Journal Club With Dr. Peter Attia | Metformin for Longevity & the Power of Belief Effects

47:02Yeah, so 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 report it as what's the mortality rate per and it's typically per hundred thousand 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 and 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.

47:49It's because there's not that many people there Right the majority of deaths in absolute terms probably occur in the seventh decade But as you go up because the denominator is shrinking you have to normalize to it So we just normalize to the number of people here are all the people that started the year here All the people that ended the year what's the death rate why are these done in a slightly more complicated way Because we we don't follow these people for their whole lives We're only following them for a period of observation in this case roughly three years so To say something like you know, we have a crude death rate of five deaths per thousand person years One way to think about that is if you had a thousand people and you followed them for one year you'd expect five to die If you had five hundred 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.

48:49Thank you for clarifying that. No, no this this stuff is I mean like I find I find epidemiology when you get in the weeds is way more complicated than following the basics of Experimental stuff where you just you get to Push all this stuff into the garbage bin and just say we're gonna take this number of people We're gonna exclude this group. We're gonna randomize. We're gonna see what happens. Yeah, that's what like the paper we'll talk about next. Yep so When you adjust for age and they don't show it in this table It's only in the text when you adjust for age a very important check to do is what is the crude Death rate of the people on metformin who are not twins versus who are twins now in this table They look different because it's 24 .93 for the metformin group and 21 .68 for the twin group in that's on metformin when you adjust for age They're almost identical.

49:45It's it goes from 29 point 24 .93 to 24 .7 One other point I'll make here for people who are going to be looking at this table is You'll notice there are parentheses after every one of these numbers What is that what is that offer in there those parentheses are offering the 95 % confidence interval So for example to take the number you know 24 .93 is the crude death rate of how many people are dying who take metformin What it's telling you is we're 95 % confident that the actual number is between 23 .23 and 26 .64 If a 95 % confidence interval does not cross the number zero It's statistically significant Okay, so the first thing that just jumps out at you I think when you look at this is there's clearly a difference here between the people Who have diabetes and those who don't It complicates the study a little bit 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 to 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 singletons the non -tales is 16 .86 so 16 .86 people die and some people will probably think how can point 86 of a person die?

51:18Well, it's not always whole numbers, but um There's a there's a bad joke to be made here, but yeah, just call it 17 versus 25 right 17 deaths per thousand versus 25 deaths yep, and the 25 is in the folks that took met for men now That to the naive listener and to me Means oh, you know met for men basically kills you right not a faster or you 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 a Sign drug it wasn't placebo drug It let's look at people taking this drug for a bad health issue and compare To everyone else that's right So now you have to go into and and I'll just sort of skip the next figure, but the next figure is a caplin myer 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 one it's a caplin myer curve Which is a mortality curve?

52:23So you'll see these in any study that is looking at death And this can be prospective randomized this can be retrospective, but these are always going to show up And I think it's really worth understanding what a caplin myer 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 zero to one One or one hundred percent and it's always decreasing monotonically meaning it can only go down or stay flat It can never go back up. So that's what a cumulative mortality curve looks like Now we're looking at you're starting it Alive and you're looking how many people die for every year that passes that's right And in each curve there's one on the left which is the matched singletons and there's one on the right which are the discordant wins You have two lines you have those that were on metformin with type two diabetes and you have their matched controls And in this figure the matched controls are the darker lines and the people with type two diabetes on metformin That's the lighter line You'll also notice and I like the way they've done it here.

53:34They've got shading around each one And we should mention for those they're 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 who are taking metformin put crudely The people who are taking metformin that have diabetes are dying at a faster rate for every single year exam and the two lines Do not overlap except at the beginning when everyone's alive It's like a foot race where basically the 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 uh to see cappin myrocrubs cross They don't have to it's not a requirement that they never cross.

54:26It's only a A requirement that they're monotonically decreasing or staying flat 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 singletons and the discordans are dropping much faster And they always stay below And I was just going to say that the shading is just showing you a 95 % confidence interval So you're just putting basically error bars along this So if this were experimental data if you were doing an experiment with A group of mice and you were watching their survival and you were you know what you 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 familiar as statistics no problem Error bars correspond to like if you were you're just going to measure the heights of a of a roomful of 10th graders You there's going to be a range right you have the very tall kid and the in the very shorter kid and you know the short kid and the medium kid you know and so there's a range There's going to be an average a mean and then there'll be standard deviations and standard errors and uh So these confidence intervals just give a sense of how much range you know some people die die early some people die late within a given year.

55:53They're going to be different ages So it a These error bars can account for a lot of different forms of variability here You're talking about the variability is how many people in each group die. We're not tracking one diabetic taken metformin versus A control i should have asked this earlier, but Well, and it's also a mathematical model at this point too that's 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 hazard, 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 It might sort of make one other point if those shaded areas overlap 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 To Raise a common myth, which is a lot of people when they look at a paper Let's say it's a bar graph You know And they see these error bars and they will say people often think oh if the error bars overlap It's not a significant difference But if the error bars don't overlap meaning there's enough separation then that's a real and meaningful difference And that's not always the case it depends a lot on the form of the experiment I often see some of the more robust Twitter battles over you know 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 that the result could be due to something other than chance of course Your confidence in that increases as it becomes typically p -value is p less than point zero zero zero zero zero one percent chance that it's due To chance right so very low probably p less than point 05 tends to be the kind of gold standard cutoff But when you're talking about data like these which are repeated measures over time people are dropping out literally Over time you're saying they've modeled it to make predictions as to what would happen We're not necessarily looking at you know raw data points here Yeah, the raw data was in the previous table that's now taken and run through this Cox model and it's smoothed out done 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 statistical significance The only way you can say it's not significant is you have to know what it was powered to detect um and statistical power is Uh a very important concept that probably doesn't get discussed enough But before you do an experiment you have to have an expectation of what you believe the differences 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 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 % 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 % power.

