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

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.320 | and I'm a professor of neurobiology and ophthalmology

00:00:13.200 | at Stanford School of Medicine.

00:00:15.200 | Today, my guest is Dr. Robert Malanka.

00:00:18.020 | Dr. Robert Malanka is a professor

00:00:19.840 | of psychiatry and behavioral sciences

00:00:21.680 | at Stanford University School of Medicine.

00:00:24.160 | He is both a medical doctor and MD,

00:00:26.640 | and a researcher, a PhD.

00:00:29.280 | His laboratory is famous for having discovered

00:00:31.480 | some of the key components allowing neuroplasticity,

00:00:34.700 | that is the nervous system's ability to change

00:00:36.960 | in response to experience.

00:00:39.040 | In addition, Dr. Malanka's research

00:00:41.400 | is considered central to the textbook knowledge

00:00:44.240 | about how reward systems in the brain

00:00:46.160 | are organized and function.

00:00:47.880 | Indeed, Dr. Malanka's research over the last 10 or 15 years

00:00:51.140 | has merged what was once two disparate fields,

00:00:53.740 | the first being the study of neuroplasticity,

00:00:56.080 | again, the nervous system's ability to change

00:00:58.180 | in response to experience,

00:00:59.640 | and the other field being the field of dopamine

00:01:02.600 | as it relates to pleasure and addiction.

00:01:04.900 | His laboratory has shown, for instance,

00:01:07.120 | that when we seek out particular forms of pleasure,

00:01:09.620 | regardless of whether or not they are healthy for us,

00:01:11.960 | that changes the way that our reward circuitry works

00:01:14.780 | and actually changes the way that dopamine is released

00:01:17.760 | and how it impacts the brain.

00:01:19.820 | And his work has also informed

00:01:21.680 | how we seek out healthy pleasures,

00:01:23.660 | including healthy food and social connection.

00:01:26.820 | Today's discussion explores all of these topics,

00:01:28.900 | and by the end of today's discussion,

00:01:30.800 | you will have a rich understanding

00:01:32.600 | of how neurochemicals like dopamine and serotonin

00:01:35.680 | work in parallel to reinforce,

00:01:37.980 | that is, to increase the probability

00:01:40.320 | that we will engage in certain types

00:01:41.960 | of thinking and behaviors.

00:01:43.920 | So if you are somebody interested in neuroplasticity,

00:01:46.460 | that is, how the nervous system can change

00:01:48.240 | in response to experience,

00:01:49.900 | and/or you are interested in reward systems,

00:01:52.600 | what motivates us and what we are likely to pursue

00:01:55.440 | in the future, given our choices of past?

00:01:58.760 | And if you are interested in things like social connection

00:02:01.340 | and empathy or lack thereof,

00:02:03.460 | today's discussion encompasses all of those topics.

00:02:06.380 | It is worth mentioning that Dr. Malenka is a true luminary

00:02:09.800 | in all of the fields I just mentioned,

00:02:11.560 | as well as several other fields.

00:02:13.260 | In fact, when you look out on the landscape

00:02:14.880 | of modern neuroscience, what you'll discover

00:02:17.520 | is that a very large percentage of the top laboratory

00:02:20.440 | studying neuroplasticity and reward systems and so on

00:02:23.440 | all stemmed from having trained in Dr. Malenka's laboratory.

00:02:27.060 | So it's a real honor and pleasure

00:02:28.520 | to be able to host him today,

00:02:30.080 | and I'm sure that our discussion

00:02:31.960 | is going to greatly enrich the way that you think

00:02:33.960 | about brain function, neuroplasticity, and reward.

00:02:37.440 | Before we begin, I'd like to emphasize that this podcast

00:02:40.180 | is separate from my teaching and research roles at Stanford.

00:02:42.940 | It is, however, part of my desire and effort

00:02:45.040 | to bring zero cost to consumer information

00:02:47.040 | about science and science-related tools

00:02:48.920 | to the general public.

00:02:50.240 | In keeping with that theme,

00:02:51.280 | I'd like to thank the sponsors of today's podcast.

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00:05:18.560 | And now for my discussion with Dr. Robert Malenka.

00:05:22.060 | Dr. Malenka, Rob, welcome.

00:05:24.580 | - Yeah, thanks for having me.

