How to Optimize Cognitive Function & Brain Health | Dr. Mark D'Esposito

1. 0:00 – 2:08

   Dr. Mark D’Esposito

   1. AHAndrew Huberman0:00

      (uptempo music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. and Professor Mark Esposito. Dr. Mark Esposito is a neurologist and a professor of neuroscience and psychology at the University of California, Berkeley. He is a world expert in the brain mechanisms controlling executive function and memory. Executive function is the way in which we are able to designate and carry out specific cognitive strategies, and it is fundamental to every aspect of our daily lives. And because so much of being effective in daily life involves using specific context-relevant batches of information in order to understand what to do and when, and what not to do and when, and to come up with strategies that are very adaptive for us to move forward in the context of relationships, work, school, and athletics, and on and on, there's really no separation between executive function and memory. And today, Dr. Esposito explains the neural circuits controlling executive function and memory, how they interact, the key role of dopamine in executive function and something called working memory, and teaches us ways to optimize executive function and memory, that is how to optimize cognitive function. In addition to discussing how to optimize cognitive function in the healthy brain, today's discussion also centers around how to restore cognitive function in disease or injury conditions that deplete executive function and memory, such as traumatic brain injury, concussion, Alzheimer's, Parkinson's, and attention deficit disorders. Dr. Esposito shares with us research findings both about behavioral and pharmacologic strategies to enhance executive function and memory. By the end of today's discussion, you will have learned from Dr. Esposito a tremendous amount about the modern understanding of cognition that is thinking and memory, and the carrying out of specific cognitive strategies. You will also learn a tremendous amount about how to optimize brain function and

2. 2:08 – 6:23

   Sponsors: Maui Nui, Joovv & Eight Sleep

   1. AHAndrew Huberman2:08

      brain health. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Maui Nui Venison. Maui Nui Venison is the most nutrient-dense and delicious red meat available. I've spoken before on this podcast, and there's general consensus that most people should strive to consume approximately one gram of protein per pound of body weight. Now, when one strives to do that, it's important to maximize the quality of that protein intake to the calorie ratio because you don't want to consume an excess of calories when trying to get that one gram of protein per pound of body weight. Maui Nui Venison has an extremely high-quality protein-to-calorie ratio, so it gets getting that one gram of protein per pound of body weight extremely easy. It's also delicious. Personally, I like the ground venison. I also like the venison steaks. And then for convenience when I'm on the road, I like the jerky. The jerky is a very high protein-to-calorie ratio, so it has as much as 10 grams of protein per jerky stick, and it has something like only like 55 calories, so again, making it very easy to get enough protein without consuming excess calories. If you would like to try Maui Nui Venison, you can go to maui-nui-venison.com/huberman to get 20% off your first order. Again, that's maui-nui-venison.com/huberman to get 20% off. Today's episode is also brought to us by Joovv. Joovv makes medical-grade red light therapy devices. Now, if there's one thing I've consistently emphasized on this podcast, it's the incredible role that light can have on our biology, and of course, I'm always telling people that they should get sunlight in their eyes as soon as possible after waking on as many days of their life as possible for sake of setting circadian rhythm, daytime mood, focus, and alertness, and improved sleep. Now, in addition to sunlight, red light and near-infrared light has been shown to have positive effects on improving numerous aspects of cellar and organ health, including faster muscle recovery, improved skin health and wound healing, even improvements in acne, or that is removal of acne, reducing pain and inflammation, improving mitochondrial function, and even improving vision itself. What sets Joovv apart and why it's my preferred red light therapy device is that it has clinically proven wavelengths, meaning it uses specific wavelengths of red light and near-infrared light in combination that trigger the optimal cellar adaptations. Personally, I use the handheld Joovv every day. The handheld Joovv is about the size of a thick piece of toast, and I also own a Joovv panel that allows for full body exposure, and I use that one approximately five times per week for about 10 to 15 minutes per session. If you would like to try Joovv, you can go to joovv.com/huberman to receive $50 off your first purchase. Again, that's Joovv, spelled J-0-0-V-V.com/huberman to get $50 off your first purchase. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. I've spoken many times before in this podcast about the fact that sleep is the foundation of mental health, physical health, and performance. Now, a key component of getting a great night's sleep is that in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees, and in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. One of the best ways to make sure that those temperature changes occur at the appropriate times, at the beginning and throughout, and at the end of your night when you wake up, is to control the temperature of your sleeping environment, and that's what Eight Sleep allows you to do. It allows you to program the temperature of your mattress and sleeping environment such that you fall and stay deeply asleep easily and wake up each morning feeling incredibly refreshed and energized. I've been sleeping on an Eight Sleep mattress cover for almost three years now, and it has dramatically improved the quality of my sleep. If you'd like to try Eight Sleep, you can go to eightsleep.com/huberman to get $150 off their Pod 3 mattress cover. Eight Sleep currently ships in the USA, Canada, UK, select countries in the EU and Australia. Again, that's eightsleep.com/huberman. And now for my discussion with Dr. Mark Esposito.Dr.

3. 6:23 – 10:31

   Brain & Frontal Lobes, Prefrontal Cortex, Executive Function

   1. AHAndrew Huberman6:24

      D'Esposito, welcome.

   2. MDDr. Mark D'Esposito6:26

      Hey, Andrew. Thank you so much for inviting me. I'm really looking forward to our conversation.

   3. AHAndrew Huberman6:30

      Yeah. You may not remember me, but I remember you when I was a first year graduate student and, uh, you showed up at Berkeley, one of the first people to really bring functional imaging of the human brain to Berkeley, bring a neurology and a clinical, um, s- emphasis to the neuroscience studies there and it's really just, um, blossomed and, uh, it's been a real thrill for me to see all the magnificent work out of your laboratory over the years, and I know you also still see patients, so the topics that are of interest to you, I know are of great interest to our audience. Maybe we'll just start off with a few of the basics and, um, do a little functional neuroanatomy lesson for folks. Not to scare anyone. Don't worry. This will be accessible to everyone. And just talk about the frontal lobes and prefrontal cortex and a little bit of what those structures do, because many times on this podcast I've said, "Okay, the neural real estate right behind your forehead is involved in context and planning, et cetera." But you're the real expert here. Um, how should we think about what the frontal lobes do and, and their various roles in health and disease?

   4. MDDr. Mark D'Esposito7:32

      Yeah, so there's four lobes. There's the frontal lobes, parietal, temporal, occipital. And the frontal lobes probably take up more... do take up more territory than the other lobes, probably about a third of, of the, uh, cortex. And within the frontal lobes, uh, I, I don't... I'm gonna use sort of frontal lobes probably in our conversation a lot, but what I really mean is the prefrontal cortex. So within the frontal lobes, there's also mo- areas that are important for motor function as well. Um, but when we're talking about the frontal lobes and talking about its, you know, involvement in higher level cognitive abilities, we're really talking about the prefrontal cortex, and this is what's considered sort of the highest level of cortex in the brain. So yeah, when you think it, when you think about it, people assign it, uh, all sorts of functions. Almost every function you can think of, people have sort of put into the frontal lobes. But I think what we've all ki- kind of, uh, moved towards is this idea of executive function, this abil- this ability to, to plan, to organize, uh, to really transfer our thoughts, you know, i- into an action and really to be guided by goals and, and intentions and not be kind of take, you know, kind of ruled by sort of just automatic behaviors. Uh, a word we use in cog- neuroscience is called cognitive control. So cognitive control, executive function's what we attribute to the frontal lobe. And so you can think of it as, you know, the CEO of the brain or the, um, you know, or the conductor of the orchestra, really the part of the brain that's, that's really controlling the, the re- the rest of the brain. So yeah, if you had to choose which part you wanted to not leave home, (laughs) it's your fron- it's your frontal lobes.

   5. AHAndrew Huberman9:06

      Uh, speaking of which, um, what are some of the, uh, symptoms of mild frontal lobe damage, um, and severe frontal lobe damage, uh, damage brought about either through, uh, neurodegenerative disease or physical injury? I know we're gonna talk a, a bit about both today, or a lot about both. Um, but how would lack of executive function, uh, show up, um, on, uh, maybe on in kind of a subtle level?

   6. MDDr. Mark D'Esposito9:32

      Yeah, I mean, at first I should say is that it, it shows up all the time because when, when, uh... And, and frontal lobe behavior is probably much more prevalent than, than we realize. Certainly we think about it when you have a brain injury to the frontal lobes, and there's lots of neurological disorders like stroke and traumatic brain injury and Alzheimer's disease that can affect the frontal lobe, and there's a number of, you know, psychiatric disorders, obsessive compulsive disorder and schizophrenia and depression that are thought to be frontal lobe dysfunction. But when you're sleep deprived and when you're stressed and just normal aging, the frontal lobe seems to be the first system that's affected because it really is involved in the highest level. So when we're having a bad day, when we're having difficulty sort of setting priorities, when we're having difficulties achieving the goal that we've set out, when we get distract- you know, when we get distracted, um, you know, when we're not able to sort of adapt and be flexible, these are all the type of things that are... reflect that our frontal lobes are not functioning optimally.

4. 10:31 – 14:12

   Frontal Lobe Development, Children

   1. MDDr. Mark D'Esposito10:32

   2. AHAndrew Huberman10:32

      Approximately what age does the frontal lobe circuitry, uh, come online, so to speak? I mean, when I see a baby, uh, babies can orient their eyes towards things, but they're rather reflexive in, in where they'll place their eyes, but, um, by the time kids are three or four, they can certainly, you know, play with blocks or interact with other children or their parents, but it seems that, you know, full functionality of the frontal lobes is, it's really gradual. At least that's my non-clinically trained assessment, you know?