59:31I'm being a little bit So there's going to be a statistician listening to this who's going to want to kill me But this is directly 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 to look at 10 % yeah, and um very important point that you're making another point that's just uh More general one about statistics in general the way to reduce variability in a data set is to increase sample size I mean that kind of makes sense right if you if I just walk into a 10th grade class and I'm going to Measure height and I look up by the first three kids that I see And I happen to look over there and it's the three that all play on the volleyball team together I my sample size is small and I'm likely to get a skewed representation in this case taller than average So increasing sample size tends to decrease variation so the that's why when you hear about a study from the UK biobank or from you know Half a million Danish citizens like for instance in this study That's those are enormous sample sizes.

1:00:47So 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 this time That's the way that epidemiology will make up for its deficit So you could never do a randomized assignment study on half a million people 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 doing an experiment where you have tens of thousands of people is prohibitive I mean if you look at the women's health initiative, which was a five -year study on I don't know what was it 50 ,000 women I mean that was a billion dollar study so This is this is the balancing act between epidemiology and randomized prospective experiments and They so they both offer something, but you just have to know they're blind spots of each one So let's just kind of wrap this up.

1:01:56I mean, I think let's just go to table four which I think is the most important table um In here which now lays out the the the final results in terms of the hazard ratio So this is this is the way we 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 sorry if it's number greater than one You subtract one and that tells you the relative harm So if the hazard ratio is 1 .5 you subtract 1 .5 is a 50 % increase in risk Um, if the number is negative you may recall on the banister paper the hazard ratio is 0 .85 So if it's an estimate.

1:02:40So 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 singletons you've got twins They're showing you three different ways that they do it. They do an unadjusted model If you just look at the singletons with and without metformin and you make no adjustments The hazard ratio is 1 .48 Meaning that people on metformin had a 48 % greater chance of dying in any given year Then they're 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 Novel from in that I've read some epidemiological studies before but it's not normally where I spend the majority of my time But up until now I was thinking okay people taking metformin are are dying more than those that aren't I just and I Just relieved to know that I wasn't um looking at all this backwards.

1:03:38Yeah, 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 uh Has diabetes and you know is taking metformin plus something else So again, we're only dealing with these constrained Yeah, now there's a lot of other harm to this study that I'm not Getting into because it adds more complexity, which is they also have another group that's got diabetes takes metformin and takes sulfonia Reyes, which is a bigger drug and those people die 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 accelerating death due to diabetes possible We could never know that from this because we're we don't see we would need to see Diabetics who don't take metformin 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.

1:04:47They 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 there on the cardiovascular psychiatric pulmonary dementia meds and marital status I don't know why they threw marital status in there, but they did I don't know maybe being married or unmarried I'm sure 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 to 1 .32 Which means yep you still have a 32 % greater chance of dying in any given year All right, what if we also adjust for the highest level of Education along with any of the other covariates well.

1:05:33That doesn't really change it at all It ends up at 1 .33 or a 33 % chance increase in death. Okay. I always knew that more school wasn't gonna save me It 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 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 doesn't and the one with diabetes on metformin still has 115 % greater chance of dying than the non diabetic co -twin When you make that first adjustment of all the meds and marital status you bring it down to a 70 % increase in risk and when you throw Education in it goes up to an 80 % chance of risk Now they did this really cool thing which was they did the analysis on Within without censoring so everything I just said here was based on no censoring tell me about censoring Sensoring is when you stop counting the metformin people who have died Okay, so In the singleton group When you unadjusted and the reason I'm doing the unadjusted is that's where they did the sensitivity analysis I don't think it really matters that much It's you just have to draw a line in the sand somewhere you'll recall that that was a 48 % chance of increased mortality all cause mortality if you stop counting and if you if you apart me if you don't censor Meaning if you include everybody including when people on metformin with diabetes die if you censor them It comes down to 1 .39 In other words, this is a very important finding It did not undo the benefits that we saw in the banister study banister saw a 15 % reduction in mortality when they censored When keys censored It got better but not that much better it went from 48 to 39 % in the twins It went from a hundred and 15 % down to only 97 % So in some ways this presents a little bit of an enigma Because it's not entirely clear to me having read these papers many times exactly why banister found such an outlined it like such a different response There's another there's another technical detail of this paper which is they you can see on the right side of table 4 They did something called the 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 another Pretty elegant way to do case control studies where you sample by year and you you you sort of normal 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 key's paper Makes it undeniably clear that in that population there was no advantage Offered by metformin that undid the disadvantage of having type two 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 my 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, you know, it's not quite that simple in the sense that as you said there are ways to Try and isolate the metformin contribution somewhat Yep Because they're on a bunch of other meds And presumably that was done and analyzed in in other figures that where they they can sort of try and They can never attach the results specifically to metformin right but There must be some way of waiting The percentage that are on psychiatric meds or not on psychiatric meds is a 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 in in the in the partial adjustment is there actually come they're actually doing their best to say Oh right, you're not married.

