforcing properties. Okay, this study is remarkable because what they did is they had people come into the laboratory. They gave them a vape pen. These are s- these are smokers, so these are, um, experienced smokers. Typically, there's a washout before they come in, so they're not smoking for a bit, so they can clear their system of nicotine, and they measure-

    2. PAPeter Attia1:43:23

       How long is that needed?

    3. AHAndrew Huberman1:43:24

       Um, typically it's a couple of days.

    4. PAPeter Attia1:43:25

       Oh, okay. Wow.

    5. AHAndrew Huberman1:43:26

       Yeah. Um, which must be miserable for those people.

    6. PAPeter Attia1:43:28

       That must be, I was just about to say-

    7. AHAndrew Huberman1:43:28

       It must be miserable

    8. PAPeter Attia1:43:28

       ... 'cause they can't have Nicorette gum or anything.

    9. AHAndrew Huberman1:43:30

       No, nothing. They must be dying, and I wonder how many cheat.

    10. PAPeter Attia1:43:33

        But they, they can measure-

    11. AHAndrew Huberman1:43:34

        They measure the-

    12. PAPeter Attia1:43:34

        ... carbon monoxide, right?

    13. AHAndrew Huberman1:43:35

        Yeah. They measure carbon monoxide, and they're measuring nicotine in the blood as well.

    14. PAPeter Attia1:43:38

        Okay.

    15. AHAndrew Huberman1:43:38

        So they do a good job there. So then what they do is they have them vape, and they're vaping either a low, medium, or high dose of nicotine. The dosages don't really matter, um, because tolerance varies, et cetera. And Then they are putting them into a functional magnetic resonance imaging machine, so, uh, where they can look at... It's really blood flow. It's really hemodynamic response. For those of you that wanna know, it's the oxy- it's the ratio of the oxygenated to deoxygenated blood because when blood, blood will flow to neurons that are active to give it oxygen, and then it's deoxygenated, and then there's a change in what's called the BOLD signal. So fMRI, when you see these, like, hotspots in the brain, uh, is really just looking at blood flow. And then there's some interesting physics around, and I'll probably get this wrong, but I'll take an attempt at it so that I get beat up a little bit by the physicists and engineers. Um, do you remember the right-hand rule?

    16. PAPeter Attia1:44:28

        Yep.

    17. AHAndrew Huberman1:44:28

        Right? Okay, so do I have this right, uh, correct? Um, the right-hand rule, if you put your thumb out with your first, uh, with your index finger, and your middle finger, and your thumb facing up, I think that the thumb represents the charge, the direction of the charge, right? And then isn't the electromagnetic field is the downward facing figure, and then it's, uh... Do I have that right? Um, I have to look this up.

    18. PAPeter Attia1:44:46

        I don't, I actually don't know the right-hand rule.

    19. AHAndrew Huberman1:44:47

        Okay. Well, someone will look it up.

    20. PAPeter Attia1:44:48

        Yeah.

    21. AHAndrew Huberman1:44:48

        But what you do is when you put a person's head in this big magnet and then you pulse the magnet, what happens is the oxygenated and deoxygenated blood, it interacts with the magnetic field differently, and that difference in signal can be detected. And you can see that in the form of activated brain areas.

    22. PAPeter Attia1:45:05

        Yeah, I mean, MRI all works by proton detection.

    23. AHAndrew Huberman1:45:08

        Mm-hmm.

    24. PAPeter Attia1:45:08

        So presumably there's a difference in the proton signal-

    25. AHAndrew Huberman1:45:11

        Mm-hmm

    26. PAPeter Attia1:45:11

        ... when you have high oxygen versus low oxygen concentration.

