Decoding the Gurus - Andrew Huberman and Peter Attia: Self-enhancement, supplements & doughnuts?

Episode Date: November 9, 2023

In a kind of meta cross-over with our Decoding Academia series, we're going to decode a journal club discussion between two well-known health optimisers: Dr. Peter Attia and Dr. Andrew Huberman. So you get to listen to two academics talk about two other academics talk about academic papers... we know...We've already been introduced to the bulging biceps and morning sun-drenched routines of Huberman elsewhere but this is our first introduction to Peter Attia, MD. Attia is a former ultra-endurance athlete and a physician in the field of longevity and performance, a podcaster (who isn't amirite?!?) and author of "Outlive: The Science And Art Of Longevity".Attia introduces us to a paper that casts doubt on the supposed general life-extending properties of a diabetes drug called Metformin. This is a drug that is apparently very well known in the biohacker/life extension communities and one that Attia administered to himself for a number of years despite the rather preliminary evidence. This is the first of many indicators that both gentlemen are certainly on the bleeding edge of self-medicating experimentation, doggedly pursuing the elusive goals of huge pectoral muscles, minds that laugh at the concept of cognitive decline, and bodies that will live... well for a lot longer than Matt and Chris!We get to hear about week-long starvation regimes, medications that take the edge of pizza and doughnut binges, dealing with month-long nausea from self-dosing experimental treatments, and frequent prick-blood tests all for the sake of optimising, optimising, optimising...Huberman's paper (a preprint, actually) falls more into the "big, if true" category - although he seems fairly confident himself. Does *believing* you are getting a treatment generate the relevant physiological and neurological effects in the body that could mean we can bypass the need for certain pharmacological substances entirely, including some vaccines?!? Based on the results of a small-N, fMRI study that reports mixed results, Huberman muses... maybe! Or how about those other small-N studies, with p-values hovering suspiciously close to 0.05 that report other counterintuitive findings? We will leave it to Huberman to explain.But the bad stuff aside, Huberman and Attia (especially Attia) actually do a pretty decent job talking about how to approach research papers and some of the pros and cons of different approaches. Chris and Matt thus have ample opportunities to give credit where credit's due and demonstrate that they are the fair-minded souls everyone knows them to be! In any case, it's an interesting peak into an alternative health optimiser world. It seems to be a rather "serious" hobby a bit like body modification or tattoos. But who are we to judge? Matt likes cultivating succulent plants and Chris is into eating sushi in lush forests. So biohacking, self-experimentation for longevity? Well, at least it's an ethos.Also featuring, an introduction that covers Irish history, the most humble guru in the gurusphere, and our very own theory of guru cringeosity!LinksJournal Club with Dr. Peter Attia | Metformin for Longevity & The Power of Belief EffectsThe Most Arrogant thing Bret Weinstein has ever said? Bad Stats ThreadKeys et al. (2022) Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study.

Hello and welcome to Decoding the Gurus, the podcast where an anthropologist and a psychologist listen to the greatest minds the world has to offer and we try to understand what they're talking about. I'm Professor Matt Brown, Chris Kavanagh is my co-host. Welcome Chris. Now we start the podcast. I forget how my spiel ends like i've just so i've noticed that yeah cognitive decline it's it's horrifying to witness in person but i know i've done it too many times um that's all right that should make it that should make it into non-reflexive memory you should be you know just able to read it off but you would think so wouldn't you yeah you got too comfortable that's your problem you're too relaxed

now that's it that's true before there was a frisson attention now like ah whatever i know i can do with my eyes closed yeah yeah so yeah yeah, I'll tell people why we are here. But first, Matt, I have a little surprise clip to play for you. It's from someone we barely mentioned. So you probably even forget who he is when you'll hear it. But let's see if you can work out who it is and what the issue is with this clip i'll i'll keep it very vague for you so just here you go okay all right a test um but there's a piece of the story that haunts me um and it will probably sound arrogant for me to describe it but i'm going to do it anyway because it's later than we think. You'll remember that in the

Hitchhiker's Guide, the Earth is actually a sophisticated computer designed to discover the meaning of life, the universe, and everything. After the initial computer that was designed to do this after, I think, thousands of years, spit out an insane answer, which was 42, which didn't mean anything. And then when asked to explain it, it said, well, what was the question? So the Earth was the 2.0 version of the investigator for what is the meaning of life, the universe, and everything. And as you will recall, the computer actually produced its result. The earth did figure out what the meaning of life, the universe, and everything was in the form of a young woman on whom it dawned. And she picked up the phone to convey the answer at the exact moment that the Vogons destroyed the place.

So anyway, the point is the earth spits out the answer, but we still don't know what it is because lo and behold, it was destroyed at exactly the moment that the answer was ready to be delivered. I feel a little bit like I might be the young woman in that story because I believe that actually evolutionarily, I do know what the next thing is supposed to be. And it isn't that complex. And it's, um, we describe it.

Heather and I, in our book, in the last chapter, it's called the fourth frontier. There we go. did you recognize that figure brett weinstein get your dirty hands off that book hitchhiker's guide to the galaxy is not your play thing you cannot use it you're banned it's too good for you the least of his crimes though is there's a couple of bits where his description goes slightly awry from the plot. I think he got the broad contours right.

Yeah, he probably got it right. I didn't like how he said that the computer, after delivering the answer of 42, said, what was the question? As if it had forgotten it or something. That's not right. Yeah, it was designed to provide the answer. That was the thing, And it gave an answer.

But then the issue is, well, how do you interpret just 42, right? Like, so. Yeah. But, yeah, so there's a little dimension on our garometer. And, well, which one is it? I was going to say Cassandra, but it kind of is. Yeah. It's basically he has the secret, the riddle that unlocks the future he knows it just

like the young lady in the hijackers god of the galaxy but unfortunately isn't able to tell anyone about it yeah an amazing display of hubris there chris brett has excelled himself yeah so the important thing from brett's perspective is she is the person provided the most important information in the universe right and that she tragically is ignored or you know faces calamity because of what the Vogons are doing and that kind of thing so brett is saying he feels a bit like the most in insightful person in the universe like he says it's it's gonna sound a bit arrogant it's not a bit arrogant that's like that has just smashed the wheel of the narcissism measure in the garometer it spun around so many times it came off the hinge yeah i mean brett brett and heather both really do believe that their insights into evolutionary

biology means that they can understand everything everything that happens in the world whether it's covert or ukraine or israel you it. He obviously famously explained the German invasion of Russia during World War II in terms of evolutionary biology. So, yeah, it really is quite amazing. No normal evolutionary biologist would think that, that you could riddle out conundrums in modern history and politics using evolutionary biology. So it's galaxy brainness as well, I guess, isn't it?

Yeah, yeah. So he gets some things wrong about the pot. That's a sin. And perhaps more significantly, he draws a parallel between himself and the most insightful person in the entire universe yeah i think i think one of the reasons um douglas adams chose a young lady to be almost a christ-like figure like he explicitly compares her to jesus christ right he basically figured it all out but jesus christ had to get nailed to a cross unfortunately but she'd figured it out no

one has to get nailed to a cross yada y But she'd figured it out. No one has to get nailed to a cross, yada, yada, yada. But I think he chose a young woman because rather than, say, a middle-aged man and an academic. A evolutionary biologist. Yeah, because the sort of joke in Hitchhiker's Guide is that, like, she really had figured it out. Like, she wasn't deluding herself. She wasn't just full of hot air.

But, yeah, that doesn't apply to brett no no so yeah i thought this was up your alley because you know the theme music for the show has a little hitchhiker's trying to add your username on twitter obviously fond of it so thought this would get you in the fields and again this is a clip from bad stats worst crossover ever chris worst crossover ever hitchhiker's guide to the galaxy exists in a part of my mind that is unsullied by the tawdry goings-on of the gurus so thank you brett for that um yeah yeah what will what depths will he plumb next who can tell it's uh it's always a surprise well i'm really loving

succulents at the moment so if any of the gurus start talking about succulents i'll be very upset oh this this is a good time to unveil our revolutionary theory about the secular gurus some of them at least and why they might be particularly appealing in a sense to to yeah yourself and me why can we withstand them i think these are slightly different because in some respect matt and i are slightly different in our characters you may not have noticed but i probably have a greater tolerance and appetite for consuming people's nonsense or that kind of thing like i can tolerate that more than most people including matt and it's helped by the fact that i can listen to things

at like two and a half times speed that makes a difference so but you have been listening to garth merengue's or watching garth merengue's dark Dark Place and consuming a kind of British dark comedy, cringe comedy, Alan Partridge, The Office, Garth Marenghi's Dark Place, this kind of... Yeah, imagine if Alan Partridge was Stephen King. That's Garth Marenghi. And he's also written a book called Terratome. Best listened to as an audiobook, highly recommended.

Just like in the TV series, it commits every sin of terrible terrible horror fiction genre fiction so but the fun thing about these characters and i think the reason why you and i both like them is that the humor is all character based alan partridge garth the idea is is that they are this arrogant, you know, what's the word? What are our gurus? What do we call them? They're always narcissists.

That's right. Narcissists, like totally lacking in self-awareness. And that's where a lot of the humor comes from. And they're kind of pompous, middle-aged men who believe that their insights are being ignored. Typically, not all of them, but this is a common theme in that kind of character study. And they're like tragic comic figures

because they regard themselves with such self-importance and gravitas. But you as the viewer can see that it's a very insecure and needy personality. And yeah, there are clear parallels there in some of the people we cover. Yeah. And I think the other thing I like about that humor is that I think all of us can detect, I think that the best character comedies win is when you can detect a little bit of

that in yourself, you know, like lot of british humor is like that right it's that cringe kind of thing like um the office for instance you know the character in the office yeah um we sort of wince and and we hate the idea of that others might see us like the audience sees yeah yeah peep show is another one which captures this quite well, you know, gives the internal monologue of the characters. And yeah, that's one where I can see various parallels. Yes. Too many, too many parallels with my life, Chris. So good.

So good. The gurus are basically all of that comedy, but none of the appealing aspects. Like they have no redeeming features. comedy but but none of the appealing aspects like they have no redeeming features we actually noted that the fictional versions that are enjoyable to consume if they did what the actual secular gurus did it would be too broad the company would seem like too on the nose right well i'll say that i think the thing that sets alan partridge apart from characters like that is that it's not superficial it's not two-dimensional like there are there are layers to alan partridge's character it isn't simply that he's whatever politically incorrect or something

it's more interesting than that you know he understands about political correctness and he wants to be politically correct and he sometimes succeeds and sometimes fails because he doesn't quite get it but he's not a total caricature you know there are there are layers to him and some of them are kind of appealing layers and many of them are totally cringeworthy and awful and yeah it's a great it's a great mix so i'd call characters like that deep garth merengue that character is a bit more broad it's a bit more straightforward like government he does compare himself to jesus christ like brett weinstein just sort of did there really um and that's funny too but yeah yeah he's like a

an arrogant horror writer making like 80s slasher and pulp horror but regarding it as a high art form discussing you know the plants turning into carnivores as a metaphor for a capitalist society and all this so yeah there was a great there's a great quote from him which was uh i've met writers who use subtext and they're all cowards yeah so it's just to say that those characters often have redeeming features that the actual guru people lack but they you know they maybe they're perfectly nice in their personal lives or whatever but like a when you can set up the narrative so that ultimately the character you know has some kind of self-awareness or whatever that doesn't actually tend to happen like our girls tend to become worse and become openly anti-vaccine or hard right apologists and stuff so yeah yeah reality is worse i think i think gad sad is probably the

one that approaches fictional characters more than any other simply because he is so obviously bunging it on sometimes transparently and sometimes apparently in earnest but it is still obviously an act um so a shtick yeah except he's except he's not funny yeah that's the that's the killer that's the killer And he's not a fictional character, unfortunately. But, oh yeah, Matt, one more thing. Just one, one more thing I need to mention. I know that you like history podcasts and you like to hear factoids and repeat them. So I'll just mention that I was listening to The Rest is History

and I went back into their back catalog and was listening about the Easter Rising, you know, Irish independence movement. Very interesting about the Hollywood Dublin, Dublin Wood story, you know, the fairytale version of it and the actual complexities of all the groups involved and their levels of support and how the events went and you know now how they are immortalized but how they were perceived at the time so it was very interesting so just and the takeaway was history's always more complicated always more complicated than a hollywood movie who would have thought i i remember i remember the most astonishing factoid i think i learned about that was that they like a an english warship like shells oh yeah yeah i remember when i first

heard about that i didn't actually know much about all that stuff i was like what like to my mind it was like an english warship is shelling newcastle or something like it just just didn't seem it's also an interesting case alone like because it's sort of utterly failed it wasn't a very well conducted uprising and it was actually cancelled by half of the uh participants the people that were supporting it because the whole shipment of arms from the kaiser were intercepted and and uh then they weren't going to go ahead with it but they went ahead with it anyway and it kind of went to shambles and but the thing is Matt that as the historian pointed out when describing that even though they go to shambles and that the

narrative is they were executed and that is what completely changed everything but you don't just get that from like a dozen executions or so there has to be latent sympathy and uh that as a catalyst so the the narrative is a bit too simple in either way if you want to say like they didn't have any popular support or they they had complete support so yeah it's all mixed and uh yeah and ireland wouldn't have been able to have a mass independence movement if that sentiment wasn't at least fermenting in the general populace so anyway interesting thing it's you know we learned about history and there was an Irish historian there, representation for my Southern Irish. Southern Irish people.

So there we go. Do the Southern Irish think of you guys as properly Irish or are you kind of a little bit... Oh, you're opening a can of worms there. That's a long-standing dispute. It depends on the Southern Irish, I guess, that you ask. But there are... There are degrees of parochialism, I assume.

Yeah. Really, do you ask a bastard or a reasonable person? The way that you go about it. But no, I will say that the general dynamic is Northern Irish Catholics might have a little bit of a chip on their shoulder about being authentically Irish. And the Southern Irish might have a tendency to dismiss the people in the North as not properly Irish. And this creates friction with the Northern Irish saying, we are up here defending the unified Ireland, the ireland this argument that's right that's right you were left in the lurch and you leave us you agree with the oppressors yeah that's the dynamic

that tends to go down so i'm imagining a australia new zealander type relationship that makes sense they got a chip on their shoulder too yeah i can tell you a funny story about that but maybe i'll do it off air involving young chris in a southern irish town and too many alcohol now set aside that that whole kerfuffle and let's turn to the topic for today now it's fair to say that you have been taken to this topic, the subject for this podcast this week, at my urging. You were a little bit unenthusiastic to cover this topic, it can be said. But I think you will change your tune as you realize through the decoding,

all of the things that you noticed which you didn't realize were so insightful and i'll tease it out to you it's fine it's fine i'm accustomed to this now i know he wears the pants in this podcast you're like don't worry about it'll be great it'll be great you'll see you'll see it i'm like okay yes you'll be a star man you'll be a star hey your name will be up yeah and well i will say that the reason that you're not enthusiastic i think is partly because on the one hand you watch things at times one speed so when we cover something which is like two hours long it is two hours for you it ultimately adds up the same for me because i have to watch it multiple times to remind myself by the time you get around to watching it so and then i have to clip it at times so anyway who

suffers more it's unclear it's unclear but it is journal club with dr peter atia and andrew huberman met foreman for longevity and the Power of Belief Effects. And it's from a month ago. So it's an episode that was out on Huberman's feed and Addy's feed, a kind of crossover. Yeah, so they're doing like what we do on Decoding Academia, talking about some journal articles. And now we're going to be decoding their decoding of the academic articles. I mean, it sounds riveting already. I could tell well look matt

listen up i i hear what you're saying but one thing is that like we've covered huberman but we only covered like a 15 minute segment thing about you know grinding this is longer form huberman and it's kind of an episode where he's presenting what I think you could say is like his better aspects, looking at studies, digging into research and talking about the ways that you can critically examine papers. So if you thought that us covering him when he's discussing grounding was a bit unfair, this would seem to be a better piece of content, potentially, right? Sure, yeah. And Peter Adia, we haven't covered him.