1:10:03They're going variable by drug by drug all the way through high blood pressure non -high blood pressure smoking non -smoking etc Right and the way they would do that presumably is um By saying okay married not married. That's what that's a simple one um 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 no no differences jumping out That can be purely explained by these other variables. Yes, although 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 all lifespan advantage.

1:10:49Yes, and we can or disease you know incidents uh studies And yeah, it might be tempting to say well, therefore eating meat is bad Um 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 That'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 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.

1:11:23I picked a silly example because the whole meat discussion then gets into Well, you know when when we say eating meat, what do we mean? It's like deli meat versus grass, but we're out there So there's no deer that you hunted with your ball that's right 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 command That's about the time I stopped taking that form and 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 this informative censoring thing is That's a little fishy and I think we weren't looking at a true group of real type two 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 their matched cohorts were on nothing would have been dying at You know a hazard ratio of three and this brought it down to 1 .5 in which case you would say there is some zero protection there It is putting the brakes on this process All of this is to say absent a randomized control trial.

1:12:51We will never know the answer Has there been a randomized control trial? Not on that form. Not when it comes to a hard outcome now there has been in the ITP So the interventionist testing program Which is kind of the gold standard for animal Studies which is run out of three labs. So it's it's an NIH funded program that's run out of three labs they They basically test molecules for zero protection The ITP was the first study that really put rapa mice on the map in 2009 that was the study that's For two it isly demonstrated that even when rabamycin was given very very late in life It was given to 60 month old mice.

1:13:30It's still afforded them a 15 % lifespan extension has a similar study been done in humans. I mean it's hard to know we can't really control with rapa mice. No 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 ITP 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 sizing And so when something works in the ITP it's pretty exciting rapa mice and has been studied several times It's always worked Another one we should talk about it in subsequent time is 17 alpha estradial This continues to work in male mice and it produces comparable effects to rapa mice and estrogen doesn't work in female rice makes but this is alpha not beta This is 17 alpha estradial not beta estradial which is the estradial that we all that that is bioavailable in all of this and just as 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 negative symptomology because of the importance of estrogen for libido for brain function tissue Health bone health Trushing estrogen and raising testosterone is just silly right there's not let's just leave raising testosterone out of it but Many of the approaches to raising testosterone that are pharmacologic in nature also raise estrogen a lot of people try and Push down on estrogen and that is just again unless people are getting um hyperestrogenic effects like got a comastia or other issues Is the exact wrong direction to go you want estrogen?

1:15:17Estrogen is a very important hormone for men and women Yeah, that's it um Can agaflose in an sgt2 inhibitor also very successful in the itp But again interestingly rapa my metformin not so metformin has failed in the itp So you no longer take a metformin? I stopped five years ago. I mean, you're not a diabetic. So presumably you're taking it for a geroprotection to buffer blood glucose Yeah, and ultimately potentially a longer yes exactly and the reason I stopped and this will be the last thing before we move on Because you couldn't go to the dairy queen at the buffet or that no finally the nausea went away after a few weeks or month maybe um But once I got really into lactate testing.

1:15:57I noticed how high my lactate was Uh at rest so a resting fasted lactate should be in a healthy person should be below one like somewhere between point three point six millimole And only when you start to exercise should lactate go up and in 2018 was when I started blood testing for my zone two so previously when I was doing zone two testing I was just going off my power meter and heart rate But this is when this is after I met in you go son Milan and I started Like wanting to use the lactate threshold of two millimole as my As my determinant of where to put my wattage on the bike And I'm like To in fingerpricks before I start and I'm like 1 .6 millimole and I'm like what the hell is going on?

1:16:41I 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 right but but and and when I being generous to your fit No, but but but that's when I started digging 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 lactate. Could you feel it?

1:17:16Sorry to know Could you feel it in your body because maybe now I'll just briefly describe I took burberry I During the period of maybe somewhere in the 2012 to 2015 stretch. I don't recall what you gave me before well I'll tell you so I I wasn't I still am a big fan of Tim Ferriss's slow carbure hydring diet because I like to me 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.

1:17:56I mean because if I can't sleep at night. I'm not going to replenish I don't replenish. I'm going to 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 four -hour body to be a very good plan for me. It's pretty easy You drop some things like bread etc. You don't drink calories I'm except after a resistance training session etc But one day a week you have this so -called cheat day and on the cheat day 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 an item of food at all.

1:18:28So 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 um What was it anal um anal seep it yeah, you know seep was I did not have that but since you said that I Um, 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 um and What I read was that burberry in 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 um spiking my my blood sugar and insulin Because you're having ice cream and you know, et cetera And indeed it worked So if I took burberry and and I don't recall the milligram count and then I ate you know a 12 donuts I felt fine.

1:19:27It was as if I had eaten one donut. Wow. I thought sort of okay in my body and it felt much much better now Um presumably because it's buffering the spike simple sugar I wasn't crashing in the afternoon nap and that whole thing And do you remember how much you were taking? I think it was a couple hundred milligrams. Does that sound about right? Um is that right yellow capsule um, I forget the source but in any case One thing I noticed was That if I took burberry 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.

