How Your Brain’s Reward Circuits Drive Your Choices | Dr. Robert Malenka

1. 0:00 – 2:37

   Dr. Robert Malenka

   1. AHAndrew Huberman0:00

      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. Today my guest is Dr. Robert Malenka. Dr. Robert Malenka is a professor of psychiatry and behavioral sciences at Stanford University School of Medicine. He is both a medical doctor, an MD, and a researcher, a PhD. His laboratory is famous for having discovered some of the key components allowing neuroplasticity, that is the nervous system's ability to change in response to experience. In addition, Dr. Malenka's research is considered central to the textbook knowledge about how reward systems in the brain are organized and function. Indeed, Dr. Malenka's research over the last 10 or 15 years has merged what was once two disparate fields, the first being the study of neuroplasticity, again, the nervous system's ability to change in response to experience, and the other field being the field of dopamine as it relates to pleasure and addiction. His laboratory has shown, for instance, that when we seek out particular forms of pleasure, regardless of whether or not they are healthy for us, that changes the way that our reward circuitry works, and actually changes the way that dopamine is released and how it impacts the brain. And his work has also informed how we seek out healthy pleasures, including healthy food and social connection. Today's discussion explores all of these topics and by the end of today's discussion, you will have a rich understanding of how neurochemicals like dopamine and serotonin work in parallel to reinforce, that is, to increase the probability that we will engage in certain types of thinking and behaviors. So if you are somebody interested in neuroplasticity, that is, how the nervous system can change in response to experience, and/or you are interested in reward systems, what motivates us, and what we are likely to pursue in the future given our choices of past, and if you are interested in things like social connection, and empathy, or lack thereof, today's discussion encompasses all of those topics. It is worth mentioning that Dr. Malenka is a true luminary in all of the fields I just mentioned, as well as several other fields. In fact, when you look out on the landscape of modern neuroscience, what you'll discover is that a very large percentage of the top laboratories studying neuroplasticity and reward systems and so on all stemmed from having trained in Dr. Malenka's laboratory. So it's a real honor and pleasure to be able to host him today, and I'm sure that our discussion is going to greatly enrich the way that you think about brain function, neuroplasticity, and reward.

2. 2:37 – 5:21

   Sponsors: ROKA & Levels

   1. AHAndrew Huberman2:37

      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 ROKA. ROKA makes eyeglasses and sunglasses that are of the absolute highest quality. The company was founded by two all-American swimmers from Stanford, and everything about ROKA eyeglasses and sunglasses were designed with performance in mind. I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly. ROKA understands those challenges, and the biology of the visual system such that they've designed sunglasses and eyeglasses that always allow you to see with crystal clarity. Now initially, ROKA eyeglasses and sunglasses were designed for sports performance, and as a consequence, all of their glasses are designed to be very lightweight and to not slip off your face if you get sweaty. However, the design of the glasses include some that are specifically for sport and others whose aesthetic really allows you to use them for sport as well as out to dinner or to work, et cetera, and that's how I use them. If you'd like to try ROKA eyeglasses and sunglasses, you can go to roka.com, that's R-O-K-A .com, and enter the code Huberman to save 20% off your first order. Again, that's ROKA, R-O-K-A, .com and enter the code Huberman at checkout. Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods and behaviors affect your health by giving you real-time feedback on your diet using a continuous glucose monitor. One of the most important factors impacting your immediate and long-term health is the way that your body manages its blood glucose, or sometimes referred to as blood sugar, levels. To maintain energy and focus throughout the day, you want to keep your blood glucose steady without big spikes or dips. Using Levels, you can monitor how different types of foods, and different food combinations, as well as food timing, and things like exercise combine to impact your blood glucose levels. I started using Levels a little over a year ago and it gave me a lot of insight into how specific foods were spiking my blood sugar and then leaving me feeling tired for several hours afterwards, as well as how the spacing of exercise and my meals was impacting my overall energy. And in doing so, it really allowed me to optimize how I eat, what I eat, when I exercise, and so on, such that my blood glucose levels and energy levels are stable throughout the day. If you're interested in learning more about Levels and trying a continuous glucose monitor yourself, go to levels.link/huberman. Right now, Levels is offering an additional two free months of membership. Again, that's levels.link, L-I-N-K, /huberman to get two free months of membership. And now for my discussion with Dr. Robert

3. 5:21 – 11:31

   Dopamine & Reward Circuitry

   1. AHAndrew Huberman5:21

      Malenka. Dr. Malenka, Rob, welcome.

   2. RMRobert Malenka5:24

      Yeah, thanks for having me.

   3. AHAndrew Huberman5:26

      Delighted to have you here, both for sake of your medical knowledge and training as a psychiatrist, and of course, as a luminary in the field of neuroplasticity, dopamine and reward systems, social systems, your knowledge of autism and social interactions, a newer interest in, or perhaps old interest-

   4. RMRobert Malenka5:47

      (laughs)

   5. AHAndrew Huberman5:47

      ... in psychedelics and what they're doing in potential for mental health. Uh, there are just so many things that, uh, you've done in this field. I've been a long, long time fan of your work since your days as an assistant professor. I've tracked your career. I've learned a tremendous amount from you by observing you and-... from being your colleague, so really delighted to have you here.

   6. RMRobert Malenka6:07

      You're making me blush and-

   7. AHAndrew Huberman6:08

      Mm-hmm.

   8. RMRobert Malenka6:08

      ... I don't blush easily (laughs) .

   9. AHAndrew Huberman6:10

      Well, it's all, it's all, it's all true and I, and I will say-

   10. RMRobert Malenka6:13

       Oh, thank you.

   11. AHAndrew Huberman6:13

       ... as well, you've also trained an enormous number of incredible scientists, um, Karl Deisseroth, the Karl Deisseroth, um, Anna Lembke always speaks incredibly highly of you as a mentor and, um, somebody she's learned a tremendous amount from, and pretty much anyone that's worked on neuroplasticity-

   12. RMRobert Malenka6:30

       Mm-hmm.

   13. AHAndrew Huberman6:31

       ... on dopamine and reward systems, addiction, and now in the f- fields of autism and soon psychedelics as well, references you often, and you've been mentioned many times before on this podcast, if not by name, by work. So again, thank you for being here. I'd love to kick off the conversation-

   14. RMRobert Malenka6:47

       Thank you.

   15. AHAndrew Huberman6:47

       ... by talking about something which is very fundamental to everything we're going to talk about, but certainly fundamental to our daily lives, which is dopamine.

   16. RMRobert Malenka6:56

       Mm-hmm.

   17. AHAndrew Huberman6:56

       You know, we hear so much about dopamine, people talk about dopamine hits, people think about dopamine as pleasure-

   18. RMRobert Malenka7:01

       Mm-hmm.

   19. AHAndrew Huberman7:01

       ... dopamine reward. For the novice, how, how would you frame the dopamine system? I mean, it bu- does a bunch of different things in different areas of the brain and body, but to you, what, what does dopamine represent as its major function in the brain and could you give us a kind of general contour of the neural circuits that allow this chemical to m- more or less, um, put value on our experiences?

   20. RMRobert Malenka7:27

       Yeah, that's very well put. Um, as you point out, dopamine is one of the major what we term neuromodulators in the brain, a chemical signaling messenger that the brain uses to mediate a complex array of actions. Um, its best well-known function is in what we call the brain's reward circuitry. So this is a circuit in the brain, and when we use the term circuit, what we really mean is one part of the brain communicating with another part of the brain, because the brain is this very complex, you know, the most complex organism, organ in the universe, um, with lots of different nerve cells talking to each other simultaneously. And as neuroscientists, we try to parse what different brain areas are doing and what different neuromodulators might be doing. And dopamine was discovered, oh, I should know this, many decades ago, um, and it's, it's, as I said, the major chemical messenger molecule in the so-called brain's reward circuitry. And when you're talking about... So w- what is the brain's reward circuitry? This is a part of the brain that tells us something is reinforcing in our environment, some stimuli, or in quotes, is "rewarding," makes us feel better or good, although that's a gross oversimplification. Uh, and b- before getting into the details of dopamine and its function in the reward circuitry, I think it's useful to talk about wh- why do we need a reward circuitry? Why do we need something in our brain that tells us this feels good or this feels bad? And it goes back to evolution. I, I am a biological scientist, that means I believe in evolution, um, and if you think about the evolution of our species, um, everything is driven by developing mechanisms that increase our survival and it's really useful, you need something in your nervous system that tells you some stimuli in your environment is important for your survival or some stimulus in your environment is dangerous. So it's not magic that, um, sugary, high fat laden foods are highly reinforcing and rewarding, rewarding. It's not an accident, there has to be a mechanism in the brain that tells us that. It's not an accident that most of the time, for most of us, a sexual experience is pretty reinforcing, is pretty rewarding. It's not an accident that warmth feels really good when you're cold, that water tastes much better when you're really thirsty. There has, what evolved is a mechanism to tell our s- nervous systems and tell our brains, "This feels pretty good. I should repeat the behavior that leads to that rewarding experience." And similarly, it's really important when you, you know, there is an event in your life that's highly dangerous for some s- mechanism in your brain to say, "Whoa, I don't want to go back to where that lion was," and we can get into that. So this was a long winded way of saying what the reward circuitry tells us is this e- event, this stimulus, it could be an external stimulus, like I said, a, you know, a Krispy Kreme doughnut, which I happen to love and I have to be very disciplined so I don't eat too many of them. Um, it, um, it could be a drug of abuse and maybe we'll talk about that a little bit. All of these stimuli seem to activate and cause the release of dopamine in this brain's reward circuitry.