   3. MDDr. Mark D'Esposito11:04

      Yeah, I mean, it's a really tough question to know when they're fully developed because these studies haven't been done. When MRI was introduced and we were able to sort of image the brain in a non-invasive way, uh, then studies did start to come out trying to sort of map out at what age does your frontal lobes fully develop, and it seemed like it was early into your, your 20s. Um, you know, I always say that it's not surprising that you can't rent a car until you're 25. That the insurance companies knew before neuroscientists did as, as to when your frontal lobes have... you know, when your decision making skills are at their highest. And so that's probably about right, into your 20s, um, is probably before your frontal lobes are fully developed. And it's a really interesting question is why, why does it take so long? It's the area of the brain that takes the longest to develop, and why is that? And I, I think there's a reason. I think that, that, that this sort of slow development of frontal lobes allows us to, to explore, a- allows us to think about novel ways of solving problems, allows us to take in the world. If they were shut off earlier, uh, it w- it would lead to maybe a much more sort of rigid kind of, you know, less flexible kind of, uh, behavior that, that we'd see and things. So I, so I think that, that it helps to be, uh, it take a long time to develop, but also it obviously leads to some problems sometimes in, in adolescence as, as, as we see sometimes.

   4. AHAndrew Huberman12:27

      Can one see a lack of frontal lobe maturity in just the sheer number of physical movements that a child makes? Um, so for instance, in a classroom of, uh, you know, let's say, um, you know, fourth graders, um, oftentimes there'll be a range of, uh, apparent ability of kids to sit still or to listen. Um, do we think that the kid that's having a hard time focusing and listening to instructions or steadying their body when they're told to sit still, um, I don't know if they still tell kids to sit still-

   5. MDDr. Mark D'Esposito12:59

      Right.

   6. AHAndrew Huberman12:59

      ... but they were telling me to sit still-

   7. MDDr. Mark D'Esposito13:00

      Right.

   8. AHAndrew Huberman13:00

      ... when I was a kid. Um, is that, um, somehow reflective of a, you know, slightly lagging frontal, frontal lobe function, um, and maturity? Whereas the, you know, the, the kids that can sit, you know, still and stoic and focus, does that mean that they're a little bit more accelerated along that trajectory?

   9. MDDr. Mark D'Esposito13:18

      Yeah, it's hard to say. I mean, the frontal lobe is bi- is a big territory and we can get into it, but there's, you know, the frontal lobe probably has 25 different sub-regions within it. And, and so grossly we think about the frontal lobes as the lateral portion of the frontal lobes, which is involved in these executive function, probably supports these executive function abilities. But then we've got another part of the frontal lobes called the orbital frontal cortex, which is probably involved more in social and emotional behavior. So, you know, when we think of, again, when we think about frontal lobe behaviors, uh, they kind of, you have to break, there's so many different type of frontal lobe behaviors. So what, that type of behavior which may be involved in sort of being able to inhibit, you know, your motor movements or maybe not being distracted may reflect that that system is a little bit delayed, but it could be that another system, the one that's involved in planning and organizes, you know, is more developed. And I do, I do think they, they develop at different trajectories.

5. 14:12 – 21:45

   Rules, Context & Impulse Control; Learning & Goals

   1. MDDr. Mark D'Esposito14:13

   2. AHAndrew Huberman14:13

      So with the frontal lobes essentially, um, serving an executive or CEO-type function, goal-directed behavior, intentions, cognitive control, uh, these are the terms you used, um, where are the rules? What do the rules look like? You know, when I think about brain function, which I've spent a lot of my life thinking about, I think about chemical and electrical signaling between neurons, different neurons communicating more or less at a given moment, reflecting some sort of circuit as we call it, and then some behavior or some decision comes out. And if I, for instance, um, I have to get my driver's license renewed soon, so if I go to the Department of Motor Vehicles, what a lovely experience that is. Um, the moment I get there th- I sort of lock into a certain rule set. Um, when I'm home, I'm in a different rule set. When I'm in, with my friends versus when I'm with my parents, different rule sets. And it seems that the frontal lobe is really good at, um, drawing on context based on knowledge of where one is, um, and then coming up with kind of algorithms that are appropriate or inappropriate to run in that context. But what is the nature of these algorithms? Are they, um, of the, "Okay, shut down all, um, cursing in this environment." Um, "Okay, you're free to just, quote-unquote, 'be you.'" I mean, when, when it really comes down to it, it has some interesting philosophical aspects too, because, uh, just be yourself, be authentic, be vulnerable, you know, all these things, uh, make sense, but of course, one needs to be appropriate with the context. So how, how does this work? Like, what, what is the, what are the algorithms? How d- how does this work?

   3. MDDr. Mark D'Esposito15:54

      Right. Because, because that's a pretty common example of our patients, that they, they don't follow the rules. Um, they, they, you know, if you're sitting in a, someone's au- the doctor's office and the phone rings, you, you, you know not to pick up his phone, but, uh, the patients don't and they, they may pick up the phone. There's, there's this, uh, Dr. Lhermitte who's a, a neurologist from France, published these beautiful papers in the '80s of all these things that patients did that just, that broke the rules and, and so, and pretty much just kind of pulled to the, their environment without having any context to it. If he put a pair of glasses on the table, uh, and didn't ask them to put them on, they would put them on even if they had a pair of glasses on already. Or he took him to their apartment and they saw the bed and they'd jump into the bed and go under the covers. Or he saw, he had a nurse and she, he put a blood pressure cuff there and she picked up the blood pressure cuff and just started taking his blood pressure. Again, not asking him to do any of these things. And so they, they, they just don't follow sort of the social rules, but they're there. They, they haven't lost rules. If you ask these patients, "Was that the appropriate thing to do?" they'll say no. No, they-

   4. AHAndrew Huberman16:59

      Well, they know it's not appropriate.

   5. MDDr. Mark D'Esposito17:00

      They, they know it's inappropriate. Yeah, they say, "No, I'm not supposed to answer your phone," but w- (laughs)

   6. AHAndrew Huberman17:05

      Oh, wow. So they know better, but they can't control the impulse.

   7. MDDr. Mark D'Esposito17:07

      Exactly. So it's, it's, it's, so you, it's not a breakdown that the rules disappear, it's that they can't apply the rule, that they can't apply the rules pro- properly. And, and, and that's true for a lot of pa- patients. Even with kids, you know, you tell them, uh, "Don't have anything to eat before dinner because we're having dinner," and then they're sitting there having a sandwich and you say, "What did I just tell you?" "You said, 'Well, don't eat,' but I'm, I'm hungry," right? And so another sort of example of sort of the frontal lobe's not completely kind of developed. So when I think about rules, I, I think about the brain. You know, the brain processes information obviously, but it also stores information. The most important thing it does is store all sorts of information all over the brain. And I think what the frontal lobes do is they store rules. And what's interesting, uh, about the way it stores rules, it, it, they seem to store the rules in a hierarchical fashion. Um, and what I mean by that is that there's different levels to rules. I, I like to give the example of, uh, playing golf. I tell a story a lot about my good friend Bob Knight when he hits a ball into the, you know, off, into the woods and he has to try and hit the ball out of the woods. He's holding on to all different levels of rules on how to successfully get his ball back towards the green. So the most simplest one is just, like, where, you know, where is the fle- you know, I've got to maintain the, uh...... orientation to get to the flag, you know, so he's holding that. He also had a higher level rules, he knows that if he kicks the ball, it's a penalty, so he's not gonna do that, right? And then an- another higher level rule might be, "If I just keep doing this, you know, then this is going to be healthy for me." And so he's storing all this information at sort of, at different levels of hierarchy, and he's apply- he's sort of applying it to ultimately achieve this very simple act of... or not so simple act of hitting the golf ball. So, y- yeah, so I just, I think about sort of the frontal cortex is able to call upon the rule in the appropriate context, and if you don't have your frontal lobes, it- it- it doesn't get pulled up properly.

   8. AHAndrew Huberman19:09

      And those rules must be learned, right? They- it- there's no way I can imagine that one can be born into the world with these rules sets intact. Um, I think about the- the two marshmallow experiment.

   9. MDDr. Mark D'Esposito19:21

      Mm-hmm.

   10. AHAndrew Huberman19:21

       That's sort of famous now, um, where kids are offered to eat, uh, one marshmallow right away or-

   11. MDDr. Mark D'Esposito19:28

       Right.

   12. AHAndrew Huberman19:29

       ... defer and get two marshmallows. These, uh, adorable videos of the kids-

   13. MDDr. Mark D'Esposito19:33

       Right. (laughs)

   14. AHAndrew Huberman19:33

       ... and the various strategies they use, like turning away-

   15. MDDr. Mark D'Esposito19:35

       Right.

   16. AHAndrew Huberman19:35

       ... poking the marshmallow, and, you know, there's some debate, uh, ongoing as to whether or not a success, or lack of success, in deferring to the two marshmallow reward is, um, predictive of- of other things in life. But leaving that aside, um, am I correct in assuming that that task is a frontal lobe task? The kids are given a novel rule, "You can have one marshmallow now or wait, um, patiently, and then, uh, with an overcome the craving for that one marshmallow, and then you'll get two." Um, and presumably that, um, that experiment is engaging the frontal lobes and, you know, we can only speculate, but, um, some kids are able to defer, some are not. Um, and I can imagine that at that age, there's a lot of neuroplasticity, um, strengthening and weakening of connections is- in the brain on a- in an experience dependent way. So does that mean that, um, children, and perhaps adults as well, can train up their prefrontal cort- cortical abilities to strategize and defer in a way that's adaptive?