1:20:03I didn't feel good and then I would eat a pizza or two and feel fine And so I realized that burberry was putting me on this kind of lower blood sugar state that was the logic anyway And it allowed me to eat these cheat foods Um, but when I cycled off of the the four out because I Don't follow the slow carb diet anymore, although I might again at some point when I stopped doing those cheat days Uh, I didn't have any reason to take the burberry and I feared that I wasn't ingesting 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 a carbois?

1:20:38No, what is that? So a carbo is another glucose disposal? Yeah, it's actually a drug that but it works more in the gut And it just prevents glucose absorption Uh, a carbois 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 ITP is a very clever system Anybody can nominate a candidate to be tested and then the you know the panel over there reviews it and they decide Yep, this is interesting. We'll go ahead and study it so when I think David Allison nominated a carbois to be studied the rationale was it would be a Chloric 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 Who was passed them out that's right, okay, and What happened was really interesting one the mice lived longer on a carbois, but two they didn't weigh any less So it what it they lived longer but not through calorie restriction That's interesting.

1:21:42Yes, and it the the the speculation is they lived longer because they had lower glucose and lower insulin And I don't want to send us 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 three diabetes a diabetes of the brain And so things like burberry and metformin lowering blood glucose ketogenic diets etc 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 burberry and acarbosate 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 inhibitor So this is a class of drug that is used by people with type two diabetes, but which I don't have but Because of my faith in the mechanistic studies of this drug coupled with its results in the ITP Coupled with the human trial results that show profound benefit in non -diabetics taking it even for heart failure I think there's something very special about that drug.

1:23:14I actually that was another paper I was thinking about presenting this time maybe we'll do that the next time But do you believe in caloric restriction as a way to extend life or are you more of the Do the right behaviors and that's covered in your book outlive and elsewhere on your podcast um And buffer blood glucose Is do you still obviously you believe in buffering blood glucose in addition to just doing all the right behaviors? Yeah, 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.

1:23:59So 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 % fewer calories for the rest of your life I'll live 30 % fewer years 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.

1:24:35It's not clear right and energy balance probably plays a greater role in glucose homeostasis than From a nutrition standpoint than the individual constituents of the meal um now that's not entirely 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 caloric deficit.

1:25:19You're going to end up having to go into caloric excess So that's why it's an interesting thought experiment. I don't think it's a very practical experiment for a person to be generally satiated and an energy balance They're probably eating about the right stuff That 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'd just love to eat I so physically enjoy the sensation of chewing that you know, I'll just eat cucumber slices for For fun.

1:25:58Yeah, right, you know, that's I mean, that's not my only form of fun. Unfortunately This is an amazing paper um for the simple reason that It provides a wonderful tutorial of the benefits and drawbacks of this type of work and I think it's also wonderful because We hear a lot about metformin rapamycin and um These anti -aging approaches, but I 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 and my patients Often ask me hey should I be on metformin and I give them a much much much much shorter version of what we just talked about And I say look if the tame study Which should answer this question more definitively right?

1:26:46This is taking a group of non -diabetic And randomizing them to placebo versus metformin and studying for specific disease outcomes If the tame study ends up demonstrating that there is a A neuro protective benefit of metformin I'll reconsider everything right? So I think that's you know, we just have to I think all walk around with an appropriate degree of humility around what we know and what we don't know But but I would say right now the epidemiology the animal data My own personal experience with its impact on my lactate production and exercise performance Uh, we could there's a whole other rabbit hole we could go down another time Which is the impact on hypertrophy and strength which appears to be attenuated as well by metformin um You know, I'll I'll I'll I still prescribe it to patients all the time if they're insulin resistant for sure It's still a valuable drug But I don't think of it as a great tool for the person 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 Choloric 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 Choloric deficit You know 500 to a thousand calories for a couple of days and then go back to eating the way that I before That short Choloric restriction slash fast.

1:28:15Is there any benefit to it in terms of cell or health? Can you you know, so reset the system? Is there any idea that the the changes the clearing of sentencing cells that we hear about autophagy that we you know that you in the short term You can glean a lot of benefits and then go back to the 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? purely in the domain of longevity not 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?

1:28:52I think the short answer is no For two reasons one, I don't think that that duration would be sufficient if if one is going to take that approach but two Even if you went with something longer like what I used to do right I used to do seven days of water only per quarter Three days per month So I was basically always like it would be three day fast three day fast seven 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 at and realize is muscle mass lost You're just it's very difficult to gain back the muscle Cumulatively after all of that loss But my thought was exactly as you said like there's got to be a resetting of the system here This must be sufficiently long enough to trigger all of those systems but You're getting at a bigger problem with neuroscience Which I'm really hoping the epigenetic Field comes to the rescue on it has not come close to it to date Which is we don't have biomarkers around true metrics of aging Everything we have to date stinks so We're really good at Using molecules or interventions for which we have biomarkers right like when you lift weights You can look at how much weight you're lifting you can look at your dexascant 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 whether or not We're moving in the right direction and if we are 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 to in terms of this space and it's unquestionably this as Unsexy as it is like who cares about biomarkers But like without them.