Who's he, Matt? You don't know anything about him, do you? If I asked you. He is a medical doctor, Johns Hopkins trained physician, but also more commonly known, I think, for his optimizer health diet recommendations. He's in that whole framework and space, the same place Huberman is, the same place a lot of the kind of health optimizer types are. And we haven't done that much on them except for lex and huberman really is

there anyone else that covers the optimizer kind of area no no one's no um chris williamson kind of yeah he does but he was only incidentally covered by the proximity to god's side so right well well it's true i didn't know anything about about him but i knew that he was in that health optimizer thing just by the size of his pectoral muscles they both have very impressive pectoral muscles um this is right they are both they are both optimized individuals and look very well this is a they a, they practice what they preach. And as we'll see, they genuinely do do that in a whole variety of ways.

But yeah, so there's that, Matt. And my last piece of justification for making you cover this is, as you say, this is a purported journal club. We do something very similar on the Decoding Academia episodes, which are on the patreon and as academics we have sat in on many many journal clubs where people are discussing

papers right so this is a very familiar area for us so i think in that respect it's a bit like when we covered eric and brett talking about you know his desk rejections and stuff. This is very normal for us, but it's not that normal for non-academics. So we can approach it from the point of view of people who are not unfamiliar with this kind of format. Right. So see. Sure. Okay. Makes sense. I'm on board. So the way that this is organized is basically they've both brought a paper with them. They've read it in advance and they're going to discuss it, right? And I'll let them introduce the framing a little bit. So by the end of today's episode, you will not only have learned about two novel sets of findings, one in the realm of

longevity as it relates to metformin and another in the realm of neurobiology and placebos or placebo effects, but you will also learn how a journal club is conducted. I think you'll see in observing how we parse these papers and discuss them, even arguing in them at times, that what scientists and clinicians do is they take a look at the existing peer-reviewed research and they look at that peer-reviewed research with a fresh eye asking, does this paper really show what it claims to show or not? And in some cases, the answer is yes.

And in other cases, the answer is no. What I know is for certain is that by the end of today's episode, you will learn a lot of science. You'll learn a lot about health practices, some of which you may want to apply or avoid, and you'll learn a lot about how science and medicine is carried out. Yeah, that's the pitch. Yeah. Okay. Got any issues? Well, it's broadly fine, but yeah, I think where you and I maybe diverge from

these guys, especially human, is that I don't think it's good advice for people to be reading the primary scientific literature and because you're an academic snob you can read it you can read it but you shouldn't be going okay now i'm going to change my diet and my supplement regime based on this paper that i just read i got that yeah that bit about you know you might have some things that you can apply to your actual life i wouldn't be so keen to recommend that especially you know if you're dealing with just like one or two papers i think the part that you could possibly give them credit for is that they talk about these kind of stuff a lot so maybe they're assuming that their audience is also you know consuming other sorts of stuff and has their regimes already so they're probably gearedness towards an optimizer

audience so yeah i still don't think you should do it but i'm just saying that you know it's not the same necessarily as telling a a normie audience that you're going to get health advice you can follow um but yeah yeah that takes that takes some of the edge off it i think still on principle i mean the kinds of optimizers that are yeah like changing their their regime based on the you know the latest papers that have just come out they're sort of making a mistake to begin with anyway but that's just my opinion that's my opinion it's a different with anyway but that's just my opinion that's my opinion it's a different it's a different world just an opinion that's all right everyone has

them anyway so the two papers a little bit about a more this is still the kind of framing but bit about journal club so here you go you know people probably ask you all the time because i know i get asked all the time hey what are the do's and don'ts of interpreting, you know, scientific papers? Is it enough to just read the abstract? And, you know, usually the answer is, well, no. But the how-to is tougher. And I think the two papers we've chosen today illustrate two opposite ends of the spectrum. You know, you're going to obviously talk about something that we're going to 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 a few minutes ago, is actually a very straightforward, simple epidemiologic paper that I think has important significance. I had originally gone down the rabbit hole on 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. So the point there, you know, it is kind of framing it in the same way that we do, Matt, but, you know, it's useful to think about the way that you might assess the quality of studies, look critically at things. And that's what he's discussing that they're going to do i don't have much issue with

the framing about encouraging people to critically evaluate things although i grant that you should be aware of your limitations when doing that but you know as as saying this is what academics do that's true isn't it yeah that's basically fine i'm not super this is what academics do. That's true, isn't it? Yeah, that's basically fine. I'm not super interested myself in glucose binding and ATP inhibitors and so on. But, you know, each to their own. Each to their own. You've got your history podcasts and your...

Circulants. Circulants, yeah. Neither of which are your academic speciality. And they've got that. yes any i i admire i don't admire might be too strong but i'm kind of glad that he chose a less sexy paper than whatever he was previously considering so you know he says a bit boring but that's good boringness sometimes okay now before they get into the papers map there's just like you know there's there's some other things and i think this is not poisoning the well i just want to point out

a little bit of the dynamic because it will come up in various clips so you need this context adia describes a dream that he had about huberman do you remember this vaguely yeah so yeah you need this because it will come up in various clips so here's his dream about tuberman so i had a dream last night about you and um in this dream you were obsessed with making this certain drink that was like your elixir and it had all of these crazy ingredients in it supplements some tons of supplements in it. But the one thing I remembered when I woke up, because 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. It was so, it was like, just sounds like something that I would do. And, and so. But here's the best part. You had 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? Yeah, so I actually think that's a fairly straightforward dream to interpret, because

he is someone that is obsessed with supplementation and various things. Yeah, and natural supplementation in particular so that explains the dew yeah no that's a very plausible dream to have about human i've had dreams about you chris am i doing that am i dancing through the forest i just want to emphasize then there's nothing sexual at all no it was that yeah you were just being you yeah podcast things probably trying to convince me to listen to something i didn't want to and i was going another hooverman episode yeah seven hours no yeah so and i i appreciated hooverman's reaction is good natured like i know

this doesn't bear mentioning it's just people you know having a joke about a dream that they have but it is worth mentioning in the guru sphere because they take themselves so seriously. So to promote these creditors, you know, that does sound like something that we're doing. Yeah, so it's just an amusing little dream. But dreams can be more to them. Oh my. Some other time we can talk about dreams. Recently, I've been doing some dream

exploration. I've had some absolutely transformative dreams for the first time in my life. 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. this was drug free etc um and do you think you could have had that dream we don't have to get into it if you don't talk about it now but was there a lot of work you had to do to prepare for that dream to have taken place oh yes yeah um at least uh 18 months of intensive um analysis type type work with a very skilled psychiatrist. But I wasn't trying to seed the dream. It was just I was at a sticking point with a certain process in my life. And then

I was taking a walk while waking and realized that my brain, my subconscious was going to keep working on this. I just decided it's going to keep working on it. And then two nights later, I traveled to a meeting in Aspen and I had the most profound dream ever where I was able to sense something and feel something I've always wanted to feel as so real within the dream, woke up, knew it was a dream and realized this is what people close to me that I respect have been talking about, but I was able to feel it. And therefore I can actually access this in my waking life. It was, it was, it was absolutely transformative for me. Um, anyway, sometime I can share more details

with you or the audience, but for now we should talk about these papers very well. Um, who should go first? Yeah, that's wild. Not to be. I mean, that's fine. I mean, but Chris, are all Americans like this? Like Americans talk like this. Some of them do anyway.

They're not. They're not. They're not all. To be fair, an American I once dated did ask me various questions about dreams. It was important. Like what colors I dreamed in and stuff. And it's like, I don't know, general, normal colors. But in any case, this is not the cast aspersions of all Americans, because I think here, I just want to highlight,

like there's a little bit of mysticism to Huberman, right? Like that's talking about 18 months of presumably some kind of psychoanalysis therapy that allowed him to have a breakthrough in a dream setting that, you know, is going to transform his life and make all these important decisions of the basis of that's, you know, that's something of a kind of Jordan Peterson-esque approach to things. I know, but it's also a little bit American. Like there is a culture in America of seeing a psychiatrist regularly, even when you are really perfectly psychologically well. That's not a cultural thing in Australia. People don't see psychiatrists. I know.

We're all repressed in the non-American Anglosphere. That's right. We just push those feelings down and drink more. That's how we handle it. It works fine. But Americans are built differently. And they're a lot more prone to be talking about an issue that they've been mulling over with their psychiatrists and then having revelations and so on.

I don't know. Australians don't get revelations like that. But it's fine. It's a different culture is what i'm saying chris if i were to interpret that matt i might think it relates to his disclosure on the lex friedman about having a religious experience and becoming spiritually inclined so he referenced people he respects talking about experiences that he couldn't properly comprehend so perhaps an encounter with the divine or you know i don't know could be the cosmic dwarfs that control the universe that you usually can only contact through dmt could be them who knows but then in any case i'm just pointing out there's that vibe as well

because like now we're going to get into the hard node science right but it's the um yeah there's a crunchy vibe there yeah i know But it's the, just before that. There's a crunchy vibe there. Yeah, I know. Yeah. It's at the intersection between sort of psychiatrist culture, therapy culture, and yeah, spiritual type culture. I don't know.

Where's he from? Is he from California or somewhere else? Who knows? He's at Stanford. So presumably somewhere around there. I don't know. Do Americans ever travel to places that they weren't born in? I don't know. I don't know what they do. So, yes, the first paper, Matt, this is Addy's pick goes first. OK, and here's a little bit about the framing of this paper. This is a pretty straightforward paper. So so we're going to talk about 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 last fall. all. Why is this paper important? So this paper is important because in 2014, 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 Giro protection with metformin. So this paper, and part of the reason I kind of like this, Matt, is that it's a, as he describes, a paper looking at a previous finding and reassessing it, right? Some people that claim that there is a drug usually used to treat diabetes that seems to have a potential

life-extending property for non-diabetic people. And you can see why the optimizers and anti-aging community would be interested. Longativity, I think that's what they're, I can't remember how they describe themselves, but that whole against in essence. Yeah, life extension. Life extension. Yeah, those guys. There are a lot of rationalists hovering around the meetings in the corner with yudkowsky's fedora floating around so yes yeah you know the type yep but i guess it is a relatively common thing isn't it often they find

that a drug that's been used for something turns out to you know have these side effects which are like good side effects um so yeah yeah that's not unusual not unusual and um next clip is about describing the potential mechanism of metformin and i wanted to include this matt to just point out that this does get like pretty technical at various points and i i get the impression from the way that adia speaks and and huberman as well that they they know what they're talking about. They're very familiar with the terms, but it's not the kind of thing that I think if you were half listening to, that you would be able to follow that well. And I think a little bit of it, at least a little bit of the way that they're going to talk about it is presenting how much they know these subjects.

Maybe I'm being a little bit unfair, but just listen to this description. The mechanism by which metformin works is debated hotly. But what I think is not debated is the immediate thing that metformin does, which is it inhibits complex one of the mitochondria. So again, maybe just taking a step back. So the mitochondria, as everybody thinks of those as the cellular engine for making ATP. So the, maybe just taking a step back. So the mitochondria, as everybody thinks of those as 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. Got it? Yeah, that was pretty good. No, it was. I will say this. I think if you're immersed in this world, that's a little bit second nature. But also, to Adia and Huberman's credit, they're very good at communicating complex ideas and like kind of doing it in the technical way and then they stop and break it down and one way they do this is one asks a question of the other one to you know okay so can you clarify what you said there and they're really good at it i think this

is part of the reason that people like their content right right? Because you get both the apparent technical depth and you get the layman descriptions, right? So you can, I don't know, feel a little bit like you're listening in on the technical discussion, but you're still able to follow. I have an example of that dynamic. One question, is it fair 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 mitochondriaiting the energy production process. 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 going to be broken down. We're chewing, we're digesting, but less of that is turned into blood sugar, glucose. Well, sort of. I mean, it's not depriving you of ultimately storing that energy. What it's doing is changing the way the body partitions fuel. That's probably a better way to think about it to be a little bit more accurate. That's good, right?

Isn't it? Huberman saying, okay, so what you're saying is this accurate? And then giving Addy a time to kind of say, well, that's not exactly, you know, let me change it a bit. And yeah, I thought we could learn. They do it very well. Like this is quite impressive in the way that, I mean, the professionals at this for a reason. But that's good science communication, I think.

Yeah. Yeah. Like, you know, you can compare it to the way brett and heather do science communication where there's just layers and layers of abstraction and blather whereas you know these guys are talking in concrete terms and yeah i think they did well at least as far as i could tell you know i can't tell if they're describing atp wrong or right sounded right to me yeah and i'm gonna play one more clip that i think is good because i genuinely think I can't tell if they're describing ATP wrong or right. Sounded right to me. Yeah.

