Understanding the Impact of Chronic Stress on Your Brain | Dr. Robert Sapolsky
01:14:09 Share

Coming up on this episode of The Doctor's Pharmacy. Very high doses of cortisol are anti-inflammatory, which is why, you know, you give somebody a synthetic corticosteroid and you just flatten your inflammatory system. But then it turns out in certain parts of the brain, by the time you're dealing with chronic inflammation, stress is pro-inflammatory.

Hey everyone, it's Dr. Mark. Time is our most valuable asset and Rupa Health understands that better than anyone. They've created a game-changing solution to simplify lab ordering for functional medicine practitioners like you. With Rupa Health's online portal, you can access over 3,000 tests from dozens of lab companies like Dutch, Doctors Data, Mosaic, Genova, and Access Medical Laboratories worldwide.

all with just a few clicks. That means no more headaches or administrative nightmares that come with traditional ordering processes. Plus, you'll only receive one invoice for all your tests, making life easier than ever before. And the best part, it's completely free. That's right, there's no hidden fees or complicated billing system, just one invoice, paid online and upfront. So start saving time and energy by visiting rupahealth.com. Sign up free and take control of your lab ordering process today. That's rupahealth.com.

Have you heard the buzz about GLP-1? Well, this naturally occurring hormone is sometimes called an unhunger hormone because it actually helps curb your appetite and cravings and it helps you feel full faster. Unfortunately, GLP-1 can decline with age and with certain lifestyle choices. The good news is

Pendulum GLP-1 probiotic can help. This multi-strain probiotic is formulated with beneficial bacterial strains that actually boost your body's GLP-1 production based on preclinical studies. And the results are incredible. In a six-week consumer survey with 270 people, 91% reported reduced overall food cravings and 88% reported reduced sugar cravings. Ready to take control of your cravings? Pendulum is offering my listeners 20% off their first GLP-1 probiotic membership order.

Just head over to PendulumLife.com slash pharmacy with an F to get your discounted checkout. That's PendulumLife, P-E-N-D-U-L-U-M-L-I-F-E dot com forward slash pharmacy, F-A-R-M-A-C-Y. That's pharmacy with an F. 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 Doctors Pharmacy. I'm Dr. Mark Hyman. And

Today we have an extraordinary guest, someone who's one of my heroes in science, Dr. 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

And he spent 25 years going every summer, three or four months, and studying baboons in Kenya to understand the role of stress in our lives and how it affects our brain. And his basically work initially was...

around the biology of how stress damages the nervous system. He basically divided his work between laboratory research and his work in the field with 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 non-scientists, including Why Zebras Don't Get Ulcers, The Trouble With Testosterone, A Primate's Memoir, one of my favorite

favorites, which is about 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, Determined, A Science of Life Without Fruehl, explore really deep topics. We're going to get all that today. And today we really had a wide-ranging conversation, a kaleidoscopic view of his life, from an Orthodox Jew in Brooklyn to becoming a neurobiologist and biologist.

studying with Bruce McKeown, 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 and environment. And it's kind of an 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'll 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 Pharmacy. I've been a huge fan of yours for literally decades and have read many of your books, including A Primate's Memoir, your book on the trouble with testosterone, which I thought was very funny, and some of your more recent work about free will and determinism in our behavior. And for those who don't know your work, you really have been...

kind of leading the way and are helping us understand the nature of the neurobiology of stress. And your background, I know you studied with Bruce McEwen, who is sort of the godfather of understanding stress. And he actually wrote one of the seminal papers on stress that I read years ago in the New England Journal of Medicine that really had me understand adaptation to stress or lack thereof and how that causes many health issues. And, you know, well,

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. For better or worse or something? Yeah, no, for better. And you went for 25 years, I think consistently every summer to Kenya and

to the Masai Mara to study the behavior of baboons and to understand their stress response. And I remember the stories in your book, they're 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

Maybe you could start telling us how you got into all this. How did you even start to 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 interesting to hear your story. Well, whenever I have my advisees who –

Stanford professor there. Whenever I have my advisees hit senior year and the ones who have no idea what they're going to do afterward and sort of are in a panic about it. And inevitably at some point they say, well, 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 eight when I decided I wanted to go be a primatologist. And

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. Like Dian Fossey or who?