00:05:25.940 | - Delighted to have you here,

00:05:27.120 | both for sake of your medical knowledge and training

00:05:30.440 | as a psychiatrist, and of course,

00:05:32.320 | as a luminary in the field of neuroplasticity,

00:05:36.840 | dopamine and reward systems, social systems,

00:05:39.640 | your knowledge of autism and social interactions,

00:05:42.760 | a newer interest in, or perhaps old interest in psychedelics

00:05:48.640 | and what they're doing and potential for mental health.

00:05:51.600 | There are just so many things that you've done

00:05:53.760 | in this field.

00:05:54.600 | I've been a long, long time fan of your work

00:05:57.040 | since your days as an assistant professor.

00:05:58.720 | I've tracked your career.

00:05:59.840 | I've learned a tremendous amount from you by observing you

00:06:03.000 | and from being your colleague.

00:06:05.200 | So really delighted to have you here.

00:06:07.520 | - You're making me blush,

00:06:08.600 | and I don't blush easily.

00:06:09.980 | - Well, it's all true.

00:06:12.040 | And I will say as well,

00:06:13.760 | you've also trained an enormous number

00:06:16.580 | of incredible scientists, Carl Deisseroth,

00:06:20.820 | the Carl Deisseroth.

00:06:22.820 | Anna Lemke always speaks incredibly highly of you

00:06:24.960 | as a mentor and somebody she's learned

00:06:27.400 | a tremendous amount from.

00:06:28.280 | And pretty much anyone that's worked on neuroplasticity,

00:06:31.440 | on dopamine and reward systems, addiction,

00:06:34.280 | and now in the fields of autism and soon psychedelics

00:06:37.200 | as well references as you often,

00:06:39.240 | and you've been mentioned many times before in this podcast,

00:06:41.440 | if not by name, by work.

00:06:43.080 | So again, thank you for being here.

00:06:46.160 | I'd love to kick off the conversation

00:06:47.840 | by talking about something which is very fundamental

00:06:50.680 | to everything we're going to talk about,

00:06:53.340 | but certainly fundamental to our daily lives,

00:06:55.040 | which is dopamine.

00:06:56.400 | We hear so much about dopamine.

00:06:57.840 | People talk about dopamine hits.

00:06:59.600 | People think about dopamine as pleasure, dopamine reward.

00:07:03.640 | For the novice, how would you frame the dopamine system?

00:07:07.920 | I mean, it does a bunch of different things

00:07:09.520 | in different areas of the brain and body,

00:07:11.160 | but to you, what does dopamine represent

00:07:14.520 | as its major function in the brain?

00:07:16.380 | And could you give us a general contour

00:07:19.200 | of the neural circuits that allow this chemical

00:07:22.800 | to more or less put value on our experiences?

00:07:27.720 | - Yeah, that's very well put.

00:07:31.240 | As you point out, dopamine is one of the major,

00:07:34.560 | what we term neuromodulators in the brain,

00:07:37.280 | a chemical signaling messenger that the brain uses

00:07:40.760 | to mediate a complex array of actions.

00:07:45.140 | Its best well-known function is in what we call

00:07:49.160 | the brain's reward circuitry.

00:07:51.460 | So this is a circuit in the brain,

00:07:54.680 | and when we use the term circuit,

00:07:56.160 | what we really mean is one part of the brain

00:07:58.940 | communicating with another part of the brain,

00:08:01.820 | because the brain is this very complex,

00:08:04.780 | it's the most complex organ in the universe

00:08:09.280 | with lots of different nerve cells

00:08:11.120 | talking to each other simultaneously.

00:08:13.040 | And as neuroscientists, we try to parse

00:08:17.360 | what different brain areas are doing

00:08:19.860 | and what different neuromodulators might be doing.

00:08:23.060 | And dopamine was discovered, oh, I should know this,

00:08:26.500 | many decades ago, and it's, as I said,

00:08:31.500 | the major chemical messenger molecule

00:08:36.120 | in the so-called brain's reward circuitry.

00:08:39.640 | And when you're talking about,

00:08:40.620 | so what is the brain's reward circuitry?