And I'm going to play one more clip that I think is good because I genuinely think Adia is good at this. So this is him talking about the process associated with diabetes. And again, get a fair amount of medical jargon or biological jargon, but explained nicely, Matt, the kind of thing Eric never does. So again, what's happening when you have type 2 diabetes? The primary insult probably occurs in the muscles, and it is insulin resistance. Everybody hears that term. What does it mean? 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, because 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, 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 ATP donates a phosphate group. And 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. 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. That's the job of insulin. I understand insulin now. I feel like it reads in the metrics. matrix but that was and again not qualified to judge seemed like he was doing i know like so this you know we are not mindless haters i'm actually highlighting this to say i think this is pretty good i think this is why people like adia and huberman because this is the stuff that they do which actually if you listen to a proper academic who isn't good at science communication they could explain the exact same process and it would make no sense and they wouldn't factor in that people aren't going to follow along so they they add in the little descriptions to kind of keep you going along and i i think they pitch it

at generally the right level but it is clear that they're really comfortable talking about this kind of stuff so you know it it isn't really that difficult for them and matt you know we were saying that maybe people can't put things into practice that they hear here or maybe they shouldn't i just did want to note there was a bit of bad news related for me here, maybe some health advice. 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. Wow. Which is, I mean mean that's a staggering amount of you're basically inducing profound insulin resistance in just a week of sleep deprivation fucking hell this is terrible and you've had some blood tests done haven't you you don't need to tell us yeah so it's like oh my god yeah so see look what they're giving me we cover the girls they give me actionable health advice but yeah anyway i already knew

you're supposed to sleep longer than i currently am but let's you know just yeah i'll then enjoy hearing that so thank you peter had information um you might recall me, Chris, often recommending you just go home, go to sleep, get a good night's sleep for God's sake. And you're like, yeah, yeah, yeah, Matt. You think you're built out of cast iron steel, but you're a human just like the rest of us. You need to sleep. So well, so it turns out if I did that,

I just imagined the human I could be. Imagine the blood test I could get if I slept eight hours but I actually related to this but this is from much later in it there was a a discussion it's it's kind of comes later but they're talking about uh who comments binging tendencies but anyway Addy has said something which again I think endorses something that you've been talking about your kind of humans are rats thesis. So listen to this clip and we'll see if you think it endorses your worldview. I can imagine a scenario where a person could be in a negative energy balance,

eating Twix bars all day and drinking, you know, big gulps. But I also don't think that's a very sustainable thing to do, because if by definition, I'm going to put you in negative energy balance consuming that much crap, I'm going to destroy you. Like you're going to feel so miserable. You're going to be starving, right? You're not going to be satiated eating pure garbage and being in caloric deficit. You're going to end up having to go into caloric excess. So that's why it's an interesting thought experiment. I don't think it's a very practical experiment. For a person to be generally satiated and in energy balance,

they're probably eating about the right stuff. But I don't think that the specific macros matter as much as I used to think. I'm a believer in getting most of my nutrients from unprocessed or minimally processed sources, simply because it allows me to eat foods i like yeah and more of them and i just love to eat i i so physically enjoy the sensation of chewing that you know i'll just eat cucumber slices for for fun yeah right you know that's i mean that's not my only form of fun fortunately um so they there was it was sandwiched there with some things which you haven't advocated for like consuming crap at a caloric deficit being a good thing but yeah you know you have argued the macros are not that important it is calories and right that ultimately matter and they kind of mention that hooverman doesn't agree with you he likes you know organic jew drenched food he nibbles on organic cucumbers

for pleasure yeah yeah yeah definitely on the idea side of this one where um i just i do think people are rats and you know it's surprising how you know people get by pretty okay even if they're not super optimizing with regard to the micronutrients or whatever and you know if you basically eat a bunch of different things you know you're not eating twix bars and big gulps and you don't eat too much then you can forget about it you know it's you're probably fine yeah so i'm gonna go back to the idea paper here and he's talking about the the old paper the one from 2014 and some issues that might make it the finding that it was healthy more questionable or that metformin would have general life extension properties. So the way the study worked is if you were put on metformin, we're going to follow you.

If you're not on metformin, we're going to follow you. And we're going to 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 want to know how much are people dying from anything because 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 significant drug. So all of those patients were excluded from the study. 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 going to consider the patients who were on metformin, stayed on metformin, and never progressed through it. And we're going to compare those to people who were not having type 2 diabetes. So, you know, I thought that was a good thing describing the particular, I can't remember what it's called, information censoring or something like that as a significant limitation properly highlights why that could be an issue and give you a misleading perspective and flagging it up as a limitation that's that's good isn't that it's very good uh i like these methodological details it's uh it's a big issue with longitudinal studies um your data is censored for various reasons um sometimes

at the researcher's discretion sometimes not like with dropout. So it's good that he talks about it. This is just riveting, Chris. We're listening to people talking about a very technical academic article, and it's fine. It's all fine. It's fine. Look, it's going to get – trust me, we're not on Huberman's page. So, well, you're really going to like this.

So that was him describing the finding from that 2014 paper. Here's him emphasizing it in the science communication way that I've highlighted. Type 2 diabetes on average will shorten your life by six years. I see. So that's the actuarial difference between having type 2 diabetes and not all comers. 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 thousand patient years studied. far worse crude death rate. And the fact that it was statistically significant in the other

direction, and it turned out on 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-cause death over 2.8 years, which was the median duration of follow-up. Well, that seems to be the number that makes me go, wow. Yeah. Right? That because, could you repeat those numbers again? Yeah.

So 15% reduction in all-cause mortality over 2.8 years. That's a big deal. Yeah. So there, Matt, i'm highlighting the science communication dynamic right of like you know tell me those figures again right but also the reason that that initial banister at all study got attention was because of this right like they're they're finding 15 relative reduction in in death that's a big reduction right so you can you can see huberman's like antennas go up yeah 15 less likely to die yeah

that's it's good i mean that that is is that a big effect chris i'm not no i think yeah it has to all be counted into, it is significantly qualified by the way that they've compared the populations and all that. So yeah, I think he does highlight before, it depends what way you look at it, but this is the kind of result that had people at least a little bit exercised. And highlighting the type of audience that they have. You know, we sometimes

point out when people say people ask me these kind of questions a lot or whatever, they do mention this. 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 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 outside of do i mean people definitely want to know if you should be consuming do but but after that it's metformin fresh off the leaves has to be while viewing morning sunlight yeah so you wouldn't cut that joke ma if Matt, if I played the dream one. Good thing you played the thing about the dream at the beginning.

To keep that context. But, you know, there, Matt, how often are our audience asking us for advice about Metformin? It's the frigging question that comes up all the time on the Patreon, you know. So I know this is their particular thing, I'm on the Patreon, you know, what should we do? So I know this is their particular thing, but I'm just noting that obviously this was a big deal in the longevity community. If this is your second most common question or whatever it is,

and it's on the basis of this, primarily this banister at All Study, like I am thinking that this seems very flimsy evidence to make that such a big deal. But, you know, that's what their audience are there for. They want these hacks that are going to give them 50% reduction and like some metric about mortality that, you know, might be significant for them. So, yeah.

Yeah. Yeah. That's the dream to live till 105 with huge pectoral muscles. It's a good dream. Yeah, it's the dream, to live till 105 with huge pectoral muscles. It's a good dream. Yeah, it's a good dream. So just a note here as well that kind of ties into the naturalism aspect as well as the optimizer bit. So there's an aside a little bit earlier where Huberman is talking about

his own kind of dalliances around these kind of chemicals or things which might cause that effect of metformin. Metformin tackles the problem elsewhere. It tamps down glucose by addressing the glucose, the hepatic glucose output channel. GLP-1 agonists are another drug. They increase insulin sensitivity, initially causing you to also make more insulin. So that's Ozempic? Yes. Yeah. And is it true that berberine is more or less the poor man's metformin? Yeah. Okay. It's from a tree bark. It just happens to have the same properties of reducing mTOR and reducing blood glucose. Yeah. And metformin, by the way, 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. So you need a prescription for metformin. You don't need a prescription for berberine. Correct. But yeah, we can talk about berberine a little bit later. I had a couple great experiences with berberine

and a couple bad experiences. I just noticed that, again, the kind of, you know, it comes from a tree bark oh this one comes from a lilac plant that's important right it's not purely synthetic because presumably that would be worse and uh and that huberman so this is our first mention of a substance that huberman is taking berberine which he says is the poor man's version of metformin and is available without a prescription so was it the berberine that he had a couple of good experiences and a couple of bad experiences with yeah and he'll return to that later this is what we call in the

uh what the fuck i forgot the word what do you call it when you plant something that will come back later uh um it's not priming god damn it man damn you is it a word oh it's on the tip of my tongue foreshadowing foreshadowing i had it exactly i got that no i had it foreshadowing foreshadowing another clip that we i mean this is a super mild thing it's not even a criticism but you know the little the little ways in which it does deviate from you know like a normal academic journal club is the working in of the personal lived experiences of hoobman in that case where it's kind of relevant that he's been taking this and he had some good experiences and bad experiences and and that's kind of weaved into the scientific evidence

um so you know it's a small observation what you could just say it's keeping it personal keeping it real um adding a bit of flavor um but i don't know it just does demark a slight difference well i think the difference that you're talking about a bit is not injecting personal references because I think that just naturally happens in this kind of long-form podcast, but it's more the self-experimentation aspect of it, right? Because like Hubert was just saying,

you know, this study I read at first when I was taking my cat out to the vet or whatever, you know, that's just, what you're just talking about. But it's this element of their personal experiences being tied into the way that you assess this literature, right? Yeah, that's right. Yeah. So Journal Club, Matt, they're actually up to now have been talking about the background.

They haven't been talking about the individual paper. This is the paper before the one that Adia is focused on. And actually, just one last thing, to be fair to Mr. Huberman, I've mainly played Adia doing good science communication. I think this is Huberman doing a little bit of good science communication. I'll just play an example of it. 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 gradient, but once the action potential fires, it's passive outside, right? Yeah. So what Pierre's referring to is

the way that neurons become electrically active is by the flow of ions from the outside of the cell to the inside of the cell. And we have both active conductances, meaning they're triggered by changes in the gradients, by changes in electrical potential. 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 normally have to go through a process of of you know transcribing genes and making sure that the specific proteins are made and then 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 channel and it makes sense as to why that would be required but it's just oh so very cool was that okay you're the neuroscience expert what's your grade for that yeah it's it's the intersection of what i know about this stuff and what he knows that bit sounded totally fine i think it is true that axon potentials are once they get going they just they just go they don't need sort of active support um i never really learned about how like the neural cell actually regenerates its energy in terms of like these guys are interested in ATP and how cells get energy to be stronger and so on.

Whereas psychologists don't care about that. We just go, okay, this is what it did. The support system to keep the actual cells alive is sort of not something we care about. A telling difference. So you're learning something. That's what you're telling me. Uberman's giving you new information. Well, I didn't really follow the other bits, his explanation, but it sounded good.

It just sounded like it's probably just me being stupid. Okay. Well, if you are an expert in this, you can let us know. Did Uberman do good or was he terribly wrong? Sounded okay to me. Yeah, sounds fine. See, you Huberman haters on Reddit, you got Huberman all wrong. He's fine.

It's great. We'll see. Let's move on. Oh, we were talking about self-experimentation. We saw Huberman talking about his barbering or whatever it is. So Adia is in on this too, Matt. Let's just make that clear. So 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 shareholder meeting, which is the Buffett shareholder meeting. And 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. Is that characteristic of your approach to things? Yes. I think that's safe to say. Next time I'll give you a thermos of this dew that I collect in the morning. Oh, really? next time i'll give you a thermos of this dew that i collect in the morning 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 because you do all the buffett things when you're there right like i couldn't have an ice cream at dairy queen you couldn't i mean i couldn't i'm so nauseous

again the dewey came in just pointed out again it was worth investing in that do clip um otherwise everybody's saying what's all this do about but uh so adia is interested in metformin before the banister at all paper self-experimenting apparently with a high a high dose immediately which caused bad reactions but's actually, it's that thing that he's dosing himself on this, you know, purely experimental treatment, right? But enough that he doesn't mind being extremely nauseous at a conference. So, yeah, this is the first sign about the self-experimentation kick that they're both on.

about the self-experimentation case that they're both on um so yeah so why remind me why would why is he taking metformin like why would he have been taking metformin to live longer to reduce his chance of 15 percent geroprotection or whatever they call that thing yeah life extension so presumably there were some indicators that it might be useful outside of diabetics before the banister study um so it's just an odd i just don't get it like like i rate my chance of death in the next five years as being extremely low so i'm not going to make myself nauseous to reduce that by 15 like yeah what's the thinking i don't get it it's a different well matt listen listen here you go i can let him answer for you but regardless that's the story on metformin there were a lot of reasons i was interested in it um i wasn't thinking true giro protection that term wasn't in my vernacular at the time

but what i was thinking is hey this is going to help you buffer glucose better it's got to be better and this was sort of my first foray into you know self-experimentation buffering glucose better that's just not something that's on my list of priorities yeah and um a gyro protection right that's what he said. It wasn't in his vocabulary. It's not in my vocabulary. It is now. Yeah, so geron as in gerontology, geriatric protection against being old.

I see. Yeah, like gerontocracy or whatever it is. So we've got Huberman on his poor man's metformin. Adia is ahead of the curve, doxing himself to the state of nausea on metformin, even before the Banister et al study. And I may as well follow this line a little bit. There's more clips that go down.

So here's the next stage when they're looking back at this period. So metformin has failed in the ITP. So you no longer take metformin. I stopped five years ago. I mean, you're not a diabetic. So presumably you were taking it. I was taking it has failed in the ITP. So you no longer take metformin. I stopped five years ago. I mean, you're not a diabetic. So presumably you were taking it for a giro protection to buffer blood glucose. Yeah. And ultimately, yes, exactly. And the reason I stopped and this will be the last thing before we move on. Well, because you couldn't go to the Dairy Queen at the buffet. No, finally, the nausea went away after a few weeks or a month, maybe. But once I got really into lactate testing, I noticed how high my lactate was at rest.

So resting fasted lactate in a healthy person should be below one, like somewhere between 0.3, 0.6 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 this is after I met Inigo San Milan, 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 but ran the flight of stairs up the back of the empire state building yeah well that's i i but this is the most relatable thing i'm just constantly pinpricking myself throughout the day to check my millimoles of lactase and just fretting constantly so this is the optimizer world but you were shaking your head of disbelief but um yeah it is really micro managing your whole internal system right like yeah it's fascinating to me i mean no judgment um you know it's fine is there no judgment no chance right there i can't judge them my pictorial muscles are nowhere near as big i'm sure they i'm sure they're much healthier than me is is like the thing which is doing that though I don't know. Because like this is a good example.

So he mentioned he's off the Met form now. And we'll see why because we talk about this paper. But he stopped five years ago. Right. But that means he was on it for a number of years. If I was taking something that made me nauseous, I would stop immediately. The nausea only lasted for one month, Matt. I would last about 15 minutes before I'm like, screw this.

That's why you don't have the pectoral muscles. This is true. This is the optimizer mindset. I get it. Matt likes his succulents. I like whatever the fuck I like. And these guys like measuring the millimoles before they go for a run, right? And Discovery, though,

is the thing that he was taking to extend his life was seemingly doing something, like, bad. So this is the hazards of, like, self-experimentation, presumably, because you're never quite sure about the exact effects. And maybe it is undoubtedly that this is not the only thing that they are taking, right? So isolating out the causal factor, it's not going to be a thing.

But yeah, so it's an interesting mindset. It is very different, I think, from the ordinary worker Joe. They are micromanaging their blood levels and a level huge for unheard of mortal man yeah i mean there's a lot involved in being a health and wellness optimizer right like we've got some little insight into the amount of testing the amount of calculation the amount of supplements, but just thinking and how it must affect all aspects of your day. I'm just amazed that people take all of that on.