1:31:19I 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 Well I'm grateful that you're sitting across the table for me telling me all this and that Everyone can hear this But again, we will put a link to the paper is plural that Peter just described and for those of you They're 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 papers is 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 you know tell me what yeah, I was just about to say what's your 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 to do you read it sequentially or do you 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 um My process is always the same and actually this is fun because I Used to teach a class when I was a professor at UC San Diego Called neural circuits and health and disease and it was an evening course that grew very quickly from 50 students to 400 plus students And we would do exactly this we would parse papers and um and I had everyone ask What I called the four questions um and it wasn't exactly four questions But I have a little three by five card next to me or a piece of a main 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's the general question?

1:33:18What'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 You can get into immunos to chemistry and they did you know PCR for this it It's not so important uh for most people that they understand every method But it is Worth while that if you encounter a method like PCR or um You know chromatography or fmri that you at least look up on the internet what its 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 anyway by reading the figure headers Right what are you know figure 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 um 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 substantiated by what they found and what they did and that involves some thinking it involves really You know spending some time thinking about what what they identified now This isn't something that anyone can do straight off the mat 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 of teaching undergraduates And I think graduate students as well of how to read a paper and Again, it's something that can be cultivated um And it's still how I approach papers.

1:34:49So what I do typically is I'll read title abstract I Usually then we'll skip to the figures and see how much of it I can digest without reading the text and then go back and read the text but In fairness journals great journals like science like natures oftentimes will pack so much information The cell press journals to into each figure and it's coded with no definition of the acronyms that almost always I'm into the introduction and results within a couple of minutes wondering what the hell this acronym is or that acronym is and it's um It's just yeah, it's just wild how much um How much in omen clature there really is I can't remember was it you or was it our friend Paul Conti when he was here Who said that oh no, I'm sorry it was neither it was Cherub ophthalmology at Stanford Dr.

1:35:36Jeffrey Goldberg who was a guest on the podcast recently who off camera I think it was told us that if you look at the total number of words and terms that a physician leaving Medical school Owns in their mind and their vocabulary. It's the equivalent of like two additional full languages of fluency Beyond their native language. So you're trilingual at least now. Do you speak a language other than English? Corley okay, so you're 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 know substantial training Yeah, no, I 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 Uh, well again if I'm reading papers that are something that I know really well.

1:36:27I can basically Glean everything I need to know from the figures Um, and then sometimes I'll just do a quick skim on methods Um, but I don't need to read the discussion. I don't need to read the intro. I don't need to read anything else Uh, if it's something that I know less about then I usually do exactly what you say I try to start with the figures I usually end up generating more questions like what what what do you mean what it how what is this how do they do that? And then I got to go back and read methods typically And one of the other things that's probably worth mentioning is a lot of papers these days have supplemental information that are not attached to the paper so You're amazed at how much stuff gets put in the supplemental section 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 to pull out of the supplemental paper for example when they did the sensitivity analysis on the censoring versus nonsensoring 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.

1:37:44Yeah, 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 going to look different maybe even quite a bit different than the one that we're going to discuss Nonetheless, there are a couple of things that make me confident in the data that we're about to talk about first of all The group that publish 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 not going to mispronounce her first name, but I think it's Charles C.

1:38:51Gooh at Who's at the econ school of medicine mount Sinai runs a laboratory there study 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 to hopefully Entice people into listening further Because this is an important paper This paper basically addresses how our beliefs about the drugs we take impacts how they Effect us at a real level not just at a subjective level but at a biological level So just to back up a little bit a former guest on this podcast doctor Ali Krum um Whose name is actually Ali Akrum, but she goes by Ali Krum talked about belief effects belief effects are different than placebo effects placebo effects are really just category effects.

1:39:46It's okay. I'm going to give you this pill Peter And I'm going to tell you that this pill is molecule x5952 and that it's going to make your memory better And then I give you a memory test, right? And your group performs better than the people in the control group who I give a pill to and I say This is just a placebo or there are other variants on this where People will get a drug and you tell them it's placebo. They'll get a placebo. You tell them it's drug It's it's a binary thing. It's an 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 cooler ones I was never the subject of this But there was kind of lore in high school that you know like kids would do this mean thing.

1:40:29It'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 would start acting drunk and then they go gotcha You know it doesn't even have alcohol in it now. That's a mean joke Um and just reminds me of some of the the horrors of high school maybe that's right and 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 effects are not A or B in placebo or non placebo belief 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 Krums lab in the psychology department at Stanford Although some of this works she did prior to getting to Stanford for instance If people are put into a group where they Watch a brief video just a few minutes of video about how stress really limits our performance Let's say at archery or at mathematics or at music or at public speaking and then you test them In any of those domains or other domains In a stressful circumstance they perform less well Okay, and we know they perform less well because we're by virtue of a heightened stress response You can measure heart rate you can measure stroke volume of the heart you can measure a peripheral blood flow Which goes down when people are stressed narrowing a vision etc You take a different group of people and randomly assign them to another group where now they're being told that stress Enhances performance It mobilizes resources at narrows your vision such that you can perform tasks better etc Etc and their performance increases above a control group that receives just useless information Or these useless as it relates to the task So in both cases by the way the groups are being told the truth Stress can be Depleeting 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 it's striking their opposite interaction 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 some point between 10 and 30 percent Worse at performance than the control group and stresses enhancing is Approximately equivalent improvement so they're in opposite directions even more striking is the the studies that Alice 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 grellen secretion in the blood and Grellen is a marker of hunger that increases longer.