   17. MDDr. Mark D'Esposito20:41

       Absolutely. I mean, definitely you can learn strategies to not only sort of learn rules, um, but- but h- how to apply goals. When- when you start to think about that task in particular, some of it has to do with sort of maintaining a goal and- and maintaining a- a goal at different, you know, timescales, right? And children tend to sort of act on goals that are much more short, on a shorter timescale. "You know, I'm going to have the sandwich right now because I'm hungry," as opposed to wait till- till dinner, which is a longer- longer term goal. And so, yeah, this default to sort of the shorter... You can- you can learn that maintaining a longer type goal, uh, c- can be much more beneficial, uh, than- than the short term goal, even though it doesn't seem obvious to... And we all learned that, right? We, as we, it, as we get older-

   18. AHAndrew Huberman21:25

       Most of us.

   19. MDDr. Mark D'Esposito21:25

       (laughs)

   20. AHAndrew Huberman21:26

       (laughs)

   21. MDDr. Mark D'Esposito21:26

       We keep our eye on the ball sort of more long term goals and that's very predictive of how successful we can- we can be, the farther out we can maintain a goal, and that's what the- that's what the prefrontal cortex does. It maintains goals and then applies those goals, and if you don't apply 'em, then you loo- you know, then you- then all of this executive function breaks down.

6. 21:45 – 26:04

   Focus, Improving Executive Function

   1. MDDr. Mark D'Esposito21:45

   2. AHAndrew Huberman21:45

      Do you think that these algorithms and rules that the prefrontal cortical circuitry can learn, and indeed does learn, can generalize? So, for instance, when I... uh, my first year of college was this disaster, uh, for reasons that aren't interesting right now, but then when I came back my sophomore year, really spring of my freshman year, I was like, "Okay, it's on." It was- I had to rescue myself. And so one of the things I used to do was I would study, um, and I would set a timer so I refused to get up, even if I had to use the- the restroom ver- very, very badly. I would, um, set up all sorts of behavioral constraints, um, and I like to think that I was building up my prefrontal ability to refocus on the material, and fortunately for me, there were no smartphones back then.

   3. MDDr. Mark D'Esposito22:27

      (laughs)

   4. AHAndrew Huberman22:27

      It was much easier-

   5. MDDr. Mark D'Esposito22:28

      Right.

   6. AHAndrew Huberman22:28

      ... internet. You know, we had email-

   7. MDDr. Mark D'Esposito22:30

      Yeah.

   8. AHAndrew Huberman22:30

      ... but no-

   9. MDDr. Mark D'Esposito22:31

      Yeah.

   10. AHAndrew Huberman22:31

       ... no real internet browsing to- to speak of, and I like to think that the, uh, I sometimes call it, uh... And this is terrible, but, um, to call it this because it's not, uh, nearly exhaustive of the underlying function, but I call it sort of, like, limbic friction. It's like there's this friction that one feels mentally, like you want to get up, you want to use the restroom, you want to eat something, you want to call a friend, but you stay focused on the task at hand. Do you think that that business of, quote-unquote, "staying focused" on the task at hand can generalize because of the sensations it generates in the body, and then you go, "Oh, yeah, that's- this is familiar. This is just like studying." But in a different context, you- one is- one stays focused? Or do you think that the prefrontal cortex is- is so context specific that it needs to learn a ru- the rules for every individual situation? And th- and this has all sorts of implications for behavioral restraint and focus and attention deficit. So, uh, if you could just speculate, um, I- I know a number of people-

   11. MDDr. Mark D'Esposito23:27

       Yeah, no.

   12. AHAndrew Huberman23:27

       ... are interested in how they can be more focused, and people often defer to, like, "What supplement? What drug?" Okay, tha- those are interesting conversations, but I think ultimately, we're talking about neural circuitry.

   13. MDDr. Mark D'Esposito23:37

       Yeah, I mean, it absolutely can generalize. It- that's been a frustrating thing in dev- trying to develop what we call cognitive therapy, where we- we teach, we try to improve someone's memory ability, or we try to improve someone's executive function ability, that the disappointing early results was always that, yeah, they get very good at the task that you've trained them at, but it doesn't seem to generalize to anything else. So if you teach them a, you know, a task they can do amazing things, like match a finger to a color to a shape and put together all sorts of rules, and then... And they're really good at that task very quickly, and then nothing's really changed in their real life. But- but I think we've learned on how to sort of- on how to try and make it, uh, translate to real life. And- and so, for example, there's- there's a therapy called goal management training, which is developed, um, by Brian Levine and colleagues at the Rotman Research Institute, Toronto, where they've been very successful in teaching, uh, patients how to i- improve your executive function.... uh, and how to make that translate into your real world. But it's, it's very hard work. It's, it's very therapist-driven. It, it requires, um, it requires a series of, of trainings. For example, people learn, uh, they develop individual projects, like planning a meal or planning a family vacation or planning a podcast, and then they work through what's involved in that sort of very specific project. How you, how you stay focused, how you don't dis- get distracted, how you, you keep your eye on the ball, how you break it down to sub-goals, how you, um, you monitor what you're doing, how you don't let anxiety and procrastination get involved. But it, it's a v- it's a very active sort of process. But when you add all that to it in a very disciplined way over the course of many hours and many weeks, it does translate. Patients and individuals just say, "Yeah, I'm just better at doing things." I mean, the whole goal is to do things, right? And, and "I'm just better at it. I don't know what it is, but I'm, I'm not just better at what you taught me, I'm just better at, at other things." So I do have a lot of hope that these kind of therapies will generalize to the r- you know, to people's real life.

   14. AHAndrew Huberman25:40

       I threw out the term limbic friction. Again, not a technical or clinical or official term in any way, but just a way to kind of capture, um, some of the interactions of the frontal cortex with other circuitry. I mean, there's far more, um, involved in agitation and challenges focusing than the limbic system, but it's, uh, it certainly is involved. Um,

7. 26:04 – 29:02

   Connections & Top-Down Signals

   1. AHAndrew Huberman26:05

      i- when thinking about the frontal cortex, I often think about its connections with other areas of the brain, so maybe we could talk a little bit about those connections, and, and in particular, the connections from the frontal cortex to, let's call it, um, circuitry that controls reflexive behaviors. Um, w- what are, what is the nature of that circuitry, and, um, can we make any general statements? Like, does the frontal cortex really serve to, um, provide a quieting, um, suppressive function on reflexes, or is it more of an orchestra conductor where it's saying, "Okay, a little bit of that and a little bit of that," um, and then what's, what comes out in behavior or speech is something that looks very organized, but is actually the, the, the reflection of a lot of selective filtering?

   2. MDDr. Mark D'Esposito26:52

      Yes. I mean, the prefrontal cortex, what's so fascinating about it is that it, I would say it connects to every part of the brain, uh, uh, cortex and the subcortex, and almost every part of the brain connects to it. So that, I mean, that right there tells you it's a pretty important area. (laughs) And it, it has to if it's gonna be in this CEO, you know, conductor-type experience, uh, role. And so it's in this privileged position, just anatomically, so that, that gives us great insight to how important it is. And so it is connecting. And then, of course, we could talk about it, how it's connected to th- the body as well, how it controls heart rate and respirations as well, so it's not just this brain, so. Um, but it's really interesting, like y- like you said, is, is it really just sort of maintaining, telling you what's relevant and what's not relevant, or is it allowing you to switch? I, I, I think it does all those things. It, it, it definitely what we call sends these top-down signals. It's sending signals to the other brain about what you should be paying attention to and what you shouldn't be op- paying attention to. So for example, if you, we've done studies with functional imaging where we have them look at pictures of faces and scenes, and that lights up the back of your brain. Your visual cortex has areas that are, can process faces and process scenes. And, um, but sometimes when we have you just on pay attention to the faces and not the scenes, and other times we want you to pay attention to the scenes and not the faces, well, you know, even though it's getting the same bottom-up visual input, the prefrontal cortex will, will show greater activity to the relevant information. It'll, it'll, it'll sort, it's sending a signal to say, "Pay attention to the faces, ig- ignore the scenes," and, uh, or vice versa. So it's, it's directing all of this information that we're bombarded with to what's, what's relevant. But at the same time, it's also, uh, sw- allowing us to switch, i- if, if that, if we now have to go switch to another task, it says, "Okay, this is not important now. We're gonna move over to this, this other, other task." So there's many different components of how it can, you know, how it can kind of control behavior, but it does all of these things in this incredible way that we still don't completely understand, but we know that's the source of, of all of this control is coming from the prefrontal cortex.

8. 29:02 – 30:29

   Sponsor: AG1

   1. MDDr. Mark D'Esposito29:02

   2. AHAndrew Huberman29:02

      I'd like to take a brief moment and thank one of our sponsors, and that's AG1. AG1 is a vitamin mineral probiotic drink that also contains adaptogens. I started taking AG1 way back in 2012. The reason I started taking it, and the reason I still take it every day is that it ensures that I meet all of my quotas for vitamins and minerals, and it ensures that I get enough prebiotic and probiotic to support gut health. Now, gut health is something that, over the last 10 years, we realized is not just important for the health of our gut, but also for our immune system and for the production of neurotransmitters and neuromodulators, things like dopamine and serotonin. In other words, gut health is critical for proper brain functioning. Now, of course, I strive to consume healthy whole foods for the majority of my nutritional intake every single day, but there are a number of things in AG1, including specific micronutrients that are hard to get from whole foods, or at least insufficient quantities. So AG1 allows me to get the vitamins and minerals that I need, probiotics, prebiotics, the adaptogens, and critical micronutrients. So anytime somebody asks me if they were to take just one supplement what that supplement should be, I tell them, "AG1," because AG1 supports so many different systems within the body that are involved in mental health, physical health, and performance. To try AG1, go to drinkag1.com/huberman, and you'll get a year's supply of vitamin D3K2 and five free travel packs of AG1. Again, that's drinkag1.com/huberman.

