What Chronic Stress Does to Your Brain with Dr. Robert Sapolsky

Mark Hyman, MD

Full Transcript

Automatically generated. Please forgive any typos or errors in the following transcript. It was generated by a third party and has not been subsequently reviewed by our team.

Dr. Robert Sapolsky
Very high doses of cortisol are anti inflammatory, and which is why, you know, you give somebody a synthetic corticosteroid and you just flatten your inflammatory system and but then it turns out in certain parts of the brain, by the time you're dealing with chronic inflammation, stress is pro inflammatory.

Dr. Mark Hyman
Before we jump into today's episode, I'd like to note that while I wish I could help everyone via my personal practice, there's simply not enough time for me to do this at this scale. And that's why I've been busy building several passion projects to help you better understand, well, you. If you're looking for data about your biology, check out function health for real time lab insights. If you're in need of deepening your knowledge around your health journey, check out my membership community, Hyman Hive. And if you're looking for curated and trusted supplements and health products for your routine, visit my website, supplement store, for a summary of my favorite and tested products.

Welcome to The Doctor's Farmacy. I'm doctor Mark Hyman, and today we have an extraordinary guest, someone who's one of my heroes in science, doctor Robert Sapolsky, where we dive deep into the topic of stress and free will and neurobiology. He is one of the funniest and most insightful thinkers, I think, of our modern time. He's a professor of biology, neurology, and neurosurgery at Stanford University, and he spent 25 years going every summer or 3 or 4 months in studying baboons in Kenya to understand the role of stress in our lives and how it affects our brain. And his his basically work initially was around the biology of how stress damages the nervous system.

He he basically divided his work between laboratory research and his work in the field with the wild baboons, studying their relationships and social behavior and stress physiology, which we can learn about and applies to humans. He's written a number of incredible books, for nonscientists, including why zebras don't get ulcers, the trouble with testosterone, a primate's memoir, one of my favorite favorites, which is about his his journey to become a primatologist. He's sort of like the Jane Goodall of baboons. His new work is really around our behavior, understanding behavior, and free will. His book called Behave, the Biology of Humans at Our Best and Our Worst, and his most recent book, Determine a Science of Life Without Freewell, explore really deep topics.

We're gonna get all that today. And today, we we really had a wide ranging conversation, kaleidoscopic view of his life from an orthodox Jew in Brooklyn to becoming a neurobiologist and studying with Bruce McEwen, who is the father of modern stress physiology. And we dive deep into the reasons, for example, why zebras don't get ulcers because they are under acute stress and don't have the chronic stress. We dive deep into how chronic stress affects us and our physiology, and then we talk about the implications for what we can do about it, how genes affect our stress response. And then we get into this whole conversation about free will and behavior and whether or not we are agents of our own free will or that our behavior is determined by our genetics and epigenetics and biology and childhood conditioning and life experiences environment, and it's kind of a interesting and often challenging conversation because who doesn't think that we are in charge?

And maybe we're not. So I think we should just dive right in. I think you're gonna love this conversation. Again, he's one of my favorite thinkers, scientists, and philosophers, Robert Sapolsky. So let's jump in.

So, Robert, welcome to The Doctor's Farmacy. I've been a huge fan of yours for literally decades, and I've read many of your books, including a primate's memoir, your book on the trouble with testosterone, which I thought was very funny, and and some of your more recent work about free will and determinism in our behavior. And, you know, for those who don't know your work, you you really have have been kinda leading the way and are helping us understand the the nature of the neurobiology of stress. And your background, I know you you studied with Bruce McEwen who sort of the godfather of this understanding stress, and he, you know, he actually wrote one of the seminal papers on stress that I read years ago in the New England Journal of Medicine that really helped me understand our adapt adaptation to stress or lack thereof and how that causes many health issues. And, you know, going back to your book on the Primates memoir, which I read on a trip to Africa 20 years ago, it was hysterical, first of all.

And what most people probably don't know about you is you're sort of like the Jane Goodall of baboons.

Dr. Robert Sapolsky
For better or worse or something.

Dr. Mark Hyman
Yeah. No. For good or better. You you and you went for 25 years, I think, consistently every summer to Kenya, to the Masai Mara to study the behavior of baboons and to understand the stress response. And I remember the stories in your book are hysterical around you hiding, you know, in the bush, with a blow gun trying to shoot tranquilizer darts at baboons and then study their cortisol levels and stress response.

And, you know, instead of maybe you could start telling us how you got into all this. Like, how did you even start to, you know, kinda get interested in going to Africa and studying baboons and stress and all this? Because your book, why zebras don't get ulcers, is sort of like a seminal work in the whole field of stress. So I think it's it's it's interesting to hear your story.

Dr. Robert Sapolsky
Well, when whenever I have my my advisees who I'm a Stanford professor there. Whenever I have my advisees hit senior year and the ones who have no idea what they're gonna do afterward and sort of are in a panic about it. And inevitably, at some point, they say, well, when when did you figure out you wanted to do this sort of thing? And my answer always makes things much worse for them because I was about 8 when I decided I wanted to go be a primatologist and was fairly obsessed with all of it from an early age. I was writing fan letters to primatologists when I was in high school.

Dr. Mark Hyman
Diane Fosse or who?

Dr. Robert Sapolsky
Yes, with her. Some baboon researchers, including the guy who I I wound up sitting at the feet of for 4 years at college. So, yeah, I kinda focused on that early on.

Dr. Mark Hyman
It's kinda remarkable. I actually the the primatology thing is kinda fascinating. I remember being at Cornell, and Dian Fossey had apparently got kicked out of Rwanda for a minute, and she came to back to the states. And during that tour, she made a stop in my Cornell biology class, and I got to hear her speak, and it just was mind bending. And and and and always wanted to go.

And, actually, last year, I did end up going to Rwanda and saw the silverback and the mountain gorillas. In fact, I proposed to my wife in front of the silverback. Woah. Well, that's I had him stand there. He was very cooperative.

Dr. Robert Sapolsky
He was very cooperative. Hopefully, there's a picture. That's wonderful.