Um, yes, with her, um, some baboon researchers, including the guy who I, I wound up sitting at the feet of for four years of college. Um, so yeah, I kind of focused on that early on. It's kind of remarkable. I actually, uh, uh, the, the primatology thing is kind of fascinating. I remember being at Cornell and Diane Fossey had apparently got kicked out of, um, Rwanda for a minute and she came to back to the States. And during that tour, she made a stop in my, uh,

Cornell biology class and I got to hear her speak and it just was mind-bending 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 in fact I proposed to my wife in front of the silverback whoa well I had him I had him stand there he was very cooperative hopefully there's a picture that's wonderful there is there is there's a picture

Yeah, I had the guy have all the other people who were on the trip with us sort of go off somewhere to look at something else. Right.

But then he got up right after and he pounded his chest and kind of ran around. A harbinger of something. Something. God, I don't know what. So when you went there and you were studying baboons, you were really trying to understand the role of their social structure and the hierarchy in the society and aggression and trying to understand what role –

you know, 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 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? 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 is,

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 the

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 as 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 going to 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 and

going each summer, three, four 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, they live out in the savannah, these big social groups, 50 to 100 animals or so, and big groups.

Imposing animals, the predators don't mess with them much. Infant survival among baboons is better than among the neighboring humans. You spend about three hours a day having to forage to get your food.

And what that means is you've got nine 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 manipulative jerks.

Wow.

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?

Yeah. And what you found was that, as I remember from the reading of the book, was that 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.

And, yes, it turned out, you know, when the world is unstable, like your baboon hierarchy is unstable during these periods, the last place you want to 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 and

Um, so what I thought I was learning was if you're a baboon and you get a choice in the matter, um, you want to be high ranking. And it turns out I wasted my first 20 years out there finding that because I

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 going to have a much healthier body if you go for the grooming partner route. Interesting. Now, one of the things that I think you kind of highlighted was this sort of difference between acute stress and chronic stress. And the title, Why Zebras Don't Get Ulcers, is sort of a kind of a humorous attempt to describe that, which is zebras...

are stressed for a very short period where the lions are chasing them. And then once the lion kills the zebra, 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. Yeah, basically. And, you know, you look at something like a zebra and it's just had this life threatening sprint for the 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, 10 million 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 evolved for a three-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. Yeah. I mean, I think the science is so clear on this, that chronic long-term stress either exacerbates or causes almost every known illness.

And the thing that is your focus is really the biology of the brain and the role of the stress on the brain. And I think people don't understand the impact on not only the physiology, but

even the structure and function of the brain as a result of chronic stress. And 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 a real or imagined threat to your body or your ego. So it could be a real threat, 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

So it's basically the same physiological response. The body is not that smart and differentiated, but it creates this pattern of damage to all your physiology, but particularly the brain. I think that the role in the hippocampus and cognitive decline and mood and anxiety, depression, 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,

And I think the consequences are quite, quite severe as a doctor when I treat patients. And I 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 and what the consequences are that drive the diseases and particularly the issues around our brain health.

Well, sort of starting off with the hippocampus, which is a part of the brain I, I love dearly. Um, and it's involved learning and memory. You want to have a hippocampus. Um, if it gets damaged, you wind up with a very characteristic dementia, Alzheimer's, the hippocampus is ground zero for damage and Alzheimer's disease. Um,

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 stress.

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 three 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 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 got to 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 kind of 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. And that clearly can lead to cognitive decline and dementia. 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. Well, yeah, good news and bad news. That turns out exactly the same in humans with Cushing's syndrome. You get hippocampal atrophy, dysentery.

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, right?

or at least long-lasting than you get with Cushing's. So that one's kind of bad news. Yeah, well, you know, also just from my lens, inflammation is a big driver of depression, and inflammation has many causes, including stress. And that inflammation does lead to this kind of chronic disease

state of depression 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 the inflammation in the brain, maybe that's why the brain doesn't recover. 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 are anti-inflammatory, which is why you give somebody a synthetic corticosteroid and you just flatten their inflammatory system. And yeah, it decreases. 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 stress.

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.

Hey everyone, it's Dr. Mark. Now sometimes when I'm traveling, I need snacks. I don't always snack, but I like to have healthy snacks available. But if I'm traveling, I'm often tempted to reach out for what's ready and available rather than what's good for me. But thankfully, Thrive Market has made it easy for me to order my favorite snacks online to travel with in my emergency snack pack. And I literally have days worth of rations in my backpack at all times so I don't get into a food emergency. The convenience of getting my food quickly shipped to my doorstep is a huge time saver and helps keep me eating the

right kinds of food that help me meet my health goals. Now, some of my favorite snacks from Thrive Market include Chomps free-range turkey sticks, human chocolate snacking gems, and Gimme Organic olive oil and seaweed snacks. They're so good. And they're private label green olives. They're yummy. And they even have a price match guarantee, so you know you're getting the best prices on your favorite brands.