00:08:42.700 | This is a part of the brain that tells us something

00:08:47.700 | is reinforcing in our environment, some stimuli,

00:08:54.220 | or in quotes is rewarding, makes us feel better or good,

00:08:59.220 | although that's a gross oversimplification.

00:09:04.240 | And before getting into the details of dopamine

00:09:07.560 | and its function in the reward circuitry,

00:09:09.640 | I think it's useful to talk about

00:09:11.760 | why do we need a reward circuitry?

00:09:13.780 | Why do we need something in our brain

00:09:16.560 | that tells us this feels good or this feels bad?

00:09:20.560 | And it goes back to evolution.

00:09:23.200 | I am a biological scientist.

00:09:25.680 | That means I believe in evolution.

00:09:27.900 | And if you think about the evolution of our species,

00:09:32.120 | everything is driven by developing mechanisms

00:09:37.580 | that increase our survival.

00:09:39.640 | And it's really useful.

00:09:41.460 | You need something in your nervous system

00:09:44.220 | that tells you some stimuli in your environment

00:09:47.480 | is important for your survival,

00:09:49.580 | or some stimulus in your environment is dangerous.

00:09:53.800 | So it's not magic that sugary high fat laden foods

00:09:58.800 | are highly reinforcing and rewarding.

00:10:05.360 | It's not an accident.

00:10:06.520 | There has to be a mechanism in the brain

00:10:08.320 | that tells us that.

00:10:09.620 | It's not an accident that most of the time for most of us,

00:10:14.600 | a sexual experience is pretty reinforcing,

00:10:17.760 | is pretty rewarding.

00:10:19.200 | It's not an accident that warmth feels really good

00:10:23.260 | when you're cold, that water tastes much better

00:10:26.800 | when you're really thirsty.

00:10:29.020 | What evolved is a mechanism to tell our nervous systems

00:10:33.900 | and tell our brains this feels pretty good.

00:10:37.400 | I should repeat the behavior that leads

00:10:40.680 | to that rewarding experience.

00:10:42.580 | And similarly, it's really important

00:10:45.320 | when there is an event in your life that's highly dangerous

00:10:50.320 | for some mechanism in your brain to say,

00:10:53.640 | "Whoa, I don't wanna go back to where that line was."

00:10:57.160 | And we can get into that.

00:10:58.480 | So this was a long-winded way of saying

00:11:00.960 | what the reward circuitry tells us is this event,

00:11:05.240 | this stimulus, it could be an external stimulus.

00:11:08.640 | Like I said, a Krispy Kreme donut, which I happen to love,

00:11:12.960 | and I have to be very disciplined so I don't eat too many

00:11:15.520 | of them, it could be a drug of abuse,

00:11:19.560 | and maybe we'll talk about that a little bit.

00:11:21.860 | All of these stimuli seem to activate and cause the release

00:11:27.800 | of dopamine in this brain's reward circuitry.

00:11:31.640 | So now we need to get into a little bit of detail.

00:11:35.000 | Neuroscientists use these very unfriendly terms

00:11:41.120 | to describe different brain regions.

00:11:44.920 | So the home of dopamine cells,

00:11:47.880 | or brain cells are called neurons,

00:11:50.920 | so the home of dopamine neurons are in a part of the brain,

00:11:55.840 | sort of what we call the lower midbrain.

00:11:58.860 | The dopamine neurons that are part of the reward circuitry

00:12:02.960 | are found in this area called the ventral tegmental area,

00:12:07.240 | which I'm sorry to have to use such technical jargon.

00:12:10.600 | And we call it the VTA, that's the acronym.

00:12:13.640 | - I think the roof of the midbrain is the tectum,

00:12:17.180 | it means roof and the base of the midbrain,

00:12:20.280 | it means floor, which is tegmentum.

00:12:22.800 | I think that's the, so there's a rationale,

00:12:24.560 | but it doesn't help much at all to know the names.

00:12:27.040 | - And in fact, you are absolutely correct,

00:12:29.560 | and I always forget that, so thank you for pointing that out.

00:12:33.240 | - It's a side effect of teaching your anatomy.

00:12:35.040 | - And then, which I once did back in the early '80s,

00:12:38.840 | but I've forgotten everything I taught.