1:43:19It's been since you've eaten and what you notice is that suppresses grellen To a great degree and for a long period of time you give another group a shake You tell them it's a low calorie shake That it's got some nutrients in it, but that doesn't have much fat not much sugar etc They drink the shake less grellen suppression and it's the same shake and it's the same shake And satiety lines up with that also in that study and then the third one which is also pretty striking as they took hotel workers They gave them a short tutorial or not Informing them that moving around during the day and vacuuming and doing all that kind of thing is great helps you Lower your BMI, which is great for your health you get you incentivize them And then you let them out into the wild of their everyday job You measure their activity levels the two groups don't differ They're doing roughly the same task leaning down cleaning out trash cans etc Guess what the group that was informed about the health benefits of exercise lose 12 % more weight Compared to the other group and no difference in actual movement Apparently not now how could that be?

1:44:18I mean literally this was sparked by in Alley's words, you know This was sparked by her graduate advisor saying What if all the effects of exercise are 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 Alley told us because it just really speaks to how like really smart people think they sit back and they go Yeah, like exercise obviously has benefits But like what if a lot of the benefits so 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 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 little zin pouches or taken in capsule form Does improve cognitive performance?

1:45:13I'm not suggesting people run out and start doing any of those things I did a whole episode on nicotine the delivery device often will kill you some other way or is bad for you But it causes vasoconstriction which is also not good for certain people But nicotine is cognitive enhancing why? Well, you have a couple sites in the brain namely In the basal four brain nucleus psalis In the back of the brain structures Like locus ceruleus, but also this what's called it's got a funny name the pedunculo punt tying nucleus Which is this nucleus in the in the the ponds in the back of the brain in the brain stem That sends those little axon wires into the thalamus the thalamus is a gateway for sensory information And in the thalamus the visual information the auditory information It has nicotinic receptors and when the pedunculo punt tying 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?

1:46:15Oh, um Well, it's going to be a cital coline binding to nicotinic receptors. I see we're not making nicotine We're just binding so this is a this is a nicotinic acetyl coline receptor Of which there are at least seven and probably like 14 subtypes but um So Right they're called nicotinic receptors in an annoying way in the same way that cannabinoid receptors are called cannabinoid receptors But then everyone thinks oh, you know those receptors are there So because we're supposed to smoke pot or those receptors are there because we're supposed to ingest nicotine No, the drugs that we're used to study that they're receptor that's right.

1:46:47Yeah, exactly Receptor is named after the drug and so The important thing to know is that whether or not it's basal four brain a pedunculo puntine nucleus or a locusts At least in the brain because we're not talking about muscle wear acetyl coline does something else via nicotinic receptors They're in general. It just tends to be a signal to noise enhancer And so for the non -engineering types out there no problem signal to noise just imagine I'm talking right now and there's a lot 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 um For instance, and that's really what acetyl coline does that's why when people smoke a cigarette they get that boost of nicotine And they just feel clearer it really works the other thing that happens is the phalamus sends Information to a couple of places first of all it sends information to the reward centers of the brain the mesolimic 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.

1:47:50It's a we seek it out It's done beautiful experiments with honey bees even where you know you put nicotine on certain plants or it comes from certain plants And they'll forage there more you get you know the kind of like buzzed that was upon bad pun Um in any event There's also an output from this thing the phalamus to the venture medial prefrontal cortex Which is an area of the forbrain 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 Yeah, y 'all an ADHD So ADHD typically ADHD drugs so things like add or all five ants methamphetamine for that matter um riddle in Yeah, 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 They're like a laser and the reason is that ventramedial Prefrontal cortex circuit can engage is when the kid is interested and engage 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 that 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?

1:49:18It's real does every kid need ADHD meds? No, are there other things like nutrition more playtime outside etc 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 too high And generally should be you know titrated down maybe some kids need a lot some kids need a little I probably just you know gained and lost a few enemies there so um the point is that These circuits are hardwired 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 they is it a dose effect or a timing effect?

1:50:03How 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 some muscle relaxation So it's kind of the perfect drug if you think about it again It's it was reflecting on this how when we were growing up people would smoke on plane They had 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.

1:50:38Okay, 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 smokers. So these are experienced smokers Typically, there's a washout before they come in so they're not smoking for a bit So they can clear their system of nicotine and they measure how long is that needed? Typically, it's a couple of days. Oh, okay. Yeah, um, which must be miserable for those people Must because they can't have nicker right gum or anything. No, nothing. They must be dying And I wonder how many cheat but they they can measure they measure an oxide right?

1:51:10They measure carbon dioxide and they're measuring nicotine in the blood as well So they do a good job there So then what they do is they have them vape And they're vaping either a low medium or high dose of nicotine the doses just don't really matter because tolerance varies etc and Then they are putting them into a functional magnetic resonance imaging machine So where they can look at it's really blood flow. It's really hemodynamic response for those people 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 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 engineers Do you remember the right hand rule?