    27. AHAndrew Huberman1:45:14

        Mm-hmm. Yep, yep. That's right. Um, and what they'll do is they'll pulse with the magnet because my understanding is that, um, and this is definitely getting beyond my expertise, but that the, the spin orientation of the protons, then it, it's, it's going to relax back at a different rate as well. So wh- by the relaxation at a different rate, you can also get, um, not just resting state activation like, oh, look at a banana. What areas of the brain light up? But you can look at con- connectivity between areas and how one area is driving the activity of another area, so very, very powerful technique. Um, so what they do is they, they put people in a scanner, and then you'll like this 'cause you have a back-

    28. PAPeter Attia1:45:49

        What, what are the, what are the limitations of, of fMRI?

    29. AHAndrew Huberman1:45:52

        Oh.

    30. PAPeter Attia1:45:52

        In, in terms of, I mean-
19. 1:52:02 – 2:00:45

    Analyzing the fascinating results of the Perl paper

    1. AHAndrew Huberman1:52:02

       absolutely wild. Now, there are a couple of other things that could have confounded this. First of all, it could have been that if you believe you got a lot of nicotine, you're just faster, or you're reading the lines better, or your response time to hit the button is quicker. You know, I tell you you have a drug that's gonna improve reaction time.

    2. PAPeter Attia1:52:18

       Yep.

    3. AHAndrew Huberman1:52:18

       You might believe that about nicotine, and so you're quicker on the trigger and you're getting... They have a desi-

    4. PAPeter Attia1:52:23

       More activation as a result.

    5. AHAndrew Huberman1:52:23

       More activation. Um, there could be... They rule that out. They also rule out the possibility-

    6. PAPeter Attia1:52:28

       And how, how did they rule that out?

    7. AHAndrew Huberman1:52:30

       By looking at rates of l- of pressing.

    8. PAPeter Attia1:52:32

       And there was no difference.

    9. AHAndrew Huberman1:52:32

       Nothing. And in sensory areas of the brain that would, that would, um, represent that kind of difference, they don't see that. The other thing that, um, is very clear is that the connection between the thalamus and the ventromedial prefrontal cortex, that pathway scales in the most beautiful way such that people that were told they had smoked a low or vaped a low amount of nicotine got a subtle activation of that pathway. People [chuckles] that were told that they got a moderate amount of nicotine got a more robust activation of that pathway, and the people that were told that they got a high amount of nicotine in the vape pen saw a very robust activation of the thalamus to this ventral prefrontal cortical pathway. Now, of course, this is all happening under the hood of the skull simply on the basis of what they were told and what they believe.

    10. PAPeter Attia1:53:19

        And technically, the fMRI is showing the activation of those two areas, and that's how you can infer-

    11. AHAndrew Huberman1:53:26

        That's right

    12. PAPeter Attia1:53:26

        ... the strength of that connection.

    13. AHAndrew Huberman1:53:27

        That's right. There's a separate method called diffuser tensor imaging, which was developed, I believe, out of the group in Minnesota, Minnesota has a very robust group in terms of neuroimaging, um, that can measure f- activation in fiber pathways.

    14. PAPeter Attia1:53:40

        Hmm.

    15. AHAndrew Huberman1:53:40

        This is not that, but you can look at the timing of activation and it's a known, what we call monosynaptic pathway. So we haven't talked so much about figures here, but, um, I guess if we were gonna look at any one figure, um, and I can just describe it for the audience that's not paying-- uh, doesn't have the figure in front of them. The, uh... Let's see. Uh, the, the most, um, probably the most important figure is figure two. Remember I said I like to read the titles of figures, which is that the belief about nicotine strength induced a dose-dependent response in the thalamus. Basically, if you... And figure 2B, um, can tell you if they believe that they got more nicotine, that's, uh, that's essentially the response that they, that they saw. So if you look... Or, or sorry, panel E, if you look at the belief rating as a function of the estimate in the thalamus of, of what, how much activation there was, it's a, it's a mess when you look at all the dots at once, but if you just separate it out by high, medium and low, you run the statistics, what you find is that there's a gradual increase, but a legitimate one from low to medium to high. In other words, if I tell you, "This is a high dose of nicotine," your brain will react as if it's a high dose of nicotine. Now, what they didn't do was give people n- zero nicotine.