00:12:41.760 | Anyhow, so these dopamine neurons,

00:12:43.360 | and we can talk about other types of dopamine neurons,

00:12:46.300 | they send messages, what we call projections,

00:12:50.760 | using telegraph wires that we call axons.

00:12:54.840 | They send projections to many different brain regions.

00:12:58.120 | The key one in the brain's reward circuitry being an area,

00:13:02.800 | again, with a very complicated name

00:13:05.480 | called the nucleus accumbens,

00:13:07.640 | and maybe, Andrew, you know,

00:13:09.120 | I actually don't know how that name evolved,

00:13:12.440 | the nucleus accumbens, and I'm sure I should know,

00:13:15.480 | because I've been studying it for 30 years,

00:13:19.280 | but I have never looked up the genesis of that name.

00:13:22.640 | - Well, the fortunate thing about this podcast

00:13:24.680 | is it's both on audio platforms like Spotify and Apple,

00:13:28.000 | but also on YouTube, and so now we can be absolutely sure

00:13:30.800 | that somebody has put it into the YouTube comments

00:13:34.080 | underneath this episode,

00:13:35.560 | and therefore everyone will learn, including us.

00:13:37.520 | So I don't know the origins of the word nucleus accumbens.

00:13:40.560 | - And it's a gross oversimplification,

00:13:45.160 | but it's the activity of these dopamine neurons

00:13:48.120 | in the ventral tegmental area

00:13:50.200 | that then cause the release

00:13:53.440 | of this powerful neuromodulated, neuromodulator dopamine

00:13:58.440 | in the nucleus accumbens,

00:14:00.820 | which is part of another brain structure

00:14:04.760 | with a tough-to-remember name called the ventral striatum,

00:14:09.760 | and then magic happens, and when I say magic happens,

00:14:13.480 | even though we've been studying

00:14:15.400 | how dopamine modifies the properties of cells

00:14:20.400 | in this nucleus accumbens,

00:14:23.680 | the truth is we don't have a deep mechanistic understanding

00:14:28.200 | why, when dopamine is released in the nucleus accumbens,

00:14:33.000 | we experience that as, I'm being very cautious here.

00:14:37.440 | The simple way would be to say as highly rewarding,

00:14:41.160 | but it's a little more complicated than that.

00:14:43.520 | What it tells us is that there's something

00:14:46.360 | really important happening in our environment.

00:14:49.840 | - So could we say that it cues the arousal system?

00:14:53.600 | - It gets the arousal system going.

00:14:56.640 | There's close ties to our memory systems,

00:15:00.560 | which hopefully intuitively makes some sense.

00:15:02.880 | If something really important

00:15:04.760 | is happening in your environment.

00:15:06.580 | Because again, I think what's helpful for your audience

00:15:10.440 | is to always be thinking about how these systems evolved

00:15:13.760 | from an evolutionary perspective.

00:15:16.040 | And if dopamine is signaling something really important

00:15:19.520 | and salient is happening in your environment,

00:15:23.400 | you wanna remember that.

00:15:25.200 | It could be a highly rewarding experience,

00:15:27.720 | like a source of food.

00:15:30.600 | For me, I like all donuts.

00:15:33.720 | So I don't wanna emphasize any one manufacturer

00:15:37.600 | of one donut versus the other.

00:15:39.480 | I like sugar-laden, fat-laden foods.

00:15:42.880 | That's why I never eat them because I like them so much

00:15:45.640 | and I use that as an example.

00:15:47.320 | But because that was an important event for my survival,

00:15:50.880 | this reward circuitry,

00:15:52.420 | yes, it stimulates my arousal system.

00:15:55.360 | It gets me to pay attention.

00:15:57.800 | It also has very close ties to memory systems.

00:16:01.720 | And to go off on a little bit of a tangent,

00:16:04.660 | I think the one...

00:16:06.120 | I don't wanna say it's a mistake.

00:16:10.440 | I think perhaps somewhat oversimplification

00:16:14.640 | of how people conceptualize dopamine's role in the brain

00:16:19.520 | is even though it's a major important role,

00:16:22.920 | is for it to be active and released

00:16:25.780 | during highly reinforcing experiences,

00:16:28.700 | like sex, like really good food, like drugs of abuse.