You can join Thrive Market with my exclusive offer and get 30% off your first order plus a free $60 gift. Head over to thrivemarket.com forward slash hyman today. Plus orders over $49 are shipped free and delivered with carbon neutral shipping from their zero waste warehouses. That's thrivemarket.com forward slash hyman.

I'm a firm believer that using your kitchen regularly is one of the most important things you can do to be healthy. And it gives you complete control over what food goes in your body. And that's why I cook most of my meals at home. But have you ever thought about whether your cookware itself was healthy? Well, the problem is that so much nonstick cookware contains PFAS. Those are those nasty little chemicals that can

permanently damage our health and the environment. They're so bad that the EU, the European Union, is in the middle of banning them. And the U.S. government has committed $9 billion to address and limit them in a rare bipartisan agreement. And that's why I made the change to OurPlace. OurPlace's cookware and appliances are PFAS-free and offer the most durable, toxin-free ceramic coatings, ensuring a healthy,

safe, easy to clean cooking experience. My team and I have been using their products and raving about them for nearly five years now. And I love that I can use them to whip up truly healthy meals on my own in my own kitchen without having to worry about food sticking to the surface or chemicals leaching into my meals. So check out Our Place's cookware, appliances, and more. Just go to fromourplace.com and enter my code Hyman.

H-Y-M-A-N at checkout to receive 10% off sitewide. That's F-R-O-M-O-U-R-P-L-A-C-E.com and use the code Hyman. Our place offers a 100-day trial with free shipping and returns. Yeah, it's interesting. And of course, 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 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 got to do something to discharge that

that response, which is something that we all have living in our modern society. So it almost seems like it's almost as essential as eating or sleeping or exercising. And yet it's not something we learn. What have you learned about therapies or treatments or approaches addressing this chronic activation of our stress response? Well, what I've mostly learned is I personally am terrible at stress management. I'm like 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 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 one, figure out the things you really can't change. So don't try to change those, all of that. Yeah, yeah, you don't want to 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, et cetera, are just rotting you away, that's where interventions help enormously. The meaning we make of things is what causes stress, I think, in a lot of the cases. I mean, sometimes there are real stresses. There's war or

natural disasters or real crazy stuff that happens but a lot of times it's our mind that's making us stressed and absolutely and it's our own like you mentioned the neuroticism 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 they work work around determinism and free will and human behavior which sort of follows off from your previous work um you

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 lives or our beliefs or our perceptions that are mistaken, 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,

Maybe you could call it stress too. Maybe that's another word for the suffering. I wonder, you know, in terms 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 very curious how this sort of intersects with your more recent work around

your hypothesis that we don't have free will and that we're determined in our behaviors and our responses to what happens to us in life.

Yeah, well, it fits into it very well. Let me give a last shout out to my baboons to show 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 my baboons are smart enough for that. You look at their dominance hierarchy and you look at number five and

And say when the hierarchy is stable, nobody's having many fights. Five knows just where he is in the hierarchy and all of that. But then you look at what would be called rank reversals. Number five has a fight with number four and wins.

Number five has a fight with number six 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 five. You're having a dominance reversal with number six, and your cortisol levels are through the roof. You're having a dominant reversal with number four, and they're not. Having a reversal with number four means you're pushing for a promotion.

Having a reversal with number six means this guy is breathing down your neck. Same fight, same canine, same all, but totally different social meanings. Um,

But, you know, in terms of this, this before, before we jump to the new question I asked you, I want to, I had a thought I wanted to ask you about. And I think it's, 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 harms of the stress hormones like cortisol.

I found that very fascinating. And it seems sort of, you know, I think, well, we just meditate, right? But you're like, no, we're going to do gene therapy to fix this. So can you just talk about that for a little bit? And then I want to get kind of veered back into the free will determinism behavior conversation.

Yeah, this was sticking a gene. Sticking a gene, you figure out a cell in your body isn't doing enough of what it needs to do. Sticking a gene that will boost it up, a cell in your body is doing too much of something.

thing, 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 good to go. You're all set. It should be wonderful. And we started that work in the sort of mid-90s, a few groups of trying to do gene therapy in the brain. And

And what was clear was the field was going to be about 30 years behind everybody doing gene therapy on livers and gene therapy on pancreases 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 sub parts. 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 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. They thought, oh, 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 sort of retired from the neuronal gene therapy business around 2010 or so. It's been a big disappointment. We were so damn giddy back when we were going to be able to like, just all you had to do was figure out how to get the stuff and

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. Wow.