Dr. Mark Hyman
There is. There is. There's a picture. Yeah. I had the guide have all the other people who were on the trip with us sort of go off somewhere to look at something else.

And, you know, I don't know. But then he got up right after he pounded his chest and, you know, kinda ran and ran around. A harbinger or something. Something, I don't know what. So, you know, when when you went there and you were studying baboons, you were really trying to understand the the role of their social structure and the hierarchy you know, the the stress response played in all of it.

And so you ended up writing this book, why zebras don't get ulcers, which I think was sort of came out of some of that understanding. So would you mind sort of unpacking your understanding, your conclusions, what you discovered, what you found out about that?

Dr. Robert Sapolsky
Yeah. Well, just to sort of put it chronologically, by college, I sort of had this crisis where I was planning to spend my entire life wearing hiking boots and doing field work, and I took an intro neurobiology class and was blown away by that. So I spent college sort of in a crisis of whether I was a neurobiologist or a primatologist, and very, very fortunately, I've been able to do both and spent all those years sort of oscillating between lab and field. And the commonality to both ends of it was stress. And in the lab, what I spent my centuries on was looking at the effects of stress on the brain, and what that had to do with clinical depression, brain aging, how well your neurons survive various neurological insults, and eventually getting it down to sort of the molecular level, us sticking genes and hippocampal neurons to try to make them more stress resistant.

So I guess I could summarize all those years of saying it turns out stress is not good for you. So that's what I figured out from that, and it's especially not good for your brain. And it was, like, all things considered, fairly depressing stuff, because I'd become extremely expert at not telling people how to handle stress, but telling them all the things that were gonna go wrong if they didn't learn how to handle stress. So it was kind of a grim picture, and the baboon stuff sort of emerged in parallel going each summer 3, 4 months a year, focusing on the fact that, you know, not everybody collapses into puddles of stress related disease. We cope, and some people are amazing at it.

And baboons turned out to be a fantastic sort of model system for studying stress in us, us in westernized lives. You know, baboons who live out in the savannah, these big social groups, 50 to a 100 animals or so, and big, imposing animals, the predators don't mess with them much. Infant survival among baboons is better than among the neighboring humans. You spend about 3 hours a day having to forage to get your food. And what that means is you've got 9 hours of free time every day to devote to making other baboons miserable.

All they do is generate social stress for each. Other. They're not getting ulcers because predators are chasing them. They're getting ulcers because they're psychosocially, like, manipulative jerks. And Wow.

That's what they spend all their time and they're perfect model systems for westernized stress. So what what I went out there to try to study was what does your social rank have to do with how well your body deals with stress? And wanting the majority of the time doing sort of the Jane Goodall scene of, like, observing them and figuring out who's doing what with who in the bushes when no one isn't looking and things of that sort. But then also darting them, anesthetizing them, and being able to hold on to each baboon for a day or so and just running a whole clinical profile with them to see how's this guy's blood pressure, how's this guy's immune system working, And what does that have to do with his behavior?

Dr. Mark Hyman
Yeah. And and what you found was that, you know, as I remember from the reading of the book was that the the ones at the top of the hierarchy often had the most stress because they were the ones who were constantly being under the threat of being taken down and challenged.

Dr. Robert Sapolsky
And, yes, it turned out, you know, when the world is unstable, like your your baboon hierarchy is unstable during these periods, the last place you wanna be when everybody is out rioting is in there in the palace with the doors locked because you're at the center of all of this going on. And during periods of instability, high ranking males were miserable and elevated cortisol levels, suppression of reproductive endocrine profiles, things of that sort. But what I mostly sort of got out of it I mean, what that seemed to suggest when you looked at unstable periods where all it's about is psychological stress. You're sitting there on top of an unstable hierarchy, and you got no control. You got no predictability.

Everybody's threatening you. Positions are shifting every other day or so. But during stable periods, it's great because you've got all the psychological control if you're high ranking. So what I thought I was learning was if you're a baboon and you get a choice in the matter, you wanna be high ranking. And it turns out I wasted my first 20 years out there finding that because it turned out that was so much more idiotically simplistic than what was actually going on, which is, yeah, yeah, yeah.

Your rank is important, but so does your psychological makeup, so does the stability of your rank, so does using a word that's actually scientific, so does the culture of the particular baboon troop that you're living in, and most importantly, so do your patterns of social affiliation. And if you got a choice in the matter and you could choose between being a high ranking male baboon or one with a lot of grooming partners, you're gonna have a much healthier body if you go for the grooming partner route.

Dr. Mark Hyman
Interesting. Now one of the one of the things that I think you've kinda highlighted was the sort of difference between acute stress and chronic stress. And the the title why zebras don't get ulcers is sort of a kind of a kind of a humorous attempt to describe that, which is zebras are stressed for a very short period when the lions are chasing them. And then once the lion kills the zebra, the the rest of the zebras go back to eating the grass, and the lion eats the dead zebra, and then everybody's just hanging out. And I literally saw this when I was in Africa recently.

You see, you know, there's all these prey and predators hanging out, but the prey are not worried because the predator already has one of them.

Dr. Robert Sapolsky
Right? Yeah. Basically. And, you know, you look at something like a zebra and it's just had this life threatening sprint with a lion after it and thank God it got the guy next to you instead of you sort of thing. And, you know, one is projecting.

But as far as I can tell, 30 seconds after it's over with, all that zebra is thinking about is, do I eat this blade of grass or that blade of grass? It's a rapid emergency stress response with a physical crisis, which you either survive or you don't, and the same exact thing for the lion chasing the zebra. And what you're looking at there is what stress is about for 99% of the beasts out there, which is a short term physical crisis. And everything your body does at that point is fantastically adaptive for getting you through that emergency. And then you get smart primates who in the last, I don't know, 10000000 years or so have gotten socially sophisticated enough that what they can do instead is chronically activate each other's stress responses for psychological reasons.