00:16:32.840 | It also can get activated subdivisions of this system

00:16:36.780 | during painful stimuli and during aversive stimuli,

00:16:41.260 | which again are really important for you to be aware of,

00:16:44.480 | to say, "Oh my God, that's really bad for me."

00:16:48.960 | And so the dopamine system, this reward circuitry

00:16:53.140 | and its subcomponents that maybe perhaps signal

00:16:57.400 | more salience or aversion in the environment

00:17:00.740 | are closely tied to arousal systems and memory systems.

00:17:05.380 | Again, hopefully for somewhat obvious reasons.

00:17:09.440 | You wanna remember powerfully reinforcing events

00:17:14.200 | in your life as well as powerfully emotionally

00:17:18.600 | or physically painful events in your life.

00:17:21.480 | So I hope I answered your question to a modest degree.

00:17:26.480 | - Far better than a modest degree.

00:17:29.380 | That's an excellent description of the dopamine system

00:17:31.880 | from a true expert.

00:17:33.540 | And the question I have is about some of the context

00:17:38.000 | and nuance of the system.

00:17:39.680 | But in sort of real world terms,

00:17:42.960 | how should I think about this?

00:17:44.460 | Even in my training as a neuroscientist,

00:17:46.080 | I know neurons can be a little active, a lot active,

00:17:48.920 | everything in between.

00:17:49.840 | They can be active over long periods of time

00:17:51.440 | or short periods of time.

00:17:52.720 | But let's use the example of the donut.

00:17:55.280 | I like a glazed old fashioned donut.

00:17:57.840 | I actually don't have a craving for sweet things,

00:17:59.880 | but donuts is an exception.

00:18:02.320 | I like the glazed old fashioned donut.

00:18:04.420 | But if I were to see just a little piece

00:18:06.980 | of a glazed old fashioned donut

00:18:09.520 | versus a full glazed old fashioned donut,

00:18:12.560 | could I expect that more dopamine is released

00:18:16.480 | to the anticipation of the complete donut?

00:18:19.280 | And then the other question is,

00:18:20.840 | how does context influence the dopamine system?

00:18:23.920 | For instance, if I'm very full,

00:18:26.000 | a glazed old fashioned donut might be aversive to me.

00:18:29.160 | Whereas if I'm just a little bit hungry

00:18:31.640 | or if I'm actually more on a schedule of rewarding myself

00:18:35.360 | for abstaining from sweet, fatty foods,

00:18:39.200 | then abstaining from the food

00:18:40.640 | might be its own form of reward.

00:18:43.000 | And so to me, the dopamine system seems incredibly simple

00:18:45.960 | and yet incredibly prone to immediate context

00:18:50.000 | and the kinds of nuance that...

00:18:52.240 | I mean, we're constantly juggling...

00:18:55.000 | I'll interrupt myself to say that we're constantly juggling

00:18:57.000 | a bunch of different reward contingencies.

00:18:59.160 | We want to have good health metrics

00:19:01.760 | and maybe have a certain aesthetic qualities to our body,

00:19:04.080 | but we also want the donut.

00:19:05.320 | And so how does a system as simple

00:19:08.600 | as a one neuromodulator system

00:19:10.520 | and the VTA to nucleus accumbens

00:19:13.000 | and with some connections to the memory area,

00:19:15.520 | how does it balance all of that information in real time?

00:19:19.680 | To me, that's just like staggeringly complex,

00:19:22.360 | but also incredibly interesting.

00:19:24.440 | - I think you beautifully put, very eloquent description.

00:19:30.360 | You just said it, it's staggeringly simple,

00:19:33.520 | simultaneously staggeringly complex.

00:19:36.280 | And you asked several different questions.

00:19:39.520 | So context makes an enormous importance.

00:19:42.800 | And that's one of the reasons I became interested

00:19:46.680 | in the dopamine reward circuitry is, as you know,

00:19:51.080 | as a colleague in the academic neuroscience world,

00:19:53.680 | but your listeners probably don't,

00:19:56.040 | I started out my career studying

00:19:57.720 | very basic mechanisms of plasticity.

00:20:00.560 | How does the brain modify itself?

00:20:03.560 | And what makes the brain different

00:20:06.120 | than the computer hardware is the physical connections

00:20:11.120 | in the brain are constantly changing,

00:20:14.680 | the strength of the communication.