Well, I wouldn't be too disappointed because it seems like there's a lot of research now understanding 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 lower capacity to deal with stress, serotonin transporter genes, receptor genes for cortisol,

And monominoxidase 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 Holocaust survivor children, or even the babies who were born to women who were...

in New York during 9/11 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 much data there that you're aware of about how to sort of modulate these? For example, like COMT, you can give methylating cofactors like B vitamins that actually help this gene work better, for example.

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 not.

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 cancer.

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-threats?

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 if they could measure your telomeres in your white blood cells, they would have recovered ever so slightly from the previous misery of stress they'd been going through.

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, one of those pathways is a more effective, a more 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, there are fault lines, there are 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 non-adverse 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.

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

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 are things that are vitamin D that we can actually use to sort of modulate these pathways, flavonoids and magnesium, for example. And so...

It's not hopeless. Even if you have certain genes, you can modify how those genes are expressed 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.

Exactly. And 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, you know,

swarming out of Gaza or something and you change gene regulation in a part of your brain having to do with the stress response and

That's what you give birth and you smell your newborn baby's tush. And as a result, you activate oxytocin genes in your hypothalamus. Whoa, those genes are not controllants. 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. Yeah.

Well, this sort of leads me to sort of ask you about, you know, we can modify some of these things. How this fits in with your sort of seems to be a little bit of shift in your hypothesis from the trouble with testosterone where you're

you kind of argue that there was self-determinism. It wasn't completely a deterministic kind of world we live in. But 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 independent, free-thinking, free-acting human beings.

You're coming at this not from the perspective of a sociologist, but as a biologist and as a neuroscientist. And I found it really fascinating to sort of

Try to understand your perspective because it's sort of it's a little bit abrasive to our own our own self delusional view that that we're in control of everything. Yeah, it's potentially immensely demoralizing, although.

You know, what most people who suggest, you know, there's less free will than 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're,

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. 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 two 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. And you put all those- Like growing up a Jewish guy in Brooklyn, you mean? Yeah, exactly. Sort of 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

Right.

And when you look at sort of, you know, 95% of philosophers by polls that are done are what are called free will compatibilists, right?

They're willing to admit there's things like cells and molecules and 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. Um,

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 not how subatomic 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 obvious.

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

And getting rid of the sense of free will over and over is a liberating thing. Tell us how, because it doesn't sound like that to the average person listening in. I know. Well, you know, just as one historical example of it, there used to be a commonly held view that if you were a certain type of person and you could do the certain right types of behavior, you could control the weather.

Oh my God, there's a hailstorm that destroyed everybody's crops. Or what caused that? The old lady in the hut on the edge of the village who everybody gets kind of creeped out by, who's obviously a witch. And you then do a medical intervention for her witchness, which is you burn her at the stake. And somewhere about 400 years ago, people figured out that, you know, witches really can't control weather. And it's like...

There's no free will with that. And it's a much better planet that we don't burn people at the stake for being witches. It's a much better planet that somewhere in the 19th century, people figured out that epilepsy was not a sign of demonic possession.

It's a sign of like screwed up potassium channels in your temporal lobe. And they stopped harassing people and treating people with epilepsy as if they were demonically. That's a much somewhere in the last 60, 70 years, people thank God figured out schizophrenia is not caused by mothers who were terrible at mothering.

schizophrenogenic mothering where secretly they have an unconscious hatred of their child. And no, it's a neurogenetic disorder and hundreds and hundreds of thousands of mothers of people with schizophrenia finally were told it's not your damn fault. Like autism, the refrigerator moms, you know? Exactly. Autism and obesity and

and learning differences? No, it's not that you're lazy and unmotivated. We just figured out you got some screwy microarchitecture in this part of your cortex, and the letters B and P get reversed when you looked at them. And you got dyslexia. No, you're not lazy and unmotivated.

It's something you had no control over. There's no free will in it. It's just part of the practical level. This is because I know people are going to be, I'm just going to be, I imagine what people are saying. For example, I had a patient who lost 106 pounds and she decided, I don't want to be overweight anymore. I'm very unhealthy. I'm in turn 60. I want to get my life under control. And in her mind, she decided to change her life and she lost 106 pounds. Is that not free will?

