Welcome to the huberman live podcast where we discuss science and science based tools for everyday life. I'm Andrew huberman. And I'm a professor of neurobiology and Ophthalmology at Stanford school of medicine. Today marks, the first Journal Club episode between myself and dr. Peter Atia, for any of you that are not familiar with dr. Peter Atia. He is a medical doctor. An m.d. who is an expert in all aspects of health, and life span. He is the author of
A best-selling book entitled outlive, which is a phenomenal resource on all things, Health span and lifespan. And he is the host of the very popular podcast, the drive where he interviews, various experts in all domains of medicine and scientists as well today. Peter and I hold our first online collaborative Journal club. For those of you that aren't familiar with what a journal Club is Journal. Club is a common practice in graduate school and we're medical school. Whereby students get together to discuss one or two papers to critique those papers.
And to really compare their own conclusions of those papers with the conclusions of the authors and to highlight any key takeaways Peter, and I have been wanting to do a journal club together for a very long time. And we decided to do that journal club and to record it for you. So today you will be sitting in on the first huberman. A t, a journal club, by the way, it could just have easily been called the Atia huberman Journal club and we will discuss two papers first. Peter is going to discuss a paper on Metformin, which
is a drug that many people are interested in for its potential role in longevity. I want to highlight potential there, he's going to compare that paper to previous findings on Metformin. And by the end of that discussion, he will advise as, to whether or not he himself, would take metformin. And whether or not other, people might be well, advised or ill advised to take Metformin based on the data in that paper. And at this time, then I present a paper, which is about the placebo effect. Have to imagine that most of you have heard of the placebo effect.
It's interesting about the paper that we discussed today is that it shows that the placebo effect can actually follow a dose-response. So it's not just all or none. It actually is the case that you can scale the degree of placebo effect depending on whether or not, you're thinking you're taking low doses, moderate doses, or high doses of a particular drug and the particular drug that's discussed in the paper that I cover is nicotine. So for those of you that are interested in cognitive enhancement by way of pharmacology or frankly for people who
Simply interested in how our beliefs can shape our physiology. I think you'll find that discussion to be very interesting. So by the end of today's episode, You Will Not only have learned about to 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 an 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 before we begin, I'd like to emphasize that this
cast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme. I'd like to thank the sponsors of today's podcast. Our first sponsor is Helix sleep, Helix sleep, makes customized mattresses to give you the best possible night's sleep. Now, sleep is the foundation of mental health, physical health, and performance when we are sleeping. Well and enough mental health, physical health and performance, all stand to be at their best.
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Offering an additional two free month of membership again, that's levels. Dot link. Link-16 huberman to get two free month of membership and now, for my journal Club discussion with dr. Peter, a TIA Peter. So good to have you here.
So, great to hear my friend,
this is something that you and I have been wanting to do for a while and it's basically something that we do all the time which is to peruse the literature and find papers that we are excited about for whatever reason. And
Oftentimes that will lead to a text dialogue or a phone call or both. But this time we've opted to try talking about these papers that we find particularly exciting in real time for the first time as this podcast format, first of all, so that people can get some sense of why we're so excited about these papers. We do feel that people should know about these findings and second of all that it's an opportunity for people to learn how to dissect information and think.
The papers they hear about in the news, the papers they might download from PubMed if they're inclined. Also, just it start thinking like scientists and clinicians and get a better sense of what it looks like to pick through a paper, The Good, the Bad and the Ugly. So we're flying a little blind here, which is fun. I'm definitely excited for all the above
reasons. Yeah, no this is you. And I've been talking about this for some time and, you know, actually we used to run a journal.
Inside the practice where once a month, one person would just pick a paper and you would go through it in kind of a formal Journal Club presentation. We'd gotten away from it for the last year just because we've been a little stretched then I think it's something we need to resume because it's it's a great way to learn and it's a skill 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 then you know, you
So 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 Etc 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 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.
Paper about atp-binding, cassette sin, cholesterol absorption. But ultimately I thought this one might be more interesting to a broader audience, but I got to tell you a funny story. So I had a dream last night about you and 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 that but the one thing I remembered when I woke up because I forgot most of them, I was really trying so hard to remember.
Ember them. One thing that you had in it was do like you had to collect certain amount of do off the leaves every morning to put into this drink. Who's so. It's like, just
sounds like something that I would do.
And, and so but here's the best part, you had, you had like a thermos of this stuff that had to be with you everywhere and all of your clothing, had to be tailored with a special pocket that you could put the thermos into so that you were never without the special Andrew drink.
And again, you know how dreams when you're having them seem so logical and real. And then you wake up and you're like that doesn't even make sense, like, why would he want the thermos in his shirt like that? I would warm it up like it all these. But boy, it was a realistic dream and there were lots of things in it. Including do spaz special, do off the leaves every
morning. I love it. Well, it's not that far from reality. I'm a big fan of yerba mate. I'm drinking it right now. In fact.
In its many forms. Usually the loose-leaf. I don't tend to drink it out of the gourd, my dad's Argentine. So that's why I picked it up. I started drinking it when I was, like, 5 years old or younger, which I don't recommend. People do is heavily caffeinated. Don't drink the smoked versions either, folks, I think that was a potentially carcinogenic, but this thing that you described of carrying around the thermos close to the body, if you are ever in Uruguay, or if you ever spot grown men in a restaurant anywhere, in the world, carrying a thermos with them, and to their me,
Eels? And and hugging it, close chances are. They're Uruguayan, mmm. And they're drinking yerba mate. They drink it. Usually after their meals supposed to be good for your digestion, so it's not that far from from reality. I don't carry the thermos, but I do drink mate every day and I'm going to start collecting, do off the
leaves. Just a few drops every morning.
Some other time we can talk about dreams recently. I've been doing some dream exploration. I've had some
Lutely transformative dreams for the first time in my life, one dream in particular that it 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 as ever impacted me. And this was drug-free. Etc.
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. At least 18 months of intensive analysis type work. With a very skilled psychiatrist but I wasn't trying to seed the dream. Yeah 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.
Travel 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 realize 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 anyway, sometime I can share more details with
You or the audience. But for now we should talk about these papers very well who should go first?
I'm happy to go first, try this one. Is this one? 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 keys and colleagues, this was published last fall. Why is this paper important? So this paper is important because in
714 Bannister published a paper that I think in many ways, kind of got the world very excited about metformin. So there's 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 gyro protection with metformin. And I should probably just Define for the audience. What gyro protection means? When
we think of Lee, also, sorry to interrupt what? Metformin?
It is just for the
uninformed, that's a great point. So I'll start with the with the ladder. So metformin is a drug that has been used for many years. Depends, you know where it was first approved I think was in Europe but you know call it directionally 50 plus years of use as a first-line agent for patients with type 2 diabetes and the u.s. maybe 40 plus years. So this is a drug that's been around forever, trade name glucophage
Brand name. And but again, it's, you know, to generic drug today, 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 is, everybody thinks of those is the cellular engine for making ATP. So the most efficient way that we make ATP is through oxidative phosphorylation.
As for relation, 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 and food taking the energy that's in those bonds making electrical energy.
The mitochondria, those electrons pump, a gradient that allow you to make ATP. To give a sense of how Primal and important. This is if you block that process, completely you die. So everybody's probably heard of cyanide, right? Cyanide is something that is incredibly toxic even at the smallest. Doses cyanide is a complete Blocker of this process and if my memory serves me correctly, I think it blocks complex for of the mitochondria. I don't know if you recall if a complex 3 or complex for
I know a lot about toxins that
Fact, the nervous system, but I don't know a lot about the ways mitochondria. But if ever you want to have some fun, we can talk about all the dangerous stuff that animals make and insects make, and how they kill you.
Yeah. Like I just wrote a toxin and all these things that blocks our deal at rotox and
bungo to, I Really geek out on this stuff because it allows me to talk about Neuroscience animals and scary stuff. It's like combines it so we could do that some time for fun, maybe at the end if we have a few
moments. So so you know something like cyanide that is a very potent inhibitor of this electron transport chain will kill you.
Instantly people understand that, of course, a drop of Cyanide and you would, you would be dead literally instantaneously. So metformin works at the first of those complexes, I believe there are four of my memory serves correctly for electron transport chain complexes. And but of course, it's not a complete inhibition of it. It's just kind of a weak Blocker of that. And the net effect of that is what the net effect of that is that it changes, the ratio of adenosine monophosphate to adenosine diphosphate. What's less?
Clear is why does that have a benefit in diabetics? Because what it unambiguously does, is reduces the amount of glucose that the liver puts out. So hepatic glucose output is one of the fundamental problems that's happening. In type 2 diabetes. You may recall I think we talked about this in a previous podcast. You and I sitting here with normal blood sugar have about 5 grams of glucose in our total circulation, that's it 5 G think about how quickly the brain will go through that.
Within minutes. So the only thing that keeps Us Alive is our livers ability to titrate out glucose. And if it puts out too much, for example, if the glucose can, if the glucose level was consistently 2 teaspoons, you would have type 2 diabetes. So the difference between being metabolically healthy and having, you know, profound type 2. Diabetes is one teaspoon of glucose in your blood stream. So the ability of the liver to Tamp down on high glucose output is important. Metformin
To do that. So can I just ask one?
Question, is it fared to provide this overly simplified summary of the biochemistry, which is that when we eat the food is broken down but the breaking of bonds creates energy that then our cells can use in the form of ATP. And the mitochondria are Central of that process and that metformin is partially short-circuiting, the energy production process. And so, even though we are eating, when we have met,
Foreman 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 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. So for example, like it
Not depriving you of the calories that are in that glucose. That would be you know,
fantastic. But that was the, that was the Lester upper left. Remember the Alaska from the 90s olestra folks. For those of you don't remember, by the way, if you ever ate the stuff, you'd remember because it was a fad that was not easily digested. It had sort of in sort of analogous to plant fiber or something like that. So it was being put into potato chips, and whatnot. And the idea is that people would would simply
We excrete it and I don't know what happened except that people got a lot of stomach aches and well everyone seepage or in the world. We know
that the anal seepage is what really did that
Chronicle seepage only a physician because after all Peter's a clinician for physician and MD and I'm not could find it a an appropriate term to describe.
Yeah. When you have that much, when you have that much fat malabsorption, you start to have access.