00:20:16.680 | Similarly, for the dopamine reward circuitry,

00:20:20.240 | it's highly plastic and it's highly contextually dependent.

00:20:24.200 | And so you gave the example of donuts and feeding,

00:20:29.160 | and I'll answer your question about the cues.

00:20:32.360 | Yes, I used to give the example of Thanksgiving.

00:20:35.800 | So let me give that example.

00:20:38.080 | In the morning of Thanksgiving,

00:20:40.120 | all for most of us in the United States,

00:20:44.960 | the morning of Thanksgiving,

00:20:46.440 | if you're at home visiting your parents,

00:20:48.480 | the smells of the apple pie,

00:20:50.480 | the smells of the turkey cooking

00:20:52.880 | are highly repetitive, highly reinforcing.

00:20:56.440 | You're anticipating that fun event.

00:20:58.920 | You're anticipating Uncle Joe

00:21:00.720 | coming to visit you for Thanksgiving.

00:21:03.720 | And that's all because these cues,

00:21:07.480 | the smells, the anticipation of Uncle Joe's,

00:21:10.600 | your previous experiences are part of your memory system,

00:21:15.080 | sort of talking to, in a simple way, your reward circuitry.

00:21:19.960 | So you're building up this anticipation.

00:21:22.320 | One could almost say this craving,

00:21:24.120 | which maybe we'll talk about in the context of addiction,

00:21:27.160 | and then make a long story short,

00:21:29.680 | think about that evening at the end of Thanksgiving,

00:21:34.280 | those exact same cues,

00:21:37.240 | the exact same smell of the apple pie,

00:21:39.320 | turkey, and Uncle Joe himself.

00:21:41.800 | At the very least, they're no longer repetitive,

00:21:45.600 | meaning they might actually be a versa.

00:21:48.280 | The last thing you want is a piece of apple pie.

00:21:51.120 | You can't wait for Uncle Joe

00:21:52.600 | to leave your Thanksgiving dinner.

00:21:54.800 | And I always argue that does not happen magically.

00:21:58.000 | That happens because your brain has been modified

00:22:02.120 | by the context in which it sits.

00:22:04.800 | And this very important modulatory system,

00:22:07.160 | this reward circuitry, is responding

00:22:09.720 | to the exact same stimuli with a very different response.

00:22:14.600 | So I'm just telling you, I'm repeating what you said,

00:22:17.360 | the phenomenology, and again, my other favorite example

00:22:20.960 | is any of us who have been in an intimate relationship

00:22:24.680 | knows that the love of your life

00:22:27.360 | can turn to the bane of your existence in 20 seconds.

00:22:31.680 | And again, that doesn't happen magically.

00:22:34.280 | This person who you crave, who you love, does something,

00:22:38.400 | and two minutes later, your brain is saying,

00:22:40.600 | "Oh my God, I may have to break up with this person,"

00:22:44.920 | or, "This is an incredibly painful emotional experience."

00:22:49.120 | And what fascinates me about the brain

00:22:51.320 | is how does the brain mediate that rapid change?

00:22:55.000 | So now back to, so yes, context is everything

00:23:00.000 | about how this powerful neuromodulatory system

00:23:03.560 | that uses dopamine works.

00:23:05.680 | And the truth is we don't know.

00:23:08.000 | It's because the inputs onto these dopamine neurons,

00:23:11.520 | the other nerve cells that are driving the activity

00:23:14.840 | of the dopamine neurons, and I've actually studied this

00:23:17.760 | in my lab at Stanford University with a colleague

00:23:21.440 | you know well, Li-Chen Luo,

00:23:23.560 | who's a world-class neuroscientist.

00:23:27.640 | We've studied the complexity of the neuroanatomy

00:23:30.840 | of the dopamine system, and these dopamine neurons

00:23:34.080 | in the ventral tegmental area,

00:23:36.120 | the source of the reward circuitry dopamine,

00:23:39.200 | are receiving inputs from all over the brain.

00:23:42.480 | They're receiving indirectly or directly inputs

00:23:46.240 | from visual areas, from somatosensory areas.