    16. PAPeter Attia1:54:57

        Yeah, I was about to say.

    17. AHAndrew Huberman1:54:58

        Yeah.

    18. PAPeter Attia1:54:58

        There's a control that's missing here, right?

    19. AHAndrew Huberman1:55:00

        Yeah. Yeah. So what they didn't do is give people zero nicotine and then tell them, uh, this is a high amount of nicotine. It's sort of the equivalent of the cruel high school experiment.

    20. PAPeter Attia1:55:08

        Yeah.

    21. AHAndrew Huberman1:55:09

        No alcohol, but then the, the, the kid acts drunk. Now, in the, uh, in the high school example, it's unclear whether or not the kid actually felt drunk or not. Um, it's unclear whether or not they had been drunk previously, if they even knew what it would be like to feel drunk, et cetera, and there's the social context. What I find just outrageous and outrageously interesting about this study is simply that what we are told about the dose of a drug changes the way that our physiology responds to the dose of the drug. And in, and in my understanding, this is the first study to ever look at dose dependence of belief effects, right? To really... And, and why would that be important? Well, for almost every study of drugs, you look at a dose-dependent curve. You look at zero, low dose, medium dose, high dose, and here they, they clearly are seeing a dose-dependent response simply to the understanding of what they expect the drug ought to do. In other words, you can bypass ... pharmacology somewhat, right?

    22. PAPeter Attia1:56:14

        Now look at figure 2B.

    23. AHAndrew Huberman1:56:16

        Mm-hmm.

    24. PAPeter Attia1:56:16

        Am I reading this correctly? So it's got, um, four bars on there. You've got the group who were told they got a low dose, the group who was told they got a medium dose, the group that was told they had a high dose, and then these healthy controls-

    25. AHAndrew Huberman1:56:29

        Right

    26. PAPeter Attia1:56:29

        ... who presumably were non-smokers who were just put in the machine.

    27. AHAndrew Huberman1:56:34

        That's right. You need-

    28. PAPeter Attia1:56:35

        This-

    29. AHAndrew Huberman1:56:36

        Yeah.

    30. PAPeter Attia1:56:36

        Yeah, this is measuring parameter estimate. Uh, what... Is that referring to, um, their ability to play the, the, the, the trading game?
20. 2:00:45 – 2:11:12

    Exciting implications of the findings about “belief effects”

    1. AHAndrew Huberman2:00:45

       Now that actually could be leveraged, I believe. If somebody were trying to quit nicotine, for instance-

    2. PAPeter Attia2:00:52

       Yeah

    3. AHAndrew Huberman2:00:52

       ... and they were going to do that by progressively reducing the amount of nicotine that they were taking, but you told them that it was the same amount o- from one day to the next, you could whittle it down to presumably to a low amount before taking it to zero, and if they believed it to be a greater amount, then it might actually not, uh, disrupt their reward pathways, meaning they would feel, um, presumably they'd feel rewarded by whatever nicotine they were bringing in.

    4. PAPeter Attia2:01:18

       What would be your prediction if this experiment were repeated, but it was done exactly the same way with non-smokers?

    5. AHAndrew Huberman2:01:26

       Well, one thing that's sort of, um, interesting, you asked about art- um, potential sources of, of artifact, uh, problems with fMRI. One of the challenges that they note in this study was you have to stay very still in the, in the machine, but the subjects were constantly coughing because they're smokers [chuckles] . So okay, so presumably the data would be higher fidelity. Started chuckling at that one, but I, I was like, had to read that one twice. I'm like, "Oh, that makes sense. They're smokers. They're coughing. They can't stay still," so movement artifact. Um, but in all seriousness, I think that for people that are naive to nicotine, even a small amount of nicotine is likely to get this pathway activated to such a great degree, sort of like the first time effect of pretty much any drug.