4. 11:31 – 17:34

   Reward, Arousal, Memory & Dopamine

   1. RMRobert Malenka11:31

      So now we need to get into a little bit of detail. Um, neuroscientists use these very unfriendly terms (laughs) to describe different brain regions. So the home of dopamine cells, or b- brain cells are called neurons, so the home of dopamine neurons, um, are in a part of the brain, sort of what we call the lower mid-brain. Um, the dopamine neurons that are part of the reward circuitry are found in this area called the ventral tegmental area (laughs) .... which I'm sorry to have to use such technical jargon. Um, we call it the VTA. That's the acronym. And-

   2. AHAndrew Huberman12:13

      I think, uh, the roof of the midbrain is the tectum, it means roof, and the base of the midbrain, it means floor, which is tegmentum.

   3. RMRobert Malenka12:22

      Yeah.

   4. AHAndrew Huberman12:22

      I think that's the... So there's a rationale, but it doesn't help much-

   5. RMRobert Malenka12:25

      (laughs)

   6. AHAndrew Huberman12:26

      ... at all to know the names, right? (laughs)

   7. RMRobert Malenka12:27

      And in fact you are absolutely correct and I always forget that. (laughs) So thank you for pointing that out. Uh-

   8. AHAndrew Huberman12:32

      It's a, it's a, it's a side effect of teaching neuroanatomy.

   9. RMRobert Malenka12:35

      A- And then, uh, which I once did back in the early '80s, but I've forgotten everything I taught.

   10. AHAndrew Huberman12:40

       It's okay.

   11. RMRobert Malenka12:41

       Um, anyhow, so these dopamine neurons, and we can talk about other types of dopamine neurons, they send messages, what we call projections, um, using telegraph wires that we call axons. They send projections to many different brain regions, the key one in the brain's reward circuitry being an area, again, with a very complicated name, called the nucleus accumbens, and maybe, Andrew, you know, I actually don't know w- how that name evolved, the nucleus accumbens.

   12. AHAndrew Huberman13:13

       I don't know.

   13. RMRobert Malenka13:14

       And I'm sure I should know because I've been studying it for 30 years, but I have never looked up the, uh, genesis of that name.

   14. AHAndrew Huberman13:22

       Well, the fortunate thing about this podcast is it's both on audio platforms-

   15. RMRobert Malenka13:26

       (laughs)

   16. AHAndrew Huberman13:26

       ... like Spotify and Apple, but also on YouTube, and so now we can be absolutely sure-

   17. RMRobert Malenka13:30

       (laughs)

   18. AHAndrew Huberman13:31

       ... that somebody has put it into the YouTube comments underneath this episode.

   19. RMRobert Malenka13:35

       (laughs)

   20. AHAndrew Huberman13:35

       And therefore everyone will learn, including us.

   21. RMRobert Malenka13:37

       (laughs)

   22. AHAndrew Huberman13:37

       So I don't know the origins of the word nucleus accumbens.

   23. RMRobert Malenka13:40

       Um, and, uh, it, it's, it's a gross oversimplification, but it's the activity of these dopamine neurons in the ventral tegmental area, um, that then cause the release of this powerful neuromodulator to mo- neuromodulator dopamine in the nucleus accumbens, which has a, is part of another brain structure with a tough-to-remember name called the ventral striatum. (laughs) Um, and then magic happens. And when I say magic happens, even though we've been studying how dopamine modifies the properties of cells in this nucleus accumbens, the truth is, we don't have a deep mechanistic understanding why when dopamine is released in the nucleus accumbens, we experience that as... Uh, I'm being very cautious here. The simple way would be to say as highly rewarding, but it's a little more complicated than that. What, what it tells us is that there's something really important happening in our environment. Um, th- and-

   24. AHAndrew Huberman14:50

       So di- could we say that it cues the arousal system?

   25. RMRobert Malenka14:53

       It, it, it, it gets the arousal system going. There's close ties to our memory systems, which hopefully intuitively makes some sense if something really important is happening in your environment, because again, we... Uh, uh, I think what's helpful for your audience is to always be thinking about how these systems evolved from an evolutionary perspective, and if dopamine is signaling something really important and salient is happening in your environment, you want to remember that. It could be a highly rewarding experience, like a source of food. For me, it's a criti- uh, I hope... I, I like all donuts, so I don't want to-

   26. AHAndrew Huberman15:34

       I do too.

   27. RMRobert Malenka15:34

       ... emphasize any one manufacturer of one donut versus the other.

   28. AHAndrew Huberman15:39

       That's okay.

   29. RMRobert Malenka15:39

       I, I like sugar-laden, fat-laden foods. That's why I never eat them because I like them so much and I use that as an example but because that was an important event for my survival, this reward circuitry, yes, it, it stimulates my arousal system. It gets me to pay attention. Um, it also has very close ties to memory systems. Um, and to, to go off on a little bit of a tangent, I think the one... Um, I don't want to say it's a mistake. I think s- perhaps somewhat oversimplification of how people conceptualize dopamine's role in the brain is, even though it's a major important role, is for it to be active and released during highly reinforcing experiences like sex, like really good food, like drugs of abuse. It also can get activated subdivisions of this system during painful stimuli and during aversive stimuli, um, which again, are really important for you to be aware of, to say, "Oh my God, that's really bad for me." Um, and so the dopamine system, this reward circuitry and its subcomponents that maybe perhaps signal more salience or aversion, aversion in the environment are closely tied to arousal systems and memory systems. Um, again, hopefully for somewhat obvious reasons, you want to remember powerfully reinforcing events in your life as well as powerfully emotionally or physically painful events in your life. So I hope I answered, um, your question to a modest degree.

   30. AHAndrew Huberman17:26

       No, um, far better than a modest degree. That, that's an excellent description of the dopamine system from a true expert. Um, and the

5. 17:34 – 25:38

   Context, Cues & Dopamine Modification

   1. AHAndrew Huberman17:34

      question I have is about some of the context and nuance of the system, but in, in sort of real world terms, how, how should I think about this? Even in my training as a neuroscientist, I know neurons can be-

   2. RMRobert Malenka17:47

      Mm-hmm.

   3. AHAndrew Huberman17:47

      ... a little active, a lot active, everything in between. They can be active over long periods of time or-

   4. RMRobert Malenka17:51

      Yeah, yeah.

   5. AHAndrew Huberman17:51

      ... short periods of time. But l- let's use the example of the donut. I'm, I'm, I like a glazed old-fashioned donut.

   6. RMRobert Malenka17:57

      (laughs)

   7. AHAndrew Huberman17:58

      I actually don't have a craving for sweet things-

   8. RMRobert Malenka17:59

      (laughs)

   9. AHAndrew Huberman18:00

      ... but donuts is, is, is an exception. I like the glazed old-fashioned donut.

   10. RMRobert Malenka18:04

       Ah.

   11. AHAndrew Huberman18:04

       But if I were to see just a little piece of a glazed old-fashioned-

   12. RMRobert Malenka18:08

       Yeah, yeah.

   13. AHAndrew Huberman18:08

       ... donut versus a full glazed old-fashioned donut...... could I expect that more dopamine is released to the anticipation of the complete doughnut?

   14. RMRobert Malenka18:19

       (laughs)

   15. AHAndrew Huberman18:19

       And then the other question is-

   16. RMRobert Malenka18:20

       Yeah, yeah.

   17. AHAndrew Huberman18:20

       ... how does context influence the dopamine system? For instance, if I'm very full-

   18. RMRobert Malenka18:25

       Yup.

   19. AHAndrew Huberman18:26

       ... a glazed old-fashioned doughnut might be aversive to me.

   20. RMRobert Malenka18:28

       Yeah.

   21. AHAndrew Huberman18:29

       Um, whereas if I'm just a little bit hungry, um, or if I'm actually more, uh, on a schedule of rewarding myself or abstaining from-

   22. RMRobert Malenka18:36

       Mm-hmm.