It's wow. And so that that did away with that product,
right? It was either that or the diaper industry was gonna really take off. Okay. That's why you don't hear about
olestra. That's right. So so we've got this drug, we've got this drug, metformin, it's considered a perfect First Line agent for people with type 2 diabetes. So again, what's happening when you have type 2 diabetes, 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
Is 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 in to 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 this cell that leads to a phosphorylation, so ATP. Donates a
Sweet group and a transporter, just think of like a little tunnel at 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.
By the way, I did not know that. I mean, I certainly know active and passive transport as it relates to like, neurotransmitters and ion flow. But I've never heard that when insulin binds to a cell that literally a little straw is placed into the membrane of the Cross.
Doesn't need a pump to move it in because there's much more glucose outside the cell than inside. So it's just but the energy required is to move the the straw up to the cell.
So biology is so cool.
Yeah, it is. So so what happens is as
And Gerald Shulman at Yale, did the best work on elucidating this as the intramuscular fat increases. And I by intramuscular, I mean, intracellular fat, try acyl and diacylglycerol Ides, accumulate in a muscle cell that signal gets interrupted and all of a sudden, I'm making these numbers up. If you used to need two units of insulin to trigger the little transporter, now you need three and then you need for and then you need five, you need
more and more insulin to get the thing up. That is the definition of insulin resistance. The cell is becoming resistant to the effect of insulin and therefore the early Mark of insulin resistance, the canary in the coal, mine is not an increase in glucose, it's an increase in insulin. So normal glycemia with hyperinsulinemia, especially postprandial, meaning after you eat hyperinsulinemia is the thing that tells you hey you're five ten years away from this.
A real problem. So fast forward. Many steps down the line. Someone with type 2. Diabetes has long passed that system. Now not only are they insulin resistant where they just need a boatload of insulin, which is made by the pancreas to get glucose out of the circulation? But now, that systems not even working well, and now they're not getting glucose into the cell. So now their glucose level is elevated. And even though it's continually being chewed up and used up because again the brain alone would account for most of that glucose.
Disposal, the liver is now becoming insulin resistant as well, and now the liver isn't able to regulate how much glucose to put into circulation and it's over doing it. So now, you have too much glucose being pumped into the circulation by the liver and you have the muscles that can't dispose of it. And it's really a vicious brutal Cascade because the same problem of fat accumulating in the muscle, is now starting to happen in the pancreas. And now the relatively few cells in the pancreas called beta cells, that make insulin are undergoing.
Inflammation due to the fat accumulation within the pancreas itself. And so now the thing that you need to make more insulin is less effective at making insulin. So, ultimately way, way, way down the line. A person with type 2. Diabetes, might actually even require insulin. Exogenously,
could you share with us a few of the causes of type 2, diabetes of insulin resistance? I mean, one, it sounds like is accumulating too much fat
yesso energy imbalance would be an enormous one in activity or insufficient
She is probably the single most important. So when Gerald Shulman was running clinical trials at Yale, they would be recruiting undergrads to study obviously, because you're typically recruiting young people and they would, you know, be doing these very detailed mechanistic studies where they would require actual tissue biopsies. So you're going to biopsy, somebody's quadriceps and actually, look at what's happening in the muscle. Well, I remember him telling you this, when I interviewed him on my podcast, he said the most important criteria of the people we interviewed is because they were still lean. These weren't people that were
Wait, but they had to be inactive. You couldn't have active people in these studies. So, exercising is one of the most important things you're going to do to ward off insulin resistance. But there are other things that can cause insulin resistance sleep, deprivation has a profound impact on insulin resistance. I think we probably talked about this previously, but if you to some very elegant mechanistic studies, where you sleep deprived people, you know, you let them only sleep for 4 hours for a week, you'll reduce their glucose disposal by about half. Wow, which is, I mean, it's a
Staggering amount of your basically inducing profound insulin resistance, in just a week of sleep deprivation hypercortisolism, Mia is another factor and then obviously energy imbalance. So we're when you're when you're accumulating excess energy, when you're getting fatter, if you start spilling that fat outside of the subcutaneous fat cells into the muscle, into the liver into the pancreas, all those things are exacerbating in, got it, okay? So, enter metformin, first line drug. So, most of the drugs, so every drug you give a person with type 2 diabetes.
Trying to address part of this chain. So some of the drugs tell you to make more insulin, that's that's one of the strategies. So here are drugs like sulfonylureas they tell the body, make more insulin other drugs, like insulin just give you more of the insulin thing. Metformin tackles the problem elsewhere, it tamps down glucose by addressing the glucose dispose. The hepatic glucose output Channel, glp-1 agonists, or another drug, they increase insulin sensitivity and
Actually causing you to also make more insulin Geo. This is that so sembach. Yes.
Yeah. And is it true? That berberine is more or less the poor man's metformin. Yep. That's it from a tree bark. It just happens to have the same properties of. Yeah. And by the way 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.
Yeah, we can talk about burying a little bit later. I had a couple great experiences with berberine and a couple bad experiences interesting or agree. Yeah.
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 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, you know, the Buffett shareholder meeting and you know, it's 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 2 grams a day which is kind of like the full dose and we went to this is a
characteristic of your approach to things.
Yes, I think that's safe to say
next time. I'll give you a thermos of this do that I collect in the morale.
So, I remember being so sick that the whole time we were in Nebraska, 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 could have so
nauseous because I would say, if you got metformin in your system you're going to buffer glucose. You get out for ice cream cones
and about looks, if I couldn't put, I couldn't keep anything down. I mean, I was so nauseous. So so clearly metformin has this side effect initially, which is a little bit of appetite suppression, but regardless, that's the story.
E on Metformin. There are a lot of reasons I was interested in it. I wasn't thinking true gyro 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. Do you want to Define gyro
protection? Yeah. It's a good term to the
frontier geriatric gyro.
Yeah, so yeah. Gyro from, from geriatric, old protection. So protection from aging and when we talk about a drug like meth
Foreman or rapamycin or even NAD and are these things. The idea is we're talking about them as gyro protective to signal that they are drugs that are not targeting a specific disease of Aging. For example, a pcsk9 inhibitor is sort of Gyro protective but it's targeting one specific pathway, which is cardiovascular disease and dyslipidemia. Whereas, the idea is a gyro protective agent would Target Hallmarks of Aging. There are nine Hallmarks of Aging.
He's don't ask me to recite them. I've never been able to get all nine straight but people know what we're talking about, right? So decreased at apogee, increase in essence decreased nutrient, sensing or defective nutrient, sensing proteomic instability genomic, instability methylation. All of these things. Epigenetic changes. Those are all the 90 marks evasion 7. Yeah. So a gyro protective agent would Target those deep down biologic Hallmarks of aging and in 2014 a paper came
By Bannister that basically got the world focused on this problem by the world. I mean the world of anti-aging. So what what banister and colleagues did was they took a registry from the UK and they got a set of patients who were on Metformin with type 2 diabetes but only metformin. So these were people who had just progressed to diabetes, they were not put on any other drug just metformin and then they
And from the same registry, a group of matched controls. So this is a standard way, that epidemiologic studies are done because again, you don't have the luxury of doing the randomization. So you're trying to account for all the biases that could Exist by saying we're going to take people who look just like that person with diabetes. So can we match them for age? Sex? Socioeconomic status, blood pressure BMI everything we can.
And then, let's look at what happened to them over time. Now again, this is all happening in the future, so you're looking into the past its retrospective in that sense. And so let me just kind of pull up the sort of table here, so I can kind of walk through. And this is not in the paper, we talked about, but I think this is an important background, so they did something that at the time, I didn't really notice. I didn't notice what they did. I probably did and I forgot, but I didn't notice this until about five years.
Years ago when I went back and looked at the paper and they did something called informative censoring. 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 a cm and its 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
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 to. They can just stop taking their metformin, three, and more commonly. They can progress to needing a more significant drug.
Ugh.
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 two people who were not having type 2 diabetes. So an analogy here would be imagine we're going to do a study of two groups that we think are almost identical.
Nickel one of them are smokers and the other are identical in every way, but they're not smokers and we're going to follow them to see which one's get lung cancer. But every time somebody dies in The Smoking group, we stopped counting them. When you get to the end, you're going to have a less significant view of the health status of that group. So with that caveat, the banister study found a very interesting result which was the crude death rate.
Was. And by the way, the way these are done, this is also one of the challenges of epidemiology is the math gets much more complicated. You have to normalize death rate for the amount of time you study, the people. So everything is normalized 2000 person years. So the crude death rate in the group of people, with type 2, diabetes, who were on Metformin, including the censoring was fourteen point four. So fourteen point four deaths, occurred per thousand patients
Years. If you looked at the control group, it was 15.2.
This was a startling result, and I remember reading this in again, 2014 and being like, holy crap. This is really
amazing. Is there, could you explain? Why? Because I hear those numbers and they don't seem that striking. It's a difference of about a year and a half. Now, of course a difference of about a year and a half and lifespan is.
Well, it's remarkably, like, it doesn't even translate to that. So taking a step back, Diabetes Type 2 diabetes on. Average will shorten your life by six years. I see. So that's the
L 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,
okay, butter. And by the way, up here, just point out, my mouth was wrong when I said about a year and a half, but but the point here is you would
expect the people in the metformin group
to have a far worse,
outcome ie2 have a far worse, crude death rate and the fact that it was statistically significant in the other direction,
And it turned out on the What's called the Cox proportional Hazard, which is where you actually model the difference in life span, the people who took metformin and had diabetes had a 15 percent 15, 15 percent relative reduction in all cause death over two point. Eight 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?
Yep. So 15 percent reduction in all cause mortality over two point, eight years.
That's a big deal, it is. And again, there's no clear explanation for it, unless you believe that metformin is doing something Beyond helping you lower blood glucose because the difference in blood glucose between these two people was still in favor of the non-diabetics
So again the proponents of Metformin being a gyro protective agent and I put myself in this category at one point, I would put myself today in the category of undecided, but at the time, I very much believed this was a very good suggestion, that metformin was doing other things. You mentioned a couple already. Metformin is a week inhibitor of mtor. Metformin. Reduces inflammation. Metformin potentially tamps down on senescent cells and their secretory products. You know, there are lots of
Metformin could be doing but are off Target and it might be that those things are. Conferring the advantage
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hubermann so fast forward until a year ago and I think most people took the banister study as kind of the best evidence we have for the benefits of metformin. And I'm sure you've had lots of people come up to you and ask you should I be on, Metformin, should I be on Metformin? I mean, I probably get asked that question almost as much as I'm asked any question outside of, dude. I mean, people definitely want to know if you should be consuming do but, but after that, it's met
form brush off. The leaves has to be well
Viewing morning, sunlight.