Like I'm all for hobbies and obsessive type interests, but it's a big commitment. Let's stick on this a little bit. So Huberman's now going to talk about like why he was taking the berberine or right so what he was up to and basically he's talking about following a fasted eating schedule like a caloric restriction and various things but having a cheat day where you go mental and like binge all the cakes and stuff that you want. But then the next day, introducing like a complete fast, right? So anyway, let's let him explain that. So the last thing you want to do is eat

any food, I would just hydrate, and oftentimes to try and get some exercise. And what I read was that berberine, poor man's metformin, could buffer blood glucose in some ways make me feel less sick when ingesting all these calories and in many cases spiking my blood sugar and insulin because you're having ice cream and you know, et cetera. And indeed it worked. So if I took berberine and I don't recall the milligram count and then I ate, you know, 12 donuts, I felt fine. It was as if I had eaten one donut. Wow. I felt sort of okay in my body and I felt much, much better. Now, presumably because it's buffering the spikes in blood sugar, I wasn't crashing in the afternoon nap and that whole thing. And do you remember how much you were taking? I think it was a couple hundred milligrams. Does that sound about right?

It was a bright yellow capsule. I forget the source. But in any case, one thing I noticed was that if I took berberine and I did not ingest a profound number of carbohydrates very soon afterwards, I got brutal headaches. I think I was hypoglycemic. I didn't measure it, but I just felt I had headaches. I didn't feel good. And then I would eat a pizza or two and feel fine. And so I realized that berberine was putting me on this lower blood sugar state. That was the logic anyway.

And it allowed me to eat these cheat foods. But when I cycled off of the four out, because I don't follow the slow carb diet anymore, although I might again at some point, when I stopped doing those cheat days, I didn't have any reason to take the berberine. And I feared that I wasn't ingesting enough carbohydrates in order to really justify trying to buffer my blood glucose. It's such a complicated relationship with food, isn't it? It's, yeah. I know he's being tongue-in-cheek probably, but if you're eating 12 donuts at once or eating two pizzas at once, and you're buffering with berberine or whatever it is and then if you do take it,

it does this and if you don't, I mean, you're really screwing with things and I don't know. I guess I've got a kind of a, is it committing the naturalist fallacy to just say maybe just don't screw with it, just let nature take its course and let your body do its thing and don't screw with it just let just let nature take its course and let your body do its thing and don't be sort of oscillating between you know like weird diets and calorie restriction and cheap days where you just like stuff two pizzas and 12 donuts into your mouth and you need to take a chemical so you're like not really nauseous but if you if you don't eat

enough calories you're getting like these brutal headaches because something is good like this yeah it's pretty extreme but like to me matt the contrast here is like huberman and rogan and all these people they're always talking about nature being out in the forest sun bathing you know how great this is and you know you want to get tree bark supplements what they're talking about now is not natural it's and then they're doing you know, you want to get tree bark supplements. What they're talking about now is not natural. And then they're doing, you know, the cold plunges and the hormone replacement therapy and injecting, you know, taking ivermectin for prophylactic purposes or all those things. So it's like this weird mix of like, yeah, I guess this is what optimizers do, though. But, you know, nature is good. You need to be out in the though but you know nature is good you need to

be out in the wilderness you know getting the sun's rays to power you up plus you should be micromanaging your fucking blood glucose level and the lactose uh amounts to the micro millimeter so yeah it's there's a contradiction there isn't there like between the natural thing or the paleo thing where you're trying to replicate the natural interactions of of human bodies with foodstuffs and environments and make it as paleolithic and as natural as possible but at the same time they are really interfering with the mechanisms to an unholy degree and and i do i do actually mean it when i say kind of no judgment because i figure you know people could do what they want if you know if you want to make it your hobby to you know then

and play with yourself look it could be risky i wouldn't necessarily advise it but you know that's that's it's a bit like tattooing or body modification or something like that right it's like you know it's not for everyone but it's your body, do what you want with it. And, you know, as you say, they're both, they look at least outwardly, I don't know what their blood levels are, but they outwardly look, you know, very healthy individuals and they are doing exercise and stuff as well.

So it's, you know, I agree. I don't think this is the worst thing in the world for people to be doing by any stretch. It might even turn out, you know, that they do hit on something that's healthy, but it is a very odd way. And I guess I would say the way that they square the circle, reduce the dissonance, is that they are saying all that natural stuff is, you know, evolutionarily programmed to gel well with our biology. But now we can go a step further we can actually scientifically look at the aspects so that's why it's the negative ions that are out

in nature which are important right and this was part of my critique about you know the the scientism kind of creeping into hooverman's recommendations about being out in nature um because it yeah it very much wants to say it is because there's a scientific underpinning to all of this no you're right actually and i take that back because even though there's an apparent contradiction there it does actually make sense that they're kind of starting from a natural is good foundation but then optimizing further based on what science and stuff can can tell us and you, whether they're right or wrong, you know, it's a hobby.

You know, I'm into succulents. They're inter-optimizing their bodies. But that's not all, Matt. It's not just those drugs. Clearly exercise, meaning regular exercise, is the best way to keep that system in check. But in the absence of that tool, or I would say in addition to that tool, is there any glucose

disposal agent, because that's what we're talking about here, metformin, berberine, acarbosit, et cetera, that you take on a regular basis because you have that much confidence in it? The only one that I take is an SGLT2 inhibitor. So this is a class of drug that is used by people with type 2 diabetes but which i don't have but because of my faith in the mechanistic studies of this drug coupled with its results in the itp coupled with the human trial results that show profound benefit in non-diabetics taking it even for heart failure i think there's something very special about that drug so matt

matt foreman has been replaced with an sdlt inhibitor uh so yeah so he's he's taking it based on his understanding of the scientific literature thinks it's going to do some good even though it's not sort of medically prescribed um yeah i can see why right he might be right yeah that's right i can see why optimizers who are wanting to be at the bleeding edge of self-improvement who would be keen to listen to this because he's a medical doctor and he's probably got all kinds of qualifications and he does know how to read literature he's a smart guy i can tell so you're getting his kind of he's expressing it as this is what he does personally he's not he's not telling other people to do this

but definitely people who are listening to this are going okay that could work for me i might do that too yeah yeah so um we'll get off this self-experiment um tation with one more clip but the the last one but um so huberman you know he was doing his like fasting for our whatever consumption protocol from Tim Ferriss. And Adia himself has experimented with calorie restrictions. I think the short answer is no. For two reasons. One, I don't think that that duration would be sufficient if one is going to take that approach. But two, 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'd 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. Now, I certainly believed, and to this day, I would say I have no idea if that provided a benefit. But my thesis was the downside of this is relatively circumscribed, which is profound misery for a few days. And what I didn't appreciate at the time, which I obviously now look back at and realize is muscle mass lost. It's very difficult to gain back the muscle cumulatively after all of that loss so i i just highlight that because you know this means that for a couple of years he was on like an extreme cyclical uh like water only fast right and And describes it as inducing profound misery

for a couple of days. And now he isn't sure if that actually has any benefit. Like that was Herman's question was, do you recommend caloric restriction? He was like, no, not intermittent caloric restriction. Not really, but he did for years. And on the one hand, it's kind of good to see somebody moderate their position

but it just does speak to that level of you know that's a hell of a commitment to do for a significant amount of years and then now i'd be like well maybe actually it was damaging my muscle mass and i'm not sure it actually produced any benefit like i have to respect the commitment yeah these guys are really into it and he's okay with the profound misery that's hardcore yeah but it's it's the loss in muscle mass that's that's a real concern that's a bigger concern yeah the pectoral muscles it is kind of deflating yeah we're making we're making fun but i i do you know it's a hobby it's an interest they take it seriously so that's that's okay you know we don't but look at us you wouldn't want to look at us naked um well you know

um so matt journal club back to the journal club so we'll get to the papers now we'll do it quick we'll be efficient don't worry so here's the Journal Club for me. The Bannister study used, 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 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 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 factors during childhood that might 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, and signal. So now turning this back into a little bit of a journal club, virtually any clinical paper you're going to read, table one is the characteristics of the people in the study. You always want to take a look at that. So there we go, Matt, you know, introducing the paper, starting off, let's look at table one. You're familiar with this. You've said it yourself a million times. The approach to papers, you know, this is normal.

Yeah, yeah, yeah. Table one. I think table one is the participant characteristics. Have a look at the people. Let's see. So table one in the keys paper shows the baseline characteristics. And again, it's almost always going to 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 are the inclusion criteria. These are 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 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 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 that column, Andrew. Notice how pretty much everything else is perfectly matched until you get to the medication list? I know that was long. I'm playing with this show like that's normal,

highlighting people, looking at the characteristics of the participants and I'm playing with this show. That's normal, highlighting a paper, looking at the characteristics of the participants and noting good advice that see if anything jumps out, especially if it's between groups. Is there something notable about the differences in the demographics or the medications? It's good. And I think he did spot some important differences

between the test and the control group. And he does talk about limitations here and also a nice way. Full credit, listen to this. Exactly. So this is, again, a fundamental flaw of epidemiology. You can never remove all the confounders. This is why I became an experimental scientist. So that we could control variables. That's right. Because without random assignment,

you cannot control every variable. Now you'll see in a moment when we get into the analysis, they go through three levels of corrections, but they can never correct this medication one. So just keep that in the back of your mind. Okay. good he's right highlighting the weakness of epidemiology studies right yeah or overlapping treatments that people are receiving it is good it is good um recent study of mine chris i was looking at um demonstrating the effects of problem gambling on quality of life we can't do an experimental study we can't give a group gambling problem we can't give that to people the bloody ethics board won't let us do it so we're forced to do this kind of epidemiological thing we do our best to balance the groups both methodologically statistically we try to control for all the comorbidities but i know chris

i know that there are other confounders out there. And Adia makes that point very forcefully. Yeah. And here's him again, I think, doing a good job correctly identifying strengths and limitations of this epidemiological approach. 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. 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 survey people over the course of their lives and we can have the biggest sample size possible because 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. So this is the balancing act between epidemiology and randomized prospective experiments. And so they both offer something, but you just have to know the blind spots of each one. Yeah, I think elsewhere too, he talks a lot about those complementary strengths and weaknesses of experimental studies, very expensive as a result in normal circumstances. COVID was a bit of an exception. You can't do really large-end experiments. So the small end, on the flip side, you get to do random allocation

and you've got a really strong argument for causality. The other approach where it's more observational or epidemiological, you could say, you've got the capability of getting a huge number of participants. There's a big advantage there. It could be ecologically valid, all sorts of things like that. But you don't have that strong argument for direct causality of the thing you're manipulating.

No, and I'm going to give more credit. I'm a credit-giving machine today. I'm doing it like it's Christmas over here. Adia discusses confidence intervals i think does a pretty good job of that so here's him discussing confidence intervals 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, it goes from 29 point 24.93 to 24.7. One other point I'll make here for people who are going to 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 no issues with any of that, right? That was a good summary there. Yep.

Okay. And then Huberman follows up that, talking about a similar sort of thing. So to your point, the people with diabetes taking metformin in both the matched singletons and the discordance are dropping much faster and they always stay below. And I was just going to say that the shading is just showing you a 95% confidence interval. So you're just putting basically error bars along this. So if this were experimental data, if you were doing an experiment with a group of mice and you were watching their survival and you were, you know, you'd have error bars on this, which you're actually measuring. So this is because you have much more data here. You're just showing this in this fashion.

For those that haven't been familiarized with statistics, no problem. Error bars correspond to like if you were just going to measure the heights of a room full of 10th graders, there's going to be a range, right? You have the very tall kid and the very shorter kid and the short kid and the medium kid. And so there's a range. There's going to be an average, a mean, and then there'll be standard deviations and standard errors. And so these confidence intervals just give a sense of how much range. Uh, so these confidence intervals just give a sense of how much range, you know, some people, um, die, die early. Some people die late within a given year, they're going to be different ages. Um, so it, these error bars can account for a lot of different forms of variability here.

You're talking about the variability is how many people in each group die. We're not tracking one diabetic taken metformin versus a control i know why you played this clip poor old huberman his explanation of confidence intervals isn't quite as good as that is it's a bit confused but you know he was just on the fly you know how dare you ma i was just i thought it wasn't that bad but yes he does get a bit lost tongue-tied because when he's describing it but he's not fundamentally doing things wrong he's using examples that people use about the distribution of heights and if you take a small sample you could end up with a skewed average or representation of the average height and so on so So yes, a little bit mean, but I'm just playing

clips math. That's all I'm doing. And well, let's see. There's some discussion about p-values and that kind of thing. So there's another chance, Matt. So they're using this quite complicated type of mathematics called a Cox proportional hazard, which is what generates hazard ratios. And basically any model has to is what generates hazard ratios. And basically any model has to have some error in it. And so they're basically saying this is the error. So you could argue when you look at that figure, we don't know exactly where the line is in there, but we know it's in that shaded area. Sorry to make one other point. If those shaded areas overlapped, you couldn't really make the conclusion.

You wouldn't know for sure that one is different from the other. Yeah, that's actually a good opportunity to 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, and they see these error bars, and they will 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. I often see some of the more robust Twitter battles over, you know over how people are reading graphs.

And I think it's important to remember that you run the statistics, hopefully the correct statistics for the sample, but determining significance, whether or not 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 0.00001% chance that it's due to chance, right? So very low probability, less than 0.05 tends to be the kind of gold standard cutoff. But when you're talking about data like these, which are repeated measures over time, people are dropping out literally over time, you're saying they've modeled it to make predictions as to what would happen. Hoobman again getting a bit confused there.

What? What? What? I don't know what you mean. Like, it is mean, Matt. This is mean. It is mean. Because people are notoriously pretty.

They're difficult to explain. I know. Yeah. Yeah. But two slight red flags there a little bit bit he's not wrong about the error bars right uh he is correct that you can have overlapping and it still be statistical significance but the gold standard being p less than 0.05 i think that i like gold standard suggests that's when you get that you're really happy with it.

And I'm like, no, that is actually a very marginal cutoff, which is arbitrary in a lot of ways. And it's actually a relatively high error rate that isn't accepted in most card sciences, would not accept 0.05. I think I lost track of how many zeros he was saying. So he was referring to 0.05 um so i think i lost track of how many zeros he was saying so he was referring to initially he said 0.00001 percent but he but he got confused there and said that it's due to

chance it's not a percent it's not a percent either right it's a probability so yeah yeah and then but then he said p less than 0.05 is the gold standard cutoff. Now, again, this is nitpicking, but I think it matters because you'll see when we look at the paper that he's discussing later, if we go and look at the P values in that paper, a lot of them are hovering just below 0.05. Yeah. And if you look at it as a gold standard, that's not a problem. I'm nitpicking too a little bit, but I did raise my bar a little bit

when Hillman was talking about how it all depends on the methodology, whether it was repeated measures and things like that. And actually not so much, yeah. Like a p-value, the method that goes into the calculation of it takes into account extracting variance attributable to the repeated measures, for instance. So actually you don't need to kind of keep in mind the methodology when evaluating a p-value so much, except in a very broad sense.