   23. AHAndrew Huberman18:37

       ... sweet, fatty foods, then abstaining from the food might be its own form of reward.

   24. RMRobert Malenka18:42

       Yeah. I mean-

   25. AHAndrew Huberman18:43

       And so to me, the dopamine system seems incredibly simple and yet incredibly prone to immediate context and the kinds of nuance that, uh, I mean, we're constantly juggling. I'll interrupt myself to say that we're constantly juggling a bunch of different reward contingencies. We want to, um, you know, have good health metrics and maybe have a certain aesthetic qualities to our body, but we also want the doughnut. And so how does a simp-

   26. RMRobert Malenka19:07

       (laughs)

   27. AHAndrew Huberman19:07

       ... a system as simple as a one neuromodulator system in the VTA to nucleus accumbens-

   28. RMRobert Malenka19:12

       Yeah.

   29. AHAndrew Huberman19:13

       ... and with some connections to the memory area, s- how does it balance all of that information in real time? To me, that's just, like, staggeringly complex, but also incredibly interesting.

   30. RMRobert Malenka19:24

       Um, I, I think you, uh, beautifully put, beauti- very eloquent description. Um, you just said it, it's staggeringly simple, simultaneously staggeringly complex. And y- you asked several different questions. So context makes an enormous importance, and that's one of the reasons I became interested in the dopamine reward circuitry, is, as you know, as a colleague in the ner- academic neuroscience world, but your l- listeners probably don't, I started out my career studying very basic mechanisms of plasticity. How does the brain modify itself? And what makes the brain different than compute, the comp- computer hardware is our, the physical connections in the brain are constantly changing, the strength of the communication. Similarly for the dopamine reward circuitry, it's highly plastic and it's highly contextually dependent. Um, and so you gave the example of doughnuts and feeding, and I'll answer your question about the cues. Um, yes, it's, I used to give the example of Thanksgiving, so let me give that example. You know, the morning of Thanksgiving, all, for most of us, in a, in the United States, um, the morning of Thanksgiving, if you're at home visiting your parents, the smells of the apple pie, the smells of the turkey cooking are highly appetitive, highly reinforcing. You're anticipating that fun event. You're anticipating Uncle Joe coming to visit you for Thanksgiving. And that's all because these cues, the smells, the anticipation of Uncle Joe's, your previous experiences, are part, are part of your memory system sort of talking to, in a simple way, your reward circuitry. So you're building up this anticipation. One could almost say this craving, which maybe we'll talk about in the context of addiction, and then, uh, make a long story short, think about that evening at the end of Thanksgiving, those exact same cues, the exact same smell of the apple pie, turkey, and Uncle Joe himself. At the very least, they're no longer appetitive, meaning they might actually be aversive. The last thing you want is a piece of apple pie. You can't wait for Uncle Joe to leave your Thanksgiving dinner. And I always argue that does not happen magically. That happens because your brain has been modified by the context in which it sits, and this very important modulatory system, this reward circuitry is responding to the exact same stimuli with a very different response. So that, I'm just telling you, I'm repeating what you said, the phenomenology and, and again, my other favorite example is any of us who have been in an intimate relationship knows that the, the love of your life can turn to the bane of your existence in 20 seconds. Um, and again, that doesn't happen magically. This person who you crave, who you love does something, and two minutes later, your brain is saying, "Oh my God, I, you know, I may have to break up with this person," or, "This is an incredibly painful experi- emotional experience." And what fascinates me about the brain is how does the brain mediate that rapid change? So now back to, so yes, context makes, is everything about how this powerful neuromodulatory system that uses dopamine works, and the truth is, we don't know. It's because the inputs onto these dopamine neurons, the other nerve cells that are driving the activity of the dopamine neurons, and I- I've actually studied this in my lab at Stanford University with a colleague you know well, Liqun Luo, who's a, uh, uh, you know, a world-class neuroscientist, um, we've studied the complexity of the neuroanatomy of the dopamine system. And these dopamine neurons in the ventral tegmental area, the s- the- the source of the reward circuitry dopamine are receiving inputs from all over the brain. They're receiving, you know, indirectly or directly inputs from visual areas, from somatosensory areas. Um, a- and I'm not giving you a really good answer because that's one of the goals of my research to try to understand how context, how the history that you've had with these cues, which we're gonna get back to, of the doughnut or of a drug, how has that modified how this neuromodulatory system responds? Um, similarly, the- the nucleus accumbens, the- the target of this powerful modulator dopamine is receiving-... communications, what we call inputs from all sorts of brain regions that you know about, Andrew, your audience may not. They, it receives inputs from an area called the hippocampus, which you may have covered in previous podcasts, which is very powerfully, very important for memories, both establishing new memories... And again, remember, that makes sense. You want this system, this dopamine reward circuitry to be very connected to memory systems. So the, the nucleus accumbens, the activity in the nucleus accumbens is modulated by dopamine while it is receiving information from the hippocampus, which helps encode new memories, while it's receiving information from a brain area called the amygdala, which tells, i- is a part of the brain involved in our emotional experiences. The accumbens also receives inputs from the prefrontal cortex, which is this brain area, as you know better than me, (laughs) Andrew, um, is important for decision-making, for planning our activity and I could go on and

6. 25:38 – 30:50

   Memory & Reward Scaling

   1. RMRobert Malenka25:38

      on. Um...

   2. AHAndrew Huberman25:38

      Well, can we talk about prefrontal cortex-

   3. RMRobert Malenka25:40

      Yeah.

   4. AHAndrew Huberman25:40

      ... for a moment? Um, because, um, it always was surprising to me that prefrontal cortex is talked about as this higher executive function area. But then when you look at the neuroanatomy-

   5. RMRobert Malenka25:54

      Mm-hmm.

   6. AHAndrew Huberman25:55

      ... it's, as we say monosynaptically, as y- you and I know, w- one connection, um, away from structures like the amygdala, one connection-

   7. RMRobert Malenka26:03

      Mm-hmm.

   8. AHAndrew Huberman26:03

      ... away from structures like the, the nucleus accumbens. In other words, prefrontal cortex to me is every bit as ancient, um, as some of these other structures that we think of as more ancient. And really the whole ancient evolves then gets a little bit dicey because-

   9. RMRobert Malenka26:17

      Yeah.

   10. AHAndrew Huberman26:17

       ... certain areas are, like the prefrontal cortex, are more elaborated in humans but, but to me the prefrontal cortex seems to be especially important in the context of this thing of scaling the reward response or context of the reward response because it can set rules. It- it seems to know, um, okay, we're recording a podcast now and there are certain rules or certain things that we're going to do-

   11. RMRobert Malenka26:41

       (laughs)

   12. AHAndrew Huberman26:41

       ... and not do.

   13. RMRobert Malenka26:42

       Yeah.

   14. AHAndrew Huberman26:43

       Um, but what's fascinating about the... And I'm so glad you gave a bunch of different examples because what's fascinating, for instance, about the, uh, the relationship example is that, yes, at one moment, um, we can adore somebody and another moment later they do something or don't do something.

   15. RMRobert Malenka26:59

       (laughs)

   16. AHAndrew Huberman26:59

       We can be incredibly frustrated with them. They can even become aversive to us.

   17. RMRobert Malenka27:03

       Yeah.

   18. AHAndrew Huberman27:03

       Um, hopefully that doesn't happen too frequently.

   19. RMRobert Malenka27:05

       Hopefully.

   20. AHAndrew Huberman27:05

       But, um, I think we've all had the experience of a donut, an event, or a person actually looking different to us-

   21. RMRobert Malenka27:16

       Mm-hmm.

   22. AHAndrew Huberman27:17

       ... in a, you know, from one moment to the next, hopefully not at random, right? And so to me it seems like, um, the prefrontal cortex is uniquely positioned to really say, okay, right now we are in a mode of, for lack of a better word, love and loving. Like being the, in the verb-

   23. RMRobert Malenka27:33

       Mm-hmm.

   24. AHAndrew Huberman27:33

       ... tense of loving or be in the verb tense of arguing. We're now arguing.

   25. RMRobert Malenka27:37

       Yeah.

   26. AHAndrew Huberman27:37

       We know, we're in the verb tense of, of, of reconciliation.

   27. RMRobert Malenka27:40

       Mm-hmm.

   28. AHAndrew Huberman27:41

       You know, kind of somewhere in between or something of that sort. And how a structure in a circuit as s- simple as the dopamine system, right, one molecule-

   29. RMRobert Malenka27:50

       Yeah.