00:23:50.280 | And I'm not giving you a really good answer

00:23:53.320 | because that's one of the goals of my research,

00:23:56.440 | to try to understand how context,

00:23:58.880 | how the history that you've had with these cues,

00:24:03.040 | which we're gonna get back to, of the donut or of a drug,

00:24:06.360 | how has that modified

00:24:08.000 | how this neuromodulatory system responds?

00:24:13.000 | Similarly, the nucleus accumbens,

00:24:16.280 | the target of this powerful modulator dopamine,

00:24:21.160 | is receiving communications, what we call inputs,

00:24:27.040 | from all sorts of brain regions that you know about, Andrew,

00:24:31.160 | your audience may not.

00:24:32.640 | It receives inputs from an area called the hippocampus,

00:24:36.080 | which you may have covered in previous podcasts,

00:24:39.040 | which is very powerfully, very important for memories,

00:24:43.360 | both establishing new memories.

00:24:45.520 | And again, remember that makes sense.

00:24:47.560 | You want this system, this dopamine reward circuitry

00:24:51.320 | to be very connected to memory systems.

00:24:54.200 | So the activity in the nucleus accumbens

00:24:59.200 | is modulated by dopamine,

00:25:02.200 | while it is receiving information from the hippocampus,

00:25:05.760 | which helps encode new memories,

00:25:07.680 | while it's receiving information

00:25:09.440 | from a brain area called the amygdala,

00:25:12.680 | which is a part of the brain

00:25:16.000 | involved in our emotional experiences.

00:25:18.960 | The accumbens also receives inputs

00:25:21.720 | from the prefrontal cortex,

00:25:24.160 | which is this brain area, as you know better than me, Andrew,

00:25:29.160 | is important for decision-making,

00:25:35.160 | for planning our activity, and I could go on and on.

00:25:38.560 | - Well, could we talk about prefrontal cortex for a moment?

00:25:41.200 | Because it always was surprising to me

00:25:46.200 | that prefrontal cortex is talked about

00:25:50.160 | as this higher executive function area.

00:25:53.200 | But then when you look at the neuroanatomy,

00:25:55.120 | it's, as we say, monosynaptically, as you and I know,

00:25:59.040 | one connection away from structures like the amygdala,

00:26:03.320 | one connection away from structures

00:26:04.920 | like the nucleus accumbens.

00:26:06.600 | In other words, prefrontal cortex, to me,

00:26:08.400 | is every bit as ancient as some of these other structures

00:26:12.640 | that we think of as more ancient.

00:26:14.420 | And really the whole ancient evolved thing

00:26:16.160 | gets a little bit dicey because certain areas are,

00:26:18.200 | like the prefrontal cortex, are more elaborated in humans.

00:26:20.680 | But to me, the prefrontal cortex seems to be

00:26:23.420 | especially important in the context of this thing

00:26:26.600 | of scaling the reward response

00:26:29.560 | or context of the reward response,

00:26:32.880 | because it can set rules.

00:26:35.580 | It seems to know, okay, we're recording a podcast now,

00:26:39.940 | and there are certain rules.

00:26:40.780 | There are certain things that we're going to do and not do.

00:26:43.720 | But what's fascinating about the,

00:26:45.580 | and I'm so glad you gave a bunch of different examples,

00:26:47.740 | because what's fascinating, for instance,

00:26:49.640 | about the relationship example is that, yes, at one moment,

00:26:54.280 | we can adore somebody, and another moment later,

00:26:57.040 | if they do something or don't do something,

00:26:59.280 | we can be incredibly frustrated with them.

00:27:01.120 | They can even become aversive to us.

00:27:03.760 | Hopefully that doesn't happen too frequently.

00:27:05.880 | But I think we've all had the experience of a donut,

00:27:10.760 | an event, or a person actually looking different to us

00:27:17.200 | from one moment to the next, hopefully not at random, right?

00:27:20.120 | And so to me, it seems like the prefrontal cortex

00:27:23.560 | is uniquely positioned to really say, okay, right now,

00:27:27.220 | we are in a mode of, for lack of a better word,

00:27:30.040 | love and loving, like be in the verb tense of loving,

00:27:34.520 | be in the verb tense of arguing.

00:27:36.420 | We're now arguing.

00:27:37.860 | We're in the verb tense of reconciliation,

00:27:41.400 | kind of somewhere in between or something of that sort.