So okay. So let's so let's kind of fast forward to now the paper that I wanted to spend a few more minutes
on. Thanks for that background. I'm still dazzled by the insertion of the straw, by way of of insulin, I don't think I've ever heard that described. I need to, I need to go get a better. Textbook.
It's a, pretty Short Straw In fairness. You know, it's just, it's just a little
trap, just, I just to give people a sense of why I'm so dazzled by. I am always fascinated by how
Quickly how efficiently and how specifically biology can create these little protein? Complexes that do something really important. When you're talking about an on demand creation of a little of a portal, right? I mean these are cells engineering their own machinery and real time in response to chemical signals where
my name is, it's it's great. Yeah, but 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 to restore the gradient. But once the action potential fires, its passive outside, right?
Yeah. So what peers referring to is the way that neurons become electrically activist by the flow of ions across the cell from the outside, the cell to the inside of the cell and they have both active conductances mean, they're triggered by electrical changes in the gradients Via changes in electrical potential and then their pass a gradient where things can just flow back and forth until there's a balance equal inside and outside the cell.
I think, what's, 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 sales very quickly. Normally at they go through a process of, you know, transcribing genes and making sure that the specific proteins are made. And then it does our 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
Of a channel. And it makes sense as to why that would be required, but it's just so very cool. It's cool. Yeah,
so keys and colleagues came along and said we would like to redo the entire Bannister analysis. And I think their motivation for it was the interest in this topic is through the roof. There is a clinical trial called the tame trial that is, I think pretty much funded now and maybe getting underway soon, the tame trial, which is an
And trial is going to try to ask this question, prospectively and through random assignment.
So this is the targeting aging with metformin trial, that's
correct. Okay. Nir barzilai is probably the senior Pi on that and I think in many ways the banister study along with some other studies but of lesser significance, probably provided some of the motivation for the time trial. So they said okay look, we're going to do this we're going to use a different cohort of people so the
The first study that we just talked about 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 his
Quickly 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 in 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 give you you know, allow you to see if there's any sort of difference in signal. So now turning this back into a little bit of a journal Club,
Virtually any clinical paper, you're going to read table. 1 is the characteristics of the people in the study. You always want to take a look at that. So when I look at table one here, you can see it's. And by the way, just for people watching this, we're going to make all these papers and figures available. So if you're, you know, don't you know, we'll have nice show notes, that will make all this clear. 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. You
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 people that got excluded, this is how we randomized etcetera. And you can see here that there are four columns so that the first two are The Singletons. These are people who are not related, and then the second two are the twins who are matched. And you can see, remember how I said, they sampled about 500,000 people. You can see the numbers. So they got, you know, 7840 to Singleton's 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, coach wins 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, Etc. The one thing I want to call out here that really cannot be matched in a study like this. So, this is a
Very important, limitation is the medication. So look at, look at that column enter. Notice how pretty much everything else is perfectly matched, until you get to the medication
list. It's all over the place. Yeah, it's just you, it's not even
close. They're not where they're nowhere near matched, right? In other words, just to give you a couple of examples right on the end. Let's just talk about The Singletons because it's basically the same story on the twins. If you look at what fraction of the people with type 2 diabetes or on lipid lowering medication, it's forty five point six percent.
His 15.4% in the Matched without diabetes. It's a 3X difference. What about antiplatelet therapy? That's 30 percent versus 14 percent antihypertensives. 65% verse 63 percent versus 31 percent
because people who have one health issue and are taking metformin, are likely to have other health issue.
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. Yeah, so that we could control
All 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, your mind. Okay. So the two big things that we're done in this experiment or in this survey or, you know, study to differentiate it from Bannister was one the twin trick, which I think is pretty cool. The second thing that they did was
they did a sensitivity analysis with and without informative censoring. So, one of the things they wanted to know is hey does it really matter if we don't count the metformin patients, who progress? So, so let's see kind of what? What transcribed. So, the next figure figure to a part of the next table table to walks you through the crude mortality rate in each of the groups. So, the most important,
Row, I think in this table is the one that says crude mortality per thousand person years. Now you recall that in the previous study in the banister study those were on the ballpark of about 15 per okay. So let's look at each of these. So in the single The Singletons with without so the non twins who were not diabetic, it was sixteen point, eight, six. And
could you put a little more Contour on?
What this thousand-person years, what it is. I'm talking about pooling the lifespans of a bunch of different people until you get to the number 1000. Yeah. Because your normalizing not so it's not who's going to live a thousand years because they weren't expecting that, you're essentially taking. So you've got some people that are going to live 76 years, 52 years, 91 years, and you're pooling all of those until you hit 1,000 and then that becomes kind of a a it's like a normalized.
You're basically like still let's say the control group. You're asking if there were 1,000 person years available to live, How likely is it that this person would live another
50 s, a couple ways to think about a simple. So taking a step back. We always have to have some way of normalizing. So when we talk about the mortality from a disease like cancer in the population, we would we record it as what's the mortality rate per? And it's typically per 100,000 persons
Okay, that's a much more intuitive. Way to express
it. It is. But the reason we can do it that way, is because we're literally looking at how many people died this calendar year and we divide it by the number of people in that age group. So it's typically what you're doing when you look at aged groups in buckets of like decades. So that's why we can say the highest mortality is like people 90 and up even though the absolute number of deaths is
Small. It's because there's not that many people there, right? The majority of deaths in absolute terms, probably occur in the seventh decade, but as you go up, because the denominator is shrinking, you have to normalize to its. We just normalize to the number of people. Here are all the people that started the year here. All people that ended the year. What's the death rate? Why are these done in a slightly more complicated way? Because we don't follow these people for their whole lives. Were only following them for a period of observation. In this case, roughly three years.
So to say something like, you know, we have a crude death rate of five deaths, per thousand person years, one way to think about that is if you had a thousand people and you followed them for one year, you'd expect five to die if you had 500 people and you followed them for two years, you expect five to die. If you have a thousand people and you follow them for one year, you expect five to die. Those would all be considered equivalent mortalities.
Great. Thank you for clarifying that.
No, not this. This stuff is, I mean like I find I find epidemiology when you get in the weeds is way more complicated than following the basics of experimental stuff where you just, you get to push all this stuff into the garbage bin. And just say, hey, we're going to take this. Number of people were going to exclude this group. We're going to randomize, we're going to see what
happens. Yeah, that's what like the paper will talk about now. Yeah.
So
When you adjust for age and they don't show it in this table, it's only in the text when you adjust for age, a very important check to do is what is the crude death rate of the people on Metformin, who are not twins versus? Who are twins. Now, in this table they look different because it's 24.93 for the metformin group and twenty one point six eight for the twin group in that's on Metformin. When you adjust for age they're almost identical. It's goes from 20.
I'm 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 you'll notice, there are parentheses after every one of these numbers. What does that, what does that offer in their? 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%.
Ain't that the actual number is between twenty three point two three and twenty six point six four if a 95% confidence interval does not cross the number 0, it's statistically significant.
Okay. So the first thing that just jumps out at you, I think when you look at this is, there's clearly a difference here between the people who have diabetes and those who don't it, complicates the study a little bit because it's basically two studies in one. But you're comparing 95, pardon me 24.93 to 16.86 which, by the way, remains after age adjustment, when you go to the twin group, it's 24.73 to
12.94. So maybe
Just a zoom out for that. What you're describing. If I understand correctly, is this crude deaths per 1000 person years. Let's just talk about the Singleton on. Yes. Is 16.8 6 0. 16 .8, six people died. And some people probably think how can .86 of a person die. Well, it's not always whole numbers, but there's a, there's a bad joke to be made here but
yeah, just call it 17 verses 25, right?
17 deaths, per thousand verses 25.
Deaths. Yep. And the 25 is in the folks that took metformin. Now that to the naive listener and to me means oh, you know, metformin basically. Kills you, right? Not a faster or you know, you're more likely to die, but we have to remember that these people have another, they have a major health issue that the other group does not have. That's right, because people weren't assigned drug or not assigned drug. It wasn't Placebo drug. It's let's look at people taking this drug for a
Health issue and compared to everyone else. That's right.
So now you have to go into and I'll just sort of skip the next figure. But the next figure is a kaplan-meier curve. I think it's actually worth looking at it because they show up in all sorts of studies. So, if you look at Figure 1, it's a kaplan-meier curve, which is a mortality curve. So you'll see these in any study that is looking at death, and this can be prospective. Randomized, is going to be retrospective.
But these are always going to show up, and I think it's really worth understanding, what a kaplan-meier curve shows you. So, when the x axis is always time and on the y-axis is always the cumulative survival. So it's a curve that always goes from 0 to 1, 1 or 100% And it's always decreasing monotonically. Meaning, it can only go down or stay flat. It can never go back up. So that's what accumulative mortality curve. Looks like
now we're looking at
Starting at alive. And you look at how many people died for every year that passes.
That's right. And in each curve, there's one on the left, which is the Matched Singleton's and there's one on the right which are the discordant twins. You have two lines. You have those that were on, Metformin with type 2 diabetes, and you have their matched controls. And in this figure, the Matched controls are the darker lines and the people with type 2 diabetes on Metformin. That's the lighter line.
You'll also notice and I like the way they've done it here. They've got shading around each one
and we should mention for those that are just listening that in both of these graphs, the downward trending line from the controls. So again non-diabetic not taking metformin is above the line. Corresponding to the diabetics or taking metformin, put crudely, the people who are taking metformin to have diabetes.
These are dying at a faster rate for every single year examined, the two lines, do not overlap accepted the beginning. When everyone's alive, it's like a foot race where basically people with metformin and diabetes are falling behind and dying as they fall.
That's right. And I'm glad you brought up a good point. It's not uncommon in treatments to see kaplan-meier curves cross, they don't have to. It's not a requirement that they never cross. It's only a requirement that they're monotonically decreasing or staying flat.
Lat. So I've seen cancer treatment drugs where they have, like two drugs going head-to-head in a cancer treatment and like one starts out looking really, really bad, but then all of a sudden it kind of flattens while the other one goes bad and then it actually crosses and goes underneath but that's not the case here. So to your point the people with diabetes taking metformin in both the match Singleton's and the Discord ins are dropping much faster and they always stay below and I was just going to say that the shading is just showing you.
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 group of mice and you were watching their survival and you were, you know what, 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 familiarize, just statistics, no problem, error bars correspond to like. If you were just going to measure the heights of a roomful of 10th graders you, there's going to be a ranger.