    6. PAPeter Attia2:02:10

       But I wonder if they would be more or less susceptible to the belief system

    7. AHAndrew Huberman2:02:16

       Yeah, that's a really good question. Right, because they have no prior to compare it to

    8. PAPeter Attia2:02:20

       They have no pleasant-- They have no experience to compare it to with respect to the obviously beneficial effects of nicotine that the smokers are well used to.

    9. AHAndrew Huberman2:02:29

       So this is the, the poor kid that got duped into thinking the non-alcoholic beer was had alcohol, though they're actually the winner we know because they didn't have so an alcohol. Alcohol's bad for you. So in the end, that kid wins and the other ones lose, poetic justice. But, um, that kid having never been actually drunk before presumably would experience it more-

    10. PAPeter Attia2:02:48

        I would feel like they'd be more susceptible potentially

    11. AHAndrew Huberman2:02:50

        ... more susceptible. That's my guess as well.

    12. PAPeter Attia2:02:52

        Yeah.

    13. AHAndrew Huberman2:02:52

        So, you know, my glee for this experiment is not, or this paper rather, is not because I think it's the be all end all or it's a perfect experiment. I just think it's so very cool that they're starting to explore dose dependence of belief because that has all sorts of implications. I mean, um, use your imagination, folks. Whether or not we're talking about, um, a drug, we're talking about a behavioral intervention, we're talking about a vaccine, and I'm not referring to any one specific vaccine. I'm just talking to vaccines generally. I'm talking about y- psychoactive drugs. I'm talking about s- um, illicit drugs. I'm talking about antidepressants. I'm talking about all the sorts of drugs we were talking about before, metformin, et cetera. Just throw our arms around all of it. What we believe about the effects of a drug, presumably, in addition to what we believe about how much we're taking and what those effects ought to be, clearly are impacting at least the way that our brain reacts to, to those drugs.

    14. PAPeter Attia2:03:56

        Y- y- yeah, it, it's very interesting. I mean, when you consider how many drugs that have peripheral effects, um, or peripheral outputs begin with central issues. So again, I think the GLP-1 agonists are such a great example of this, right?

    15. AHAndrew Huberman2:04:11

        Ozempic.

    16. PAPeter Attia2:04:11

        Yeah.

    17. AHAndrew Huberman2:04:12

        Yeah.

    18. PAPeter Attia2:04:12

        Um, y- you know, I, I don't think anybody fully understands exactly how they're working, but it's hard to argue that they're impacting, that the GLP-1 analog is, is having a central impact. It's doing something in the brain-

    19. AHAndrew Huberman2:04:28

        Mm-hmm

    20. PAPeter Attia2:04:28

        ... that is leading to a reduction of appetite. I mean, I think that-

    21. AHAndrew Huberman2:04:30

        We believe that.

    22. PAPeter Attia2:04:31

        Yeah.

    23. AHAndrew Huberman2:04:31

        Yeah. And I think the mouse data point to different areas of the hypothalamus that are r- related to satiety.

    24. PAPeter Attia2:04:37

        Yep.

    25. AHAndrew Huberman2:04:37

        That, that, it's, it's at least possible.

    26. PAPeter Attia2:04:40

        Yeah. I mean, that, it, the, you know, there's no quicker way to make a mouse overeat or undereat than by lesioning its hypothalamus, depending on where you do so.

    27. AHAndrew Huberman2:04:49

        Mm-hmm.

    28. PAPeter Attia2:04:49

        So presumably these drugs work there. But again, it speaks to like what do you need to believe in order for that to be the case?

    29. AHAndrew Huberman2:04:56

        Have they done placebo trials there where people get something and they're told this is ozemp-

    30. PAPeter Attia2:05:01

        Oh, they do. I mean, of course, those drugs have all been tested via placebo, and the placebo groups, you know, don't do anywhere near as well. That's how we know that there's activity of the drug. But, uh, but again, there's y- you know, that's a little bit different than being told you are absolutely getting it, right? 'Cause in the RCTs, you're just told you might be getting it, you might not be getting it. So it's not quite the same as this experiment.

Episode duration: 2:11:12