9. 30:29 – 37:26

   Frontal Lobe Injury; Emotional Regulation

   1. AHAndrew Huberman30:30

      You mentioned connections between the prefrontal cortex and the body. Um, that's the first I've heard of that, um, and I'm not challenging that. Uh, to the contrary, I'm just intrigued by it.Um, I'm aware that the hypothalamus and some of these deeper brain structures associated with more, um, let's call them primitive drives, um, temperature regulation, uh, hunger, et cetera, connect to the body. But, uh, what are, what's the nature of some of the connections with the frontal lobes to the body?

   2. MDDr. Mark D'Esposito30:56

      Well, I was just talk... Yeah. I was just sort of talking in terms of, of our knowledge of how, you know-

   3. AHAndrew Huberman31:00

      Hm.

   4. MDDr. Mark D'Esposito31:00

      ... changing... I, I wanted to ‎in your podcast, you talked about how TMS to the prefrontal cortex can slow heart rate, so I meant in that, in that sort of way.

   5. AHAndrew Huberman31:07

      Got it. Got it.

   6. MDDr. Mark D'Esposito31:08

      That, that, that yeah, by, by, by influencing f- uh, cortical function, well, eh, obviously we can influence, uh, uh, organs like the...

   7. AHAndrew Huberman31:16

      Got it.

   8. MDDr. Mark D'Esposito31:16

      Yeah.

   9. AHAndrew Huberman31:16

      So through some intermediate stations.

   10. MDDr. Mark D'Esposito31:18

       Yes.

   11. AHAndrew Huberman31:19

       Yeah. I mean, it's... You know, not to, um, not to be hyperbolic, but, eh, I mean, it seems like the prefrontal cortex, w- what here we're referring to as the frontal lobes, um, are essentially the seat of what makes us human and what makes us functional or dysfunctional in a given context. Right? I mean, uh, I recall there's a syndrome, Kluver-Bucy syndrome, which has some vague, um, uh, similarities to how you describe frontal cortex damage. But there, uh, I, as I recall, humans or animals, um, with that syndrome will act in a way that's not appropriate to context, but more inappropriate. Like they'll, they'll try and eat a, a ceramic cup or draw with a piece of paper, which obviously won't work. It seems like with the frontal cortex, it knows that a pen is for writing, it just, the person might say, "Yeah, I know I'm not supposed to write this, but I'm just gonna..." or write with it, "but I'm gonna take your pen and write something inappropriate with it." But it, it's not that they, that people forget that there's a, that it's a pen. So it seems like it's drawing on, um, sort of rule sets, but that something's intact. It's like th- it's not like Kluver-Bucy syndrome where, um, th- uh, like animals and people can try and, uh, like mate with inanimate ar- objects, um, which is o- one of the more salient, um, symptoms.

   12. MDDr. Mark D'Esposito32:40

       Right. Right. (laughs)

   13. AHAndrew Huberman32:40

       I'll never forget that. Uh, don't forget that from, from my cognitive neuroscience course, which you taught, by the way.

   14. MDDr. Mark D'Esposito32:45

       (laughs)

   15. AHAndrew Huberman32:45

       Um, just throw that in there. So yeah, l- uh, so how, how should we think about this? And here I'm trying to get at a kind of a broader understanding of brain function and context-specific behavior. Um, it w- so f- frontal cortex is like super sophisticated, um, but it doesn't have all the information, right? It seems like someone without a frontal cortex probably knows that you write with a pen, you don't write with a piece of paper.

   16. MDDr. Mark D'Esposito33:10

       Yeah. I, I think it's... You know, we think about it as it's, you know, the frontal cortex allows us to take thought and move it towards action, and there's this disconnect between the, the knowledge and, and action, and the separation of action from knowledge. And I guess I can reflect on my patients, you know? When I s- I've seen a lot of patients with damage all over the brain, and all of the families of patients who have frontal lobe injury always say the same thing.They're, they're just no longer that person. "They're no longer my spouse. They're no longer my best friend. They're no longer my father." Just something, they can't put it into words, but they're not them anymore. There's, something has changed. Whereas if you talk to a patient with Broca's aphasia who's, has this inability to speak, they can't get any words out, now this is a devastating problem. They're still the same person. They, they, they, their personality hasn't changed. They, they feel the same person, they just can't speak. The way they get around in the world is different. Or if you take a patient with prosopagnosia, which is, uh, this inability to recognize faces, of course the way they navigate around the world is, is, is difficult, and it's not the same, but they're still the same person. So there's something really special about the frontal cortex that allows us to be, as you said, sort of who we are. And that's the difficult part. Like, how does the frontal lobes allow us to sort of take, um, take who we are and translate that into knowledge? So we're not... I guess, in other words, saying that just, just having knowledge isn't what makes us who we are. Right? It, it's the being able to take that knowledge and, and, and present it in a way that allows us to live life based on our intentions and our goals and our desires.

   17. AHAndrew Huberman34:49

       So much of things like stoic philosophy and, um, and even the online wellness culture, uh, are about, um, having routines, um, you know, overcoming reflex by just having recipes, scripts to follow each day. Um, I certainly try to have my mornings be as what I call linear as possible, and I find it's much easier in the earlier part of the day to just decide, "Here's what I'm gonna do," write out a list, do things in a certain sequence. If I don't do that, I go non-linear, as I refer to it, (laughs) and will get distracted and things of that sort. But, um, earlier you mentioned sleep deprivation can impair frontal lobe function. Uh, it does seem that, um, as the day progresses, and certainly in the middle of the night, it just becomes much harder to, um, control our, our thinking, maybe even our behavior, but, um, and certainly our emotions. Is there a frontal lobe, uh, regulation of emotional states as well? I know you have some recent work on this, so I'd love to hear more.

   18. MDDr. Mark D'Esposito35:49

       Yeah. Yeah, I mean, as I was saying earlier, the frontal lobes is a big place, and, and half of it is involved in these high level executive functions, but the other half of it is inv- is, uh, part of the limbic system, or that we call it the paralimbic system, that's involved in social and emotional behavior. And so, uh, there's this intimate back and forth between these two areas of the cortex. If you have just damage to these frontal, to these areas that are kind of in the overall frontal lobe, you will have many different impairments that are, we would call sort of social or emotional impairments, and their executive function will be quite normal. And then you'll have the, the opposite, where patients with a lot of damage will have executive functions, but they seem emotionally intact. But, but, you know, in real life when we have both these intact, they're, they're communicating with each other, so right? Emotion and context, and, is gonna influence our executive function. We make bad decisions a-... in stressful situations or situations we're not comfortable with. It's, it's where we might make a better decision if it's a quiet, you know, kind of c- quiet place. Um, but i- it is something that we can... I think you, you're right, you can, you can sort of get into a routine and learn how to do things, you know, if you've h- have them very much planned out. But what's so unique about us is how we can be flexible and adaptable, right? When, when something novel comes up or there's something un- something unexpected comes up, we can adapt to it. And that's really what the frontal cortex is really important for. Um, not just sort of making these plans, routines, and setting all the rules, but being able, when things don't go right, how to, how to right the ship, right?

10. 37:26 – 44:37

    Smartphones, Social Media

    1. MDDr. Mark D'Esposito37:26

    2. AHAndrew Huberman37:26

       I will never ask you to, um, demonize technology. Um, I certainly use a, a smartphone, um, from waking til sleep. Um, generally not in the middle of the night if I can avoid it, uh, and I generally avoid it. But I'm trying to take what we've discussed thus far and superimpose the, the notion of smartphones and ask, "What are the rules? What are the algorithms that we're learning when we use these devices?" And I'm not calling them adaptive or maladaptive. They're clearly here to stay. They've assisted in medicine, I'm sure it makes it easier for doctors to communicate on the, on the ward, and, and for, um, clinic and rep- It's so useful, right? But contained in this small device, um, there are things like, uh, for instance, text messaging, where, unlike 20 years ago, we can have four or five different conversations very quickly while boarding a flight. Um, there's a task switching element that was just not present in our life, um, prior to that. Um, social media in particular, this notion of being able to scroll. So move, if we really step back from this, move one's thumb and access hundreds if not thousands of video content from disti- which, each of which has a distinct context. Um, and so I have to imagine that kids and adults have frontal cortices that are learning these rules, and the rule is, "Move your thumbs, stay engaged." Emotions, either positive valence emotions or negative emotions, I mean, it's, it's a fairly limited r- um, landscape there when you really think about it, but, but the algorithm that's learned is, to me, doesn't seem exportable. It doesn't help me prepare for a podcast at all. I know that for sure. Doesn't help me go for a run, doesn't help me listen with more focused attention to a family member or a friend or a significant other. Um, it may make me more empathic or more angry. I d- you know, we can, we can speculate, but, um, again, with no i- with no intention of demonizing social media, does it seem that the, the algorithms that are being run in our brain... I mean, are they neutral? Are they positive? Are they negative? Should we be worried? Um, th- it doesn't seem like they translate to much else. Th- they w- I can't see a way in which they help us be better people in other domains, whereas reading a book line by line and then going back, "Oh, I didn't even remember anything from that page," going back line by line, um, playing a game of squash or something like that, th- there, I can see the real value of the rule sets that generalize.