1:52:03Yep, 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 your 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 uh do I have that right? Um, I have to look at it actually okay, so someone will look it up But what you do is when you put a person's head in this big magnet and then you pulse the magnet What happens is the oxygenated and deoxygenated blood It interacts with the magnetic field differently and that difference in signal can be detected And you can see that in the form of activated brain areas.

1:52:40Yeah, I mean mri all works by proton detection So presumably there's a difference in the proton signal When you have high oxygen versus low oxygen concentration. Yeah, that's right Um, and what they'll do is they'll pulse with the magnet because my understanding is that um And this is definitely getting beyond my expertise But that the the spin orientation of the protons then it's 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 very very powerful technique Um, so what they do is they they put people in a scanner and then you'll like this because you'll have a What are the what are the limitations of of fmri in terms of i mean How fine is the resolution?

1:53:30I mean where are the blind spots of the technique? So resolution you can get down to sub -centimeter they talk about it always in these paper as a voxels Which are these little cubic pixels um things um You know sub sub -centimeter, but you're not going to get down to millimeter. Okay There are a number of little confounds that maybe we won't go into now that have been basically worked out over the last 10 years 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 when you're in the mri and just went for one of these recently for a clinical not a problem But just for a diagnostics and you're leaning back in 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 Just as you try and then subtract that out So now you'll always see resting state versus activation state.

1:54:31Yeah, 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 I have a dead salmon that demonstrated like some interesting signal I didn't know that but it we got to find this one for the for the show notes I we should do one of these wild papers ones There's what there are papers of you know people putting don't do this folks putting elephants on LSD that were published in science And things like like crazy experiments. We should definitely do a crazy experiments journal club um 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 because a lot of neural transmission is happening on the you know 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 ventramedial prefrontal cortex and it's a very simple game.

1:55:40You'll like this because um 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 or the the price of p's 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've given them Or they can short it they can say it's gonna go down and try and make money on the on the prediction It's gonna 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 engage this type of circuitry now remember These groups were given a vape pen prior to this where they've vaped what they were told is either a low medium or high dose of nicotine And they do this task The goal is not to get them to perform better on the task 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 That includes the mesolimic reward pathway in dopamine It includes the ventral medial 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 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 they were told they were told they got a you that this is a low amount a 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.

1:57:33Yes, that's is this is the sneak I was gonna offer it as a punchline But that's okay. No, I think that the 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 they basically 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 and 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's subjective feeling of Being on the drug matches what they were told so if they were told hey, this is a high amount of nicotine Like yeah, it feels like a high amount of nicotine and these are experienced smokers If it was a medium amount and like now that feels like a medium medium amount if it's a low amount they think it was a low amount Now that's perhaps not so surprising that's you're just a placebo and that's a placebo.

1:58:28Yeah, but If you look at the activation of the thalamus In the exact regions where you would predict a cedocoline transmission to impact the function of the thalamus So these include areas like what's called the central median nucleus the ventroposterior nucleus the names that really don't matter But these are areas involved in attention It scales with what they thought they got in the vape pen meaning if you were told that you got a low amount of nicotine You got a little bit of activation in these areas if you were told that you got a medium amount of nicotine And that's what you've raped 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 it 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.

1:59:27Oh, 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 faster where you're reading the lines better or your response time to hit the button is quicker You know, I tell you you have a drug that's 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 disser activation as more activation There could be they rule that out They also rule out the possibility how to bid rule that out by looking at rates of of pressing and there was our Nothing and in sensory areas of the brain that would would Represent that kind of difference.

2:00:13They don't see that The other thing that is very clear is that the connection between the thalamus and the ventral medial 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 pathway now of course This is all happening under the hood of the skull Simply on the basis of what they were told and what they believe and technically the fmri is showing the activation of those two areas And that's how you can infer the strength of that connection.

2:01:02That's right There's a separate method called diffuser tensor imaging which was developed. I believe out of the group in minnesota Minnesota has a very robust group in terms of neuroimaging um That can measure 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 um, I guess if we were going to look at any one figure Um, and I can just describe it for the audience that's not paying doesn't have the figure in front of them the uh, let's see i the the most um Probably the most important figure is figure two remember I said i like to read the titles of figures which is that the belief about nicotine strength induced a dose dependent response in the phthalmous basically If you and figure two b Can tell you if they believe that they got more nicotine that's uh That's essentially the response that they that they saw So if you look or sorry panel e if you look at the belief rating as a function of the estimate In phthalmous of of what how much activation there was it's a it's a mess when you look at all the dots at once But if you just separated 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.

2:02:32Yeah, it's about to say there's a control that's missing Yeah, so what they didn't do is give people zero nicotine and then tell them This is a high amount of nicotine sort of the equivalent of the cruel high school experiment Yeah, no alcohol, but then the 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 knew what it would be like to feel drunk Etc. And there's the social context what I find just outrageous and Outragiously interesting about this study is simply That what we are told about the dose of a drug Changes the way that our physiology responds to the dose of the drug and in and in my understanding This is the first study to ever look at dose dependence of belief effects Right to really and and why would that be important?

2:03:25Well 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 2b. Mm -hmm. 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 right who presumably were non -smokers Who were just put in the machine?