   30. AHAndrew Huberman27:51

       ... could suddenly say, oh, you know what? Now getting over my anger is rewarding. Whereas five minutes ago being right and being the most angry was rewarding and then five minutes before that, again we're accelerating this movie, but five minutes or five days or five years before that, this person could do no wrong.
7. 30:50 – 39:07

   Dopamine, “Addictive Liability” & Route of Administration

   1. RMRobert Malenka30:50

   2. AHAndrew Huberman30:50

      Let's talk about that because you've done a, a ton of important work in this area of addiction. I mean, one of the basic questions I have about addiction is, you know, we hear that certain drugs are more addicting than other drugs or certain behaviors.

   3. RMRobert Malenka31:02

      Mm-hmm.

   4. AHAndrew Huberman31:02

      We also hear that e- that we can become addicted to anything.

   5. RMRobert Malenka31:04

      Yeah.

   6. AHAndrew Huberman31:04

      When Anna Lembke was on this podcast, um, I said, "What's the most, um, unusual addiction you've ever seen?" And she talked about a patient, um, who sadly, um, committed suicide at some point later that she told us had been addicted to water-

   7. RMRobert Malenka31:18

      Mm-hmm.

   8. AHAndrew Huberman31:18

      ... to drinking of any kind. First alcohol, but then water eventually.

   9. RMRobert Malenka31:22

      Yeah.

   10. AHAndrew Huberman31:22

       Um, and so, a- so my question about addiction in the dopamine system is, you know, for, let's pick a drug, um, like cocaine.

   11. RMRobert Malenka31:30

       Mm-hmm.

   12. AHAndrew Huberman31:31

       Um, I've never done cocaine.

   13. RMRobert Malenka31:33

       Mm-hmm.

   14. AHAndrew Huberman31:33

       Um, but people who have done cocaine tell me that it feels very good, um, and one of the more salient features of the cocaine high is that it comes on very fast and it ends pretty quickly too.

   15. RMRobert Malenka31:47

       Mm-hmm.

   16. AHAndrew Huberman31:47

       Is the rate of dopamine increase related to the addictive property, uh, of a drug or behavior, um, as much as how much dopamine is released?

   17. RMRobert Malenka31:59

       And that's a very sophisticated question and the answer is yes. And that's usually the, (laughs) uh, the lecture I give. The way I think about addiction, um, and obviously my friend and colleague Anna Lembke is one of the world's experts in terms of the understanding the human experience of addiction. I have studied it as a cellular molecular neuroscientist trying to understand how addictive substances modify reward circuitry, modify the connections in the reward circuitry, modify how dopamine neurons act. And the way I, you know, like any what appears to be s- a simple term, it's layered with complexity, um, addiction is somewhat of a continuum. And I like to think about whether you're talking about substances like cocaine, and I will a- explicitly answer your question soon, or opioids as we, as you know we're going, in this country there is an opioid epidemic, um, I, I, I do like to think about addictive liability.

   18. AHAndrew Huberman33:06

       Mm.

   19. RMRobert Malenka33:06

       And it is th- in my view it is pretty clear that when we're talking about drugs they have different degrees of addictive liability. I mean, I had a cup of coffee this morning. Am I a... And many of us l- listening to this podcast, it's really hard to start our day without getting that hit of caffeine. But are we addicted to caffeine? That's a tricky question because I've never heard of anybody robbing a bank to get caffeine, d- destroying their personal life to get caffeine. Um, so I would say caffeine causes tolerance but I would not say it has a particularly high addictive liability whereas drugs like psychostimulants like cocaine, um, have a very, or opioids, have a very high addictive liability. So to answer your mechanistic question, there have been some famous studies done, um, by the director of the National Institute on Drug Abuse, Nora Volkow. Um, simultaneously there have been studies in animal models of addiction where y- you nailed it. The, in a rough way, the addictive liability of a substance is directly correlated with two aspects of dopamine. How much dopamine is released in the accumbens and the kinetics of the dopamine release as you said. How rapidly it's released. To get a little technical, even with a drug like cocaine or opioids, it's not only the drug itself, it's the route of administration because the route of administration influences the kinetics, meaning how fast that drugs gets into your brain influences the reward circuitry and how fast it causes a big rapid release of dopamine. And some of your podcast listeners may be old enough to remember the crack cocaine epidemic or freebase cocaine. And cocaine does have, like methamphetamine, a very high addictive liability. I teach the neurobio- I, I give lectures to students at Stanford about neurobiology of addiction as part of a team course, team taught course. I have kids, um, who I had to deal with and what, you know, what I s- always say is, you know, you, it's not that if you use this drug you're automatically going to become an addict, um, but you're taking that risk and it is impossible to become addicted to a substance if you've never used it by definition, but back to the route of administration. So I, I went off on a tangent there.

   20. AHAndrew Huberman35:50

       Well, that's actually an interesting statement-

   21. RMRobert Malenka35:52

       Yeah.

   22. AHAndrew Huberman35:52

       ... um, you know, because I think we may have heard that in high school though I, um, to be honest, wasn't the most attentive-

   23. RMRobert Malenka35:58

       (laughs)

   24. AHAndrew Huberman35:58

       ... high school student and I regret that. High school students pay attention.

   25. RMRobert Malenka36:01

       You did okay for yourself (laughs) .

   26. AHAndrew Huberman36:02

       I, eventually I came around but, but it, it was an uphill battle there.

   27. RMRobert Malenka36:05

       (laughs)

   28. AHAndrew Huberman36:06

       Um, but you, that you can't become addicted to something that you've never done which, um, I just want to earmark that because I think it's a profound statement because it points to the importance of the memory system but also plasticity.

   29. RMRobert Malenka36:20

       Yep, absolutely.

   30. AHAndrew Huberman36:20

       And so I, I want to make sure that eventually we get around to talking about how, um, the amount of dopamine released and the kinetics, how that might influence plasticity.
8. 39:07 – 40:04

   Sponsor: AG1

   1. RMRobert Malenka39:07

   2. AHAndrew Huberman39:08

      As many of you know, I've been taking AG1 daily since 2012, so I'm delighted that they're sponsoring the podcast. AG1 is a vitamin mineral probiotic drink that's designed to meet all of your foundational nutrition needs. Now, of course, I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits every day, but oftentimes, I simply can't get enough servings. But with AG1, I'm sure to get enough vitamins and minerals and the probiotics that I need, and it also contains adaptogens to help buffer stress. Simply put, I always feel better when I take AG1. I have more focus and energy and I sleep better, and it also happens to taste great. For all these reasons, whenever I'm asked, "If you could take just one supplement, what would it be," I answer AG1. If you'd like to try AG1, go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs plus a year supply of vitamin D3 K2. Again, that's drinkag1.com/huberman.

9. 40:04 – 50:51

   Drugs of Abuse & Brain Changes; Addiction & Individual Variability

   1. AHAndrew Huberman40:04

   2. RMRobert Malenka40:04

      So where do you want to go from here? You asked a question about, you know, the, the neural mechanisms of the, of what we call addiction.

   3. AHAndrew Huberman40:12

      Yeah, I'd like to know about the role of neuroplasticity in addiction.

   4. RMRobert Malenka40:15

      Yeah.

   5. AHAndrew Huberman40:15

      I, I do want to highlight something you said, and I apologize for, um, interrupting a, a moment ago-

   6. RMRobert Malenka40:20

      No, absolutely. (laughs)

   7. AHAndrew Huberman40:20

      ... and then, and then I refrained, but it was an interruption based on real excitement because a, a, um, uh, a person I know quite well who is a recovered cocaine addict-

   8. RMRobert Malenka40:30

      Mm-hmm.

   9. AHAndrew Huberman40:30

      ... told me, and that by the way, folks, this isn't I have a friend and I'm actually, you know... I truly have never tried cocaine.

   10. RMRobert Malenka40:36

       Mm-hmm.

   11. AHAndrew Huberman40:36

       Um, and this person said that the first time they did cocaine, his thought was, "I hate this and I can't wait to do it again."

   12. RMRobert Malenka40:46

       Ex- And, uh-

   13. AHAndrew Huberman40:47

       And that's exactly how you described it.

   14. RMRobert Malenka40:49

       And I think that is a fairly common experience with people suffering from an addiction disorder. We're not supposed to use the word addicts anymore because that's a little bit judgmental, um-

   15. AHAndrew Huberman41:04

       Oh, is that the, that's the new nomenclature?

   16. RMRobert Malenka41:06

       Uh, something along those lines.

   17. AHAndrew Huberman41:07

       Got it. Oh, calling someone an addict-

   18. RMRobert Malenka41:09

       Onalinkini, you know-

   19. AHAndrew Huberman41:09

       ... as opposed to being addicted.

   20. RMRobert Malenka41:11

       Yeah, being, um-

   21. AHAndrew Huberman41:11

       Got it.