And the punchline of the whole field is that's not what it evolved for. It it evolved for a 3 minute emergency. And if you instead are constantly mobilizing it because the alpha male in your group is a jerk and keeps harassing you, or because you've got a horrible job and your boss is terrible and you're trying to pay the bills. If you do it chronically, you're more at risk for all sorts of stress related diseases. It's a system that's meant to be a short term solution to a short term crisis.

Do it chronically, and it just corrodes away at your health.

Dr. Mark Hyman
Yeah. I mean, I think the the science is so clear on this, that chronic long term stress either exacerbates or causes almost every known illness. And the the thing that is your focus is really the the biology of the brain and the role of of the stress on the brain. And I think I think people don't understand the impact on the not only the the physiology, but even the structure and function of the brain as a result of chronic stress. And, now I think, you know, the way I always sort of think of stress, I don't remember where I heard this definition, but it's it's it's a real or imagined threat to your body or your ego.

So it could be a real threat, like, a lion's chasing you, or it could be an imaginary threat because your husband comes home a half an hour late from work, and you think he's having an affair, and he was just going to get you flowers. Right? And so it's basically the same physiological response. The body is not that smart and differentiated, but it creates this this pattern of damage to to all your physiology, but particularly, you know, the brain. I think that the role in the hippocampus and cognitive decline and mood and anxiety and depression, you know, we're living in such a chronically stressed time right now where we're inundated with pressures from society in terms of the divisiveness and conflict, the the, you know, inundation of, you know, social media, which is constantly stressing us out.

The the financial stresses of living in this modern world where there's all these inequities, the environmental stresses of climate change. So just all these layers upon layers of of both metal level stress as as well as individual personal life stress. And and I think the consequences are quite quite severe as a doctor when I treat patients, and and I'm would love to hear your perspective on, you know, what are the specific physiological things that happen and the mechanisms by which those harm us? Because everybody knows stress is bad. I'm not sure everybody knows how it actually happens in the body that and what the consequences are that drive drive the the the diseases and the and particularly the issues around our our brain health.

Dr. Robert Sapolsky
Well, sort of starting off with the hippocampus, which is a part of the brain I I love dearly, and it's involved learning and memory. You wanna have a hippocampus. If it gets damaged, you wind up with a very characteristic dementia, Alzheimer's. The hippocampus is ground 0 for damage in Alzheimer's disease. And it happens to be a part of the brain that's exquisitely sensitive to this one class of stress hormones called glucocorticoids, cortisol, corticosteroids, all of that, which are the hormones I've spent all my time thinking about.

And what you see is exactly the point you raised before, which is this distinction between short term stress and chronic. Short term stress, what happens is glucocorticoids get into your hippocampus and make it work better. You get more oxygen delivery. You get more glucose delivery to the hippocampus. Your synapses become more plastic, more flexible in terms of learning new stuff.

What's this about? You have, like, an hour's crisis or a day's crisis or whatever, and you're alert, and you're focused, and you are remembering every bit of this forever after, your flashbulb memory, and you were thinking clearly and this sort of tunneled sensory sort of acuity at that point. And there's a whole bunch of mechanisms by which glucocorticoids are doing that in the hippocampus. And then instead come back 3 weeks later, and the same exact stressor has still been going on. And what you see is do all that same stuff in the hippocampus for months or years or decades instead of, you know, short term, and it's damaging the neurons there.

Because what you do is you set the neurons basically on an emergency energy budget. Don't bother storing energy. Don't do it wisely. Don't do it because it's an emergency and you gotta run for your life. And if you do it chronically, what my lab and others spent years on was you get a hippocampus that's a little bit energy deprived.

And thus, over the course of whatever, it's got a little bit less energy to mop up oxygen radicals as they accumulate, a little less energy to do DNA repair, a little less energy to get rid of misfolded proteins, and you just kinda kick away at the ankles of these hippocampal neurons and make them more likely to keel over after a while, and that turned out to essentially be the mechanism for it.

Dr. Mark Hyman
And and that clearly can lead to cognitive decline dementia. And I think I remember actually reading a study where they looked at, I think, Cushing's, induced Cushing's in rats, which is a disease where you secrete high levels of cortisol or the glucocorticoids without any feedback loop. So that basically for those listening, it's just a tumor that just pushes out cortisol. And in those rats, the hippocampus shrink. And then when they took the tumor out, it grew back.

So it seems as though the hippocampus can grow back and then get larger.

Dr. Robert Sapolsky
Well, yeah. Good news and bad news. But that turns out exactly the same in humans with Cushing's syndrome. You get hippocampal atrophy, potentially within the ballpark of how much the hippocampus shrinks in Alzheimer's disease, and you get memory problems. And, yeah, you go in and you fix things up, and you get rid of the tumor.

And over the next couple of years, the hippocampus grows back to its normal size, and you recover your memory stuff. And that's wonderful. Then on the other side of town, they figured out that something similar happens with chronic depression. And depression in a significant subset of individuals is a disease of elevated cortisol levels. It's a stress And you see people with long term major depression.

You also get atrophy of the hippocampus. And the more atrophy, the more memory problems. And this is now a 30 year old observation. And at this point, the best evidence suggests that get the depression under control, get it finally sorted out, and you don't necessarily get the recovery. So the damage with major depression appears to be more permanent or at least long lasting than you get with Cushing's.

So that one's kinda bad news.

Dr. Mark Hyman
Yeah. Well, you know, also just from my lens, inflammation is a big driver of depression, and inflammation has many causes, including stress. And and that inflammation does lead to this kind of chronic state of depression as as part of what it can do. But I'm wondering if that may be causing part of the persistent brain damage. In other words, you may treat the symptoms of depression, but if you don't deal with the underlying cause that's driving inflammation in the brain, maybe that's why the brain doesn't recover.