2:04:09That's right. Yeah, this is measuring Carameter estimate. What is that referring to Um their ability to play the the the trading game? The parameter estimate is the is the activation Reward related activities from independent to alimus mask right so what they're doing is they're just saying if we just look at the Salamis 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 phalamus to the venture media prefrontal cortex That's where you start to identify the is that figure four that is yes, so this is where you see So figure four b If you look at parameter estimates, so this is the degree of activation between The phalamus and the venture media prefrontal cortex and it's called the instructed belief you can see that there's a Low medium and high scatter of dots for each and that each one of those is significant.

2:05:17So isn't it interesting that At the phalamus which is and you'll you'll you'll immediately appreciate my stupidity when it comes to neuroscience Which is more proximate to the nicotinamide or nicotin 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, so that surprised 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 phalamus to activate this pathway But they too were surprised that they could not detect a raw difference in the activation of thalamus But in terms of its output to the prefrontal cortex that's when the that figure Forb is more convincing than figure two because even figure two e If you read the fine print the r the correlation coefficient is 0 .27 that's we it's not that strong right it's weak 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 and we're underpowered how many subjects were in 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.

2:06:47Yeah, it's expensive I mean, 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 a dainier study Yeah, you do this with a thousand people this could all be statistically significant right? It was um, so they talk about this you know based on this we estimate that an end of 20 end of 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 in a two -tilled 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'll want to be 95 % confidence.

2:07:31We need 60 people 20 per group, right? Yeah, but if the difference is smaller than what they expected They'll miss out on some of the significance which that looks like they're missing between the medium and high group 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 three talks about their belief about nicotine strength did not modulate the reward response the dopamine response How was that measured also just in FMRI So if you look at figure three B 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 then 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 who Well one thing that's sort of um interesting you asked about art potential sources of Artifact problems 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 sort of chuckling at that one But I was like I had to read that one twice and that makes sense like they're 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 Activated to such a great degree sort of like the first time effective 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 they have no Pleasant they have no experience to compare it to with respect to the obviously Beneficial effects of nicotine that the smokers are well used to so this is the the poor kid that got duped into thinking the non -alcoholic beer Was at alcohol though.

2:10:10They'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 um that kid having never been actually drunk before Presumably I would feel like it could be more susceptible more potentially. That's my guess as well. So You know my glee for this experiment is not Or this paper rather is not because I think it's the be all end all or it's a perfect experiment I just think it's so very cool that they're starting to explore dose dependence of belief because that has all sorts of implications. I mean Use your imagination folks whether or not we're talking about um A drug we're talking about a behavioral intervention.

2:10:53We're talking about a vaccine and I'm not referring to any one specific vaccine I'm just talking to vaccines generally I'm talking about psychoactive drugs. I'm talking about illicit drugs. I'm talking about antidepressants. I'm talking about All the sorts of drugs we were talking about before metformin etc. 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.

2:11:33I mean when you consider How many drugs that have peripheral effects um or peripheral outputs begin with central issues. So again, I think the GLP1 agonist are such a great example of this. 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 GLP1 Analog is is having a central impact. It's doing something in the brain That is leading to a reduction of appetite. I believe that. Yeah, yeah And I think the malstata point to Different areas of the hypothalamus that are related to satiety. Yep. That that It's at least possible.

2:12:14Yeah, I mean that you know, there's no quicker way to make a mouse over eat or under eat than by Leesioning its 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 oh these are 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 cold.

2:13:03No, you're absolutely getting it You're 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 maybe as effective simply on the basis of belief and and this is the part that makes it so cool To me is that and it's not A kid tricking themselves or the parents tricking the kid So much as the brain activation is corresponding to the belief right?

2:13:47So that's where this is 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 I think of the implications for example of blood pressure Right like we don't really understand essential hypertension Which is the majority of people walking around with high blood pressure.

2:14:30It'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 eye opening Yeah, it's cool stuff and alley 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 are 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 is less awful and they report more relief From the primary symptoms that they're trying to target So our believe about what side effects are that's Can really impact how quickly and how compatible We feel about how quickly a drug works.

2:15:24Excuse me and how compatible we feel that drug is with our entire life So maybe if we call them something else like not side effects, but like additional benefits or something It's kind of crazy and you 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 When 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 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?

2:16:24Is 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, and I'm referring to right. 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 that you spend so much time thinking about that you have a very warped sense of their prevalence You know like in medical school. There's this condition called sarcoidosis like we I feel like we never stop talking about sarcoidosis I've seen like three cases in my life right like it's just not that common Does it provide a great teaching tool or something?

2:17:05I don't know like I just some of these things I don't know How much time did we spend talking about cytos and versus this is when people Emberiologically have a reversed rotation and everything in their body is flipped literally everything is flipped So their heart is on the right side their liver is on the left side their appendix is on the left side like And so I'm not making this up. I'm calling on is this I've never seen it. Okay I was thinking about boxing in the liver shot like it's so you could 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 that they have diverticulitis You'd think they could have appendicitis in the context of cytos and versus Like the fact that I would even register in the top 10 things that it could possibly be while yes You just have a totally warped sense of what's out there.

2:17:57Oh, man. Well This has been pure pleasure for me. I don't know about you I don't know about 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 white and the 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 dude if you've got it. Oh, yeah Yeah, yeah, I'll bring a low medium and high medium and high Thanks Peter you're the best.

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2:20:40Peter Atia And last but certainly not least thank you for your interesting science