   22. RMRobert Malenka41:12

       And, um, uh, uh, that is a beautiful description. I hate it, but I want to do it again. Um-

   23. AHAndrew Huberman41:19

       Amazing.

   24. RMRobert Malenka41:19

       ... and again, it just shows the pow- the power of this system, which remember evolved for our survival. So a very simple way of thinking about it is these drugs are tricking the reward circuitry to say, "This stimulus, this experience is really important for my survival. I have to go do it again and again." And, uh, a- again, a side question is, the huge question is, why does some people develop an addiction problem and others who have used this substance j- just don't? Um, and as, again, as a world-class neuroscientist yourself, you know the answer. It's always a complex combination of underlying genetics, the environment in which they find themselves, the environment in which they grew up, and how that modified their reward circuitry. So to get at your question, um, one set of experiments my lab did, which other labs did too, I don't deserve the sole credit for this, is showing that drugs of abuse cause powerful plasticity in th- the neurons that make up the cells that make up the reward circuitry. And in fact, drugs of abuse like cocaine, methamphetamine, opioids like morphine, heroin...... change the, what, the synapses. The synapses are the connections from other nerve cells onto dopamine neurons, onto the nerve cells in the accumbens. And these connections, these synapses can change, and drugs of abuse cause powerful changes in those connections and therefore powerful changes in the activity of the dopamine neurons and the neurons in the, in the ventral, in the, in the nucleus accumbens. And in fact, the types of changes that occur appear to be similar to the types of changes that have evolved for good uses, for adaptive forms of learning and memory. Um, so again, this is an example that this epi- superf- superficially simple dopamine reward circuitry is changing all the time. It is highly plastic and can become more sensitive to certain experiences, you know, et cetera, et cetera.

   25. AHAndrew Huberman43:48

       Well, could I ask a question about some of the general contours of the plasticity-

   26. RMRobert Malenka43:52

       Mm-hmm.

   27. AHAndrew Huberman43:52

       ... and the dopamine system?

   28. RMRobert Malenka43:53

       Mm-hmm.

   29. AHAndrew Huberman43:53

       Um, you said before, and, and I love this statement even though-

   30. RMRobert Malenka43:57

       (laughs)
10. 50:51 – 57:50

    Reinforcement vs. Reward, Wanting vs. Liking

    1. AHAndrew Huberman50:51

       Um, you know-

    2. RMRobert Malenka50:51

       I can relate. I mean, can I tell you a little vignette about me, which I love to tell? (laughs)

    3. AHAndrew Huberman50:56

       Sure, sure.

    4. RMRobert Malenka50:56

       Um, and it gets into how the reward circuitry is so closely associated with m- memory systems and how cues associated with powerful experiences develop their own reinforcing or aversive quality. So long story short, when I was a young kid, in, I can't remember, in my 20s, maybe 20, I spent a few weeks in Paris. I started smoking cigarettes. I mean, this is a long time ago. And I got, it's, cigarettes are very interesting. Nicotine is highly addictive as are, as the tobacco companies were fully aware of.

    5. AHAndrew Huberman51:37

       High addictive liability?

    6. RMRobert Malenka51:38

       Very high addictive liability.

    7. AHAndrew Huberman51:40

       People will rob people for the money to buy cigarettes?

    8. RMRobert Malenka51:42

       Um, they may not rob because, although they're, uh, b- my understanding is they've become quite expensive, but-

    9. AHAndrew Huberman51:53

       I guess they'll devote significant income.

    10. RMRobert Malenka51:54

        Count- counterfeit cigarettes are a huge market for organized crime. There are thir- parts of our, of our, in the world, third world countries where organized crime produce counterfeit cigarettes and are making hundreds of millions or billions of dollars. Um, and s- so I, I think nicotine as it is delivered in cigarettes, as you know, I mean, tobacco companies put in a lot of work to figure out the exact dose of nicotine that will make you get that kind of feeling that only lasts for a few minutes, so you want to do it again and again. Um, so, uh, we can talk about the... And nicotine, you know, what becomes a, an, a problem, uh, i- i- in a specific society with addiction is not only based on the neurobiological actions, if we're talking still about drugs or substances, of that substance. It's heavily influenced by the availability of the substance too. But my, my little story is I smoked some cigarettes in Paris. I, I, I end, I, I learned why people like to smoke. It was very satisfying to have a cigarette in a Parisian café just, you know, and it's very interesting because the first few times you inhale tobacco, you get dizzy, it's kind of aversive, and it's exactly what you articulated. Despite that, you want to do it again. So I, I, it was just a lot of fun for me, I enjoyed it, and I was disciplined, you know, at some point whenever this was, I came back to the United States, I didn't smoke, um, because I knew it was bad for you. But to this day, 40 years later, every time I go back to Paris, I get cravings. I actually just want to get a pack of cigarettes. I want to, um, f- have that feeling again of inhaling the smoke. But th- the point is of how, you know, powerful these rewarding experiences can be, or reinforcing experiences, and for your audience, it, technically, uh, you know, what I have been taught by some of my psychology colleagues is we use the term reinforcing in a very behaviorally defined way. Something is reinforcing is if it m- the behavior that led to that stimuli, y- it makes you want to do that behavior again. Rewarding means it actually felt, in quotes, good. Um-

    11. AHAndrew Huberman54:30

        (laughs) Hmm. That's an important distinction.

    12. RMRobert Malenka54:31

        ... no, they, they actually can be different. Again, as you defined by your friend who his, I forget, it w- I think it was cocaine. Cocaine was highly reinforcing, but it was not necessarily enjoyable or rewarding.

    13. AHAndrew Huberman54:44

        Mm-hmm.

    14. RMRobert Malenka54:45

        And isn't that fascinating? I have a, some colleagues in the addiction field, um, I, one of them is retired now, Kent Berridge and Terry Robinson, they, they coin, they distinguish between the terms, uh, wanting and liking. And think about that.

    15. AHAndrew Huberman55:04

        Mm-hmm.

    16. RMRobert Malenka55:05

        Liking something means it's something you like, you enjoy.Um, wanting means you want it, but you don't necessarily like it or enjoy it, and that's a description of your friend's experience with cocaine. Some of us have been in destructive relationships where you want that individual, but you're not sure you necessarily like that individual.

    17. AHAndrew Huberman55:32

        And sometimes people will be in relationships where they actively dislike the other person-

    18. RMRobert Malenka55:36

        Yeah, isn't that-

    19. AHAndrew Huberman55:37

        ... which is, which is a bit foreign of a concept to me, but well, it's interesting this, this separation of reinforcing and rewarding, wanting and liking-

    20. RMRobert Malenka55:44

        Mm-hmm. Yes.

    21. AHAndrew Huberman55:44

        ... because, um, one of the things that's very prominent in 12-step programs-

    22. RMRobert Malenka55:48

        Mm-hmm.

    23. AHAndrew Huberman55:49

        ... is to create rewards around abstaining from the drug or behavior.

    24. RMRobert Malenka55:53

        Yes. Yep.

    25. AHAndrew Huberman55:54

        And I should mention that programs like 12-step, when followed, seem to have very high success rates.

    26. RMRobert Malenka55:58

        Mm-hmm.

    27. AHAndrew Huberman55:58

        At least that's what Anna Lembke tells me.

    28. RMRobert Malenka56:00

        Mm-hmm.

    29. AHAndrew Huberman56:00

        Um, that in some ways they are modifying the wanting and liking. They're splitting the wanting and liking of, you know, alcohol, for instance. Creating a, a liking of sobriety more than the wanting of alcohol, for instance.

    30. RMRobert Malenka56:17

        That's beautifully put, um, and I think that's right. Um, how that plays out in the neural mechanisms, that as a neuroscientist I'm interested in, man, that's a tough one. Um, but I think that's why th- those programs are pretty successful. It's helping the person make those dissociations. Um, and I, I don't know that much about those programs because I have not seen patients myself for whatever it's been, 27, 28 years, but I think part of them are to help that individual find, as you said, both other sources of liking and reward, um, getting some satisfat- satisfaction and reward from the actual abstinence, being able to cognitively teach themselves that I deserve a pat on the back, I deserve credit, I feel good that I did not take a drink at that party, that I did not use that substance again. And how that plays out in our brains is a really tough one.
11. 57:50 – 1:03:38

    Opioids, Psychostimulants & Dopamine

    1. AHAndrew Huberman57:50

       Um, as long as we're talking about donuts, cigarettes, alcohol-

    2. RMRobert Malenka57:55

       (laughs)

    3. AHAndrew Huberman57:55

       ... cocaine, um, I'm curious, uh, before we move to, um, a bit more on neuroplasticity, is there anything that people ought to know about how different substances and behaviors that are addicting might impact the dopamine reward circuitry differently? So for instance, um, we talked about cocaine as having this very rapid onset, big increase in dopamine, then a crash as we know. Um, a certain pattern of kinetics as you describe it. Um, the opioid crisis is, is, you know, an incredibly serious problem right now, uh, as is methamphetamine. Uh, but it sounds like methamphetamine functions a bit like cocaine in terms of its kinetics.