And yeah, I don't know, it's just a bit odd. A little aside, Chris, by the way, is that nobody or very few people seem to understand how to understand confidence intervals in the context of repeated measures. Because when you put confidence intervals on bar graphs and there are repeated measures, then typically it's not straightforward to actually extract the variance attributable to individual differences variance and take that out of the error bars. And many researchers don't they just they just calculate your standard confidence intervals and they actually don't apply now a little aside

everyone knows that yeah yeah like i i know it's a little bit cruel, right, to focus on somebody's offhand description of statistics because everybody can make mistakes. And it's sometimes people perfectly know what they're talking about, but just on the fly, they say something, you know, which isn't accurate. I'm sure I do it all the time as well. But I also think there is an element where from this conversation, I would judge that Adia has a much stronger grasp of the relevant statistics and whatnot. But if you were a layman, I think you would have the impression

that they are both equally competent. And I don't get that impression. I get the impression. I'm not saying Huberman doesn't know anything about statistics and whatnot, but I do think he has a little bit of a pre-replication crisis mindset, as we'll see as he goes on to talk about the other studies. But I think that's what gets him in trouble is because he overhypes studies that other people regard as not being so impressive. So I don't think it's completely irrelevant, these small indicators about just maybe some issues around interpreting things, whereas Addy is much clearer about these are significant limitations

and that we have to adjust our level of confidence accordingly. Yeah, yeah, I think that's correct. I definitely, I'm never going to ding someone for not being confident in talking about statistical nuances off the top of their head. But, you know, it's fair to say Addy is a lot more confident talking about these technical things than Huberman. And also, Huberman is more bullish on interpreting the results. I think you're right to say those two things are connected. Yeah, when we get to the conclusions drawn from Piper, I think it'll be clearer. So I'll get off Adia's paper quite

shortly. So here's just an example, for instance, about Adia correcting an inference. But again, this paper is in his wheelhouse. So it's reasonable that this would happen. The more you need these medications, they're never able to erase the effect of diabetes. But in this case, it seems that they might be accelerating, possibly accelerating death due to diabetes, possibly. We could never know that from this because we don't see, we would need to see diabetics who don't take metformin, who take nothing. And I would bet that they would do even worse. So my intuition is that the metformin is helping, but not helping nearly as much as we thought before. Oh, and maybe for context, Matt, if I just play the summary of the paper, that will make clear, right, what they find from the re-examination of metformin for potential

life extension properties. The point here is the Keys paper makes it 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. So basically in this paper, when they compared and they did additional things in the paper to make the comparisons better, it's a better powered study. It controls for more things. They basically didn't see this dramatic improvement that was reported in the Bannister paper. So people who were taking metformin and had diabetes died more than a matched group that weren't taking metformin, but also they don't have diabetes. So that's something because it's a diabetes treatment. So what you don't have is a population who's taking metformin and doesn't have diabetes but in any case there isn't a signal that it's this wonder drug and that's the issue so it is what you would expect and then so when huberman suggests that it's potentially doing harm to be taking metformin

he's like no because it we don't know We can't say that from this data, right? Because they're doing worse than a healthy control. That's the comparison. Yeah. So you got it? You're right. You're not going to take Metformin now. Have I talked you out of it?

You have. So now, Matt, and this is coming to the end, so don't worry, don't worry. You're getting to Huberman's paper now. But on our Decoding Academia, we've talked about the way that you should approach papers, and they have some general advice about reading papers that I thought is interesting to look at. So here's one piece of advice that comes first. You see these big stacks of numbers numbers and it can be a little bit

overwhelming. But my additional suggestion on parsing papers is, notice that Peter said that he's read it several times. Unlike a newspaper article or an Instagram post, with a paper, you're not necessarily going to get it the first time. You certainly won't get everything. So I think spending some time with papers, for me, means reading it and then reading it again a little bit later. So read a paper that you want to understand multiple times. Good advice. I've often read that.

You don't oppose that, right? No. You're not anti that. If you have time and if you're not busy doing other things, then by all means. Yeah. This is what you can, you know, you're giving people advice. And Huberman goes on in greater detail about the way he approaches people.

And it actually sounds very similar to advice I give undergraduates, Matt, which is he outlines trying to find the key question, you know, what the topic is. Then how did they address it? What's the methodology? What is their result that they claim? And then lastly, does the evidence that they provided support the conclusions that they want to draw? And generally, I agree with all of that. That's a reasonable questions to add. There's more questions you can add in, but that's a pretty good initial way to approach a paper,

understand the question, check the methodology, look at the results, and then compare the quality of the evidence that the conclusion is drawn. Yeah, that's fine. Yeah, they talked a lot about sort of stepping backwards and forwards for the paper. And, you know, I think by all means, read any paper any way you like. I think it's okay. I think there's an argument for just reading it from the beginning all the way through to the end, personally.

Listen, here's their approach so what i do typically is i'll read title abstract i 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 the cell press journals too into each. 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 just, yeah, it's just wild how much nomenclature there really is. Yeah, but that's, I ain't gonna say Matt,

especially with more recent papers, I advise students that they should read the abstract and like, well, basically I know that students aren't going to read the full paper. So I tell them to go and read the figures and when they don't understand something in the figure, go and read the part of the paper to let them understand it right because i'm i i also make them do things like identify the outcomes and the

predictors and this kind of thing and they are usually plotted on graphs so figures can be very useful save you a lot of time yeah yeah i guess. If you're trying to speed read stuff and, you know, extract stuff. Optimize your consumption. I guess this is a bit of an optimizer approach, but it's a realistic one. You are doing the old professor thing of, well, you should just read 50 papers and you'll get the, if you do the literature review, but your students aren't going to do that, Matt. They're going to be in chat GPT, getting chat gpt to generate the summaries and stuff so you have to

play with the play-doh that is available not your dream play-doh yeah yeah fair enough i know like you listen to things at two and a half speed so you're always trying to you know maximize your time efficiency or whatever yeah look i think it's fair enough, you know, maximize your time efficiency or whatever. Yeah, look, I think it's fair enough. If you know the area really well, you might well just, you know, skip the introduction and the discussion and you just. Depends what you're doing. Wow. Yeah.

Depends. It all depends. It all depends. Sounds like something I heard. Did someone say that? 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. And then sometimes I'll just do a quick skim on methods. 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. 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 do you mean? What is this? How did they do that? And then I got to 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 you're amazed at how much stuff gets put in the supplemental section so look right he had some advice come over you know if you know the topic and he i've actually also agreed that discussion sections often that's a lot of offers spin on the results so you have to

that's the stuff you can actually take with a pinch of salt usually yeah i agree i agree it all depends who you are what you know and right what your purposes are for reading the paper like you might be just kind of doing a brief skim of literature to figure out the the weight of evidence for and against such and such an area you know intimately in which case you might well just be looking at abstracts and checking the basics of the results so yeah depends i'm just giving credit map because we're going to talk about huberman's paper selection die so i'm just saying that's example of what i would consider good advice to people who may not have read that many scientific papers and want to know how to approach them in a potentially efficient way. You shouldn't overestimate your abilities. In many cases, I think, especially

with students that I teach, they don't have the capacities to understand the statistical analysis that's in the paper. So if they're reading a regression table and they don't know what regressions are not that helpful but nonetheless overall i sign off on this approach to reading papers there are many that you could do and this one is not bad so adia had a big large epidemiology study which essentially looked back at a previous finding that people were all excited about in the longevity area and said, actually doesn't look like it works very well. And he summarizes the paper nicely and says, I'm not taking metformin now.

You're fucking crazy. So now let's look at the last bit, what paper Huberman picks and what takeaways he has. I would hope Adi's takeaway is maybe I should be less automatically enthusiastic on the basis of like single studies or, but if you want to be on the cutting edge, you got to take risks with your lactose levels or whatever the hell it is. So here we go. Paper two from Huberman. Well, should we pivot to this other paper? Yeah. 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 want to 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 bio archive.

The only reason I was able to get this paper is because it's on bioarchive. 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. I'm going to mispronounce her first name, but I think it's Chao-Ci Gu, who's at the Econ School of Medicine in Mount Sinai, runs a laboratory there studying addiction in humans. And the first author of the paper is Ofer Pearl. This paper is wild. And I'll just give you a couple of the takeaways first as a bit of a hook to hopefully entice people into listening further, because 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. Okay. at a real level not just at a subjective level but at a biological level okay so yes so a very exciting experimental study showing these uh placebo type effects are actually reflected

biologically physically not just psychosomatic or mental or whatever i was inclined to complain about the framing about preprints being a new innovation, but I actually think he's correct. It is a trend that has, you know, become more popular in five or six years. They're long term things. But I mainly like I remember Brett Weinstein discovering during the pandemic that preprints were a thing and kind of treating it as there's this whole new system. It just goes to show how little that ecosphere is immersed in research or actual stuff that they weren't familiar with preprints. But Huberman is not doing that because he's correct.

There is a trend for this being more common in recent years. So just gonna say my instinct was to dunk but i i would have been wrong to do so well done well done yeah and there is that element though you know that i'm just gonna point it out again you know americans is it americans or is it the people that we cover that i'm so excited i love this paper it's the it's really this is hugely influential we need to talk about this you know like i know what you mean like we covered a paper recently that we both liked quite a bit yeah that's wallet finding paper it's into coding academia subscribe now listen um but um you know i i don't think i've ever really had a feeling of excitement about

papers even ones i really like oh i i get excited but like i i put it in context of like you know i think here to me matt the inclination would be saying this is an important paper at the same time as pointing out it's not been peer-reviewed and as we go on we might see some other issues but like is it an important paper yeah like even even if it was completely valid the finding that he's going to report it's a single paper right a small experimental study if you were a psychologist especially you might be wary of touting single studies claiming dramatic effects on small sample sizes just yeah yeah as being exciting yeah that's okay that's this is the framing so it's okay to be excited it's okay to be excited about things it's okay to be enthusiastic it is i'm just pointing out a

difference i'm just pointing out different saying. I'm just pointing out a difference, saying, you know, our American brethren, they're more expressive than us repressed Australians and Irish people. Anyway, it was about the placebo, the framing there. So here's another clip, a little bit more Huberman, you know, introducing placebo effects and their purported power. more Huberman introducing placebo effects and the purported power? Even more striking is the studies that Ali's lab did 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 doesn't have much fat, not much sugar, et cetera. They drink the shake, less ghrelin suppression. And it's the same shake. 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 lower your BMI, which is great for your health. 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. And no difference in actual movement? Apparently not. Now, how could that be? So that is like a huge if true kind of finding, isn't it? That you tell these workers about the health benefits of doing it, their activity levels don't differ,

but your experimental manipulation of just people believing that it's good for them to do this hotel work makes them lose more weight, be healthier. Chris, I think you looked into some of these articles that Huberman references. Yeah, I did. And like, because whenever I hear this kind of description about studies that are counterintuitive and dramatic,

it rings the replication crisis warning bells, right? They jingle in my ear because this sounds very much of a piece like hurricanes that have female names lead to more fatalities because people don't take them as seriously. Himmikines and hurricanes. Yeah, the title did a lot of the work, I think. But yeah, so I'm wary of it for good reason, because, you know, cute results get lots of press, but the replication crisis has shown that many of those studies don't hold up when you dig into it or whenever you have a more robust replication. And I didn't do a huge deep dive, but I did go back and look at some of the studies that he's citing. And one of them is mind over milkshakes.

Mindsets, not just nutrients, determine ghrelin response, right? And this claim is saying that if you give people the exact same milkshake and you tell them in one case, like it's this super sweet one and then the other one that's a zero percent fat one that you see um this difference in the production of grayling or like in any case you see a physiological difference in the body in response to that and it's not such a dramatic claim because priming the body that it's about to receive a certain type of food maybe it could induce a type of reaction. But when I went and looked at the study, these are the kind of warning signs you would have for a pre-replication crisis or post-replication crisis questionable study. We'd want the study that isn't pre-registered, that has a small amount of participants that has measures which are noisy, right? And in particular, people might think that physiological measures allow you to be more precise because you can

measure heart rate or you can measure different hormones in the blood or so on. And it's a quantifiable objective measure. But anybody who's worked with physiological data should know that there's a lot of noise in it and there's a lot in exactly how you measure things which measures your kind what you're comparing to and this is especially the case if you have longitudinal heart rate measures or something like that right i've worked with heart rate can confirm yeah yeah so in any case following huberman's recommendation about looking at the figures in the paper two of them are showing the different advertisements they use one of them is showing the self-reported perceived difference in healthiness of the milkshake and the fourth one which is the key one is showing graylin over time

as a function of shake mindset and it has um 20 60 and 90 intervals and it's comparing the graylin production or whatever pattern and there is a difference And the amount of subjects in it were 53 participants. However, two did not attend. So 51 participants divided by two conditions, around 25 in each condition. P equals 0.02, 25 per condition study. Yeah. Doubt. Doubt about the little meme with doubt flashing above my head.

And similarly, there's a paper about hotel maids being told that they were doing exercise, right? That like their housework was exercise and they lost a bunch of weight if they were told that whereas the same maids doing the same amount of effort didn't lose as much weight in the control condition now again this would be a important result because it would mean you should just tell everyone everything they're doing this exercise because apparently their body will switch into like some burning calorie mode or whatever because they're saying the amount of physical exercise that they did was consistent according to self-reported measures but the group that was told that doing housework was exercise, lost weight, the kind of power of mindset over physical reality.

So here, Matt, looking at the sample size first, 84 subjects this time, 44 in the informed group, 40 in the control condition. So bigger, at least than the previous study, but still 40 odd per condition, not huge, right? And looking at the not the self-reported differences, the differences in terms of mean weight loss, the kind of objective measures the weight difference between the the two was 143.72 this was in the informed condition whereas the control condition had a weight of 146.71 i guess that's in pounds so around three pounds difference and the starting weights are

similar 145.5 146.92 so you're talking about a difference of around two pounds right over the period and it does reach high levels of significance like under 0.001. But again, Matt, color me skeptical here. It is possible that they've found a very large effect here. But when you have a sample size of 40 and you have a claim that just telling people over the course of 10 weeks one thing and then the rate decreases right like there's so many other aspects and of course they try to control for them or whatever but i seen in skeptical reporting somebody said okay well if you report people that it's exercise it might make them do more physical activity. But I also seen other people saying,

you know, just that they were skeptical that the result would replicate. And this is the kind of thing where like, I think you could report this in a manner which is responsible saying some studies that have small samples, but we're not pre-registered, have not been replicated,

that we might be wary of, have found these kind of effects. But that's not the way Huberman reports it, right? Huberman is like, these guys are stellar. These are the leaders in this field. And they find these incredible studies with amazing effects that demonstrate the placebo effect is just beyond powerful, right? Like it's kind of TED talky as opposed to post

replication crisis talk yeah yeah that's right i mean you know you do have to you don't have to do bayesian statistics but you i think you can apply that slightly bayesian reasoning which is that your prior expectation on the probability that just telling someone that something is good for you makes it better for them should should be pretty low right that there's an actual physical effect going on there and it and you know one small end study it shouldn't move the needle so far that you're breathlessly excited about these jaw-dropping earth earth-shattering results. Like you said, even in an experiment like that, there's all kinds of other mechanisms that could be at play. Like it could be true, right? It's possible. But it could also be that the people who are told that exercise is really great for

them, that their work is really good for them, could have been doing some other exercise or even eating a little bit less or who knows and they failed to measure that or self-report it exactly that there's a thousand possible explanations so you know you really would want to get excited about this kind of thing once it's been triangulated and confirmed using multiple different methods because if it really is true and it really is earth shattering, then you should see a bunch of different groups looking at it in different ways and confirming it. Exactly.