    3. MDDr. Mark D'Esposito40:10

       Yeah, I mean, I can... You know, just historically, I grew up in a world when there was no smartphones as a resident, and, and so one of the most difficult things I do in practice is have to take care of patients in the emergency room when there's a real emergency, someone's having uncontrolled seizures or they're having a stroke. And, you know, doing this back in the '80s or '90s and early 2000s when you went down there and you didn't have any smartphone, you, you could only rely on what's, what's in your head. And I could say now, having the smartphone, it hasn't, it doesn't help me at all. I, I never, you know, it does not help me at all in making the kind of decisions that I have to make in the emergency room. I'm, I'm trying to decide, you know, what, what, what's the problem here, what's the differential diagnosis, what, how should I treat it. I'm just trying to make very, going through an algorithm, like you said, in a common sense way, and there's nothing on my phone that I can turn to to help me do that. It has helped with giving me knowledge. Uh, like, back in the day I had to remember what the Dilantin dose was and have that in my head or go look for the piece of paper in my pocket, and so I can quickly pull up, you know, I guess, I'm a little bit... You know, th- there's information that I can access that I don't have to worry about keeping every single dose in my head or keeping everything in my head, just facts in my head. But, uh, outside of that, there's nothing I can turn to that it's, it's making me, you know, better, making me make better decisions, so I, I don't even need my cellphone. I don't go searching m- for my cellphone if I'm gonna go to emergency room or I gotta take a, take a phone call, so I don't see how it's helping sort of make your frontal lobe... It can't be your frontal lobes, I mean, is another way of, of saying it. But, but on the flip side, can it help you optimize frontal lobe function, technology? Certainly it can. We can maybe talk about it later. There are, there's certainly th- that's one way to get, learn strategies is through a, through a device that, that's easily accessible and, uh, you know, to you, as opposed to a book or, or having a therapist, uh, in your house.

    4. AHAndrew Huberman42:02

       Yeah, I suppose I worry that, um, too much of my time and other people's time, and especially young people's time, is, um, engaging in a algorithm that does not, um, generalize for adaptive behavior elsewhere. And, and by comparison, you know, like a, a game of soccer with friends or something, right? It's social, social media is social, um, it's physical, social media is not physical. But we'll, we'll rule that, that portion out. But there's a rule set, um, there's goal-directed behavior. Um, presumably some of the things that happen in a game of soccer with friends translate to some other domain of life, um, because it's a single context, game of soccer. Whereas with social media, I don't know anybody that goes and looks at one account.And that's it. And absorbs the information, maybe comments, has an interaction and goes.

    5. MDDr. Mark D'Esposito42:55

       Right.

    6. AHAndrew Huberman42:56

       It's, it's hundreds or thousands of contexts. So is there any risk or perhaps benefit to being able to, um, get this very detailed portal into so many contexts per unit time? I mean, the, the forebrain's never had, done that in the course of human history as far as I know.

    7. MDDr. Mark D'Esposito43:15

       Yeah, I mean, I think there is a risk, but what pops to mind, you know, having kids is, is watching them navigate in their cars to places totally dependent on, on Google Maps. And I think you're probably old enough to remember real maps, uh, (laughs) where you didn't have-

    8. AHAndrew Huberman43:30

       I still have one in my car.

    9. MDDr. Mark D'Esposito43:31

       (laughs)

    10. AHAndrew Huberman43:31

        I still, I love paper maps. I love maps, so.

    11. MDDr. Mark D'Esposito43:33

        Right, where you had to really figure out, you know, you, you had to go to a certain place and you had to either look at the map or, or, or ask, stop at a gas station and ask. These, these, these skills were something that you learned and you developed and it was problem-solving, and, and, uh, and that's all gone now. I mean, it's, it's, I, I wonder even if sometimes if, if, uh, people even know the direction they're going, whether it's west, north, or what set town they're in, because they're just following the directions. So I, we'll, we'll see. I, I just can't imagine that that learned skill is not going to be detrimental to us at, at some point in generalizing the r- reverse generalize in a bad way, right? As, as opposed to a good way. Um, so I don't... yeah, it does, it does definitely worry me. But like you said, there's nothing on the phone that helps you plan a podcast, nothing that helps me in the emergency room, nothing helps a professor when he's giving a lecture. So I agree with you that, that the sort of having your head buried in a, in a cell phone, I'm not... yeah, it's, I don't see it being healthy for your frontal lobes.

    12. AHAndrew Huberman44:36

        Mm-hmm.

11. 44:37 – 52:59

    Working Memory, Dopamine

    1. AHAndrew Huberman44:37

       Let's talk about working memory. Um, some years back, but still now, you use working memory tasks and experiments in your laboratory. If you would, um, be so kind as to explain what working memory is, and then I'd love to talk about, um, some of the work you've done exploring the role of dopamine in working memory, um, because this is so critical to everyday life and I know dopamine's a bit of a buzzword these days, but, um, the listeners of this podcast anyway are, are, um, pretty sophisticated in terms of knowing that dopamine is not just about reward, it's about motivation and goal-directed behavior, and I think dopamine intrigues for a good reason, that it does govern a lot of our, you know, quality of life. So, um, what's working memory?

    2. MDDr. Mark D'Esposito45:24

       Yeah, I mean, working memory, it's interesting. I started studying it about 30 years ago, and I don't think I realized how important it was when I started. But what we mean by working memory is this ability to hold information in mind, uh, when it's no longer accessible to us. So if you tell me your telephone number and I have to put it into my phone, you know, it's no longer there, you just told me, but I'll hold it in my working memory until I can punch it into my, my phone. It doesn't have to be something that comes from the outside world. I could hold up a, you know, I, I can pull up my own... if I'm filling out a form and I want to pull up my social security number, I can hold that in mind too until I put it down. So, um, when you think about it, it's a very important, uh, sk- you know, ability that we have that we do s- very flawlessly. And what I've learned more about working memory is, is the working part of it. It's not just this passive holding information in mind, but it's being able to do things with the information. It's being able to, um, you know, when we, when we do a math problem, which we don't do that much now that we have calculators, but if you do that in your head, you're able to sort of manipulate the information and, and do the different parts of the problem. Or even if you're, you know, you're trying to find someone in a crowd and you're holding onto some face, you're able to hold that face in mind and cross-check it and search and, and so there's, there's operations to working memory. It's not just, you know, it's not just this passive maintenance. So when we started to think about working memory in that way, we started to realize how important it is for its... you know, I think of it as the foundation for, for cognition. Just think about reading comprehension. You can't understand this conversation if you can't hold in mind what's going on, you know, earlier in the, in the conversation or when you're reading a book, you know, remembering the sentence, uh, before it. So it just predicts all these abilities that, that allows us to, to read, to, to, uh, plan, to organize, and all the sort of executive functions that we're, we're doing, right? We have to hold in mind rules, we have to hold in mind goals, we have to hold in mind all of these things in order to just carry out behavior. Um, you know, so it's, it's, it's really come a long way in, in terms of how people are thinking about it. I, I, I know that, uh, Matt Walker said that like, you know, sleep is our superpower, but I guess one way to sort of use his term while we're awake, working memory is, is really our superpower because it allows us to, to translate, as we said, sort of our knowledge into action by holding this information, uh, in mind as we're thinking about what we want to do.

    3. AHAndrew Huberman47:49

       If we're going to think about dopamine in the context of working memory, is dopamine an accelerator on working memory? Is it a facilitator? I mean, what is dopamine doing for working memory? And maybe we could talk a little bit about the circuitry. Um, I've talked about dopamine before on this podcast, but there's a good chance that some of the people listening to this haven't heard those episodes, so maybe we could just quickly review the three major circuits for dopamine and the one that's relevant for working memory.

    4. MDDr. Mark D'Esposito48:15

       Yeah, let, let me start with the working memory, the circuitry for working memory-

    5. AHAndrew Huberman48:18

       Please.

    6. MDDr. Mark D'Esposito48:18

       ... because one, one of the important things about working memory is the other type of memory is, is long-term memory. It's, it's... you, you can... working memory's short-lived, it's only as long as you're able to rehearse it and then it disappears, whereas what we call long-term memory, if I... remembering what you had for breakfast or your vacation, this is information that's gets consolidated and, and gets put into a, a more durable form that we call long-term memory. And the interesting thing about memory is that these are separate systems. Everything from working memory just doesn't pass into long-term memory, they're, they're two completely different systems and-... in two completely different parts of the brain that seem to control it. Um, so working memory, uh, the frontal cortex seems to be very important for working memory. When, when we are holding information in line, the neurons, the brain cells in the frontal lobes are active and they stay kind of active as long as we're holding on that information. And they're more active when the information is relevant. Um, and if we, uh, we, we get distracted, they'll get less active, so it kind of... The frontal lobes kind of track your, uh, you know, track the, the memory that you're holding in mind. Another important thing about the circuitry is that, um, if we're holding in mind, say digits, you know, s- the phone number, well, that information's in your back of the brain and so the, the frontal lobes is sort of keeping information in the back of the brain active because it's connected to the visual areas. It's, it's able to sort of keep that information active. And so what, what we've learned is that there's not these buffers in the brain where, oh, you know, if you're holding verbal information it's in this little buffer and if you're holding visual information it's in another buffer. The whole brain acts as a buffer an- and the frontal lobe can call up any part of the brain and, and keep that part of the brain active as it's, as it's ho- you know, as it's trying to hold this information in line. So the mechanism for working memory is just this persistent neural activity within the frontal lobes. And so then the question is, what does dopamine do? Well, dopamine is one of the neuromodulators that are made in the brain stem and it projects up to different parts of the brain. There's a system that goes up into the, into the, what we call the basal ganglia which is important for motor function, and there's another dopaminergic system that goes up to the frontal lobes. And what was discovered was that if you deplete dopamine, uh, working memory drops. You, you get a significant impairment on working memory if, if you deplete dopamine and if you replace it, uh, then your working memory will be improved. And so dopamine seems to be a modulator to help this persistent activity stay persistent, uh, you know, w- during the time that you need to keep this information, uh, in mind.