    4. RMRobert Malenka58:35

       Yes.

    5. AHAndrew Huberman58:35

       So, an opioid is a very different chemical than cope- cocaine.

    6. RMRobert Malenka58:41

       Mm-hmm.

    7. AHAndrew Huberman58:41

       Um, but it sounds like it impacts the dopamine system. Um, is the dopaminergic activity caused by opioids responsible for the addictive properties of opioids, or do people also like the feeling of being under opioids? I personally hate it coming out of surgery. Like, they gave me, they gave me Vicodin once-

    8. RMRobert Malenka59:01

       Yeah.

    9. AHAndrew Huberman59:01

       ... um, and I, I hated it.

    10. RMRobert Malenka59:03

        Mm-hmm.

    11. AHAndrew Huberman59:03

        I'd rather have the pain-

    12. RMRobert Malenka59:04

        (laughs)

    13. AHAndrew Huberman59:04

        ... post-operative pain than take something like, um, you know, Vicodin or, or a Valium or fentanyl or anything like that. To me it's just completely aversive.

    14. RMRobert Malenka59:14

        Mm-hmm.

    15. AHAndrew Huberman59:14

        Um, but I realize that there are many millions of people that feel quite differently.

    16. RMRobert Malenka59:18

        Um, it's a great question. So, I think all the studies both in human beings and pre-clinical animal models, yes, would suggest that the ki- the addictive liability of opioids and psychostimulants, which are cocaine and methamphetamine, have the common final action of causing massive release of dopamine in this target of the dopamine neurons in nucleus accumbens. They do it, if we want to get a little scientifically technical here, via very different mechanisms.

    17. AHAndrew Huberman59:59

        Mm-hmm.

    18. RMRobert Malenka59:59

        So, cocaine and methamphetamine, what the drugs known as psychostimulants, um, actually bind to a protein in the brain or a molecule in the brain that is responsible for sucking up. It's a vacuum cleaner, br- su- sucking up the dopamine after it's been released. And cocaine prevents that dopamine from being vacuumed up so the cocaine hangs around longer. Meth not only prevents the dopamine from being vacuumed up, it actually causes the reverse. It actually causes the direct release of dopamine from what we call nerve terminals, from the site where dopamine is released. Opioids work very differently. They actually primarily, not solely, work where the dopamine neurons live. And it's a little complicated and it's not that critical, but they indirectly in- increase the activity within the dopamine neurons themselves, causing a big massive, bigger than normal release of dopamine. So that's one commonality.... but anybody who has used these drugs or read about these drugs, the subjective experience of the drugs are dramatically different, and that's because of the actions they're having, not only in the reward circuitry but throughout the brain. So, and it- it's interesting you talked about Vicodin. I've taken Vicodin because I've had several knee surgeries and things. Like you, I didn't like it. I've te- I've gotten other opioids for pain relief that were great. (laughs) I mean, they took, they took away a lot of pain after my ligament repair, um, and that's a different question that even when you're talking about opioids, all drugs are not cre- or they're not identical. Fentanyl has a much big- larger, um, addictive liability because of its molecular properties and how it's interacting with the opioid system in our brains and the receptors, the actual proteins in the brain that it interacts with. But the subjective experience of opioids, I mean, it's interesting. Uh, some people love it. That's, you know, if we go back in history, as you know, there were the, um, opium dens throughout, um, Asia. Um, there were wars about opioids, the- the- the famous opioid wars between China and the United Kingdom, I mean, showing you how powerful, um, the availability of a substance like an opioid can be. So I'm- I'm going off on a tangent here-

    19. AHAndrew Huberman1:02:49

        No, I think these are important.

    20. RMRobert Malenka1:02:51

        ... I apologize, but commonality is dopamine release in the accumbens, but it's a... If you remember what a Venn diagram is, all these drugs have some common actions usually on directly or indirectly causing the massive release of dopamine in the accumbens, but then they have their own individual actions because obviously when you take cocaine or methamphetamine, it's a stimulator. You're- You know, people are grinding their teeth, they're hyped up. For most people, opioids are the exact opposite. You're- I- I mean, in opium dens from the movies I watched (laughs) and watching Narcos and all those TV shows, you're often, you're lying down, you're- you're kind of in a almost a dreamlike state, so very different subjective experiences.

12. 1:03:38 – 1:04:51

    Sponsor: LMNT

    1. RMRobert Malenka1:03:38

    2. AHAndrew Huberman1:03:38

       I'd like to just take a brief break and thank one of our sponsors, which is LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means plenty of salt, sodium, magnesium, and potassium, the so-called electrolytes, and no sugar. Now, salt, magnesium, and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. LMNT contains a science-backed electrolyte ratio of 1,000 milligrams, that's one gram, of sodium, 200 milligrams of potassium and 60 milligrams of magnesium. I typically drink LMNT first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes and while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, and certainly I drink LMNT in my water when I'm in the sauna and after going in the sauna because that causes quite a lot of sweating. If you'd like to try LMNT, you can go to Drink LMNT, that's lmnt.com/huberman, to claim a free LMNT sample pack with your purchase. Again, that's Drink LMNT, lmnt.com/huberman. Yeah,

13. 1:04:51 – 1:12:40

    Self-Doubt, Confidence & Career

    1. AHAndrew Huberman1:04:51

       I had an experience with, uh, opioid recently. Uh, not voluntarily over the Christmas holiday, we went to visit friends and before, um, going to sleep, I wanted some tea and I asked if they had any non-caffeinated tea. So they gave me this tea and, um, and that night I had the most bizarre dreams I've ever had and I slept for 14 hours.

    2. RMRobert Malenka1:05:12

       (laughs)

    3. AHAndrew Huberman1:05:13

       The next morning I was like, "What was that tea?" Uh, and I felt off in the morning and I went... It was actually a blue lotus flower tea that is actually illegal in the United States-

    4. RMRobert Malenka1:05:23

       (laughs)

    5. AHAndrew Huberman1:05:23

       ... but it is sold and it has morphine-like, um, compounds in it. Um, and I am one of those people that's very susceptible, uh, to even low doses of any kind of novel drug, you know.

    6. RMRobert Malenka1:05:34

       So- So interesting. Have you ever taken cough syrup with dextromethorphan?

    7. AHAndrew Huberman1:05:38

       No. See, I avoid that stuff-

    8. RMRobert Malenka1:05:40

       Well, I, you know, I have-

    9. AHAndrew Huberman1:05:41

       ... if I can. If I can.

    10. RMRobert Malenka1:05:42

        I have a tendency when I get a cold, like, it gets into my lungs, I cough a lot. And I think this has been reported. This is my anecdotal experience. It... I'm- I'm confirming what you said. Dextromethorphan is a different sort of opioid and actually some people develop a problem with it. For me, it gives me really bizarre dreams. (laughs) Really bizar- similar to what you were describing.

    11. AHAndrew Huberman1:06:05

        Yeah. It was a very unusual experience.

    12. RMRobert Malenka1:06:06

        And that's a whole different conversation about what makes us dream and what the- what are the meaning of dreams. Fascinating. And I hope you covered- Maybe you've covered that in previous-

    13. AHAndrew Huberman1:06:14

        We have not yet, but we are intending to do a whole series on sleep and dreaming anyway.

    14. RMRobert Malenka1:06:18

        Yeah, I think that would be a wonderful-

    15. AHAndrew Huberman1:06:19

        We will definitely get into it.

    16. RMRobert Malenka1:06:20

        I started out in sleep research, so I have a fondness for it.

    17. AHAndrew Huberman1:06:23

        Well, drug research and sleep research have a long history-

    18. RMRobert Malenka1:06:25

        Yeah.

    19. AHAndrew Huberman1:06:25

        ... of overlap with Allan Hobson's work on LSD and-

    20. RMRobert Malenka1:06:28

        I worked with Allan Hobson.

    21. AHAndrew Huberman1:06:29

        Okay. By the way, folks, if you're interested in the-

    22. RMRobert Malenka1:06:31

        (laughs)

    23. AHAndrew Huberman1:06:31

        ... relationship between hallucinations and dreaming, Allan Hobson is a good name to start your, uh, your rabbit-

    24. RMRobert Malenka1:06:37

        In 19-

    25. AHAndrew Huberman1:06:38

        ... your rabbit hole.