Yeah. Yeah, and it should be, you know, if the effect is this big, you get a couple of pints for just one short intervention, then like, great, you know, this is, this is huge news and you should be able to replicate it fairly easily. But in general, this doesn't happen, right? People don't make efforts to replicate them when they do, they do it in a completely different way. So yeah, so I'm just saying, again, Hooper Midami is like a pre-replication crisis TED talk guy. Like he, hooverman to me is like a pre-replication crisis ted talk guy like he he doesn't seem to have picked up about the issues with overhyping studies and stuff yeah which is all because like he sometimes

does reference it but it's it's obvious that he's much more about the hype than he is about temper your expectations yeah that's right um so yeah if you're even if you're a member of the public it's not hard to i think absorb what um i think is good practice these days which is that if you see a small end study if it's finding a counterintuitive and very surprising result if there's a p value somewhere between 0.01 and 0.05 you know there's probably other things other red flags too but you know just you know don't assume that it's definitely definitely true the findings so here's a bit more in the study ma and i i want to get your own reaction to the cell i won't prime you by saying what i thought let's just see what you think about this little segment about the study. And to make a long story short, we know that nicotine, vaped, smoked, dipped, or snuffed,

or these little Zin 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 pons, in the back of the brain, in the brainstem, 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. And how much endogenous nicotine do we produce? Well, it's going to be acetylcholine binding to nicotinic receptors. I see. We're not making nicotine. We're not making nicotine.

So this is a nicotinic acetylcholine receptor. Right. Of which there are at least seven and probably like 14 subtypes. But so, 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 because we're supposed to smoke pot or those receptors are there because we're supposed to ingest nicotine no so what do you think there uh well there's so many little squishy parts of the brain i i'm not

super familiar with the with the exact mechanism that he's describing i'm sure i'm sure he's right he knows more about the the various neurotransmitters than I do. I think, though, you can't simplify the functions of those particular regions and even their interconnectivity into a simple thing, like activating this area is going to enhance your perceptions and make you reduce the signal-to-noise ratio. If there was some simple effect like that, then our brains would be wired to do that all the time

because it's by evolution. So it's generally not suboptimal. Tweaking something with nicotine or any other psychoactive drug is going to have a wide range of effects all over the place, and there's usually some downsides along with the plus sides those are some general thoughts you could talk about the brain forever no that was well that was interesting because you picked up on something different and i was just curious how this lands to somebody that is more familiar with the neural

anatomy kind of stuff because to me there's a lot of jargon there. And I don't think it's wrong. I think it's going to be accurate. But I, I do get the sense like sometimes when they're describing things, I feel like it's necessary, you know, that they're talking specifically about various pathways and stuff. But occasionally, it feels like a kind of flex you know just to reference all of the scientific names and stuff but i don't know if that's just my sense because i'm not as familiar with neuroanatomy well well it could be because if it's a flex then he's rattling off a bunch of extremely specialized bits of information that i'm not super familiar with at least in the but you know yeah you know i think only the researchers that are really focused on those

sorts of mechanisms would like there are some those are some pretty pretty specific little functional things that he's talking about yeah so in in this case i think part of the appeal of huberman and adia is that they get into the nitty-gritty like this but i do think that their audience generally is not well equipped to assess any of it and and i i'm certainly not well suited to assess these kind of descriptions but i i will say just on the flip side of that, that when he was talking about fMRIs, which I do know a bit about, at least, I think this description Huberman gives of how they function is kind of technical, but also pretty good in a nutshell. They measure carbon dioxide and they're measuring nicotine in the blood as well.

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 doses just don't really matter because tolerance varies, et cetera. And then they are putting them into a functional magnetic resonance imaging machine. So where they can look at, it's really blood flow. It's really hemodynamic response. For those of you who want to know, 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 hot spots in the brain is really just

looking at blood flow that seems in line with what i understand there was a neat little short description that's correct yep that's right that's fmri and he gave some details about the study right uh he mentioned that the people are receiving different doses of nicotine and then being put into an fmri right this is what the study is i thought they were just being told that they you're like peter adia you spoiled the reveal yeah so that's what adia does and one of the clips is like but weren't they all given the same he's like well yes i was gonna reveal that at the but anyway and they were told they were told they got either this is a low amount a medium amount or a high amount and then of course they looked at brain area activation during this task and what they

found was very straightforward sorry they were all given the same amount yes this is this is the sneak i was going to offer it as a punchline but that's okay no i think that the cool thing about this experiment is that the subjects are unaware that they all got the exact same amount of relatively low nicotine containing vape pen but anyway so yeah they're all receiving the same dose so their behavior should not be different based on the actual chemical stimulation right yes and oh but on the fmris map there was a discussion about the limitations of fMRIs, or at least Peter Adia brought up a relevant issue about potential issues with fMRIs. And that leads to this exchange. with the magnet because my understanding is that, and this is definitely getting beyond my expertise,

but that the spin orientation of the protons, then it's going to relax back at a different rate as well. So by the relaxation at a different rate, you can also get not just resting state activation, like, oh, look at a banana, what areas of the brain light up, but you can look at connectivity between areas and how one area is driving the activity of another area. So very, very powerful technique. So what they do is they put people in a scanner and then you'll like this. What are the limitations of fMRI in terms of, I mean, how fine is the resolution? I mean, where are the blind spots of the technique? So resolution, you can get down to subcentimeter.

They talk about it always in these paper as a voxels which are these little cubic pixels um things um uh you know sub sub centimeter but you're not going to get down to millimeter okay um there are a number of little confounds that maybe we won't go into now that have been basically worked out over the last 10 years yeah yeah so i think he missed a couple like first the most important limitation of fmi which is the temporal resolution that's the big one um in terms of it being relatively low the spatial resolution is okay um might be a stretch to call it sub centimeter i mean could be i mean the thing is it's quite blob So, you might have voxels or pixels at a higher resolution, but it doesn't necessarily mean that the resolution is

really there. The other thing too, though, of course, with fMRI is that there's so much individual variability and just your baseline resting behavior. So, it does involve a lot of those complicated signal processing transformations and spatial and temporal statistics in order to extract out signals so you know this is one of the reasons why you know i know you've been skeptical of fmi studies chris because they do produce very nice sciencey looking pictures with heat maps superimposed over a picture of a of a brain looks super sciency but um could sometimes be a little bit misleading as to yeah there have been various studies on this topic showing that like if you if you just show people a picture of a brain like an fmri result

they read the paper as as more scientifically, right? Like it doesn't matter. Any other detail is different. Well, they're so bloody expensive. I mean, we should give them points just for that. Yeah. And they did have an issue as well, which I think Huberman might be gesturing vaguely out there when he says, you know, there were some issues for a decade, but we've mostly ironed that out.

I guess he's referencing about the issue with the software that people were using to analyze fmris which turned out to be calibrated incorrectly and leading to a whole bunch of false positives uh i believe right which was a very very serious issue and i believe has been mostly rectified but but the fact that it could occur and persist for such a significant amount of time is concerning yeah yeah i mean i think fmris as a technology is a good example of like this extended concept of like researcher degrees of freedom where just the technology is super advanced and super sophisticated um produces reams and reams of of raw data but um as a

consequence of that a huge amount of pre-processing has to go on and and even then when you get your filtered pre-processed data it it's still relatively high dimensional. That is like it's got a lot of pixels, voxels. And, you know, so you have to use pretty complicated spatial temporal statistics in order to compare them. And because they are so expensive to run, you almost always have low-end studies. So I think those things have contributed to some right skepticism about the method. Correct. And there was another paper, a quite famous one, which Adia references

here and who everyone is less familiar with, which I took as diagnostic, but we'll see why you did not after. Wasn't there a really funny study done as a spoof maybe a decade ago that put a dead salmon into an MRI machine and did an, like they did an fMRI of a dead salmon that demonstrated like some interesting signal? I didn't know that, but it- We got to find this one for the show notes.

We should do one of these wild papers ones. There are papers of you know people putting don't do this folks putting elephants on lsd that were published in science and things like like crazy experiments we should definitely do a crazy experiments journal club yeah i think he was missing is at his point there though it wasn't so much like oh wouldn't it be wild if we studied scanty dead were making a very specific point about problems with the methodology. Correct. This was Craig Bennett took an Atlantic salmon and scanned it

and showed that using normal methods, its brain was lighting up in specific areas in response to being shown like some trounce. So he wasn't saying that we shouldn't use fMRIs. It was just simply, I believe it was just a poster at a conference or something. But in any case, it was just an illustration, right? We have to be somewhat skeptical about the application of these methods now i thought this was a famous study that everyone in the science reform uber was familiar with and that not knowing this was like a big

tattletale that you know you were you weren't paying attention yeah but in our pre-podcast discussion, it emerged that you didn't know what that's about. I've never presented myself as someone who's all in on the science reform movement. I'm being dragged along. I'm an unwilling participant. Look, I will say this is an example of things being falsified. Because I would say, from my experience interacting with you over statistical issues that you are that you're completely in line with all of that about like not overhyping things we've been skeptical about claims with knowing that all the bullshit

that people do with statistics so that scanning a dead fish would light up an fmri you know it would be completely in line but but here's where we're not the same chris because you see me as someone who's all in on that stuff which i am but that's just because i'm a good statistician not not because i'm part of the science reform movement this is true so i'm saying it's a kind of parallel evolution effect yes so i i learned from your reaction not knowing about this paper and being like oh that's a funny paper that okay i cannot use it as diagnostic although i think in many occasions if someone was a science communicator and they don't know the study it does talk about the blind spots right but the difference is who woman does not have your background in statistics

so you know there's have to take each person it's a special case okay so the main thing is you cannot ding him and for not knowing about that study because i didn't because you also didn't know yeah that's why i can't take him for not knowing about it yes there is that but um whether or not you know about the fish he doesn't seem to entirely get the point that Adria is pushing towards about wanting to talk about limitations, like the way he did with the epidemiology study. So anyway, they put them into the fMRI, and then what do they do? So they put people into the scanner, and then they give them essentially a task that's designed to engage the thalamus, known to engage the thalamus, reward centers, and the ventromedial

prefrontal cortex. And it's a very simple game. You'll like this because you have a background in finance. You let people watch a market. Okay, here's the stock market, or you could say, or the price of peas. It doesn't really matter. It goes up, it goes down and they're looking at a squiggle line, then it stops. And then they have the option, but they have to pick one option. They're either going to invest a certain number of the hundred units that you've given them, or they can short it. They can say, oh, it's going to go down and try and make money on the, on the prediction. It's going to go down. You could explain shorting better than I could for sure. So depending on whether or not they get the prediction right or wrong,

they get more points or they lose points, and they're going to be rewarded in real money at the end of the experiment. This is an economic game in a way, right, Matt? These are things that psychologists and behavioral economists and a whole bunch of people like get people to play little games with money because there's actual money involved. The thought is that people will be actually more invested in the outcome and a nice little like investment prediction game, right?

Yeah. This is actually an area where I'm a bit more in my wheelhouse because it's kind of related to gambling reward approach behavior and decision making and stuff so all of that sounded plausible to me the ventromedial prefrontal cortex interacting with the thalamus and they cooperate certainly in terms of finding sources of reward making decisions about about how to approach it and you know modulating emotions and things like that. Yeah, and here I would just note, Matt, that I know,

I don't know if you've heard about this trick, but like basically you should sell when things are high and buy when they're low. And this is how you can kind of beat the market. You explained this theory of trading to me. And yeah, no, no, it's it's brilliant brilliant stuff i can't believe that no one's ever thought of that one before i mean my god i i know when the line is dying that's when you're buying when it goes up i'd say anyway it would be easy for me this game

but so whoever makes a note here so they're playing this game and they're getting told that they're having different doses and you might expect them that part of the goal is to see, do they perform better in this attention demanding game? But now remember, these groups were given a vape pen prior to this, where they've vaped what they were told is either a low, medium or high dose of nicotine. And they do this task. The goal is not to get them to perform better on the task. What they were told is either a low, medium, or high dose of nicotine. And they do this task. The goal is not to get them to perform better on the task.

The goal is to engage the specific brain areas that are relevant to this kind of error and reward type circuits. And we know that this task does that. Matt, here, as on note, this claim that the goal was not to make them perform better or worse in this task. What I would want to see to know that that is true is a pre-registration where people said that, right? We're going to do the game, but we don't actually think anybody will perform better or worse. Because that's kind of what the paper says now. But I wonder if the people had performed better in the like high dose condition the one where they're told would that really have been presented as this was you know not a part of our

goal like yeah yeah this is contrary to our expectations um yeah no yeah one suspect yeah yeah because because that's pretty plausible right because nicotine like some of the things he said at the beginning were all true right it's it's it's associated with especially amongst people who are like these are all vapers or smokers or people who have some level of nicotine addiction so like speaking from personal experience give them some nicotine and you'd probably expect their attention and cognitive performance to be slightly better. Yes, correct. So that would be the expectation.

Maybe their mental expectation could trip over into performance, right? It's not implausible, but it's just highlighted here that they didn't think that was going to happen. And you're like, hmm, I'd be curious if that were the case. Anyway, what the paper found overall, here's a general summary provided from Huberman after he goes through it a bit. Now, a number of things happen, but the most interesting things are the following. First of all, people's subjective feeling of being on the drug matches what they were told. So if they were told, hey, this is a high amount of nicotine, like, yeah, it feels like a high amount of nicotine.

And these are experienced smokers. If it was a medium amount, they're like, yeah, it feels like a medium amount. If it was a low amount, they think it was a low amount. Now that's perhaps not so surprising. That's the placebo effect. not so surprising. That's the placebo effect. But if you look at the activation of the thalamus in the exact regions where you would predict acetylcholine transmission to impact the function of the thalamus, so these include areas like what's called the centromedian nucleus, the ventroposterior nucleus, the names that really don't matter, but these are areas involved in

attention. It scales with what they thought they got in the vape pen. Meaning if you were told that you got a low amount of nicotine, you got a little bit of activation in these areas. If you were told that you got a medium amount of nicotine and that's what you vaped, then you had medium amounts or moderate amounts of activation. And if you were told you got high amounts of nicotine, you got a high degree of activation. And the performance on the task, believe it or not, scales with it somewhat. So keep in mind, everyone got the exact same amount of nicotine in reality. So here, the belief effect isn't just changing what one subjectively experiences. Oh, this is the effect

of high nicotine or low nicotine. It actually is changing the way that the brain responds to the belief. And that to me is absolutely wild. Okay. So that's the key result, isn't it? So I read the paper, but I've mostly forgotten it, Chris. Refresh my memory. They basically have got these different conditions, everyone got the same amount of nicotine. People told they got given different amounts and then when they had people in the fmri machine that are doing this task they found that those attention related regions of the pfc were more activated in the higher conditions. Yes? Yeah. So there's a bunch of results that they look at and report.