You have the very tall kid and the the very shorter kid and you know, the short kid and the medium kit and you and so there's a range there's gonna be an average a mean and then they'll be standard deviations and standard errors. And so these confidence intervals. Just give us a sense of how much range you have. Some people die die. Early, some people dilate within a given year. They're going to be different ages. 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 died? We're not tracking 1 diabetic, taking metformin versus a control. I should have asked this earlier but
well and it's also a mathematical model at this point to that, smoothing it out because notice it's running for the full eight years even though they're only following people for, you know, typically I think the median was like three or four years at a time. So they're using this quite complicated type of mathematics called A Cox proportional hazards which 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 among those sort of 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
Is 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,
How people are reading graphs? And I think it's important to remember that you run the statistics, hopefully the correct statistics for the for the sample but determining significance whether or not the the result could be due to something other than chance, of course, your confidence in that increases as it becomes typically p-values P. Less than point zero zero, zero zero one percent chance that it's due to chance, right? So very low probability P less than 0.05 tends to be the kind of gold standard cut off.
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. We're not necessarily looking at, you know, raw data points. Here. You
have the raw data was in the previous table that's now taken and run through this Cox model and it's smoothed out got it. And to your point about the bar graphs? Yeah, I think the other thing you always want to understand is just because something doesn't achieve
of statistical significance. The only way you can say it's not significant is you have to know what it was powered to detect and statistical, power is a very important concept that probably doesn't get discussed enough, but before you do an experiment, you have to have an expectation of what you believe the difference is between the groups. And you have to determine the number of samples, you will need to assess whether or not.
That difference is there or not. So you use something. It's called a power table and you, you would go to the power table. So if you're doing treatment a versus treatment B and you say, well, I think treatment a is going to have a 50% response and I think treatment B will have a 65 percent response. You literally go to a power table that says 50% response. 15% difference that gives you a place on the grid. And I want to be 90% sure that I'm right. So 90%.
Percent power. I'm being a little bit so it's going to be a statistician listening to this who's going to want to kill me, but this is directionally the way we would describe it. And that tells you this is how many animals or people you would need. In this study, you're going to need 147 in each group. And by the way, if you now do the experiment with 147 and you fail to find significance, you can comfortably say there is no statistical difference. At least up to that 15%. There may be a difference at 10% but you weren't powered tool.
Ten
percent. Yeah, and very important point that you're making another Point that's just more General. One about statistics in general, the way to reduce variability in a data set is to increase sample size but that kind of makes sense, right? If you if I just walk into a 10th grade class saying, okay, I'm going to measure height and I look up by the first three kids that I see, and I happened to look over there and it's the three that all play on the volleyball team together. My sample size is small and I'm likely to get a skewed representation in this.
It's taller than average. So increasing sample size tends to decrease variation. So the that's why when you hear about studying from the UK biobank or from you know, half a million Danish citizens. Like, for instance, in this study that's those are enormous sample sizes. So even though this is not an experimental study, it's an epidemiological observational study, there's tremendous Power by way of the enormous number of subjects in an
astounding, the way that epidemiology will make
For its deficit. So you could never do a randomized assignment study on half a million people, you know. So, so epidemiology makes up for its biggest limitation. Which is it can never compensate for inherent biases by saying, we can do infinite duration if we want. Like, we could, we could survey people over the course of their lives, and we can have the biggest sample size possible because this is relatively cheap, the cost of actually
Really doing an experiment where you have tens of thousands of people as 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, this is The Balancing Act between epidemiology and randomized, prospective experiments, and they so they both offer something. But you just have to know their blind spots of each one.
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So, what's just kind of wrap this up? I mean, I think let's just go to table for which I think is the most important table in here, which now lays out the the final results in terms of the hazard ratios. So, this is, this is the way we want to really be thinking about this. So, again, Hazard, ratios. These are important things to understand a hazard ratio is a number and you always subtract one from the hazard ratio. And that tells you if it's a positive number, if it's a number. So if it's a number greater than 1, you subtract 1,
And that tells you the relative harm. So if the hazard ratio is 1.5 you subtract one point, five is a 50% increase in Risk. If the number is negative, you may recall on the banister paper, the hazard ratio is 0.85. So if it's not with, so that means it's a 15% reduction in relative risk and here you can see all the hazard ratios are positive. So what it's telling you here is, and I'm going to walk through this because it's there's a lot of information packed here. You've got Singleton's, you've got twins, they're showing you
three different ways that they do it. They do an unadjusted model. If you just look at The Singletons with and without metformin and you make no adjustments. The hazard ratio is 1.48. Meaning the people on Metformin had a 48 percent greater chance of dying in any given year than their non-diabetic
counterpart. The only reason I'm smiling. It's not because I enjoy people dying quite quite to the contrary is that this is a novel for me that I've read some
Days before, but it's not normally where I spend the majority of my time. But up until now, I was thinking, okay, people taking metformin are dying more than those that aren't, I? Just and I, I'm just relieved to know that I wasn't looking at all this backwards. Yeah. So they're dying more. But of course, we don't have a group that's taking metformin who doesn't have diabetes and we don't have a group who has diabetes and you know it's taking metformin plus something else. So again we're only dealing with these constrained.
Yeah.
Now there's opposition armed to this study that I'm not getting into because it adds more complexity which is they also have another group that got diabetes takes metformin, and take sulfonylureas, which is a bigger drug and those people died even more.
Whoa. So which again speaks to the point, right? 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
In 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. So my point is they make another set of adjustments, they say, okay, well look in the first one in the unadjusted model, we only matched for age and gender.
Okay, that's pretty crude. What if we adjust for the medications? They're on the cardiovascular, psychiatric pulmonary, dementia meds, and marital status. I don't know why they threw marital status in there. But they did
know, maybe being married or unmarried, can
I'm sure elegant, but it just seems like a random thing to throw in with all their meds. I would have personally done that adjustment higher up. But nevertheless, if you do that, all of a sudden the hazard ratio drops from 1.48 21 Point, 3 2, which means yep, you still have a 32 percent greater chance.
Chance of dying in any given Year. All right, what if we also adjust for the highest level of Education along with any of the other covariance? Well, that doesn't really change it at all. It ends up at one point 33 or a 33% chance increase in death.
Okay. I always knew that more school wasn't going to save
me was, it's not doing jack. So now let's do it for the twins. If you do the twin study, which you could argue is a slightly pure study because you at least have one genetic and environmental thing that you've attached.
T', the unadjusted model is brutal 2.15. That's 115 percent. Think about
this. These are twins who in theory are the same in every
way. Except one has diabetes in one dozen. And the one with diabetes on Metformin, still has 115 percent, greater chance of dying than the non-diabetic coach win brutal. When you make that first adjustment of all the meds and marital status it, you bring it down to a 70% increase in risk. And when you throw education, and it goes up to an 80 percent chance of risk.
Now they did this really cool thing which was they did the analysis on with and without censoring. So, everything I just said here was based on, no censoring,
tell me about censoring
censoring is when you stop counting, the metformin people who have died, okay? So in the Singleton group, when you unadjusted it and the reason I'm doing the unadjusted as that's where they did the sensitivity analysis, I don't think it really matters that much. It's just have to draw a line in the sand.
Somewhere you'll recall that that was a 48 percent chance of increased mortality. All-cause mortality. If you stop counting if you if you pardon me if you don't censor meaning. If you include everybody including when people on Metformin with diabetes die. If you censor them, it comes down to one point three nine. In other words, this is a very important finding it did not undo the benefits that we saw in the banister study Bannister saw a
Teen percent reduction in mortality when they censored.
When Keys censored it got better but not that much better. It went from 48 to 39 percent in the twins. It went from 115% down to only 97 percent
So, in some ways this presents a little bit of an enigma because it's not entirely clear to me, having read these papers many times exactly why Bannister found such an outline around it, like such a different response, there's another risk, there's another technical detail of this paper, which is they, you can see on the right side of table for they did something called a nested case control, but you'll see and I was going to go into a long explanation of what nested case controls are. It's a
Another pretty elegant way to do case control studies where you sample by year and you, you sort of normal lot, you don't count all the cases at the end. You count them one by one. I don't think it's worth getting into Andrew, because it doesn't change the answer. You can see it changes. It just slightly but it doesn't change the point. The point here, is the keys paper makes it under undeniably. Clear that in that population, there was no Advantage offered by metformin that undid.
Did 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've been but what it says is
In the way, this is what you would have expected. This is what you would have expected 10 years ago before the banister paper came out
or maybe even before metformin was used. Because in some ways it's saying what is the likelihood that sick people who are on, a lot of medication are going to die compared to not sick, people who aren't on a lot of medication. Yep. One. You know, it's not quite that simple, and that in the sense that, as you said, there are ways to try and isolate the metformin contribution, somewhat because there
A bunch of other meds and presumably that was done and analyzed in other figures that where they can sort of try and can never attach the results specifically to metformin, right? But there must be some way of waiting. The percentage that are on psychiatric meds are not on psychiatric meds. This time way to tease out whether or not there's actually some contribution to metformin to this result. Well, that's what they're doing in be in the, in the
partial adjustment is, they're actually, they're actually doing
Doing their best to say. Oh
right, you're not married are going variable by variable
by drug all the way through high blood pressure. Non high, blood pressure, smoking, non-smoking
Etc. And the way they would do that. Presumably is by saying, okay, married not married. That's what? That's a simple one.
Are you on lipid-lowering meds? Yes or no. Okay, you are not. You are not.
They and then comparing those groups. Yeah, yeah. Okay. So note no difference, is jumping out that can be purely explained by these other variables.
Yes.
So again, this is a, 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 our lifespan Advantage. Yes. And we can or disease, you know, incidents studies. And yeah, it might be tempting to say, Well they're for eating meat is bad, Until you realize that
It takes a lot of work to not eat meat. That's a very, very significant decision that a person for most people, it's a very significant decision, 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 meet discussion then gets into. Well, you know, when we say eating meat, what do we
Like this document is like deli meat versus grass-fed. We're sort of a deer that you hunted with your ball, that that's totally. 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 banister paper, which never really made sense to me. And again, I
Was first critical of the banister paper in 2018, about four years after Kim. And that's about the time, I stopped taking metformin. By the way, I stopped taking it for a different reason which we can talk about in a sec. But that was the first time I went back and said, wait a minute, this information. This this informative censoring thing is, that's a little fishy and I think we weren't looking at a true group of real type 2 diabetics. Now that said maybe it doesn't matter. In other words, maybe and even the keys paper doesn't tell us that metformin wouldn't be beneficial.