    26. RMRobert Malenka1:06:39

        I, 19... Oh my God, I'm dating myself. 1970... I can't remember if it was '76 or '77 I worked with Allan Hobson as an undergraduate.

    27. AHAndrew Huberman1:06:50

        At Harvard Medical School.

    28. RMRobert Malenka1:06:51

        Yeah. No, I, as an undergraduate at Harvard. He was at Harvard Medical School.

    29. AHAndrew Huberman1:06:54

        Right, right. Amazing. I love his writing and I learned a lot from it.

    30. RMRobert Malenka1:06:57

        Yeah, yeah. Yeah. Very-
14. 1:12:40 – 1:19:29

    Autism Spectrum Disorder

    1. AHAndrew Huberman1:12:40

       that.

    2. RMRobert Malenka1:12:40

       Sure.

    3. AHAndrew Huberman1:12:41

       I'd like to discuss one aspect of reward circuitry that I don't think most people think about, right?

    4. RMRobert Malenka1:12:48

       Mm-hmm.

    5. AHAndrew Huberman1:12:48

       It's fairly straightforward, I know nowadays I, I like to think more people know what dopamine is and understand it-

    6. RMRobert Malenka1:12:53

       Yeah.

    7. AHAndrew Huberman1:12:53

       ... thanks to your work and Anna's work and some discussions that have taken place on our podcast and other podcasts-

    8. RMRobert Malenka1:12:58

       Mm-hmm.

    9. AHAndrew Huberman1:13:00

       ... but, you know, it's all too often we think dopamine, reward, wanting, liking drugs, okay all of that is great-

    10. RMRobert Malenka1:13:06

        Mm-hmm.

    11. AHAndrew Huberman1:13:07

        ... but what about the truly adaptive stuff, right? Because it's, it's, um, easy to fall into a discussion around dopamine of, you know, the things that are bad for us-

    12. RMRobert Malenka1:13:16

        Mm-hmm.

    13. AHAndrew Huberman1:13:16

        ... but what I'm thinking about here is social interaction.

    14. RMRobert Malenka1:13:19

        Yeah.

    15. AHAndrew Huberman1:13:20

        Um, clearly we are a social species, and a lot of your work in the last, um-... decade and a half or so-

    16. RMRobert Malenka1:13:27

        Yeah, yeah.

    17. AHAndrew Huberman1:13:28

        ... has focused on the relationship between the reward circuitry, which you beautifully described for us, and social interaction and connection.

    18. RMRobert Malenka1:13:37

        Mm-hmm.

    19. AHAndrew Huberman1:13:37

        And where I'm going with this is ultimately, this has huge implications for autism and autism spectrum disorders. I don't know if nowadays, is it okay?

    20. RMRobert Malenka1:13:47

        I, I-

    21. AHAndrew Huberman1:13:47

        You're not supposed to call autism a disease, is that right? You hear about neurotypical and neuro-atypical.

    22. RMRobert Malenka1:13:52

        (laughs)

    23. AHAndrew Huberman1:13:52

        But is, but I have friends who have children who are severely autistic.

    24. RMRobert Malenka1:13:57

        Yeah.

    25. AHAndrew Huberman1:13:57

        And, um, I don't know many parents who would elect to have a severely autistic kid.

    26. RMRobert Malenka1:14:02

        Mm-hmm.

    27. AHAndrew Huberman1:14:03

        And so those people often will talk about it as autism or a child having autism. So first of all, before we get into -

    28. RMRobert Malenka1:14:10

        Mm-hmm.

    29. AHAndrew Huberman1:14:10

        ... the social piece, maybe because I just tabled it, w- what is, how are, are we supposed to talk about autism nowadays?

    30. RMRobert Malenka1:14:17

        I, I, I am very interested in the pathophysiology of what the medical profession terms autism spectrum disorder. As you pointed out, the individuals living with an autism spectrum disorder are quite heterogeneous. And it, it, it can range from individuals with severe intellectual impairments and quite severe impairments in social interactions, impairments in sensory processing, impairments in, in lots of different aspects of our behaviors that are important. And I think nobody would say, would argue those individuals on the severe spectrum do not have some sort of, in quotes, disorder. The issue we have to be sensitive to is it's, it's a heterogeneous disorder like many brain issues that psychiatrists deal with, like depression. We all, um, like obsessive compulsive disorder, like various anxiety disorders. It's always on a continuum and a spectrum. So for autism spectrum disorder, there are individuals who are high functioning, who one could argue have a different style of interacting socially, may have a different way of processing sensory information, but who have, who would prefer not to be viewed as having an illness, but rather would be viewed as having a different style of living and interaction. And I think we need to respect that. So the challenge is, again, not oversimplifying a complex heterogeneous disorder, um, and both being respectful of the people who don't want to be defined as having a neuropsychiatric or brain disorder while equally being respectful of people like your friends with severely impaired children who deserve help, who deserve research. And it's a tough one because my understanding from, to be honest, just reading articles in the lay press and going to websites from organizations that philanthropically support research related to autism, within that community of individuals who are not researchers but who are, have family members or are themselves dealing with some degree of autism spectrum disorder, there's disagreements about how to, what terminology to use, how to deal with them. Mm-hmm. And it's complicated. I think we just have to respect everybody. And if you're interacting with individuals, you, you know, I think it's appropriate. What do you prefer?
15. 1:19:29 – 1:30:30

    Pro-Social Interaction & Reward; Oxytocin, Serotonin & Dopamine

    1. RMRobert Malenka1:19:29

    2. AHAndrew Huberman1:19:29

       So in thinking about social interactions and leaving aside anything related to autism for the moment-It appears that the circuits in the brain that mediate the desire to spend time with others of the same species, maybe even with other species like a dog-

    3. RMRobert Malenka1:19:43

       (laughs)

    4. AHAndrew Huberman1:19:43

       ... um, are fairly hardwired but modifiable. They, we were born with the capacity to build them up.

    5. RMRobert Malenka1:19:51

       Mm-hmm.

    6. AHAndrew Huberman1:19:52

       Um, and that social behavior is highly rewarded. Is it rewarded through the dopamine system? And what, if any, involvement is there of the serotonergic system? And we haven't talked about serotonin yet, but I'd love to bring up serotonin at this point. Maybe you could educate us a little bit about serotonin because, um, gosh, if dopamine is fascinating, serotonin is at least as incredible.

    7. RMRobert Malenka1:20:18

       (laughs) Um, yeah, great question. So I, I think for me, the easiest way for me to answer it is actually just tell you my research history and how a lab like mine at Stanford that at one point was studying what I, what you and I would call fairly hardcore molecular mechanisms of neuroplasticity. How do connections between nerve cells change and what molecules are changing and r- pretty hardcore molecular stuff. How did I end up studying social behaviors in mice and what I hope we'll end up talking about even developing behavioral models of what I will define as empathy in mice. The answer is very simple. My lab was working on roles of classic dopamine reward circuitry and how it changes in models of addiction. We haven't talked about depression, models of depression, because just intuitively, hopefully your listeners can understand if one component of depression is what we call anhedonia, the inability to experience reward. You know, eating a donut is no longer satisfying, having sex is no longer that much fun, which is a component of depression. If there's a mechanism in the brain that tells you something is rewarding, by definition, that's not functioning normally in severe depression. So we were doing models of depression to figure out how the dopamine reward circuitry was changing, as were many other labs. We were studying addiction. Those were the obvious ones. And I mean, it might be entertaining to, to your audience to thi- learn how academic scientists think. I was thinking those are fascinating topics. They're pretty competitive. Um, lots of other labs were working on it. And I started thinking what other experiences might be modifying the reward circuitry. I actually made some attempts to look at feeding behavior, but I don't want to, I mean, we actually never pursued that for a variety of reasons. And that's obviously important because of there is an obesity epidemic in this country. Uh, and we can talk about how the reward circuitry and some of the things we've learned from our studies of addiction may be helpful to understanding obesity. But back to social interaction. I started thinking, well, for most of us, uh, what I call a prosocial, nonsexual experience is highly reinforcing. Um, Andrew, you're a pretty social guy. I'm a pretty social guy. Most of the time I'd rather go to a movie, a sporting event, a dinner with friends. Um, it's, you know, actually for me, the most meaningful component of my life other than spending time with my children is spending time with my close friends. Um, and I started thinking, well, why is that? Why do I have such a good time going to a ball game with my best friend or going out to dinner with another couple, um, and interacting? It's because, well, it's highly reinforcing and if it's highly reinforcing, it must involve the reward circuitry. And then I started thinking evolutionarily it makes a lot of sense because if you are part of a social species, there's a lot of evolutionarily, uh, uh, a lot of advantages for your survival to be hanging out with other members of your species in a non-aggressive way. It can increase your likelihood to find a mate and reproduce. It can protect you from predators. I mean, that's why any of your listeners who ever watch, um, you know, wildlife shows or National Geographic shows, there's a reason all these animals hang out together. (laughs) It's for protection from predators. So there are all these reasons. So about whenever it was, 13 or 14 years ago, my lab decided to start looking at how the reward circuitry may play a role in what I am going to call positive prosocial nonaggressive interactions. Um, another word we use is just sociability. Um, and for a variety of reasons back then, this is go- this is at least 13 years ago, maybe 15 years ago, a postdoc joined my lab named Gul Dolen. She's now a professor at Johns Hopkins. Um, and she had an interest in oxytocin. Um, and as your listeners know, um, oxytocin is this evolutionarily conserved neuropeptide that's very important for parturition, the having a baby born, for milk being produced. And it's gotten a lot of attention as a potential love neuropeptide. It's something that is released in our brains during a positive social interaction. There's a, a well-known researcher in social behavior and bonding research called Larry Young, and he did some very important, now somewhat classic work studying a species called the vole, in particular the prairie vole, and prairie voles-...are a species where they mate for life. It's called pair bonding, so one vole will find another vole, they basically get married, they have kids, and they're, they hang out together for the rest of their life.