No, it's fantastic news, but it's not true, Bill. 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 two years later, it hasn't happened with them.

And you got to 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, 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 two people.

And they're both overweight to the same extent, blah, blah, et cetera. And you teach both of them the impact of a healthy diet has on weight, right?

And one of them, it sticks and one of them, it doesn't. One of them happened to luck out with the 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 going to be happy.

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. Yeah. I mean, I think for sure. I mean, I think different people have different capacities to change, but you know, I, I, I majored in Buddhism at Cornell, so I'm a bit of a weirdo. And, uh,

And learning about Buddhism was fascinating because 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 their hypothesis, the Buddhist sort of essential ten 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 pure consciousness. Now, I don't know if you think that's a crock of shit or if you actually buy into that, but 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 that 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 this same exact

you know, event. So I just wonder, how do you see this framework?

Yeah, how does this 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 whether they just describe it from early life or past lives or whatever, karma. 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 an authentic meaning of life in the moment. Good. I understand.

Within certain parameters, that's exactly this. 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 going to, you have the 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 go, whoa, people can change. Wow. 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, parentheses, 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 that

who could reflect and build on that and apply it to yourself and be willing to face when you need to make change and learn from other examples and generalize and blah, blah. But isn't that a little bit of free will, like a little bit? Nah, 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 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, whoa, yeah.

What kind of frontal cortex did you wind up with? Get born into poverty, and by age five, 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 going to have a much better front. Same thing. Wow. I had nothing to do with my eye color. I had nothing to, 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.

So what does that apply for people who want to get healthy, for example? Are they just sort of screwed if they want to get healthy but they can't overcome their innate conditioning and they're just stuck being sick? No. Because people are thinking, yeah, I want to get healthy. I want to change these behaviors, that behaviors. I'm going to 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. Yeah.

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. 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 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 is

That doesn't mean nothing can change. That doesn't mean the universe was already set three 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 because

You sort of learn this is the circumstance that makes me more likely to change. Ooh, you come out of some inspiring movie, Hotel Rwanda or something about the Rwandan genocide. And some people come out and say, whoa, 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 want to go read more about it.

They lucked out and had the 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 going to go learn about, you know, Doctors Without Borders and what they do in refugee crisis.

That's where change comes from. - Now, what you're saying has broad implications and you write about this and I think taking it to the extremes, both in terms of our criminal justice system and our meritocracy, you're saying both of those, we have it wrong. And what are the implications of what you're saying for how we deal with criminal justice and also how we approach the structure of our society from the perspective of meritocracy?

Yeah, 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 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 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 these are the implications of it. And fully accepting these implications, I'm able to function that way for about three minutes every other month. Right.

Because it's hard. It's really hard. What does that mean? That we let everybody out of prison and that we don't reward people for good behavior? 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

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 five-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 anybody else sick. Oh my God, your child has become menacing, is potentially damaging them.

agent in society there, you got to 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 and five-year-olds or whatever. And you hope more research is done on that. And that's a quarantine model. And

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 six months without a seizure and you can drive again. But that doesn't mean we're going to 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 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 to

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 found a company and become gazillionaires or people who turn out to be really smart people.

Or really kind or really any of those things. And we somehow have to transition from saying, whoa, 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, whoa, 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. Right.

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.

Sort of removes a little bit of the ego in a way. Oh, yeah. In the same place as Buddhism, which is to kind of quiet down that ego monster. Yeah. You have earned nothing. 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're honestly, Robert, one of my favorite thinkers, philosophers, and writers. 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 Primate's Memoir and Why Zebras Don't Kill Us and The Trouble with Testosterone. But the newer ones are...

Also very good. So I encourage everybody to check out your work. And I just hope I get to see you again soon. 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. 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. Absolutely. And thank you again for being on the podcast and for your work. Good. Thanks. Take care. 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 Dr. Mark Hyman. And we'll see you next time on The Doctor's Pharmacy. I'm

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 MarksPix newsletter at drhyman.com forward slash MarksPix. 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. These are the things that have helped me on my health journey and I hope they'll help you too. Again, that's drhyman.com forward slash MarksPix. Thank you again and we'll see you next time on The Doctor's 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 my opinions and my guests' opinions, and neither myself nor the podcast endorses 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. 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 ultrawellnesscenter.com. If you're looking for a functional medicine practitioner near you, you can visit ifm.org and search find a practitioner database. It's important that you have someone in your corner who is trained, who's a licensed healthcare 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.