Because it could be that those people. If they were on nothing as they're matched, cohorts were on nothing, would have been dying. It, you know, Hazard ratio of 3. And this brought it down to one point five, in which case you would say there is some gyro protection. There it is. Putting the brakes on this process. All of this is to say absent, a randomized control trial, we will never know. The answer,
has there been a randomized control trial, not a mental
image, not when it comes to a heart outcome. Now, there has been in the ITP
So the interventions testing program, which is kind of the gold standard for animal studies which is run out of three Labs. So it's an NIH funded program that's run out of three labs. They basically test molecules for gyro protection. The ITP was the first study that really put rapamycin on the map in 2009. That was the study that's fortuitously demonstrated that even when rapamycin was given very, very late in life, it was given to 60 month old mice.
It's still afforded them. A 15% lifespan.
Extension has a similar study been done in humans. I mean sorry. I mean it's hard to now we can't really control with rapamycin. Oh,
but when the ITP studied metformin, it did not succeed. So the the there have not been that many drugs that have worked in the ITP, the IDP is very rigorous, right? It's a, it doesn't use an inbred strain of mice. It is done concurrently in three Labs with very large sample sizes.
Ting and so when something works in the ITP it's pretty exciting. Rapamycin has been studied several times. It's always worked. Another one we should talk about it and subsequent time is 17 Alpha estradiol. This continues to work in male mice and it produces comparable effects to rapamycin. Estrogen doesn't
work in female Rights Make, but this is
Alpha naught beta. So this is 17 Alpha estradiol naught beta estradiol which is the estradiol that we all that is bio available in
all of us and just
A brief aside. Thank you. And I basically agree that unless it's a problem, males, we're talking post puberty should try and have their estrogen as high as possible without having - symptomatology because of the importance of estrogen for libido. For brain function, tissue bone health, bone health body. This idea of crushing estrogen and raising testosterone is just silly, right? There's not a let's just leave raising testosterone out of it but
Many of the approaches to raising testosterone that are pharmacologic in nature. Also raised estrogen, a lot of people try and push down on estrogen and that is just again, unless people are getting hyper estrogenic effects, like gynecomastia or other issues is the exact wrong direction to go. You want
estrogen, Hester, estrogen is a very important hormone for men and women that's it, can a guy, flows in and sglt2 Inhibitors were also very successful in the ITP. But again, interestingly rapid Mighty Med form.
Not 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 to taking it for jira protection to buffer blood glucose. Yeah, no, terminally
potentially of longer. Yes. Exactly. And the reason I stopped in this will be the last thing before we move on. Well, because you
couldn't go to the Dairy Queen at the
Buffett of that know. 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 lack
Tate was at rest. So a resting fasted lactate should be in a healthy person. Should be below 1 like somewhere between point three point. Six mmol and only when you start to exercise should lactate go up and in 2018 was when I started blood testing for my zone to. So previously when I was doing Zone to testing, I was just going off my power meter and heart rate. But this is when this is after I met any goes on Milan and I started like wanting to use the lactate threshold of
Mmol. 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 mmol. 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? Well, no, that would put me a lot higher where, but and and writing, generous to your
feet, no. But but, but that's when I started doing a little digging and realized, oh, you know what, this totally makes sense, if you have a weak mitochondrial,
Toxin, what are you going to do? You're going to shunt more glucose into pyruvate and more pyruvate into lactate. I'm I'm anaerobic. Yeah, you need a baseline fuel source. That's right. So and then my zone two numbers just seemed off my Lactaid. Could you
feel it? Sorry. I didn't know it. Could you feel it in your body? Because maybe now, I'll just briefly describe. I took berberine I During the period of maybe somewhere in the 2012 to 2015, stretch. I don't recall. The, what were you taking it for? Well, I'll tell you.
I was and I still am a big fan of. Tim Ferriss has slowed carbohydrate diet because I like to eat meat and vegetables and starches. I'm an omnivore and I found that it worked very quickly. Got me very lean. I could exercise, I could think I could sleep, all, you know, a lot of my rationale for following one eating regimen or another. What I eat is to enjoy myself but also have mental energy it, because if I can't sleep at night, I'm not going to replenish. I'm not, I don't replenish them when I feel like
Garbage. I don't care how lean I am or what, you know. So, I found the Slow Carb Diet to be which was in the 4-Hour Body to be a very good plan. For me was pretty easy. You drop some things like bread, Etc, you don't drink calories. I'm except after a resistance training session cetera but one day a week you have this so-called cheat day and on the chiid a anything goes. And so I would eat, you know, eight croissants. And then I'd alternate to sweet stuff and then I go to peace and by the end of the day, you don't want to look at it. An item of food at also, the only modification I made to this
Slow carb diet for our body. Thing was the day after the cheat day, I wouldn't eat. I would just fast and I had no problem doing that because it was just basically, well, since you said, what was it? Anal anal. Seepage. Yeah, gel series. I did not have that. But since you said that, I I won't up the ante here, but I'll, at least match your anal. Seepage comment by saying I had. Let's just call it profound gastric distress after eating like that the next day. 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 and 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, etcetera and indeed it worked. So if I took berberine and I don't recall the mg count, and then I ate, you know, a 12 donuts. I felt fine. It was as if I had eaten one donut. Wow. I feel
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 I remember how much you were taking. I think, was a couple hundred milligrams. Is that sound about, right? Is it with right 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 cheap foods but when I cycled off of the for 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 interesting enough carbohydrates in order to really justify trying to buffer. My blood glucose, also my blood glucose tends to be. Did you ever
did you ever try acarbose
know what is
that? So acarbose is another glucose disposal. Yeah, it's actually a drug that but it works more in the gut and it just prevents glucose absorption acarbose. Is another one of those drugs that actually found a survival benefit in the ITP and it was a very interesting finding because the, the thesis for testing at the IDP is a very clever
System. Anybody can nominate a candidate to be tested, then the the panel over there, reviews it and they decide yet. This is interesting, we'll go ahead and study it. So when I think David Allison nominated acarbose to be studied the rationale was it would be a caloric restriction mimetic because you would literally just fail to absorb. I don't know, make up some number right? 15 to 20% of your carbohydrates would not be absorbed and therefore you would the mice would effectively be calorically restricted, it was asked them out, that's right. And
What happened was really interesting one. The mice lived longer on acarbose but to they didn't weigh any less so it what they live longer but not through calorie restriction. That's interested. Yes. And it the, the speculation is they live longer because they had lower glucose and lower insulin
and I don't want to send this down some rabbit holes here, but they're all sorts of interesting ideas about for instance, that some forms of dementia might be so-called type 3 diabetes or diabetes of
Rain and so things, like, berberine, metformin lowering blood glucose ketogenic diets. Etcetera, might be beneficial there. I mean, there's a lot to explore here and I know you've explored a lot of that on your podcast. I've done far less of that, but well, at least it seems that we know the following things for sure. One you don't want insulin too high, nor too low. You don't want blood glucose too high nor too low. If the buffering systems for that are disrupted. 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 acarbose, it Etc that you take on a regular basis because you have that much confidence in it.
The only one that I take is an sglt2 inhibitors.
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 and non-diabetics taking it even for heart failure. I think there's something very special about the drug actually, that was another paper I was thinking about presenting this time. Maybe we'll do that the next time, but do. But do you believe in
caloric restriction?
Restriction, as a way to extend life or are you more of the do the right behaviors and that's covered in your book out live and Elsewhere on your podcast and buffer. Blood glucose is, do you still obviously you believe in buffering blood glucose in addition to just doing all the right
behaviors? I think you can uncouple a little bit, the buffering of blood glucose from the caloric deficit. So I think you can be in a reasonable energy balance and buffer glucose.
With good, sleep. Hygiene, lots of exercise and just thoughtful eating without having to go into a calorie deficit. So, you know, it's not entirely clear if profound caloric restriction, would offer a survival advantage to humans. Even if it were tolerable to most which it's not right? So for most people, it's just kind of off the table, right? Like if I said Andrew you need to eat 30 percent fewer calories for the rest of your life.
LOL, live. Thirty percent fewer Years,
thank you. Yeah. Like there's just not many people who are willing to sign up for that. So it's kind of a moot point.
But the question is, you know, do you need to be fasting all the time? Do you need to be doing all of these other things? And the answer appears to be outside of using them as tools to manage energy balance, it's not clear, right? And energy balance, probably plays a greater role in glucose homeostasis, then from a nutrition standpoint then the individual constituents of the meal. Now, that's not entirely true.
True. Like 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 a caloric deficit. You're going to end up having to go into color.
Excess. So that's why it's interesting thought experiment, I don't think it's very practical. Experiment for a person to be generally satiated and 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
III. So physically enjoy the sensation of chewing that you know I'll just lie cucumber slices for for fun. Yeah. Right. You know that's I mean that's not my only form of unfortunately this is an amazing paper for the simple reason that it provides a wonderful tutorial of the benefits and drawbacks of this type of work. And I think it's also wonderful because we hear a lot about metformin rapamycin.
And these anti-aging approaches, but was not aware that there was any study of such a large population of people. So it's pretty
interesting. Yeah. So I think it remains to be seen. If my patients often ask me, hey, should I be on Metformin and I give them a much much, much much shorter version of what we just talked about. And I say, look, if the tame study, which should answer this question more definitively, right? This is taking a group of non diabetics and randomizing them to Placebo versus metformin.
In and studying for specific disease outcomes, if the tame study ends up demonstrating that there is a gyro protective benefit of Metformin, I'll reconsider everything right? So I think that's, we just have to think all walk around with an appropriate degree of humility around what we know and what we don't know. But I would say right now, the epidemiology, the animal data, my own personal experience, with its impact on my lactate production and exercise performance, we could there's a whole other
We could go down another time, which is the impact on hypertrophy and strength, which appears to be attenuated as well. By metformin, you know, I'll I still prescribe it to patients all the time if their insulin resistant, for sure. It's still a valuable drug but I don't think of it as a great tool for the person whose insulin sensitive and exercising a lot.
I can't help. But ask this question, do you think there's any longevity benefit to short periods of caloric restriction?
You know? So for instance, I decide to, by the way, I haven't done this, but let's say I were to decide to, you know, fast and do a one meal, a day type thing where I'm going to be in a slight caloric deficit, you know, 500 to 1,000 calories for a couple of days and then go back to eating the way that I before. That short, caloric restriction, / fast is there any benefit to it? In terms of cellular Health can you, you know, reset the system, is there any idea that the
The changes that clearing of senescence cells that we hear about on top of G that we, you know, that in the short term, you can glean a lot of benefits. And then go back to to your regular pattern of eating. And then periodically, you know, once every couple of weeks or once a month, just, you know, fast for a day or two, is there any benefit to that? That's, that's purely in the domain of longevity. Not. Because because there's all discipline function there. There's a flexibility function. There's probably an insulin sensitivity function, but is there any evidence that it can help us live?