Dr. Robert Sapolsky
You think that's possible? I think that's a huge piece of it. I mean, anybody, like, you know, back when we were in kindergarten, we were being taught that cortisol was anti inflammatory, and it's like the wonder drug for doing that. And it turns out he got that same double edged sword, short term, very high doses of cortisol or anti inflammatory, and which is why, you know, you give somebody a synthetic corticosteroid and you just flatten your inflammatory system and, yeah, it decreases in but then it turns out in certain parts of the brain, by the time you're dealing with chronic inflammation, stress is pro inflammatory. By the time you're dealing with chronic stress, it's doing exactly the opposite, and that includes the hippocampus.

There's, like, transcription factors that are central to cellular inflammation that are activated by chronic cortisol exposure, things like that. So that's exactly it. That's another one of those domains. Inflammation is not only exacting a big price on a neuron in terms of trying to clean up the mess that it's causing, but inflammation is causing exactly the sort of oxidative oxygen radical damage in neurons that are kind of the pacemaker of neurons just getting frayed at the edges.

Dr. Mark Hyman
Yeah. It's interesting. And, you know, of course, you know, when we think about stress, we think about how do we then navigate that. Right? Acute stress is whatever it is that you discharge it, you run from the tiger, but chronic stress is something we actually have to deal with actively.

I I always say I call it active relaxation, whether it's meditation, breath work, yoga, taking a hot bath, getting a massage, whatever it is, sauna, cold plunge is my favorite. I mean, you've gotta do something to discharge that that response, which is something that we all have living in our modern society. So almost seems like it's an it's almost essential as eating or sleeping or exercising, and and yet it's not something we learn. What have you learned about therapies or treatments or approaches that are addressing this chronic activation of our stress response?

Dr. Robert Sapolsky
Well, what I've mostly learned is I personally am terrible at stress management. I'm like I'm I'm a poster child of do what I say, not what I do sort of thing. You know, why else do you spend decades spending 80 hours a week in a lab, like, trying to understand this stuff? But from my completely untouched by knowledge stance of knowing the stress management literature, what you're tapping into is what is it that makes psychological stress stressful? When you sit there and you think about global warming or what's happening on the other side of the planet or, oh my god, what's that, like, throbbing pain in my left butt?

Do I have left butt cancer? Or, you know, any any of that neurotic stuff. What they all revolve around is a sense of loss of control and loss of predictability and loss of outlets and loss of social support. And a lot of what some of the most effective stress management techniques are out there is, yeah, yeah, step 1, figure out the things you really can't change, so don't try to change those, all of that. Yeah, yeah, you don't wanna get predictive information about stuff you have no control over whatsoever, all of that.

But once you sort of focus on the demarcated domain in which lack of control, predictability, etcetera, are just rotting you away, that's where interventions help enormously.

Dr. Mark Hyman
The meaning we make of things is what causes stress, I think, in a lot of a lot of the cases. I mean, sometimes there are real stresses. There's, you know, war or natural disasters or real crazy stuff that happens. But a lot of the time, it's our mind that's making us stressed. And Absolutely.

And it's our own, like you mentioned, the neuroticism, we're all we're all subject to that. And I think this is where where I think some of your newer work, I'm very curious in exploring because as I was sort of reading it and your work work around determinism and free will and human behavior, which sort of follows off from your previous work, you know, it kind of, in my mind, sort of echoed Buddhism. I don't know if you have ever kind of connected to that, but the whole idea of the conditioned mind and that our responses are conditioned by our past, whether it's past lives or our beliefs or our perceptions that are mistaken, you know, kind of a false filter that we have on the world, that's what seems to cause us to have the most suffering. And when Buddha talked about suffering, you maybe you could call it stress too. Maybe that's another word for the suffering.

I wonder, you know, in terms of of the sort of ways of thinking about this, you know, on one hand, you're talking about stress being a sense of lack of agency and self determination and control, but I'm I'm very curious how this sort of intersects with your recent more recent work around your hypothesis that we don't have free will and that we're determined in our behaviors and and our responses to what happens to us in life.

Dr. Robert Sapolsky
Yeah. Well, it fits into it very well. Let me let me give a last shout out to my baboons to show, like, your point of a few minutes ago. The meaning we attach to things is as impactful on our body or health, all of that, as the external reality. A great example of, like, my baboons are smart enough for that.

You look you look at their dominance hierarchy and you look at number 5 and say when the hierarchy is stable, nobody's having many fights. 5 knows just where he is in the hierarchy and all of that. But then you look at what would be called rank reversals. Number 5 has a fight with number 4 and wins. Number 5 has a fight with number 6 and loses.

So rank reversals, they're big fights. They're physically endangering. They're stressful, all of that. But you look at their stress hormone levels and you see something interesting. You're having a dominance reversal.

You're number 5. You're having a dominance reversal with number 6, and your cortisol levels are through the roof. You're having a domino reversal with number 4 and they're not. Having a reversal with number 4 means you're pushing for a promotion. Having a reversal with number 6 means this guy is breathing down your neck.

Same fight, same canines, same all, but totally different social meanings. But, you know, in terms of this this Oh, actually,

Dr. Mark Hyman
before before we jump to the the new question asked you, I wanna I I had a thought I wanted to ask you about, and I I think it's it it just goes back to the research you're doing on gene therapy for how you protect vulnerable neurons from disease and gene transfer techniques to to protect neurons against the the harms of the stress hormones like cortisol. I found that very fascinating, and and and it seems sort of, you know, I think, oh, we just meditate. Right? But you're like, no. We're gonna do gene therapy to fix this.

So can can you just talk about that for a little bit? And then I wanna get kind of veering it back into the free will determinism behavior conversation.

Dr. Robert Sapolsky
Yeah. This was, you know, sticking a gene. Sticking a gene, you figure out a cell in your body isn't doing enough of what it needs to do, stick in a gene that will boost it up. A cell in your body is doing too much of something, stick in a gene that could counteract it, go find some completely novel gene from some bizarre organism that has some amazing ability to withstand some extreme and stick a gene from it in there. And in principle, you're you're good to go.

You're all set. It should be wonderful. And we started that work in the sort of mid nineties, a few groups of trying to do gene therapy in the brain. And what was clear was the field was gonna be about 30 years behind everybody doing gene therapy on livers and gene therapy on pancreas and things of that sort because the brain's a total pain to try to do it's, like, inaccessible under your skull. It's really fragile.