    7. AHAndrew Huberman51:02

       Am I reaching too far to draw an analogy between dopamine's role in working memory, that is to keep information online, and the other established role of dopamine which is for movement, for the generation of smooth movement? Um, as evidenced by conditions like Parkinson's where people lack dopaminergic neurons or have damage to dopaminergic neurons and have a, you know, challenges in generating smooth movement. What I'm essentially asking is, can we think of dopamine as facilitating physical movement through one circuit, but also kind of mental movement, thought movement, kind of, um, I'm thinking about... For those, uh, just listening and, and not watching, I'm kind of rubbing my, um, index and middle finger against my thumb, so just keeping something online, um, it's sort of a movement of thought or information and then you kind of chuck it away and bring about the next information. Is that, is that appropriate?

    8. MDDr. Mark D'Esposito51:59

       Yeah, I think that's a good way of thinking about it and one might wonder, well, how can dopamine be important for memory but also be important for movement? And, and it's really simple. It's just that it's acting on different circuits. The, the, the neurons that go to the motor areas that carry dopamine will, will... When dopamine is expressed there then, and boosted there, then it will be involved in movement and lack of dopamine in the basal ganglia will lead to neurological disorders like Parkinson's disease that has severe movement, uh, difficulty. But when it's acting in the frontal cortex, uh, and expressed in the frontal cortex, then it's going to improve working memory. So it's just, it's just the, uh, the nature of where the circuits are, where the dopamine is that's, that's allowing it to have different kinds of actions and that's all for all transmitters. Uh, the reason why acetylcholine seems to be more important for long-term memory is because it, it's projecting to the hippocampus which was, we know is another area that's important for memory and, and that's why acetylcholine doesn't boost your working memory but dopamine does and vice versa.

12. 52:59 – 54:22

    Sponsor: LMNT

    1. MDDr. Mark D'Esposito52:59

    2. AHAndrew Huberman52:59

       I'd like to take a quick break to acknowledge our sponsor LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means zero sugar and the appropriate ratios of the electrolytes sodium, magnesium, and potassium. And that correct ratio of electrolytes is extremely important because every cell in your body, but especially your nerve cells, your neurons relies on electrolytes in order to function properly. So when you're well hydrated and you have the appropriate amount of electrolytes in your system, your mental functioning and your physical functioning is improved. I drink one packet of LMNT dissolved in about 16 to 32 ounces of water when I wake up in the morning as well as while I exercise, and if I've sweat a lot during that exercise, I often will drink a third LMNT packet dissolved in about 32 ounces of water after I exercise. LMNT comes in a variety of different flavors, all of which I find really tasty. I like the citrus, I like the watermelon, I like the raspberry. Frankly, I can't pick just one. It also comes in chocolate and chocolate mint, which I find tastes best if they are put into water dissolved and then heated up. I tend to do that in the winter months because of course you don't just need hydration on hot days and in the summer and spring months, but also in the winter when the temperatures are cold and the environment tends to be dry. If you'd like to try LMNT, you can go to DrinkLMNT, spelled L-M-N-T, .com/huberman to try a free sample pack. Again, that's DrinkLMNT.com/huberman.

13. 54:22 – 1:00:03

    Dopamine Levels & Working Memory, Cognitive Tasks, Genetics

    1. AHAndrew Huberman54:22

       So drilling a little bit more deeply into the role of dopamine and working memory, uh, you did some really lovely experiments, uh, showing that if, um, people who have low levels of dopamine, um, increase their dopamine, uh, pharmacologically, I think the drug that was used was bromocriptine, um, that working memory improves. Um, conversely, if one depletes dopamine pharmacologically, dopa- uh, working memory gets worse. Um, but as I recall, there was an important baseline that-... is important because it really mattered in terms of the outcome, meaning if somebody already had relatively high levels of dopamine in this circuit, increasing dopamine further with bromocriptine didn't i- impart a benefit. It might have even made their working memory worse. So, there's a kind of inverted U-shape function to this. Um, how does one know whether or not their baseline dopamine is low, medium, or high? Ergo, uh, how do they know (laughs) whether or not, uh, they would, uh, want to explore going about increasing dopamine through any number of different approaches?

    2. MDDr. Mark D'Esposito55:30

       Right. Well, most people probably have optimal dopamine, but there's a significant percentage that probably have too little or maybe too much, and it's, un- unfortunately, we can't measure it in the blood. Um, there isn't a blood test that I'm aware of that can, can measure, uh, dopamine because it's stuck in, it's stuck in the brain. Um-

    3. AHAndrew Huberman55:50

       Peripheral dopamine in the blood doesn't, is not a good readout.

    4. MDDr. Mark D'Esposito55:53

       Is not a good readout, yeah. And, and especially when you're talking about dopamine in, in areas like prefrontal cortex. And, um, so we don't have a good readout there. There's, there's invasive procedures like positron emission tomography where we can inject a radioisotope, um, uh, that tags dopamine, and then we can measure how much, we can do a scan that actually shows us how much dopamine. This scan was originally developed to show Parkinson's disease, that, that you can diagnose Parkinson's disease by showing that there's, there's less dopamine in, in patients with Parkinson's by looking at this, this scan. Um, obviously, it's invasive. You're injecting a radioisotope. It's expensive, and it's not something we could all do, but w- we had used it to show that it correlates very strongly with your working memory capacity, so how much information you can hold online. If you can hold four or five or six letters when I do a, a span task, um, correlated with how much dopamine we can see in the PET scan. So that, that would be a, a, a way that we could do it. Um-

    5. AHAndrew Huberman56:51

       So, if you were to read out a string of, uh, a few numbers or letters, um, and I can remember all of those a few moments later, um, perhaps, perhaps my baseline dopamine levels are, uh, moderate, um, in the, in the normal range, whereas if I couldn't keep that online, um, that might be re- might be reflective of lower baseline dopamine levels. Is that right?

    6. MDDr. Mark D'Esposito57:15

       Yeah. It's a, it's a very strong proxy for dopamine. So if your, your working memory capacity is seven letters when I, or numbers when I say four, three, seven, one, five, zero, six, if you get the (laughs) -

    7. AHAndrew Huberman57:26

       Four, three, seven, five, six, right. Yeah.

    8. MDDr. Mark D'Esposito57:27

       ... get them all back very quickly, you probably have more dop- baseline dopamine than, than someone who has five i- i- there, it, so it's g- it's a proxy for measuring someone's dopamine. So that, that's one way of doing it, and that's actually how we did it in our original studies. We, we actually, um, grouped individuals based on whether their capacity, based on this behavioral measure, was high or low. And like you said, those who were k- that could only hold five or six letters, if we gave them bromocriptine, which was the dopaminergic agonist, we improved their working memory. Uh, we got them into sort of an optimal level. But, but those who were already high, we actually made them, we wor- we got them worse. And the moral of that story was that more is just not better. We're trying to get people optimal. And so the real question is, is, you know, if we want to get people optimal, like you were inferring, it, you have to know what their dopamine is. Where, where are you on this inverted U curve? Another way of doing it, uh, is through, um, a genet- through genetic studies. So we ha- dopamine, uh, all neurotransmitters have to be broken down and reuptaked in- into the, into the brain cell in order to be used again, and there's different ways of doing it. In some cells, uh, it gets transported back into the brain cell. In other, other places, there's an enzyme that, that breaks it down. Well, there's an enzyme called COMT, uh, that is, breaks down dopamine in the prefrontal cortex specifically. In a large percentage of individuals, that enzyme is either overactive or underactive. Probably about 25% of individuals, it's overactive, in another 25%, it's underactive, so probably half the population. Now, this is gonna vary, depend on other, w- w- where you live and where you come from and things, but it, but, but maybe half the population either has an underactive enzyme or overactive enzyme. If you have an underactive enzyme, then actually more dopamine sits around, and you, you actually have more dopamine than others. And if you have an overactive enzyme, it's the opposite. So we've actually shown that if you now go and genotype people with a s- simple saliva test and figure out do they have this genetic what we call polymorphism where just one amino acid gets changed and the enzyme becomes either active or underactive, we can, we can do the same thing as, as grouping them by their capacity. Those that have the low dopamine, we will make them be- better, and those who have sort of baseline high dopamine, we'll, we'll make them worse.

14. 1:00:03 – 1:06:21

    Bromocriptine & Working Memory, Dopamine

    1. AHAndrew Huberman1:00:03

       Super interesting. Um, maybe we could talk about bromocriptine a little bit, and I'm not encouraging people to run out and take bromocriptine. Um, bromocriptine, you, as you mentioned, is a dopamine agonist. Um, relatively short-acting?

    2. MDDr. Mark D'Esposito1:00:18

       Yeah, a few, four or five hours, six hours.

    3. AHAndrew Huberman1:00:20

       So it kicks in about 90 minutes after-

    4. MDDr. Mark D'Esposito1:00:22

       Right.

    5. AHAndrew Huberman1:00:23

       ... as I recall you saying.

    6. MDDr. Mark D'Esposito1:00:23

       Right.

    7. AHAndrew Huberman1:00:24

       I've never taken it.

    8. MDDr. Mark D'Esposito1:00:24

       Yeah.

    9. AHAndrew Huberman1:00:25

       Um, w- how do people feel when they're on bromocriptine? I mean, when I hear, uh, dopamine agonist, I mean, there are a lot of illicit drugs like cocaine, methamphetamine that are increase dopamine, but then again, chocolate, sex, and food increase dopamine, but the kinetics, the time course and the levels are, are different for each of those things.