Longer. 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 to 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 basically always like it would be three day fast, three day, fast 7-Day fast, just imagine doing that all year rotating rotating running. 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 the time which I obviously now look back and realize is muscle mass loss. You're just, it's very difficult to gain back the muscle cumulatively, after all of that loss, but my thought was exactly, as you said, like, there's got to be a resetting of the system here. This must be.
Be sufficiently long enough to trigger all of those systems but you're getting at a bigger problem with jira science which I'm really hoping the epigenetic field comes to the rescue on. It has not come close to it to date, which is we don't have biomarkers around true metrics of Aging. Everything we have today, eight stinks. So we're really good at using molecules or interventions for
We have biomarkers, right? Like when you lift weights,
You can look at how much weight you're lifting, you can look at your dexa scan and see how much muscle mass. You're generating like that, those are biomarkers. Those are giving you outputs that say, my input is good or my input needs to be modified. When you take a sleep supplement, you can look at your eight sleep and go, oh, my sleep is getting better. Like there's a biomarker when you take Metformin when you take rapamycin when you fast, we don't have a biomarker that gives us any insight into
They're not, we're moving in the right direction and if we are we taking enough just don't know. So I often get asked like what's the single most important topic you would want to see more research dollars put two in terms of this space and it's unquestionably this as unsexy as it is like who cares about biomarkers? But like without them I don't think we're going to get great answers because you can't do most of the experiments you, and I would dream up.
Got it. Well, I'm grateful that you're sitting across the table from me, telling me all this and that everyone can hear this again, we will put a link to the papers plural, that Peter just described. And for those of you that are listening and not watching, hopefully you were able to track the the general themes and takeaways and it is fun to go to these papers, you see these big stacks of numbers and it can be a little bit overwhelming, but my additional suggestion on parsing
Versus notice that Peter said that he spent, you know, he's read it several times unlike a newspaper article or, or a Instagram post with a paper. You're not necessarily going to get it the first time. You certainly won't get everything. So that I think, spending some time with papers, for me, means reading it and then reading it again a little bit later or and tell me what. Yeah, I was
just about to say, what's your because because I kind of have a way that I do it, but I'm curious as to how you do it. Like, if you're, if you're encountering a paper for the first time, what do you have an
Order in which you like to go through the. Do you want it? Do you read it sequentially or do? Look at the figures first. I mean, how do you how do you go through?
Yeah. Unless it's an area that I know very, very well where I can, you know, Skip to some things before reading it, the whole way through my process is always the same. And actually this is fun because I used to teach a class when I was a professor at UC San Diego, called neural circuits in health and disease and it was an evening course that grew very quickly from 50 students to four hundred plus students and we would do exactly
That's we would parse papers and and I had everyone asked what I call the four questions and it wasn't exactly for questions, but I have a little three-by-five card next to me or a piece of a nap by 11 paper typically. And when I sit down with a paper, I want to figure out what is the question? They're asking, what is the general question? What's the specific question? And I write down the question then what was the approach? You know, how do they test that question? And sometimes that can get a bit detailed and get into him.
You know, has to chemistry and they did a, you know, PCR for this. It it's not so important for most people that they understand every method. But it is worthwhile that if you encounter a method like PCR or chromatography or fmri, that you at least look up on the Internet, what it's purposes, okay, that will help a lot. And then it was what they found and there you can usually figure out what they believe. They found any way by reading the figure headers. Right, what are you know?
You're one, here's the header. That typically, if it's an experimental paper it will tell you what they want you to think they found and then I tend to want to know the conclusion of the study and then this is really the key one. And this is the one that would really distinguish the high-performing students from the others. You have to go back at the end and ask whether or not the conclusions, the major conclusions drawn in the paper are really substantiate it. By what they found and what they did and that involves some thinking it involves really, you know, spending some time thinking about
About what they identified. Now, this isn't something that anyone can do straight off the bat. It's a skill that you develop over time and different papers require different formats. But those four questions really form the Cornerstone of a teaching undergraduates and I think graduate students as well as how to read a paper. And again it's something that can be cultivated and it's still how I approach papers. So what I do typically is I'll read title abstract eyes usually then we'll skip to the figures and see how much of
Can digest without reading, the text, and then go back and read the text. But In fairness journals, great journals, like science like Nature's, oftentimes, will pack so much information in the cell press journals to into each figure and it's coated 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 it's just yeah, it's just wild how much, how much you nomenclature there really is.
I can't remember, was it? You or was it our friend, Paul Conte, when he was here, who said that? Oh no, I'm sorry. It was, neither, it was chair of Ophthalmology at Stanford. Dr. Jeffrey Goldberg who was a guest on the podcast. Recently who off camera. I think it was told us that if you look at the total number of words and terms, that a physician leaving Medical School owns in their mind and their vocabulary. It's the equivalent of like two additional full languages of fluency Beyond
Native language. So your trilingual at least out of you speak a language other than English coralie. Okay, so you're you're at least trilingual and probably more. So no one is expected to be able to parse these papers the first time through without you. No substantial training.
Yeah, no, I think that's, that's a great format and you're absolutely right. I have a different way that I do it. When I'm familiar with the subject matter versus when I'm not well, again, if I'm reading papers that are something that I
No really well, I can basically clean 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 what do you mean? What what is this? How did they do that? And then I got to go back and read methods typically
And one of the other thing is 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. And the reason for that, of course, is that the journals are very specific on the format and length of a paper. So, a lot of the times when you're submitting something, you know, like if you want to put any additional information in there, it can't go in the main article. It has to go in the supplemental figure. So, even for this paper, there were a couple of the numbers, I spouted off that I had.
Pull out of the supplemental paper. For example, when they did the sensitivity analysis on, the censoring versus non censoring, that that was in the supplemental figure. That was actually not even in the paper, we
presented. Well, should we pivot into 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. 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
Look different. Maybe even quite a bit different than the one that we're going to discuss. Nonetheless, there are a couple 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 Charles see gu at who's at the econ School of Medicine Mount Sinai. Runs a laboratory there.
Studying Addiction in humans and the first off author of the paper is over Pearl. This paper is wild and I'll just give you a couple of the takeaways first as a bit of a hook. 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
Subjective level, but at a biological level. So just to back up a little bit, a former guest on this podcast, dr. Ali crumb, whose name is actually Alia Chrome, but she goes by Ali crumb, talked about belief effects, belief effects are different than Placebo effects. Placebo. Effects are really just category effects. It's okay, I'm gonna give you this pill Peter. And I'm going to tell you that this pill is molecule X 5952 and that it's going to make your
he better. And then I give you a memory test, right? And your group performs better than the people in the control group, who I give a pill to, and I say, this is just a placebo or their other variants on this, where people will get a drug and you tell them, it's Placebo. Then we got a placebo, you tell them, it's drug. It's, it's a binary thing, it's an honor and off thing, you're either in the drug group or the placebo group and you're either told that you're getting drug or Placebo and we know that Placebo effects exist. In fact, one of the Cruller ones I was never the subject of this but there was kind of
Lure in high school that you know, like kids would do this mean thing. It's a form of bullying. I really don't like it where, you know, they get some kid at a party to drink alcohol, free beer and then that kid was start acting drunk and then they go gotcha, you know, it doesn't even have alcohol in it. Now that's a mean joke and just reminds me of some of the horrors of high school maybe that's why I didn't go very often, which I also don't suggest but no, it it's a mean joke, but it speaks to the placebo effect, right? And there's also a social context effect
So Placebo effects are real. We know this belief effects are different. Belief of X are not a or b. It Placebo or non Placebo believe effects. Have a lot of knowledge to enrich. One's belief about a certain something that can shift their Psychology and Physiology one way or the other. And I think the best examples of these really of these belief effects. Really do, come from Ali, crumbs lab in the psychology department at Stanford or do some of this work. She did prior to getting into Stanford for instance.
If people are put into a group where they watch A Brief video, just a few minutes of video about how stress really limits our performance. Let's say it archery or it mathematics or at music or public speaking and then you test them in any of those domains or other domains in a stressful circumstance. They perform less well. Okay. And we know they perform less well, because we're by virtue of a heightened stress response. You can measure heart rate, you can measure stroke volume of the heart, you can measure
I'm prefer blood flow, which goes down. When people are stressed narrowing. A vision etcetera. You take a different group of people and randomly assigned them to another group where now they're being told that stress enhances performance, it mobilizes, resources. It Narrows your vision such that you can perform tasks better etcetera, etcetera and their performance. Increases above a control group that receives just useless information. At least useless as it relates to the task. So in both cases, by the way, the groups are being told, the truth stress can be
Be depleting, or it can enhance performance, but this is different than Placebo. Because now it's scaling according to the amount and the type of information that they're getting
and can you give me a sense of magnitude of benefit or detriment that one could experience in a situation? Like the one you just
described? Yeah. So it's striking their opposite in direction. So the stress gets us worse makes you. Let's say, I think that if we were to just put a rough percentage on this would be somewhere between 10 and 30% worse at performance and the control group,
And stresses enhancing is approximately equivalent Improvement, so they're in opposite directions. Even more striking is the 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 longer. It's been since you've eaten. And what you notice is that suppresses ghrelin to a great degree and for a long period of time you give another group Shake
You told me to low calorie shake that it's got some nutrients in it, but that doesn't have much fat, not much sugar Etc. They drink the shape less ghrelin system suppression
and it's the same shape 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, as they took hotel workers, they give 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 give you incentivize them and then you let them out into the
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 up, trash cans, Etc, guess what? The group? That was informed about the health benefits of exercise lose 12 percent. More weight compared to the other group
and no difference in actual
movement. Apparently not. Now, how could that be? I mean, literally this was sparked by in Ali's words, you know, this was sparked by her graduate advisor saying,
And what if all the effects of exercise or Placebo, right? Like which is, which is not what anyone really believes but it's just such a, you know, I love that. Anecdote, that Ali told us because it just really speaks to how like really smart people. Think they have sit back and they go. Yeah, like exercise obviously has benefits but like what? If a lot of the benefits are that you tell yourself, it's good for you and the Brain can actually activate these these mechanisms in the body. And why wouldn't that be the case? Because the nervous system extends through both. So
our winter. So interesting.