It's got all these different subparts. It's tough to get stuff in there. And from the start, we and others were able to come up with some very cool gene therapy stuff. We we even invented an artificial gene, that we could stick in a rat's hippocampus so that during stress, it became less anxious instead of more. You were flipping around the effect.

That's totally great. And all these years later, it's still not on your neighborhood grocer shelf sort of thing. Gene therapy in the nervous system remains just an intractable problem in terms of how do you get in there. With a rat, you drill a hole in his head and you inject the stuff into the very spot you're thinking of. The field kind of hit a wall in some ways.

I I, sort of retired from the neuronal gene therapy business around around 2010 or so. It's been a big disappointment. We were so damn giddy back when we were gonna be able to, like, just all you had to do was figure out how to get the stuff into your brain, into the right part of your brain, into the correct part, and not waste 99% of it that winds up in your bladder, and the problem still hasn't been quite solved. So that was a sort of big professional sort of dead end for some of my research. We were pretty damn optimistic.

Dr. Mark Hyman
Well, I wouldn't be too disappointed because it seems like there's a lot of research now understanding the the role of genes in affecting our response to stress, everything from something called COMT, which is involved in methylation, neurotransmitter breakdown of dopamine that leads to increased stress responses or variations in something called BDNF, brain derived neurotrophic factor that affects, you know, lower capacity to deal with stress, serotonin transporter genes, receptor genes for cortisol, and monoamine oxidase genes, oxytocin receptor genes. All these genes we're learning about have explained partly why some people have their unique responses to stress, which may be different than other people's or why some people are more susceptible to stress. Or we even see this in, you know, holocaust survivor children or even the the babies who are born to women who were in New York during 9/11, and and they have epigenetic changes that affect their glucocorticoid receptors and epigenetic changes. So it seems like there's a lot of ways maybe rather than gene editing to actually even influence the function and expression of these genes. Is there is there much data there that you're aware of about how to sort of modulate these?

For example, like CMT, you can give methylating cofactors like b vitamins that actually help this gene work better, for example.

Dr. Robert Sapolsky
Exactly. There's, you know, neuropsychopharmacology, sure ain't perfect, and there's oceans of people who are not helped by the drugs out there, but nonetheless, they are miraculous in some circumstances. Or, you know, you could go do gene therapy and take somebody's brain out and centrifuge it and stick in a whole new DNA and put it back in. And it's totally wonderful in terms of them dealing with stress in theory. Or you can help them figure out where's the needless stressors in their lives.

Why do they get anxious in these circumstances? Why do they have trouble telling the difference between threats and non threat? Why? Because that's as effective, if not more effective, of a way to access things like methylation of your genes. That's what's going on when psychotherapy does something good.

That's what's going on When you come back from a vacation and, like, if they could measure your telomeres and your white blood cells, they would have recovered ever so slightly from the previous misery of stress they'd be going through. You know, the system is accessible on the psychological level, on the psychosocial level, on the pharmacological level, and on the nuts and bolts level. And in some cases, you know, one of those pathways is a more effective and more, you know, pragmatic, sort of conduit into getting how things work. In that context, I mean, some of the most exciting stuff out there is seeing exactly as you say, genes having to do with brain resilience, brain responsiveness to trauma, things of that sort. And what you see over and over is this theme that these are not genes that doom you to major depression or an anxiety disorder or post traumatic stress disorder.

These are genes that make you vulnerable if you've got the crummy luck of being in the wrong type of environment. They're fault lines. They're cracks in the system where if you luck out and, for example, you don't have an adverse childhood, having a particular gene variant of one of these genes relevant exactly as you said to serotonin transport, luck out and have a nonadverse childhood, and it doesn't matter which variant you have. Have lousy luck and have lots of childhood adversity. And if you've got one variant of the serotonin transporter gene, you then have about a 30 fold increased risk of major depression than if you have the other variant.

These are genes about potential and vulnerability and fault lines, and these are not genes about genetic determinism in the slightest.

Dr. Mark Hyman
That's right. Exactly right. I think that's an important point. I think, you know, we do SNP testing in my practice as a doctor, which is measuring these variations in our genes. And, you know, you can see that people have susceptibility genes to various things that we just talked about.

And that though the the data is kind of exciting because those genes can be modified in expression by mindfulness practices, by exercise, by omega 3 fats, by certain nutrients and herbs like curcumin or green tea, which, you know, are are things that are vitamin d that we can actually use to sort of modulate these pathways, flavonoids and magnesium, for example. And and so it's not hopeless. Even if you have certain genes, you can modify how those genes are expressed and and then in turn how your stress response is and then, of course, how your mental health is, which is what this is all about at the end of the day. Right?

Dr. Robert Sapolsky
Exactly. And what what that also tells you in passing is the really important point that genes are not the be all end all. Like, saying a gene knows what it's doing when it's deciding to be activated or stuff is saying, like, a recipe in a cookbook is deciding when you make the cake. Nah. Most of what genes are about are the on and off switches.

And what turns the switches on and off? The regulatory sequences. 95% of DNA is not coding for genes. It's the instruction manuals. It's the on and off switches.

And what's that about? That's psychological state. That's the environment. That's here's oh my god. You sit there and you read about, you know, refugees swarming out of Gaza or something, and you change gene regulation in a part of your brain having to do with the stress response.

That's what you you give birth and you smell your newborn baby's tush, and as a result, you you activate oxytocin genes in your hypothalamus. Woah. Those genes are not controlled. It's that they're just things that the environment is able to impact and control exactly in the good ways you outline and exactly in all the bad ways as well.