    10. MDDr. Mark D'Esposito1:00:43

        Right.

    11. AHAndrew Huberman1:00:43

        Um, dopamine, of course, being a currency of motivation and re- reward, not, not, um, directly related to any one compound. But, um, i- I would think that based on the data you just described, that, um, and given the fact that there are a number of people out there with challenges in working memory, attention, task switching, et cetera, that-... there would be a strong interest on the part of the pharmaceutical companies, at least, and certainly the general public, um, in things like bromocriptine to increase dopamine, to increase working memory, given it is our superpower.

    12. MDDr. Mark D'Esposito1:01:18

        Yeah, I mean, one of the most disappointing things to me in my career has been that pharmaceutical companies have not picked up on this idea that we could improve cognition and very specifically improve cognitive processes with very specific neuromodulators. The, the discovery that depletion of dopamine and not other transmitters impairs working memory was made in 1979. Um, when I heard, uh, Pat Glone... He used to talk about this as a resident, I was just amazed that there could be a single transmitter can change a single behavior. I was seeing very complicated behavioral deficits and it just seemed impossible to me that it- there could be such a tight link between a single, you know, a single neuromodulator and a single cognitive process, and just opened the door for me that th- this really could be a incredibly (laughs) beneficial therapy for, for an- anyone with executive function or frontal lobe function. So, but unfortunately, there's never been a pharmaceutical company that's tried to develop a drug for improving cognition to this...

    13. AHAndrew Huberman1:02:16

        That's crazy.

    14. MDDr. Mark D'Esposito1:02:17

        ... to this day.

    15. AHAndrew Huberman1:02:17

        And they... I mean, it's crazy for several reasons. One is that the data are clearly there. Uh, two, these drugs are already established. It's not like they have to go through safety trials again. They... That's already been done. But mostly because regardless of whether one is a fan of the pharmaceutical industry or hates it, the pharmaceutical industry in principle can make a ton of money doing this, so I would think that they'd be heavily incentivized to do it. So why have they, um, turned a blind eye on this?

    16. MDDr. Mark D'Esposito1:02:42

        I'm not sure. I mean, when I realized, um, that I could test these drugs in, in healthy individuals, that, that they were s- if I gave them in low enough doses, they were safe, and, and I had so much experience of them in patients that I felt comfortable doing it, um, then I started asking pharmaceutical companies, you know, "Do you want to get involved here? We c- we can... We... This should be done. I can't do this by myself. We need to have real trials and real studies of how this will help." You know, and, and just it was... You know, their eyes would always cross and never, never got any, any sort of traction and always went back to sort of disease, you know, what, what disease are you, um, curing? You know, what, what's the market for it? Is it a Parkinson's disease thing? Is it an Alzheimer's disease thing? And this has been a general problem with neurology. It's very disease-centric, it's always sort of f- And it's always focused on, you know, how can we develop a treatment for an Alzheimer's or traumatic brain injury or stroke as opposed to, how can we develop a treatment for working memory dysfunction, which is a problem across diseases. So the answer to your earlier question is these drugs are very safe, they... We give them in such low doses to healthy individuals, they don't even know... They can't even tell the difference between the placebo and the drug.

    17. AHAndrew Huberman1:03:55

        Really?

    18. MDDr. Mark D'Esposito1:03:55

        They don't even know which one they're on.

    19. AHAndrew Huberman1:03:57

        So they're not buzzing thinking like-

    20. MDDr. Mark D'Esposito1:03:58

        No.

    21. AHAndrew Huberman1:03:58

        ... "Oh, this feels good."

    22. MDDr. Mark D'Esposito1:03:59

        They have no i-

    23. AHAndrew Huberman1:04:00

        "... and my working memory is better."

    24. MDDr. Mark D'Esposito1:04:01

        They have no idea. They don't even know their working memory's better until we, we show them that their working memory is better. So-

    25. AHAndrew Huberman1:04:06

        Love it.

    26. MDDr. Mark D'Esposito1:04:06

        Yeah. (laughs)

    27. AHAndrew Huberman1:04:07

        So they're truly blind to what's going on. Um, bromocriptine is but one of the dopamine agonists. Um, can think of a few other, um, cabergoline, like, other things like that. Um, it... Do any of these dopamine agonists, um, exert this, uh, impact on working memory or is it... um, does it vary by drug because different dopamine agonists, uh, sort of hit different receptor pathways and things like that?

    28. MDDr. Mark D'Esposito1:04:32

        Yeah, no, it's not specifically the drug. I mean, the, the reason for bromocriptine is that it's the oldest and it's the one I was most comfortable with. I had to be comfortable with it clinically before I'd give it to (laughs) undergraduates at, at Penn or Berkeley, so there's nothing special, but other agonists work similarly. Um, there's a... there's a drug that's developed for Parkinson's which is a COMT inhibitor which actually inhibits this, this enzyme that we're talking about and that, that also will improve... uh, will have the same e- uh, function. There's been some futu- uh, uh, work that norepinephrine also seems to be helpful with working memory. Uh, it, it's not as... uh, maybe not as, um, potent as, as the dopaminergic. And that, that's the point I want to make, ano- another disappointing thing about this whole field of the pharmacology of cognition. Um, you know, I, I wrote a paper as a resident... You know, sometimes your attendings say, "Hey, can you write this review paper for us?" And, and I wrote one as a resident called The Pharmacology of Cognition where I just looked at all the animal literature on, you know, uh, giving f- uh, neuromodulators, acetylcholine, bromocri- um, dopamine, norepinephrine, and there was a lot of an- There was a lot of animal literature sort of supporting that this would work in humans but was n- More striking to me was that it wasn't always just a single, uh, neurotransmitter. It, it... There were studies where you'd give dopamine and it wouldn't do anything, you give acetylcholine, it wouldn't do anything, but if you gave a low dose of both, it would... it would be really effective. So these... you know, these neurotransmitter systems don't act in isolation, so we need to also study sort of how the combinations work and that's where another... you know, where the pharmaceutical companies have the infrastructure to do these kind of studies. It's very hard to do in a single lab to, to do multiple drugs at, at, at one time, you know, and then try and look at... try and determine all the different interactions.

15. 1:06:21 – 1:12:46

    Guanfacine, Neurotransmitter Levels, Pupil Dilation & Biomarker Tests

    1. MDDr. Mark D'Esposito1:06:21

    2. AHAndrew Huberman1:06:21

       Maybe we could talk about a couple of other drugs, um, that are legal or have... and have FDA approval or known to be s- safe in the right context that, um, it seems would fit the bill here, uh, for improving working memory. One is, um, Wellbutrin, bu- bupropion? Bup- bupropion? Oh, I can never pronounce that. Um, as far as I know, it's a, uh, um, epinephrine or norepinephrine agonist. You just mentioned that increasing epinephrine may have a, a positive impact on working memory and, to some extent, a dopamine agonist. Is there any evidence that, um, Wellbutrin can improve working memory?

    3. MDDr. Mark D'Esposito1:07:00

       Yeah, an- anything that, um, boosts norepinephrine can do it. The one that we've used, uh, that's most used is guanfacine, which is actually-

    4. AHAndrew Huberman1:07:07

       Mm-hmm.

    5. MDDr. Mark D'Esposito1:07:07

       ... a blood pressure medication, so that's starting to gain some traction. In fact, I think there was a study with COVID... with brain fog for COVID showing that it improved, uh, symptoms with it. So there's actually some trials now that are, are looking at guanfacine, and so I would say anything that boosts norepinephrine would be-... would be helpful. Um, but then again, I don't, I don't want to leave out the other transmitters. It's, ser- serotonin, you know, increasing serotonin, increase in acetylcholine boosts other cognitive processes and then, you know, in a way they can help working memory. We, we talked about working memory being, being this foundation. Well, if, if you give acetylcholine and it kind of boosts memory, well that can indirectly help your executive function. Or if you give a, a drug that improves your focus, then that can indirectly help, you know, working memory. So what I'm really pushing for is, is not just a single, you know, it's going to be one dru- you know, one drug, it's going to be a cocktail. And we have to not only figure out what the cocktail is, but also figure out who we're giving it to, what's ta- you know, link it to the person's own makeup of their own neurochemistry. When we get to a point where we'll know, we can map out sort of everyone's dopamine, norepinephrine, serotonin levels, so then we'll make real progress in, in helping them. Because right now, I sort of say with my students, what we're doing is just, it's just like cutting open the skull and just sort of pouring it onto the brain. It's, it's- (laughs)

    6. AHAndrew Huberman1:08:27

       We, we're not actually doing that, but...

    7. MDDr. Mark D'Esposito1:08:28

       (laughs) We're not actually doing it-

    8. AHAndrew Huberman1:08:29

       Right.

    9. MDDr. Mark D'Esposito1:08:30

       ... but it seems that way. We're not-

    10. AHAndrew Huberman1:08:31

        Yeah.

    11. MDDr. Mark D'Esposito1:08:31

        The precision is not there yet.

    12. AHAndrew Huberman1:08:33

        Mm-hmm. Well, you, it's great that you developed this, um, cognitive task that can be a proxy for dopamine levels. The cognitive task, again, being, um, how many number or letter strings somebody can remember, um, basically working memory performance. Um, there are a lot of tests out there that claim, um, they can assess dopamine and serotonin, acetylcholine levels from a blood draw. Um, I've heard of the Dutch test, I've never taken it. Um, but a few mo- minutes ago you said that really w- one needs to do positron emission tomography imaging, which is fairly labor-intensive, most people don't have access to one of those. Um, it's a clinical tool. Um, so there are behavioral proxies, there's neuroimaging, but also to my knowledge, I, I don't know that there's any blood draw that will say, "Hey, your serotonin levels are low," or, "Your dopamine levels are, are moderate." You're s- uh, et cetera. There are a lot of companies that market these, but are you aware of any clinical or other tools for getting an accurate read of neurotransmitter levels in, in a person's brain aside from neuroimaging?