Okay, so
Fast forward to this study, which is really about belief effects, not Placebo effects. And to make a long story short, we know that nicotine Vaped smoked dipped or snuffed or these losses in 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.
I, well, you have a couple sites in the brain, namely in the basal forebrain, nucleus my solace in the back of the brain structures, like Locus coeruleus. But also this, what's called? It's got a funny name that pedunculopontine nucleus which is this nucleus in the in the ponds, in the back of the brain and the brain stem. That sends those little axon wires into the thalamus. The thalamus is a gateway for sensory information. And in the thalamus, the visual information, the auditory information, it has nicotine.
Nick 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 who? Well, it's going to be a Seto, choline binding to nicotinic
receptor. I see, we're not making - we're not just finding. So this is a, this is a nicotinic, acetylcholine receptor,
right of, which
Are at least seven in probably like 14 subtypes but so right there 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, there's receptors are there because we're supposed to smoke pot or those receptors are there because we're supposed to ingest. Nicotine know the drugs
that were used to study the receptor. That's right.
Right. Exactly. Receptor is named after the drug and so the important thing to know is that whether or not it's basal forebrain and pedunculopontine, nucleus or locusts,
Julius that, at least in the brain because we're not talk about muscle where acetylcholine does something else by a nicotinic receptors there in general. It just tends to be a signal to noise enhancer. And so for the non-engineering types out there, no problem signal the noise. Just imagine I'm talking right now and there's a lot of static in the background. There are two ways for you to be able to hear me more clearly. We can reduce the static or I can increase the Fidelity, the the volume and the clarity of what I'm saying. Okay. For instance and that's really what acetylcholine.
That's why when people smoke a cigarette they get that boost of nicotine and they just feel clear, it really works. The other thing that happens is the foulness sends information to a couple of places. First of all, it sends information to the reward centers of the brain. The means Olympic reward pathway that releases dopamine and typically when nicotine is increased in our system, dopamine goes up. That's one of the reasons why nicotine is reinforcing. We just like it. It's a, we seek it out. I've done beautiful experiments with honeybees even where you put nicotine on
Certain plants or it comes from certain plants and they'll forage there more, you get the, you know, them kind of like buzzed. That was a pun bad pun, in any event. There's also an output from this thing, the salamis to the ventromedial. Prefrontal cortex, which is an area of the forebrain that really allows us to limit our focus in our attention for sake of learning, it's allows us to pay attention. This is the
circuit. You talked about this in your fantastic podcast on stimulants
Ian ADH. So ADHD typically ADHD drugs so things
Adderall Vyvanse. Methamphetamine for that matter Ritalin.
Why it's counterintuitive that a stimulant would be a treatment for someone with difficulty
focusing. Yeah. In young kids, who have difficulty, focusing. If you give them something, they love their like a laser. And the reason is that ventromedial. Prefrontal cortex circuit can engage as when the kid is interested and engaged. But kids with ADD ADHD tend to have a hard time engaging
Their mind for other types of tasks and other types of tasks are important for getting through life. And it turns out that giving those stimulant drugs in many cases can enhance the function of that circuit and it can strengthen. So that ideally the kids don't need the drugs in the long run. All the that's not often the way that it plays out and there are other ways to get at this, you know, there's now a big battle out there. You know, is ADHD real, is it not real? Of course, it's real does. Every kid need ADHD meds know, are there other things like nutrition more, play time, outside etcetera, that can help.
Improve their symptoms without drugs. Yes, is the combination of all those things together known to be most beneficial? Yes, are the dosage is given to high and generally should be, you know, titrated down, maybe some kids need a lot. Some gives me a little I probably just, you know, gained and lost a few enemies there. So the point is that these circuits are hard-wired circuits.
Sorry one other question, Andrew. If my memory serves correctly, doesn't nicotine potentially have a calming effect as well, and that seems a bit counterintuitive to the focusing one. Are there, is it a dose effect or a timing affect? How does
that work? Yeah, it's a dosing effect. So, the interesting thing about nicotine is that it can enhance focus in the brain, but in the periphery, it actually provides a muscle relaxation. So it's kind of the perfect drug. If you think about it again, it's it was
On this. How when we were growing up, people would smoke on playing that a smoking section on the plane. You know, people smoke all the time and now hardly anyone smokes for all the obvious reasons? But yeah, it provides that really Ideal Balance between being alert but being mellow and relaxed in the body. So hence it's reinforcing properties. Okay, this study is remarkable because what they did is they had people come into the laboratory. They gave them a vape pen. These are these are
Acres. So these are
experienced smokers.
Typically there's a wash out before they come in so they're not smoking for a bit so they can clear their system of nicotine and they measure long as I'm needed typically it's a couple of days. Okay. Yeah. Which must be
miserable for those people from us because they can't have Nicorette gum or
anything? No, nothing. They must be dying. And I wonder how many cheat but they can
measure they measure an oxide. Right now, 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 their vaping. I
They're a low medium or high dose of nicotine. The dosage is don't really matter because tolerance, varies etcetera, and then they are putting them into a functional magnetic, resonance imaging machine so where they can look at its really blood flow, it's really hemodynamic response. For those of you who want to know, it's the oxygen is, 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.
Well, so fmri. When you see these, like hot spots in the brain is really just looking at blood flow. And then there's some interesting physics around and I'll probably get this wrong, but I'll take an attempt at it so that I get beat up a little bit by the physicists and Engineers remember the right hand rule? Yep, right. Okay, so do I have this right? Correct, the right-hand rule, if you put your thumb out with your first, with your index finger, and middle finger your thumb facing up, I think that the thumb represents the charge, the direction of the charge, right? And then, isn't the electromagnetic field is the downward facing figure. And then it's
That
right? I have to look it's actually okay. So someone will look it up, but what you do is when you put up person's head in this big magnet and then you pull the magnet what happens is the oxygenated and deoxygenated blood, it interacts with the magnetic field differently and that difference in Signal can be detected and you can see that in the form of
activated brain areas. Yeah, I mean MRI all works by proton detection. So presumably, there's a difference in the proton signal when you have high oxygen versus lock sir,
In
concentration. Yeah, that's right. And what they'll do is, they'll pulse 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, what, 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,
Powerful technique. So what they do is they put people in the scanner and then you'll like this because you what are the what are the
limitations of fmri? Oh, and in terms of, I mean, you know how fine is the resolution. I mean, where are the blind spots of the technique? So resolution you can
get down to sub. CM they talk about it. Always in these paper as a voxels, which
are these low cubic
pixels things, you know, Sub sub CM, but you're not going to get down to mm? Okay, there are a number of
Low confounds that maybe we won't go into. Now that have been basically worked out over the last 10 years by doing the following. You can't just give somebody a stimulus compared to nothing. I'll just tell you the experiment. It was discovered for instance, that when someone would move their right hand because, you know, when you're in the MRI, and just waiting for one of these recently for clinical, not a problem, but just for a Diagnostics and you're leaning back and you, and you can move your right hand a bit and they would see an area motor cortex lighting up. But what they noticed was that the area corresponding to, the left hand was also lighting up
So what you really have to do is you have to look at resting state. How much are they lighting up here at tranzact track that out? So now you'll always see resting state versus activation
State. Yeah. 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 effort like they did. An fmri of a dead. Salmon that demonstrated like some interesting signal know that what but it's all we got to find this.
This one for the, for the show notes,
you should do one of these wild papers ones, there's their papers of, you know, people putting don't do this folks. Putting elephants on LSD that were published in science and things like crazy experiments. We should definitely do it. Crazy experiments Journal Club. In any event. You can get a sense of which brain areas are active in when with fairly high, spatial resolution fairly high and pretty good. Temporal resolution on the order of hundreds of milliseconds. Not but it's not Ultra Ultra fast.
A lot of neural transmission is happening on the tens of milliseconds, especially when you're in talking about auditory processing, okay? So they put people into the scanner and then they give them a 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, you know. Okay. Here's the stock market or you could say that where the
Price of peas, it doesn't really matter. It goes up, it goes down and they're looking at 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 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. So this is going to be
This type of circuitry. Now, remember these groups were given a vape pen prior to this where they 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. 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 so that includes the thalamus but that includes the mesolimbic reward pathway and dopamine.
Mean it includes the ventromedial. Prefrontal cortex, first of all, they measure nicotine in the blood. They are measuring. How much people Vaped? They were very careful about this. One of the nice things about the vape, pen for the sake of experiment and not recommending people Vape, but they can measure how much nicotine is left in the vape pen before after they can measure how long they inhaled, how long they held it in there's a lot that you can do that's harder to do with a cigarette, okay? They measured people's belief as to whether or not they got low medium or high amounts of nicotine.
And if they were told, they were told they got a you that this is a low amount to medium amount, or 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, that's 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. So they basically
Easily and they're measuring it from their bloodstream. So they all have fairly low levels of nicotine. But one group was told, you got a lot. One group was told you got a medium amount in the other was told you got a little bit now, a number of things happen but the most interesting things are the following. First of all, people 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, feels like a high amount of nicotine and these are experienced smokers if it was a medium amount.
Like that, it feels like a medium amount. If there's a low amount, they think it was a low amount. Now that's perhaps not so surprising. That's you're
just a tricky bow. And that's a 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 of these include areas like What's called the center median. Nucleus the ventral posterior nucleus the names that really don't matter, but these are errors 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 that 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 or not scales with it.
Someone
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. Now there are a couple of other things that could have confounded this. First of all it could have been that if you believe you got a lot of nicotine, you're just fast.
Or where you're reading the lines better or your response time to hit the button is quicker. You know, I tell you have a drug that's going to improve reaction time, you might believe that about nicotine, and so you're quicker on the trigger and you're getting, they have a different activation as more activation. There could be a rule that out. They also rule out the possibility. How did rule that out by looking at rates of pressing? And there was are doing nothing and in sensory areas of the brain that would would represent that kind of difference. They don't see that the other thing that is very clear.
Clear, is that the connection between the thalamus and the ventromedial? Prefrontal cortex that pathway scales in the most beautiful way such that people that were told. They had smoked a low or Vaped, a low amount of nicotine. Got a subtle activation of that pathway people that were told that they got a moderate amount of nicotine. Got a more robust activation of that pathway and the people that were told that they got a high amount of nicotine in The Vape Pen, saw a very robust activation of the thalamus to this ventral. Prefrontal cortical
Way. Now of course this is all happening under the hood of the skull simply on the basis of what they were told and what they believe.