Dr. Mark Hyman
Well, this this sort of leads me to sort of ask you about, you know, if we can modify some of these things, how this fits in with your your sort of seems to be a little bit of shift in your hypothesis from the trouble with testosterone where you kinda argue that, you know, there was there was self determinism. It wasn't completely a deterministic kinda world we live in. But your your new book, which everybody should definitely check it out, it's called determined a science of life without free will, which sounds kind of scary because we all think we're these, you know, independent, free thinking, free acting human beings. You're you're coming at this not not as a from the perspective of a sociologist, but as a biologist and as a neuroscientist. And and I found it really fascinating to sort of try to understand your perspective because it it sort of it's a little bit abrasive to our own our own, self delusional view that that we're in control of everything.

Dr. Robert Sapolsky
Right? Yeah. It's potentially, immensely demoralizing. Although, you know, what most people who suggest, you know, there's less free will and people think, the the take home message at the end is usually along the lines of, well, tough luck. Suck it up.

This is how things work. And a lot of well, about half of what the book does is take you through where behavior comes from, what's happening when you think you are making a choice, when you form an intent and you do something. You pick vanilla over strawberry ice cream. You choose to shoot somebody or not shoot them. What of what's going on, and it turns out you can't make any sense of it outside the context of what your neurons were doing a second before and what the environment was triggering 2 minutes ago, and what this morning's hormone levels were, and what traumas or stimulation you had over previous and what your adolescence was like in childhood, and your fetal epigenetic programming, and your genes, and the culture in which you were raised, and the sort of ecosystems that sculpted that culture into being, and evolution, all and you put all

Dr. Mark Hyman
those Jewish guy in Brooklyn, you mean?

Dr. Robert Sapolsky
Yeah. Exactly. Sort of the the epigenetic scars that that has left. But you look at that and you look at all those pieces and how they interact, and what you see is it's one gigantic sort of arc of biology that we had no control over what we were handed, interacting very significantly with environment that we had no control over. And you look at all those pieces, and there's not a crack anywhere in there that you could shoehorn free will into.

And when you look at sort of, you know, 95% of philosophers by polls that are done are what are called free will compatibilists. They're willing to admit there's things like cells and molecules, and then there's, like, a physical reality to the universe. But somehow somehow that's compatible with still we have freedom to act free from the biology that brought us to any moment as to who we are. So, like, my song and dance with it is when you really look closely, there is no free will. We are nothing more or less than our biological luck interacting with our environmental luck.

And every explanation that philosophers or some scientists give for how somehow you can still pull free will out of the hat, the argument falls apart somewhere along the way because that's not how the brain works, that's now that's not how subatomic par particles work, that's not how nonlinear chaotic systems work, things of that sort that, you know, there's no free will. We're biological machines, which then brings us to the, like, oh, this is incredibly, like, demoralizing. And what I make the argument of in the second half of the book, which is sort of, oh my god. What would happen if everybody actually believed there wasn't free will? How are we supposed to function?

What's the world supposed to look like? And I make the argument that, historically, every time we have subtracted free will out of our view of some aspect of human behavior, not only hasn't the roof caved in, the world's become a more humane place. And getting rid of the sense of free will over and over is a liberating thing.

Dr. Mark Hyman
So tell us how because it's it doesn't sound like that to the average person listening. A rain dance. Sound like autism, the refrigerator moms. You know? What about, like, on a practical level?

This because I know people are gonna be I'm just gonna be I imagine what people are listening. And, like, for example, I had a patient who lost a £106, and she decided, I don't wanna be overweight anymore. I'm running healthy. I'm gonna turn 60. I wanna get my life under control.

And in her mind, she decided to change her life, and she lost £106. Is that not free will?

Dr. Robert Sapolsky
No. It's fantastic news, but it's not free will, because all you have to do is start with somebody who is in the exact same physical shape as her and just as intently wants to lose weight and just as intently has had quality of life impacted by it and is making the same resolutions on New Year's Eve or whatever. And 2 years later, it hasn't happened with them. And you gotta say, how did your patient turn out to be the sort of person with the neurobiological capacity to self regulate appetite? Where did they get that?

And that's not made out of magical backbone. Regulation of behavior, impulse control, you know, emotional regulation, things like that, that's made of the same neurobiology stuff that determines whether you're left handed or right handed, and that's another aspect of luck. It's luck that could be compounded by interventions. So you sit down 2 people, and they're both overweight to the same extent, blah blah, etcetera, and you teach both of them the impact of a healthy diet has on weight. And one of them, it sticks, and one of them, it doesn't.

One of them happened to luck out with a sort of brain that could generalize lessons like that into changing lifestyle. One of them had the ability to imagine themselves as thin as a result of taking your advice, and that gives them motivation with their dopamine system is enough to get their frontal cortex to tell their hypothalamus, no. Don't eat the Oreos. You're really gonna be hap one of them just wound up having a sort of brain that's more malleable to certain types of environmental shaping, and they were able to do it. And that's great.

Dr. Mark Hyman
Yeah. I mean, I think for sure. I mean, I think different people have different capacities to change. But, you know, I I I I majored in Buddhism at Cornell, so I'm a bit of a weirdo. And, and learning about Buddhism was fascinating because, you know, it talked about this idea of the conditioned mind, that all of our responses are conditioned.

And essentially, that's what you're talking about. And and their hypothesis, the Buddhist sort of essential tend of the hypothesis, is that you can decondition your mind, that you can unravel all the conditioning that happened so that you are meeting reality in the moment with with pure consciousness. Now I don't know if you think it's a crock of shit or if you actually buy into that, but but I it it I know I noticed in my own life that I've had certain behaviors or things that have been conditioned by my childhood, and I've worked really hard to unpack those and to rewire that in a way that my inner dialogue changed. So it wasn't I was just willfully changing my behavior, but I literally rewired the pattern so that I don't have the same response that I used to have to the same exact, you know, event. So I just wonder, how do you how do you see

Dr. Robert Sapolsky
this Where's that framework?

Dr. Mark Hyman
Yeah. How does the sort of the Buddhist framework fit in? Because it's sort of like it kind of agrees with you fundamentally that all of our reactions and responses are conditioned, And and whether they just describe it from, you know, early life or past lives or whatever, karma, but but the but the whole thesis of Buddhism is that you can learn to decondition your mind, and there's a set of practices that you do in order to undo those conditioned responses so that you can actually have a authentic meaning of life in the moment.