    13. MDDr. Mark D'Esposito1:09:39

        No, and it, and it's, it's even more complicated than it seems because the dopaminergic system is complicated because it's not only just the prefrontal cortex, as we talked about, it's also the basal ganglia. And, um, so not only do we have to measure dopamine just generally levels, we have to me- measure the balance of the dopamine in the striatum and the, and the prefrontal cortex. There's, there's a model of dopamine, um, function and its relation to ex- eh- executive function that has to do with sort of the balance between these two systems, that dopamine in the prefrontal cortex is promoting sort of stability, it's, it's keeping information in mind, it's keeping these representations stable. Whereas the dopamine in the basal ganglia, what it's doing is, is allowing you to update and refresh, you know, the information that you're, that you're holding in mind, this sort of stability versus flexibility. So if you have too much dopamine in the frontal cortex it could lead to a very rigid state where you, you don't let anything in and, and if you have too much dopamine in the striatum and you get too flexible then you can get very distractible. So there's a sort of balance of dopamine. So it's not just how much dopamine you have in your brain, it's, it's how much... What's the balance of the dopamine? So I don't see a blood test as ever giving us that information, but I do see there being a, a brain test that, that can, that can give us this kind of, of information of, of the two, or at least a proxy for it. So what I was thinking about when you were talking about asking this question, you know, for example if you measure pupillary, pupil dilation, that's a pretty good proxy for neuro- for the noradrenergic system.

    14. AHAndrew Huberman1:11:13

        Right, so at a given, uh, people wonder what, um, how to do it, we're not going to, um, go into too much detail here, but at a given brightness in the room, what we call luminance, uh, the pupil tends to be smaller when it's bright and larger when it's, um, you're in a dim room. That's sort of obvious. Um, but at a given luminance, the more alert, aroused somebody is, um, arousal is a general term here, um, not, not talking about a particular kind of arousal, then the pupil tends to be more dilated. It gets bigger the more, um, norepinephrine is i-

    15. MDDr. Mark D'Esposito1:11:48

        Right.

    16. AHAndrew Huberman1:11:48

        ... is in the system. So if somebody's pupils are really big-

    17. MDDr. Mark D'Esposito1:11:51

        (laughs)

    18. AHAndrew Huberman1:11:52

        ... in bright light, that person's got a lot of, uh, epinephrine and adrenaline-

    19. MDDr. Mark D'Esposito1:11:57

        Right.

    20. AHAndrew Huberman1:11:57

        ... in their system.

    21. MDDr. Mark D'Esposito1:11:58

        Right.

    22. AHAndrew Huberman1:11:58

        Do you use this clinically?

    23. MDDr. Mark D'Esposito1:11:59

        Yeah.

    24. AHAndrew Huberman1:12:00

        Like when someone comes in and they have those big old pupils?

    25. MDDr. Mark D'Esposito1:12:02

        Yeah, yeah, pupils...

    26. AHAndrew Huberman1:12:03

        And then you're like, "Okay, well, they're probably on a stimulant."

    27. MDDr. Mark D'Esposito1:12:05

        Yeah, I mean a lot of-

    28. AHAndrew Huberman1:12:06

        Mm-hmm.

    29. MDDr. Mark D'Esposito1:12:06

        ... what neurology does is, is try to look for these windows into the brain. And so I think there are a number of windows into the brain that we're going to be able to develop that can reflect these neuromodulatory systems. So that's why I've been so interested in developing biomarkers, because really what a neural biomarker is, is, is trying to, uh, develop something you can measure easily and simply and cheaply with, you know, but gives you, uh, information about how the brain is working. And so that's a bio- you know, that's a norepinephrine biomarker, working memory capacity is a dopamine biomarker and, and we're getting better at that. But again, we're not putting enough emphasis on it, in my opinion, to really sort of help, you know, improve brain health.

16. 1:12:46 – 1:19:27

    Bromocriptine, Olympics; Pharmacology & Cognitive Function, Adderall

    1. MDDr. Mark D'Esposito1:12:46

    2. AHAndrew Huberman1:12:46

       Have you ever tried bromocriptine?

    3. MDDr. Mark D'Esposito1:12:49

       Very early on but it's, it's such a low do- you know, the, at the dose that the, my subjects were getting, but like I said, it doesn't... It's so low you don't feel anything. And I should say with even with patients, um, that take it they, they rarely get any side effects. Sometimes, uh, with these drugs because there's peripheral dopamine they can get uh, uh, you know, nausea or vomiting, but it's extremely well tolerated, you don't get any, any- anything

    4. AHAndrew Huberman1:13:14

       Does it change reaction time?

    5. MDDr. Mark D'Esposito1:13:17

       It does and that's always the question of, of how much of this is that we're just sort of speeding up, we're just sort of making them faster, but for all the work we've done it's, it's pretty convincing that it's, it's not just how fast you're doing it, you're doing it better.

    6. AHAndrew Huberman1:13:31

       Uh, you might find this entertaining. Um, some years ago, uh, I learned that athletes, uh, were taking bromocriptine, uh, pre-Olympics and in the Olympics. I think it's a banned substance now. Um, and the athletes that were taking it, don't ask me how I know this, but I could tell you offline, um, and I'm not one of these athletes nor was I supplying the bromocriptine, were using it because, uh, they, they were sprinters, and it turns out that a lot of the sprint races are won, uh, by being first out the blocks. There are other factors as well, but that reaction time, you know, hundreds of milliseconds are the difference between podium and no podium. Um, and bromocriptine was one of the drugs used. It was not on the banned substance list. Uh, just a reminder that every Olympics you see, there are lots of things being used that are not on the banned substance list, and I'm not trying to be disparaging, I think there's just a lot of interest in augmenting neuromodulation for nervous system function. Bromocriptine was top of the list f- at that time. I think it's on the banned list now. Um, there's a lot of, um, use of pharmacology now on college campuses and in high school and even in elementary schools and sometimes by parents for their kids to try and improve cognitive function, most typically the use of Adderall, Vyvanse, Ritalin, and other stimulants which are noradrenergic, dopaminergic agonists. Okay, so, um, with the, uh, disclaimer, caveat, whatever you want to call it, that, you know, those decisions should always be made with a, a trained psychiatrist, um, monitoring things, what are your thoughts about, um, pharmacology for enhancing cognitive function given that the landscape of society is challenging and people want to perform well, they need to be able to focus. We've got, well, smartphones distracting us and, um, to some extent, um, you know, one could say, "Oh, well, it's cheating to use pharmacology." But a cup of coffee is a bit of a noradrenergic agonist.

    7. MDDr. Mark D'Esposito1:15:29

       Absolutely.

    8. AHAndrew Huberman1:15:29

       And, um, certainly improves my focus-

    9. MDDr. Mark D'Esposito1:15:32

       Right.

    10. AHAndrew Huberman1:15:32

        ... as long as I don't drink too much of it.

    11. MDDr. Mark D'Esposito1:15:33

        (laughs) Right.

    12. AHAndrew Huberman1:15:34

        Um, yeah, what are your thoughts? I mean, just...

    13. MDDr. Mark D'Esposito1:15:36

        Yeah, I think it, you know, it kind of gets back to w- what we talked about there being an optimal, you know, optimal level of, of dopamine in your brain. I, I think if you think about it as just more and more and more is better and that more is better, then there's really no en- there's really no en- th- how do you know how much you should be taking? There's sort of no end to it. (laughs)

    14. AHAndrew Huberman1:15:56

        An experiment was run in the '80s, it's called the cocaine...

    15. MDDr. Mark D'Esposito1:15:59

        Right.

    16. AHAndrew Huberman1:15:59

        ... uh, culture of, of Wall Street in the '80s.

    17. MDDr. Mark D'Esposito1:16:01

        Yeah.

    18. AHAndrew Huberman1:16:01

        There was, there were movies about it.

    19. MDDr. Mark D'Esposito1:16:02

        Yeah.

    20. AHAndrew Huberman1:16:02

        And it doesn't lead to good places.

    21. MDDr. Mark D'Esposito1:16:04

        Right, right. So, so I'm all for optimizing function, uh, eg- I want to optimize brain health and if you have an underactive, you know, enzyme that's not... that, that makes your dopamine levels, then I'm all for trying to optimize that along with everything else we need to optimize in the brain. So if we could figure out who, uh, yeah, who is s- sort of on the lower end and boost them up, I'm all for that. The problem is we don't know if they're on the high end and some of these athletes were actually making themselves worse. We know for sure, I mean, w- these are healthy Penn and Berkeley undergraduates that we made them worse on working memory tests, you know, by-

    22. AHAndrew Huberman1:16:40

        By increasing their dopamine. Yeah.

    23. MDDr. Mark D'Esposito1:16:41

        By, by increasing their dopamine. Uh, just a little amount just tipped them over just a little, little amount and, uh, and so we, we, you know, f- without the knowing, then it just, it seems like it's not well informed you're going to be taking it. The other thing is I, I, I... if we're gonna do this, we should do it right. I think drugs like Adderall and Ritalin, you know, they were developed because they helped patients, but they weren't necessarily developed with knowing how exactly they worked. (laughs) I mean, that's how the pharmaceutical company work, works with that.

Episode duration: 2:32:37