And they report, as he highlights at the start, the subjective thing that, you know, self-reported belief about dosage reflects what they were told, which makes sense, because why would they think otherwise and then they look at a bunch of activity in in the brain right and they have those little brain scans that you want from fmris looking at the thalamus and accumbens neural patterns. That's the other one, figure two and figure nucleus accumbens. You familiar with those, Matt? Not really. No. Well, but in any case, you've got like a little brain with bits lit up, and then you've got

various figures illustrating the effects. And the way Huberman presents it is that the effect is dramatic, that you can see it in the Brien's reactions, not just from the self-report. That's the crucial thing. But Matt, when I went and looked at these figures, okay, so first of all, you have one where you have parameter estimate representing reward-related activities extracted from an independent Falmus mask. Okay, whatever the case. So some part of the fMRI result extracted and then plotted. And then they split that out by category,

and they have the little amounts in each plotted on bar graphs with the distribution shown now here important to note is there's no significant difference between any of the groups except for the low to high group and then the significance is 0.04 0.04 right 0.036 to be precise. What was the N in this again? The N in this study overall is around 24 to 20 per condition. Yeah, yeah. So pretty typical for an fMRI study. Yeah, and the other thing too is,

like you read out with some of their methods descriptions there, this is the issue with these really high-tech studies, which is that they apply some mask that identifies a particular kind of little region. And, you know, there could be nothing wrong with that. That could be totally orthodox. But unless you are like an fMRI guy and are fully familiar with the software and all these things you really have no idea about the

research degrees of freedom that are involved there you don't know how much like was there any tinkering with with parameters are there different masks they could have had a look at there's like so many things there that are just, it's a bit of a black box. And I think that's what, you know, at least for me, it just increases my level of skepticism. But even that aside, even if it was a really simple methodology that you could really understand, you know what I mean, like a simple behavioral measure which you just counted something,

you know, something you could easily wrap your head around, it was all pre-registered. Even if all that were the case, yeah with that sample size and only finding one significant effect between the three groups that they looked at and it being p equals 0.04 all of those things would make me go yeah i mean i wouldn't put a huge degree of credence in it and this is not to say that chris i mean i wonder what you think about this because i've detected a note of skepticism from you regarding the effects of placebos having actual physical effects on the body but i mean my rough understanding of it is is that it's not a priori totally ridiculous like it is

it you know the mind and the body if we're going to do cartesian dualism are sort of intimately related they both have effects on the other and if if you believe something is true then it's going to have these psychological effects which are going to translate into physical effects at some point right yeah i have no skepticism about the placebo effect existing or that it um like you say, you know, what people expect about things that, you know, where else is it going to show up? Even the fact that the people's subjective self-reporting is different. It wouldn't be a surprise for me to find that, you know, you could find correlates with brain

activity that represent that. So it's not a huge reach, but it's the one, the evidence here is not hugely persuasive to me because like you said, the limitations of sample size, the fact that, so there is another figure towards the end, which is looking at foulness, the ventral medial prefrontal cortex functional connectivity. And there they say they do find a difference between the three conditions, right? But like, again, it's all this stuff where how many different measures you have on the fMRI, right? And you have the ones that are reported in the paper at the end.

And even then, they're highlighting ones which are on the verge of significance in a bunch of cases. But I would not be surprised if there are very many other possible candidates that are on the file drawer. And the way that you could prove me wrong about that is by pre-registering the study and saying which measures you're going to focus on right and in the absence of that and the absence of various replications my initial stance is skepticism but not skepticism overall like i and if the actual effect was validated it wouldn't destroy my worldview or anything because i expect the placebo effect to exist yeah i, I think this is a great example of where pre-registration would really, really help because you have this really sophisticated technology.

You have a bunch of different things, a bunch of different areas, a bunch of different co-activation of different areas. My assumption is that there's a huge number of options there. And, you know, it is tempting to suspect that they looked at more than just the two, the two ones where they found a significant difference. You have to suspect that they did.

But when they came to write up the paper, it's kind of human nature to focus on the interesting bits, right? Right. Yeah. And the authors often overhype things or present them in a dramatic fashion because this is what journals also like to see. So I'm not surprised at that. But the point of a journal club is that you are not the author, right? So you should be

approaching things critically. Otherwise, you're just the PR person for them. And so this is Huberman talking about the results. And let's see if he's looking at them critically or overhyping. 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 my understanding, this is the first study to ever look at dose dependence of belief effects, right? To really, 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 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. That last line. Yeah, I think that's a big stretch. There's some evidence of placebo effects having measurable physiological effects, I think, even in the treatment of depression or something like that. But they're reasonably weak, I think. It's certainly not something that you could use to bypass pharmacological interventions, I would think.

interventions i would think yeah and so i want to contrast a little bit with the way adia responds when he sees this study right so he's he's looking at the same figures that i was highlighting and listen to his response look at figure 2b 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 who presumably were non-smokers who were just put in the machine. That's right. Yeah. Yeah. This is measuring parameter estimate. What is that referring to their ability to play the trading game? The parameter estimate is the activation reward related activities from independent thalamus mask, right? So what they're doing is they're just saying, if we just look at the

thalamus, what is the level of activation? I see. So this suggests that the only statistical difference was between the low and the high. That's right. And nobody else was statistically different. That's right. But that's not the whole story. Yeah. So like him was super excited about it being a dose dependent relationship.

Right. But it's actually just the like nothing and the high one. So that's, but yeah, I mean, because... No, so he points out, Matt, just to give Huberman his jury. He does justify that claim by pointing to the 4b figure. Ah, okay, fair enough. And he says this. So figure 4b, if you look at parameter estimate so

this is the degree of activation between the thalamus and the ventromedial prefrontal cortex and it's called the instructed belief you can see that there's a low medium and high scatter of dots for each and that each one of those is significant so he he's saying no look at the solar measure you do see a difference between the conditions right on this one so just just so i understand they they observed a difference in the degree to which the thalamus was communicating with the prefrontal cortex right um but they didn't see any differences in performance on this game. So there's this activity which is supposedly indicative of better concentration, better signals and noise filtering or whatever, but it's not yielding any measurable changes in performance.

Yeah, I actually tried to go in because the reporting of the result of the behavioral measure wasn't completely clear i downloaded the file and had a look and uh i think they are claiming some signal like you know one that relies on like interpreting a particular kind of result and like way that you know you measure not not like an obvious right straightforward better performance overall but they're not they're not emphasizing that in the paper in any case so no this is about the activation in those conditions and in particular the the activation of the kind of network not the actual areas themselves yeah yeah yeah this sort of binding or whatever is going on but don't you think that's odd just

stepping back a moment that like if it were true that there was this placebo effect resulting in measurable changes in significant brain activity and that brain activity is meant to be indicative of better concentration and all of these things, that the fact that you don't see a difference in the primary behavioural measures is revealing. And I say that because the behavioural measure, like the simple scores of this game, is probably far less amenable to researcher degrees of freedom, Chris.

Like my suspicion is that you've got a lot of choices in terms of how you want to slice and dice your fMRI images. But, you know, with these standard games, economic games they set up, there isn't so much wiggle room. Yeah. So I would be inclined to think the same and actually adia is somewhat again notes

hits a skeptical note about focusing on this relationship measure instead of the the actual division in the areas yeah yeah so he says this so isn't it interesting that at the thalamus, which is and you'll you'll immediately appreciate my stupidity when it comes to neuroscience, which is more proximate to the nicotinamide or nicotine that nicotinamide. What do you call it? The nicotine acetylcholine receptor. You have a lower difference of signal strength. And somehow that got amplified as it made its way forward in the brain. Yeah. Does that surprise you? It is surprising. And it surprised them as well. The interpretation they give, again, as we're talking about before, important to

match their conclusions against what they actually found, which is what we're doing here. The interpretation that they give is that it doesn't take much nicotinic receptor occupancy in the thalamus to activate this pathway. But they too were surprised that they could not detect a raw difference in the activation of thalamus. But in terms of its output to the prefrontal cortex, that's when the difference showed. That figure 4B is more convincing than figure 2. Because even figure 2E, if you read the fine print the r

the correlation coefficient is 0.27 it's not that strong right it's weak so at the thalamus it's kind of like yeah there might be a signal and then the scatter graph he's mentioning as well like to say that there is a weak signal is perhaps a very scattered scatter graph yes it's a very scattered graph like you know color coded for high medium and low and if you can discern the pattern there you're um like yeah so anyway so idea throughout this i think i'm pretty much on board ad is coming at this stuff pretty much exactly the same way that I would. But I get the vibe that with Huberman, he's kind of got the stance of a believer, right? It's like, this is a really cool study.

It's very exciting. These results were amazing. Oh, there's some inconsistency. There's some weak spots. There's surprising that this doesn't happen. And he's kind of looking for explanations rather than saying well actually this it doesn't it's a weakness yeah and every time adia raises a point he's like this is what we do at journal club we you know we take things if i'm like but but you aren't like if adia wasn't

here basically you would have used the perfunctory you know this is a pre-print i'm not saying it's the be all and end all but adia is the one that is actually saying, well, but hold on. Like, so they didn't find this result in this one and so on. And there's a good contrast where you can see when they talk about sample size, which again, Adia raises here. By the way, this goes back to our earlier discussion. There could be a huge signal here and we're underpowered. How many subjects were in this? You wouldn't have a lot of subjects in this experiment. Yeah. No. And this just speaks to the general challenge of doing this kind of work. It's hard to get a lot of people in and through the scanner. Yeah, and it's expensive. And it's expensive. I should know this, but we can go back to the methods. But you can sort of just look at the number of dots on here. I mean, it's in the low tens, right? It's like 40, 30, something like that. So it's possible you do this

with a thousand people. This could all be statistically significant. Right. So they talk about this. Based on this, we estimate that an N of 20 and a sample size in each belief condition, the final sample would provide 90% power to detect an effect of this magnitude at an alpha of 0.5 in a two-tailed test. Okay. So that's them referring to what we just talked about, which is we believe at 90% confidence to get an alpha of 0.05, which means we'll want to be 95% confidence. We need 60 people, 20 per group. Right. Yeah. But if the difference is smaller than what they expected, they'll miss out on some of the significance, which that looks like they're missing between the medium and high group. Yep. And I too was surprised that they did not see

a difference between the medium and the high group, but they did in the output of the thalamus. I was also surprised that they didn't see a difference. This is kind of interesting in its own right. If figure three talks about the belief about nicotine strength did not modulate the reward response, the dopamine response. How was that measured? Also just in fMRI. Yeah, exactly. So if you look at figure three B, other people can't see it, but basically what you'll see

is that there's no difference between these different groups in terms of the amount of activation in these reward pathways. Right. there's no difference between these different groups um in terms of the amount of activation in these reward pathways right but adi is framing there is kind of kind right because he's suggesting that the study is underpowered and that's why you get these non-significant effects but the other possibility is that being more highly powered you would find that like uh yeah you could confirm you could confirm the effects are either non-existent or extremely small and yes exactly right yeah human keeps refining keeps referring to the findings are surprising like surprising they didn't find this difference surprising they didn't find that difference but it's it's not surprising though is

it i mean if your assumption is that if there's an effect here it's probably quite small and you've got a small and study then not surprising at all you know no no it would be surprising if you assumed the effect was huge and yeah exactly and so you know again i think that some people will regard that as like well you know this is just a difference in character you you know, Hooperman isn't allowed to get excited about a study. But I want to show the conclusion that he reaches. Having gone through this, and I talked about all these issues about small sample size, and actually they didn't find a result in two out of the three measures that they're using in the fMRI and not the behavioral measure, then... 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, use your imagination, folks, whether or not we're talking about a drug, we're, folks, whether or not we're talking about 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 psychoactive drugs. I'm talking about 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 those drugs. A little concerning. A few notes there that are concerning to me. Yeah. So, you know, because the first bit is like, you know, this isn't the perfect experiment, which is fine. That's good. But then it's like the implications about this dose-dependent effect are stunning, right?

They reach across all vaccines, like he references vaccines there. And he's quick to say, I'm not talking about any specific vaccine. This, I think, harkens to Huberman's absolute allergy to discussing vaccines in a positive way during the pandemic. But even if this were true matt right

vaccines what implication does this have because whatever your internal assessment does right like the extra power or whatever it adds it is not giving your immune system the information to help it fight a virus that it hasn't encountered right so that's right there's a huge difference i mean well first of all chris before we forget i just i just don't get his enthusiasm for this why it's so exciting that there's like a dose dependent relationship like they had a low medium and high condition in terms of the placebo that's been done heaps right you can give people a blue pill or a bright red pill or a you know medicine that tastes really strong or one that doesn't and you see these effects i mean you could vary the dose i don't understand why that's such a big deal but as you say the main thing is that you can see these

like placebo type psychosomatic effects which i accept are almost certainly real to some degree because the psychology interacts with the neurophysiology and percolates down into the body. And you could see effects even further afield in terms of cortisol levels or stress and things like that. You're going to see effects on things that are more psychosomatic or things that are more related to psychology. And that's why this study here is more plausible than, say, some of those other ones like the hotel people working

away because like that's that's just straight up metabolism right and it's happening over a period of weeks that's fairly different from from this which is about concentration and reward processing and stuff like that stuff which is actually more tightly connected to how you perceive things and like psychological effects but then when you actually go even further afield to like how the immune system works and you're talking about what t-cells getting trained to recognize antibodies and stuff like that and you're like the idea that there's going to be a placebo effect there um and that this has some implications for how other types of all kinds of drugs but including vaccines should be administered or or approached that seems nuts to me that's a huge it's not just a stretch it's it's a huge galloping flying leap yeah and and just to be clear that we're not over-interpreting. So he goes on a bit here.

Yeah. To take this to maybe the ADHD realm, let's say a kid has been on ADHD meds for a while and the parents, for whatever reason, the physician decide they want to cut back on the dosage. But if they were to tell the kid it's the same dosage they've always been taking and it's had a certain positive effect for them according to the results at least in this paper which are not definitive but are interesting the lower dose may be as effective simply on the basis of belief and and this is the part that makes it so cool to me is that and it's not a kid tricking themselves or the parents tricking the kid so much as the brain activation is corresponding to the belief, right? So that's where this is why, because it's done in the brain,

I think we can, you know, it gets to these kind of abstract, nearly mystical, but not quite mystical aspects of belief effects, which is that, you know, your brain is a prediction making machine. It's a data interpretation machine. But it's clear that one of the more important pieces of data are your beliefs about how these things impact you. So it's not that this bypasses physiology. People aren't deluding themselves. The thalamus is behaving as if it's a high dose when it's the same dose as the low-dose group. dose as the low dose group it's just like he's now kind of here apart from a couple of throwaway sentences but it's as if this fact effect is completely established right and that the

implications are stunning and what he describes is like he says you know it wouldn't be unethical but like actually telling the patient that they're receiving a different dosage that is inaccurate on the basis that their placebo reaction will potentially produce the same effect like no that is not ethical right and it's relying on you know an over extrapolation which is that you could produce these exact same effects and you know especially when he just talked about vaccines and stuff in the preceding discussion you're like yeah but that it doesn't work like that right like that you say you might be able to get it for some specific occasions or individuals or some specific drugs and maybe you can but the way that he's presenting it is like well this looks like it

can produce the same effect as taking the drug just tell someone that they're taking like a stronger drug and that will do all the same stuff and you're like yeah i know it's like the general theme and it's consistent with what we've seen of human before is just that kind of wild exuberance or you know overconfidence in in particular studies and and running with you know as you say apart from the kind of throwaway studies which is you know further research required etc but you can kind of tell that he kind of believes it and runs with it and is forms a like a view of all of these things, which is informed by the assumption that a lot of these studies are largely confirmed. The extrapolation is really quite large too.