Dr. Robert Sapolsky
Good. And within certain parameters, that's that's exactly this. Like, why has that worked for you and not for other people? Part of the random luck that you have, you wound up with a sort of mind that can introspect, that could look back on things and look for patterns and generalize from them. You have the sort of mind, it turned out, where you have the ego structure or whatever to be able to say something like, you know what?

This isn't working for me. This isn't and I'm gonna you have this sort of mind where you can go and gather information about inspiring examples of people. Wow. I could become less of a jerk because I just read this great article about this ex white supremacist. And they woah.

They could people can change. Wow. I've and you turned out to be the sort of person who could do that. And through no great, you know, moral worthiness on your part, parenthesis, and no great absence of moral worthiness for people who don't manage to lose weight or have the discipline to study hard or any of those things because it's just did you wind up turning out to be the sort of person who could reflect and build on that and apply to yourself and be willing to face when you need to make change and learn from other examples and generalize and blah blah and all.

Dr. Mark Hyman
But isn't that a little bit of free will? Like, a little bit?

Dr. Robert Sapolsky
No. No. Because you turned out that's how you turned out. How does it turn out that way? Okay.

So you notice that you've got some behavioral patterns that you've been conditioned to do that are damaging or or counterproductive or whatever, you and somebody else realizes the same thing about themselves. And what you are now asking your brain to do is regulate that conditioning to override it, to restrain it, to have some impulse control in a particular circumstance. And that's got something to do with a part of your brain called the frontal cortex, which makes you do the harder thing when it's the right thing to do. So, woah, what kind of frontal cortex did you wind up with? Get born into poverty, and by age 5, your frontal cortex's growth is lagging behind the average.

Have a trauma, and your frontal cortex is going to atrophy a bit. Have a stable, loving environment where you grow up with low cortisol levels, and you're gonna have a much better front same thing. Wow. I had nothing to do with my eye color. I had nothing to do I had nothing to do with whether life handed me a frontal cortex that's able to, like, make choices in tough circumstances or not.

Dr. Mark Hyman
So what does that what does that, apply for people who wanna, like, get healthy, for example? Are they just they're sort of screwed if they they wanna get healthy, but they can't overcome their innate conditioning and they're just, like, stuck being sick? Or I mean, I just No. Because I'm like, people are thinking, like, well, yeah, I wanna get healthy. I wanna change these behaviors, that behaviors.

I'm gonna choose to do that. You're saying all the things that led up to that second and that moment of that decision were all conditioned in advance.

Dr. Robert Sapolsky
Including the means to make change. Because if you've lucked out, you know, we're all just biological machines. There's nothing but buttons and levers. But if you've lucked out, you can learn where the buttons are and where the levers are, and which ones you're really neurotic and ineffective about accessing, and which ones you turn out to be good at, and what sort of encouragement you need, and what sort of role model can inspire you to do that. And you begin to figure out how that and if you're one of the lucky ones, that's a conduit of change.

And all of that, again, is within this framework of this is not you choosing to change, exercising free will. You lucked out. You wound up with the sort of brain where you could change your lifestyle in response to useful news about health or, like, being able to, like, imagine what a heart attack would feel like or or whatever version of it. And what that also speaks to is one of the things people freak out over unnecessarily when you push a notion that there's no free will. That doesn't mean nothing can change.

That doesn't mean the universe was already set 3 seconds after the big bang. All it means is you have to understand what conditioning has given you in terms of insights as to where your buttons and levers are, and you get massive change. People change beyond belief. Societies change all of that, but you don't choose to change. You sort of learn this is the circumstance that makes me more likely to change.

Oh, you come out of some inspiring movie, Hotel Rwanda, or something about the Rwandan genocide, and some people come out and say, woah. Depressing as hell. And some people come out and say, great cinematography. And some people come out and say, wow. I never knew about that.

I wanna go read more about it. They lucked out and had this sort of brain where that turns them into wanting to acquire more information that will reinforce the humanitarian reflexes they came out from. Wow. I'm gonna go learn about, you know, Doctors Without Borders and what they do in refugee that's where change comes from.

Dr. Mark Hyman
Now now what what you're saying has broad implications, and you write about this. And I think, you know, taking it to the extremes, both in terms of there are criminal justice system and a meritocracy, you're both you're you're saying both of those, we have it wrong. Like and and what are the implications of what you're saying for how we deal with criminal justice and also how we approach our our the structure of our society from the perspective of meritocracy? Yeah.

Dr. Robert Sapolsky
You everything has to go out the window if you really think through the implications of this. If there's no free will, if that's really how stuff works, it is both intellectually and morally unacceptable to ever blame or punish someone for its own sake, to ever praise or reward somebody, to ever feel like anybody has ever earned anything, has a right to anything, that you are more entitled to anything more than anybody else, that because you didn't earn it. And they don't deserve it, and there's no such thing as justice being served. And this person doesn't have a better moral fiber because they turned out to be a CEO, and this person doesn't have a rotten one because they turned out to have antisocial behavior or any of these. And if you really work through the implications of that, and it's somewhere around here.

This this is as far as I'm capable of going with this Buddhism stuff, but I'm told all of this has some semblance to this Buddhist concept of unselfing if you are not entitled to have your needs considered more than any other human out there. There is no person out there whose needs are less worthy of consideration than your own if you really think through this. And it makes no sense to hate anyone because that's like hating a volcano that erupts because they had no control. And, you know, these are the implications of it. And fully accepting these implications, I'm able to function that way for about 3 minutes every other month because it's hard.

It's really hard.

Dr. Mark Hyman
What does that mean? That we let everybody out of prison and that we don't reward people for good behavior?

Dr. Robert Sapolsky
Well, we figure out how to make society safe from people who turned out to be damaging and do it in a way where you constrain them from being damaging. And in a public health model, you don't go an inch further. You figure out in a sense the minimum needed and you don't preach to them about how they have a rotten soul. And you put a lot of effort into understanding the root causes of how do people wind up having problems with empathy or having problems controlling their temper or whatever. And we do that all the time.