    8. AHAndrew Huberman1:26:01

       No divorce, no 50% divorce rate. (laughs)

    9. RMRobert Malenka1:26:03

       No, no 50 di- 50% divorce rate. And what Larry elegantly showed, um, in part, in early days in collaboration with a guy named Tom Insel, who is a famous academic psychiatrist, um, they showed that oxytocin action within the nucleus accumbens, within this reward circuitry, was r- required and really important for this monogamous pair bonding. Having said that, there was just a paper that called into question that, but th- that's they're talking-

    10. AHAndrew Huberman1:26:36

        But there's 30 years of research prior to that.

    11. RMRobert Malenka1:26:38

        Yeah, yeah. And, and-

    12. AHAndrew Huberman1:26:39

        I'm glad you brought that up because, uh, we'll keep this contemporary and the, th- the reality is that that recent paper got a lot of attention.

    13. RMRobert Malenka1:26:45

        You know the paper I'm talking about.

    14. AHAndrew Huberman1:26:46

        Yeah, that maybe oxytocin isn't playing as prominent a role in pair bonding-

    15. RMRobert Malenka1:26:49

        Yeah, exactly.

    16. AHAndrew Huberman1:26:49

        ...as people had thought, and yet, folks, uh, th- that could be true. We have to be scientific about this and be open-minded, but there's, you know, three decades of work-

    17. RMRobert Malenka1:26:59

        Yeah, and-

    18. AHAndrew Huberman1:26:59

        ...uh, that, that speaks to the contrary, so I think we wanna be a li- we wanna weigh the evidence.

    19. RMRobert Malenka1:27:04

        We w- yeah, exactly. And again, the, the investigators who presented the work saying oxytocin may not be as important, there are limitations to the manipulations they did, which they would agree with. So I'm just telling you, so Gul Dolen was a postdoc in my lab, and we decided, we formulated a project to look at the actions of oxytocin in the nucleus accumbens in mice. And the reason we study mice is you... They're what are known as a genet- genetically tractable organism. We have all sorts of really cool and sophisticated tricks we can do to probe brain circuitry, the actions of neuromodulators like dopamine and serotonin and oxytocin in ways that we can't do in other species, um, and I'm gonna get back to dopamine in a second. And what we found was that oxytocin action in the nucleus accumbens was indeed important for promoting sociability, probably for promoting the reinforcing component of a social interaction, and that surprised us. You know, it was like, wow. It's, it's, oxytocin seems to be causing, enhancing the release of serotonin in the nucleus accumbens, and that wil- will, I'm... Perhaps we'll get to this. That led me off on a whole series of experiments trying to figure out how serotonin works, studying this drug we may talk about called MDMA, which is ecstasy or Molly, which actually causes release of serotonin. So we did that work and that got us working in serotonin. Simultaneously, there were some other papers reporting that dopamine release in the accumbens, that dopamine is released in the accumbens during a social interaction, a positive, non-aggressive social interaction. Truth be told, it may also be released during an aggressive interaction.

    20. AHAndrew Huberman1:29:08

        Some people like to fight.

    21. RMRobert Malenka1:29:10

        Some people like to fight, and the difference here is the dopamine release and its role in social interactions, it's not specific only for social interaction, as we have talked about. But nevertheless, that led my lab and other labs to do a series of papers. W- I'm talking about the field now showing that, and I'm giving you a lot of information here, so how might dopamine release happen during a non-aggressive social interaction? It turns out that oxytocin is not only released in the nucleus accumbens, it's released in the d- home of the dopamine neurons, in the VTA. So my lab and another lab from Northwestern showed that oxytocin can actually modulate dopamine neuron activity in the ventral tegmental area. So I hope I'm making sense here. I don't wanna get too technical.

    22. AHAndrew Huberman1:30:06

        Well, no, I think it's-

    23. RMRobert Malenka1:30:06

        But it just shows how the, you know, we discuss these neuromodulators like dopamine. I just brought in oxytocin. We're gonna talk about serotonin in a second. Unfortunately for your listeners, they don't work in isolation. They commun- they influence each other in ways that I think it's important for us to understand and elucidate. Um...

16. 1:30:30 – 1:38:28

    Nucleus Accumbens & Behavior Probability

    1. RMRobert Malenka1:30:30

    2. AHAndrew Huberman1:30:30

       That is not too much technical detail-

    3. RMRobert Malenka1:30:32

       Okay.

    4. AHAndrew Huberman1:30:32

       ...um, and I think it's wonderfully rich with areas for us to discuss. And I'm so very glad that you brought up that neither dopamine nor serotonin nor oxytocin work in isolation.

    5. RMRobert Malenka1:30:43

       Mm-hmm.

    6. AHAndrew Huberman1:30:43

       Because all too often, and admittedly sometimes even on my podcast-

    7. RMRobert Malenka1:30:47

       (laughs)

    8. AHAndrew Huberman1:30:47

       ...I'll talk about these things in isolation as a way to try and simplify them a bit, but there's just no way that the brain works that way, you know, for instance, turning on dopamine and turning off serotonin. It's a weighting of, of inputs. And I think that serotonin-

    9. RMRobert Malenka1:31:01

       Exactly.

    10. AHAndrew Huberman1:31:02

        ...uh, perhaps I should frame it this way. Just as often as dopamine is framed as this reward molecule and pleasure and dopamine hits, all too often, I think, in the popular press, serotonin is discussed, and oxytocin too for that matter, as this kind of warm, feel-good-

    11. RMRobert Malenka1:31:18

        Mm-hmm.

    12. AHAndrew Huberman1:31:18

        ...everything's mellow, um, you know, not really associated with r- reward and reinforcement.

    13. RMRobert Malenka1:31:23

        Mm-hmm.

    14. AHAndrew Huberman1:31:24

        And, uh, of course, it's not that simple. So when it comes to social interactions, it sounds like oxytocin and serotonin are playing a prominent role-

    15. RMRobert Malenka1:31:32

        Mm-hmm.

    16. AHAndrew Huberman1:31:33

        ...also in the accumbens.

    17. RMRobert Malenka1:31:34

        Mm-hmm.

    18. AHAndrew Huberman1:31:35

        Um, and that dopamine is, is activated too.

    19. RMRobert Malenka1:31:38

        Yes.

    20. AHAndrew Huberman1:31:38

        Do I have that right? Okay. So, um, I don't wanna take us too far down the rabbit hole of neural circuit function, but that, to me, um, makes at least a brief discussion about the nucleus accumbens itself interesting. Like, okay, so I'm thinking nucleus, I know that means a pile of neurons.

    21. RMRobert Malenka1:31:55

        (laughs)

    22. AHAndrew Huberman1:31:55

        An aggregation of neurons that's talking to this ventral s- striatum. So we got a bunch of neurons-

    23. RMRobert Malenka1:31:59

        It's, it's part of the ventral striatum.

    24. AHAndrew Huberman1:32:00

        Part of the vent-

    25. RMRobert Malenka1:32:00

        It's like, it's a subdivision of it.

    26. AHAndrew Huberman1:32:02

        Excuse me.

    27. RMRobert Malenka1:32:02

        Yeah.

    28. AHAndrew Huberman1:32:02

        I misspoke.

    29. RMRobert Malenka1:32:03

        Yep.

    30. AHAndrew Huberman1:32:03

        Um, yeah. It's part of the ventral striatum and it's, um...... and, and the neurons there can be active and communicate with other brain areas. But we're talking about a lot of nuance of function.

Episode duration: 2:50:02