And technically the fmri is showing the activation of those two areas and that's how you can infer the strength of that connection. That's right. There's a
separate method called diffuser tensor Imaging which was developed. I believe out of the group in Minnesota Minnesota has a very robust group in terms of neuroimaging that can measure activation in fiber Pathways this
Is not that but you can look at the timing of activation and it's a known what we call monosynaptic Pathway. So we haven't talked so much about figures here, but I guess if we were going to look at anyone figure and I can just describe it for the audience. That's not paying doesn't have the figure in front of them. The, let's see. I think the most probably the most important figure is figure to remember. I said, I like to read the titles of figures which is that the belief about nicotine strength induced a do
Dependent response in the thalamus. Basically, if you and figure to be, can tell you if they believe that they got more nicotine, that's, that's essentially the response that they, that they saw. So if you look at or sorry panel e, if you look at the belief rating, as a function of the estimate,
In Thalamus of what, how much activation there was. It's a mess when you look at all the dots at once, but if you just separate it out by high medium and low, you run the statistics, what you find is that there's a gradual increase, but a legitimate one from low to medium to high. In other words, if I tell you, this is a high dose of nicotine, your brain will react as if it's a high dose of nicotine. Now what they didn't do was give people zero
nicotine. Yeah, I was about to say there's a control that's missing. Yeah.
Yeah. So what they didn't do is give people
No nicotine. And then tell them this is a high amount of nicotine sort of the equivalent of the cruel. High School experiment. No alcohol. But then the kid acts drunk now in the in the high school example, it's unclear whether or not the kid actually felt drunk or not it's unclear whether or not they had been drunk previously. If they even know what it would be like to feel drunk etcetera and there's the social context, what I find, just outrageous and outrageously interesting about this study.
D is simply that what we are told about the dose of a drug changes, the way that our physiology response to the dose of the drug and in and in my understanding this is the first study to ever look at dos 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, they clearly are seeing a dose-dependent.
Response
simply to the understanding of what they expect the drug ought to do. In other words, you can bypass pharmacology somewhat right
now. Look at figure to be am I reading this correctly? So it's got 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.
Hers who were just put in the
machine. That's right. You didn't.
Yeah, this is measuring parameter estimate. What is that referring to their ability to play the the the the trading game
the parameter estimate is the is the activation reward related activities from independent Thalamus Mass great. 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 but that's not the whole story.
No, that's not the whole story. So when you look at the output from the thalamus to the ventromedial, prefrontal cortex, that's where you start to identify. The is that figure for that is. Yes. So this is where you see so figure for be 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
Belief. You can see that there's a low medium and high scatter dots for each and that each one of those is
significant. 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, 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, that's surprise you. It is surprising and it
surprised them as well. The, 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 the thalamus. But
In terms of its output to the prefrontal cortex. That's when because show that
figure-four be is more convincing than figure to because even figure to e if you read the fine print, the are the correlation coefficient is point two seven. That's
why it's not that strong right? It's week.
So at the thalamus it's kind of like yeah there might be a signal by the way. This goes back to our earlier discussion there could be a huge signal here in where underpowered how many subjects were in this you with this you wouldn't have a lot of subjects in this.
Experiment. Yeah, this is no you 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. Its extensive. I mean pensive we have to I should know this but we can we can go back to the
but you can sort of just look at the number of dots on here. I mean, it's in the low tens. Yeah. Right. It's like 40, 30, something like that. It's not. So it's possible. You do this with Danish study? Yeah, you do this with 1,000 people. This could all be statistically
significant, right? It was so they talked about this.
Based on this, we estimated that an end 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 point, zero zero point five and a two tailed
test. Okay, so that's, that's them, referring to what we just talked about, which is the power, we believe at 90% confidence to get an alpha of 0.05, which means we 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 significant switch 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 in the 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 3 talks about their 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 3, be other people can't see it but basically
Oh yeah. 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 if people got a low medium or high amount of nicotine, now, that actually could be leveraged. I believe, if somebody were trying to quit nicotine, for instance, and they were going to do that by progressively reducing the amount of nicotine that they were taking. But you told them that it was the same amount want from one day to the next. You could Whittle it down to presumably.
To a low amount before taking it to zero and if they believed it to be a greater amount than it might actually not disrupt, their reward Pathways meaning, they would feel presumably, they'd feel rewarded by whatever nicotine they were bringing in.
What would be your prediction if this experiment were repeated but it was done exactly the same way with non-smokers
foof. Well, one thing that's sort of interesting you asked about art potential sources of artifact,
Ones with fmri. One of the challenges that they know in this study was you have to stay very still in the in the machine. But the subjects were constantly coughing because they're smokers. So,
okay. So
presumably the data would be higher Fidelity, start chuckling at that one, but I was like had to read that one twice. Oh, no, that makes sense. Other smokers are coughing. They can't stay still so movement artifact. But in all seriousness, I think that for people that are naive to nicotine,
even a small amount of nicotine
is
Likely to get this pathway is activated to such a great degree, sort of like the first time effect of pretty much any drug
but I wonder if they would be more or less susceptible to the belief system.
Yeah. That's a really good question, right? Because they have no prior to compare it
to have no Pleasant. They have no experience to compare it to with respect to the obviously beneficial effects of nicotine that the smokers are well used to.
So this is the the poor kid that got duped into thinking the non-alcoholic beer.
Was at alcohol though. They're actually the winner. We know because I didn't have. So an alcohol alcohol is bad for you. So in the end that kid wins and the other ones lose poetic justice, but that kid having never been actually drunk before. Presumably, why would feel like they're being more susceptible or potentially? That's my guess is well so you know, my glee for this experiment is not or this paper rather it's 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.
Now 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 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 were talking about before metformin etcetera, just throw our arms around all of it.
What we believe about the effects of a drug. Presumably, in addition to what we believe about, how much we're taking. And what those effects ought to be clearly are impacting at least the way that our brain reacts to to those
drugs. Yeah, it's very interesting. I mean, when you consider how many drugs that have peripheral effects or peripheral outputs, begin with Central issues? So, again, I think the glp-1 agonists are such a great example of Zen.
Yeah. Yeah. You know I don't think anybody fully understands exactly how they're working but it's hard to argue that they're impacting. That the glp-1 analog is is having a central impact. It's doing something in the brain that is leading to a reduction of
appetite and we believe that. Yeah yeah. And I think the mouse data point to different areas of the hypothalamus that are related to satiety. Yep. That that say it's at least possible.
Yeah. I mean the
You know, there's no quicker way to make a mouse overeater under eaten by lesioning. It's hypothalamus depending on where you do. So, so presumably these drugs work there. But again, it speaks to like, what do you need to believe in order for that to be the
case. Have they done Placebo trials there where people get something? And they're
told only those, I mean, of course, those drugs have all been tested via Placebo and the placebo groups, you know, don't do anywhere near as well. That's how we know that there's activity of the drug but but again, there's, you know,
That's a little bit different than being told you are absolutely getting it, right? Because in the rcts you're just told you might be getting it, you might not be getting it. So it's not quite the same as this experiment. This experiment is is one level up where you're being told. No, you're absolutely getting it. You just getting different doses of
it. 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 are 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
wild. Yeah. I mean you think the implications for example with blood pressure, right? Like we don't really understand essential hypertension which is the majority of people walking around with high blood pressure. It's unclear etiology. So lots of people being treated. How do we know that the belief system about? It can't be changed. And yeah, this is this is I don't know. This is a opening.
Yeah.
It's cool stuff in Ali Chrome, is it onto some other really cool stuff? Like, for instance, just to highlight where these belief effects are starting to show up. If you tell a group that the side effects of a drug that they're taking our evidence that the drug really works for the purpose that they're taking it. Even though those side effects are kind of annoying people report the experience as less awful and they report more relief from the primary symptoms that they're trying to Target. So our belief about what side effects.
Our, that's can really impact how quickly, and how compatible we feel about how quickly a drug work scuse me, and how compatible we feel that drug is with our entire lives. So wait, if we call them something else, like not side effects, but like additional benefits or something, it's kind of crazy. And you don't want to lie to people, obviously, but you also don't want to send yourself in the opposite direction, which is reading the list of side effects of a drug and then developing all of those side effects.
And, and then maybe later coming to the understanding that some of those were raised through belief effects.
We definitely see that that's the nocebo effect, right? That's, that's the one we see a lot, you know, with all sorts of drugs and it's tough because, you know, how do you how do you know which is which and I think there are some people who are really impacted by that and it makes it very difficult for them to take any sort of pharmacologic agent because they basically they can't help but incur every
Possible side effect
is it or is it true that medical students often will start developing the symptoms of the different diseases that they're learning about, is that true?
Well, you know, I'll tell you, I do think that in medical school, you start to you start to think of the zebras more than the horses all the time, you know, like you know what, I'm referring to right now. You know, you see Footprints, you see hoof prints. You should think of horses. But of course medical students. You only think of the zebras. There are some really funny things in medical school. Like there are certain conditions
You spend so much time thinking about that. You have a very warped sense of their prevalence like in medical school. There's just condition called sarcoidosis. Like, we, I feel like we never stopped talking about sarcoidosis. I've seen like three cases in my life. I like it's just not that common. Does it
provide a great teaching tool or something? I don't know. I kind of
just some of these things. I don't know how much time did we spend talking about situs inversus? This is when people embryologically have a reverse rotation and
Everything in their body is flipped, literally everything is flipped. So their heart is on the right side, their livers, on the left side there appendix is on the left side. Like and so I'm not making this up, common is this, I've never seen it, okay? I was
thing about boxing in the liver shot like it so you can easily be going for the wrong side of the body. I
swear to God like as a medical student, if you were told someone had left sided lower quadrant pain to which the answer is almost assuredly like they have diverticulitis. You'd think they could have
Appendicitis in the context of situs inversus, like the fact that I
would even register in the top 10 things
that it could possibly be a while. But yes, you just have a totally warped sense of what's out there. Yeah,
well, this has been Pure Pleasure for me, I don't know about. Yeah, this is gonna be our listeners, but for me, this is among the things that I just Delight in and and even more. So because you're the one across the table for me, teaching me about these incredible findings and white wine.
And and the gaps in those findings which are equally incredible because they're equally important to know
about. Yeah. So let's do this again in Austin.
Absolutely. Next time on your home court very well and bring a little bit of
that do if you've got
it. Oh yeah. Yeah I'll bring a low medium and high low medium and high Danvers. I want to
thanks, Peter. You're the best. All right, sir.
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