And we don't even realize this is a realm in which we have subtracted out free will. Your kid your kid is sneezing. Your 5 year old kid is sneezing. And what do you do? You keep them home from kindergarten tomorrow because the rule is if your child has a cold, please keep them home so they don't get everybody else sick.

Oh my god. Your child has become menacing as a potentially damaging agent in society there. You gotta constrain them. You keep them home. You don't keep them home and tell them they can't play with their toys because they've got a rotten soul.

You don't preach to them. You sure hope somebody figures out how to prevent nose colds in 5 year olds or whatever, and you hope more research is done on that. And that's a quarantine model for how to deal with that. And we don't realize the extent to which we do that all the time. We have figured out not only do people with epileptic seizures not sleep with Satan, and that's why this happens, but we've learned what some of the rules are for how long somebody needs to be seizure free on their medication after they had an unexpected seizure, blah blah, before it's okay for them to drive again.

You know what? Let's go 6 months without a seizure, and you can drive again, but that doesn't mean we're months without a seizure, and you can drive again, but that doesn't mean we're gonna burn you at the stake, accuse you of being Satan's spore, or preach to you about it, and let's sure as hell hope that people will figure out how to prevent epilepsy. It's a public health model where you have subtracted the notion that punishment is a virtue in and of itself or reward is a virtue in and of itself. And that one's a tough one. How do you figure out a world to, say, motivate somebody to put in enough obsessive work to be like the world's expert on some obscure poet or to be really good at taking out people's brain tumors?

And how do you motivate people to do that really hard work and not have them come out at the other end and where they feel morally entitled and morally superior? And how do you do that? Not easy. So it's little steps at a time. It's very good that we figured out that people cannot be born innately meant to be the king of your nation, that there's not divine rule.

Yeah. We got past that one. We're still trying to figure out how we feel about people who've found a company and become gazillionaires and have an Or people who turn out to be really smart or really kind or really any of those things. And we somehow have to transition from saying, woah. I'm so grateful that you helped me just now To saying, I'm so grateful that you turned out to be the sort of person who was able to help me just now.

That it could have been so many different that's how you turned out. And you turned out to be standing next to me at this moment that I need to, woah. I'm so grateful that you happened. It's a it's a more global version of saying, tell your mother she did a good job. You're not responsible for the fact that you were a good human, and you just did this kind thing.

Maternal influences, hormonal influences, genetic influences, epigenetic influences, all of that. I'm so grateful that it just happened to turn out that you're somebody who's really good at that. And you do that enough times, and people will start thinking, wow, I'm so grateful that I turned out to have good dexterity and I can do microvascular surgery. Or I turned out to I'm so grateful that this is how it turned out that I could do something that helps people.

Dr. Mark Hyman
So it removes a little bit of the ego in a way. It's it's

Dr. Robert Sapolsky
Oh, yeah. In the

Dr. Mark Hyman
same place as Buddhism, which is to kind of quiet down that ego monster.

Dr. Robert Sapolsky
Yeah. There you have earned nothing.

Dr. Mark Hyman
Fascinating. Wow. Lots to think about. Lots to think about. You know, we've covered the range from baboons in Kenya to, why we may or may not have free will to understanding of the neurobiology of stress and what it means to us.

I mean, this is just you you're honestly, Robert, one of my favorite, thinkers, philosophers, and, writers. If if anybody has not come across your work before, I encourage you to go get one of your books immediately. It doesn't really matter which one. They're all funny and brilliant, but I particularly like primates memoir and why zebras don't get ulcers and the trouble with testosterone. But the newer ones are, also very good.

So encourage everybody to check out your work, and, and I just hope I get to see you again soon. I I think the last time I saw you was 20 years ago, but if I'm ever in the Stanford area, I'd love to grab a coffee and continue this conversation.

Dr. Robert Sapolsky
Well, likewise. Thanks for having me on. And I suspect that we are thinking and feeling and concluding some remarkably similar things with some parallel, routes of getting there. And that's good.

Dr. Mark Hyman
Absolutely. And thank you again for being on the podcast and for your work.

Dr. Robert Sapolsky
Good. Thanks. Take care.

Dr. Mark Hyman
Thanks for listening today. If you love this podcast, please share it with your friends and family. Leave a comment on your own best practices on how you upgrade your health and subscribe wherever you get your podcasts. And follow me on all social media channels at doctor Mark Hyman, and we'll see you next time on the doctor's pharmacy. I'm always getting questions about my favorite books, podcasts, gadgets, supplements, recipes, and lots more.

And now you can have access to all of this information by signing up for my free Mark's Picks newsletter at drhyman.com/picks. I promise I'll only email you once a week on Fridays, and I'll never share your email address or send you anything else besides my recommendations.

Dr. Robert Sapolsky
These are

Dr. Mark Hyman
the things that helped me on my health journey, and I hope they'll help you too. Again, that's doctor hyman.comforward/marxpicks. Thank you again, and we'll see you next time on The Doctors Pharmacy. This podcast is separate from my clinical practice at the Ultra Wellness Center and my work at Cleveland Clinic and Function Health where I'm the chief medical officer. This podcast represents guests opinions and neither myself nor the podcast endorsed the views or statements of my guests.

This podcast is for educational purposes only. This podcast is not a substitute for professional care by a doctor or other qualified medical professional. This podcast is provided on the understanding that it does not constitute medical or other professional advice or services. Now, if you're looking for your help in your journey, seek out a qualified medical practitioner. You can come see us at the Ultra Wellness Center in Lenox, Massachusetts.

Just go to ultra wellness center.com. If you're looking for a functional medicine practitioner near you, you can visit ifn.org and search find a practitioner database. It's important that you have someone in your corner who is trained, who's a licensed health care practitioner and can help you make changes, especially when it comes to your health. Keeping this podcast free is part of my mission to bring practical ways of improving health to the general public. In keeping with that theme, I'd like to express gratitude to the sponsors that made today's podcast possible.