I've got to keep delineating the reasonable and the unreasonable version of these kinds of things. A reasonable version is if you're wanting to quit smoking and say you're vaping, a good way to go about it is to gradually reduce the nicotine in your mix. All of the behavioral type of things are kind of the same. The sensory motor type feeling is the same.

And you're sort of disconnecting the physiological substance addiction from all of the psychological aspects of the addiction, and it's easier to sort of divide and conquer and quit that way that's that's a super reasonable application of what um he's talking about but but going on to and maybe we can do it for this and give it to kids with adhd we can tell kids and vaccines or any any supplement or any kind of medicine you can imagine just believe it and make it so um that's that's a wild extrapolation from what is a very weak set of results in this study yeah and and i know the vaccination one just like stuck with me but just that doesn't make any sense because it applies that the the kind of biological process for which vaccines work is manipulated by the

strength of believing in the vaccine but like vaccines work by giving the immune system experience of a particular kind of virus so you can store the the relative instructions for when you encounter the actual virus so just like that you can't do that through yeah your your mental power just think about covid right just think about it a lot there are some aspects of our physiology which you can control psychologically right like if you if you sit down you take deep breaths and you think calm thoughts you can reduce you can reduce your heart rate right there's lots of we could make a big list of things that are kind of controllable but there's there's a lot of things which really are not right and for the operation of the immune system except perhaps when the very limited degree of maybe if you're super stressed or something like

that then you know maybe that's going to have an effect but you know largely yeah it's just over extrapolation is how i would describe it yeah and so one last example matt before we get into rounding up on this episode so i think another good illustration it comes from much earlier in the discussion, where it shows the differences between them. And a little bit, I think, Huberman's particular interests come into play. So this is talking, Addy is talking about limitations, again, of research, and to get onto the topic of comparing mediators and non-mediators. Yes, although, again, this is a great opportunity to talk about why no matter how slick you are, no matter how slick your model is, you can't control

for everything. There's a reason that to my knowledge, virtually every study that compares meat eaters to non-meat eaters finds an advantage amongst the non-meat eaters. And we can talk about all the lifespan advantage. Yes. And we can, or disease, you know, incidence studies. And yeah, it might be tempting to say, well, therefore, eating meat is bad until you realize that it takes a lot of work to not eat meat. a person makes. And for a person to make that decision, they probably have a very high conviction about the benefit of that to their health. And it is probably the case that they're making other changes with respect to their health as well that are a little more difficult to measure. Now, there's a million other problems with that. I picked a silly example because the whole meat discussion then gets into, well, when we say eating meat, what do we mean? You're not talking about it as like deli meat versus grass fed.

Or a deer that you hunted with your ball. That's right. So how do we get into all those things? But my point is, it's very difficult to quantify some of the intangible differences. And I think that even a study that goes to great lengths, as this one does, epidemiologically, to make these corrections can never make the corrections. And so for me, the big takeaway of this study is one, this makes much more sense to me than the Bannister paper, which never really made sense to me. Yeah. Yeah. So Adia is making a good point throughout,

right? Which is worth repeating that experimental type studies and observational longitudinal epidemiological studies complement each other in a way in terms of their strengths and weaknesses and Nadia spells that out quite well the example of finding out that you know people who don't eat meat are healthier than people who do eat meat is a good example of where it's difficult to isolate and attribute causality to that one specific thing because it's confounded with a whole bunch of other things. Famous examples that people will probably remember the headlines to, which is drinking a glass of red wine every day

or eating dark chocolate or something is going to make you healthier in a variety of ways. It's almost certainly the case that it's other socioeconomic lifestyle correlates of those things that are having observed differences. But I feel like Hooverman is just kind of missing the point a bit when he's talking about, oh, well, yes, there's all these nuances, like was it grass-fed, was it deli meat,

or was it a deer that you hunted with a bow? That's really important. That's not what he was talking about. Yeah, just that bull hunting, you know the the reference there i wonder who that is pointing to but yeah so there's a there's a there's a difference um and this is not to say i think that adia is not part of that world also i i think he is but from my reading of this conversation i i think Addy really has chops when it comes to critically reading studies

and that kind of thing. And I'm not saying Huberman doesn't have them to some degree, but it definitely looks to be like a pre-replication crisis academic approach to reading papers. Yeah, yeah, I think that's fair um that is an interesting case isn't it because he like huberman is very much a self-experimenter he he talks about how he went on was it metformin i'm forgetting the metformin yeah forman he went on that based on the original study which which he said that he didn't really oh no no no he went

on it before even the banisterister study. Oh, okay. Yeah, I made that mistake. But he did kind of point out that the Bannister study was the, you know, the big thing that made it, like, become very influential. But he was on it years before. Based on even less evidence, right. Yeah. So that's interesting.

And then that one came out, and then he read this paper, which is kind of debunking the thing that he'd committed to. And he read it with like a receptive mind, shall we say. And for him, it kind of sealed the lid on this thing. And it's just an interesting combination of things because, like you said, he clearly can read studies. He's got a good sort of scientific approach to these things um that he's also a self-experimenter and is yes on one hand he does reevaluate like he is he's

reevaluating his yeah his choices based on the new evidence that comes in but it's just interesting that he he sort of is is yeah i'm impressed at the level of conviction that we see amongst like adi or whatever because you know they're talking about years of their life dedicated to taking something which they think actually it wasn't yeah and it's sometimes extremely dysphoric right like it makes yeah not eating yeah or it makes them nauseous for for days you know um yeah like i you know you gotta you gotta hand it to them it's impressive to do that um i guess yeah i so my take on this whole area like this content that we're covering is it is a separate area and it's much more aligned with the kind of academic sphere in a way

this is people sitting down and talking for hours about studies, doing critical analysis of studies, or at least purporting to, and lots of the information that they give, I think, is good, is valid. Unlike, say, a Brett Weinstein, where I think if you listen to it, you're actively being misinformed about the method. Yeah, that's right. These guys are like many many many rungs above above heather and brett for instance um yeah yeah so so our criticisms are you know a kind of a little bit subtle i suppose or not subtle well that's not the word but we're we're hitting some finer points except with the the vaccination thing that that's that's that's a big one with human yeah with human yeah

with human yeah but i mean i'm not quite sure how to think about these guys because on one hand like you can think of them as enthusiasts and as this being a very serious hobby you know some people are into model trains some people are into succulents for them this self-experimentation and optimizing their strength and their fitness and their health and their longevity and all that stuff is is like a an odd hobby like bodybuilders yeah like bodybuilders or people that are into piercings or whatever where you wouldn't necessarily recommend it to everyone everyone but it's like well you do you that's that's that's fine but i suppose you have to be careful when it comes to health and wellness because you know there's a reason why vaccines

attract so many delusional beliefs and conspiracy theories there's a reason why the supplement industry is worth untold billions of dollars and because i think it's different from model trains or or succulents in that i think people have an underlying vulnerability to these existential issues about death and about health and the relative levels of different micro particles in your blood and all this kind of thing. Like, Huberman never did an episode recommending vaccination, which is the most scientifically supported and lowest cost intervention for your health. And he steered away from it because, I'm extrapolating, but he's clearly implied that he doesn't want the alien part of his audience and that. But if you were a guy that was just about the science, about health optimizing, then you're willing to talk about these controversial things like metformin right which haven't been

proven you'll talk about them at some depth and yet you won't touch vaccination and you're good friends with joe rogan and all the influencers set and you're promoting supplements that's what makes me raise the eyebrow that it's not about that everything that Herman says is bullshit or the things that he promotes are wrong but like it is a kind of spin off the health and wellness space

I think it's health and wellness for men and that's why in a part of it I think the scientific aspect has an appeal, right? Because you're not doing dieting, you're doing optimizing, right? And so one thing that people dinged me for before when we talked about Huberman is saying like, he doesn't have his own supplement brand, right? He actually works with another company.

So let me just play the clip of him promoting supplements. Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. Not so much on today's episode, but on many previous episodes of the Huberman Lab podcast, we discuss supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like enhancing sleep, for hormone support, and for focus. The Huberman Lab Podcast

has partnered with Momentous Supplements. If you'd like to access the supplements discussed on the Huberman Lab Podcast, you can go to livemomentous, spelled O-U-S, so it's livemomentous.com slash Huberman, and you can also receive 20% off. Again, that's livemomentous, spelled O-U-S, dot com slash Huberman. So I just, as I said, if you don't think Huberman's shilling supplements,

like, my God, he gives you the discount code at slash Huberman. If you go, his picture is there with, you know, Momentous X Huberman and um and that disclaimer not everyone needs supplements right or not everybody requires it but then immediately into but there are great benefits people find tremendous benefits for blah blah it is that's a that's the nature of a disclaimer right oh yeah and the whole the whole show is all about really being quite hypey about the amazing benefits of this, that, and the other supplement. And, yeah, the obligatory caveat, which is, you know, consult your doctor and see whether this is right for you. Yeah.

It's not, it doesn't hold water. And, yes, you could be selling supplements without owning a supplement company. There's a thing called affiliate marketing. It's out there. So, yeah, I mean, and I don't really pay the defense of, oh, well, I'm not going to talk about COVID or the vaccines because that's not my speciality. I'm not qualified to. But, you know, Huberman clearly considers himself qualified enough to talk about a wide range of different things that are not in his speciality why why carve out

an exception just for this one particular thing that joe rogan and the rest of the self-optimizing bros have got to be in their bonnet about um no it's quite obvious what's going on there yeah yeah so well that's that's it matzy this is why I thought it's good to go back into these waters, because I do think there's differences here from a lot of the more dramatic secular guru types that we cover making their profound conspiratorial statements. I do think this is an ecosystem where the kind of science-y aspect gets more play. But if you're consuming the content here, my recommendation, as it is with all of the content we cover, is just be skeptical. You can like Huberman. You can find that they give really good advice about caffeine or sun exposure or

whatever. Moving bottles of water. But be wary when he's talking about small land studies and overhyping them. Yeah. That's fair enough. I've got a final thought to leave you on, Chris, which is if we take Puberman's bullish approach to these placebo effects at face value, totally re-evaluating our approach to pretty much all medications and supplements,

then we could be taking sugar pills instead of the athletic greens or that other stuff you were just talking about there. Oh, yeah. Why didn't they go there? That's an interesting thing. You don't have to pay $80 for a three-month supply of whatever, the Hyperzone X. You just take some sugar pills and believe and believe yeah that's a good point yeah i didn't think about that i wonder why that wasn't what the takeaway was so yes a nice

a nice point to end on uh if it's all in the mind supplementation is a full zerun just oh you actually just take homeopathy because there's nothing there anyway um except whenever they're producing places with low quality control and there are actual toxins and that's so maybe don't there yeah just just eat a biscuit and tell yourself it's a hyper brain enhancing no tropic or new tropic whatever you pronounce it. So there we are, Matt. There we are. That's him. Yeah, that's right.

I don't think they're going to score particularly highly on the grommeter, but they're both going to be fed into it. And we said enough positive things about them. We don't need to pick out any particular thing. No, no, we don't. Goodbye and good luck, everyone. Hope you enjoyed it.

It's kind of a decoding academia meta. Oh, yeah, you're not signing out yet, Matt. You don't. Goodbye and good luck, everyone. Hope you enjoyed it. It's kind of a Decoding Academia meta. Oh, yeah, you're not signing out yet, Matt. You don't get off that easy. Oh, God damn it. We don't have a review of reviews this week, but we do have Patreon shoutouts. I know you're so loathe to thank people, but here I am to drag you down to their level and and to get you to

reward their kindness their generosity so shall i begin matt please do please do okay uh conspiracy conspiracy hypothesizers, the fruit soldiers in the Decoding Wars. We have Sam Offit, Joe Percy, No Lips or Joints, Sonia Benito, Matty Laycock, Marco Tresh, Young Bai,

Andy Walters, Dish, Gerard Sanderson, Nico Pomato, The Rootledge,erson, Nico Pomato, TheRootledge, Stephanie, Alan, Paul, Durka Palustris, MJson,

Yuki, Amy Hendrigan, Louise Nash, Jonathan Baker, Teddy Garland, Richard Husband, Anthony Pino, NotTheBeans, and Josia Martins. Fantastic. Thank you very much, everybody.

Conspiracy, hypothesizers, thank you all. I feel like there was a conference that none of us were invited to that came to some very strong conclusions, and they've all circulated this list of correct answers. I wasn't at this conference. This kind of shit makes me think, man, it's almost like someone is being paid. Like when you hear these George Soros stories, he's trying to destroy the country from within.

We are not going to advance conspiracy theories. We will advance conspiracy hypotheses. All right, you will, you will. Now, how about matt revolutionary thinkers of a few of those the people that can get access to the decoding academia hear us over hype small end studies that would include people like dag soros the norwegian comedian gretchen Koch, cartoonist. Ben Neihardt, anonymous ethicist, not a serial killer at all, just

asking questions. I feel he's re-racked before, but nonetheless, thank him again. Jar Gar, Magnus Glerem, Lindsay Kate Frey, Will, Catherine Collins, James Glover, Ed Smith, Randy Maranon,

Gavin Boynton, Michael, Jorgen, Joseph Necht, Amy Poza, Alessio Zaccaria, Samantha Hines, Christopher Innocent, John Butler, and George Tornay. Wow. A lot of them. I'm usually running, I don't know, 70 or 90 distinct paradigms simultaneously all the time. And the idea is not to try to collapse them down to a single master paradigm. I'm someone who's a true polymath. I'm all over the place. But my main claim to fame, if you'd like, in academia is that I founded the field of evolutionary consumption. Now, that's just a guess, and it could easily be wrong, but it also could not be

wrong. The fact that it's even plausible is stunning. Thank you, everybody. Thank you, revolutionary thinkers. Well, I think we've shouted out enough people for this week, so we'll end there, Matt, with the Revolutionary Thinkers. Do you have anything you would like to let our listeners know to end with? Okay. All right.

Thank you, Chris. It's been fantastic. Good fun. Bye, everyone. Ciao. Bye-bye. Bye-bye. See you next week. Thank you.