00:27:43.800 | And how a structure and a circuit as simple

00:27:48.680 | as the dopamine system, right?

00:27:49.820 | One molecule could suddenly say, oh, you know what?

00:27:52.180 | Now getting over my anger is rewarding.

00:27:54.680 | Whereas five minutes ago,

00:27:55.920 | being right and being the most angry was rewarding.

00:27:58.940 | And then five minutes before that,

00:28:00.960 | again, we're accelerating this movie,

00:28:02.560 | but five minutes or five days or five years before that,

00:28:05.720 | this person could do no wrong.

00:28:07.760 | And the dopamine system is just cranking out dopamine,

00:28:10.760 | saying, whatever you do, I'm just delighted by it.

00:28:13.440 | - Incredible.

00:28:14.580 | Like to me, I can't think of a more interesting system

00:28:16.860 | in neuroscience.

00:28:17.700 | - Well, I mean, that was eloquently put.

00:28:22.160 | I agree with pretty much everything you said.

00:28:25.520 | I don't have much to add because what you're pointing out is

00:28:28.880 | the challenges of studying these systems,

00:28:33.780 | the importance of studying these systems,

00:28:36.440 | and the challenge of presenting how the brain works

00:28:41.800 | to this podcast audience.

00:28:43.820 | Because on the one hand, you have done a fantastic job

00:28:48.820 | over the last few years in your podcast

00:28:51.800 | of making complex subjects accessible to a lay audience

00:28:56.800 | and get them to be thinking about how our modern view

00:29:05.020 | of how the brain works could be used to enhance health,

00:29:09.680 | could enhance mental wellbeing.

00:29:12.620 | But as neuroscientists, academic neuroscientists ourselves,

00:29:17.620 | we know, you know, you are oversimplifying things

00:29:22.680 | and the actual functioning of a system

00:29:25.880 | like the dopamine reward circuitry,

00:29:28.100 | as you just eloquently point out, is so much more complex.

00:29:31.760 | It's modified by these prefrontal inputs,

00:29:37.320 | which are simultaneously telling our memory systems,

00:29:41.160 | you know, pay attention here.

00:29:42.940 | I'm repeating what you just said.

00:29:46.180 | The context makes a big difference,

00:29:47.980 | the history you have with the person or stimuli

00:29:52.980 | with whom you're interacting.

00:29:54.600 | Like to bring this back to your, you know,

00:29:56.540 | which I never, the initial question,

00:29:58.560 | is a small piece of a donut activate the cue

00:30:03.300 | that that small piece of a donut activate

00:30:05.760 | the reward circuitry and cause release of dopamine

00:30:08.560 | to the same extent as the full donut?

00:30:12.480 | Depends on your experience with donuts.

00:30:15.480 | I mean, I think for you and me,

00:30:17.840 | because we seem to both have, you know, like donuts,

00:30:20.960 | they're highly repetitive for us.

00:30:22.980 | Probably doesn't matter because we have learned

00:30:26.120 | even a little piece of a donut activates

00:30:29.740 | all of our memory systems saying,

00:30:31.260 | man, that's an old fashioned glazed donut.

00:30:34.380 | I want to eat that or I want to get one

00:30:36.680 | or I want to have the discipline not to eat it.

00:30:39.880 | So I hope I'm answering your question

00:30:41.180 | and I'm shifting topics completely,

00:30:44.940 | but that's why addiction is so challenging.

00:30:48.680 | - Well, let's talk about that.

00:30:50.260 | Let's talk about that because you've done

00:30:51.680 | a ton of important work in this area of addiction.

00:30:54.720 | I mean, one of the basic questions I have about addiction

00:30:57.200 | is, you know, we hear that certain drugs

00:30:58.940 | are more addicting than other drugs or certain behaviors.

00:31:02.360 | We also hear that we can become addicted to anything.

00:31:04.700 | When Ana Lemki was on this podcast, I said,

00:31:07.200 | what's the most unusual addiction you've ever seen?

00:31:09.920 | And she talked about a patient who sadly committed suicide

00:31:13.600 | at some point later that she told us had been addicted

00:31:17.300 | to water, to drinking of any kind, first alcohol,

00:31:20.840 | but then water eventually.

00:31:22.820 | And so my question about addiction in the dopamine system

00:31:26.520 | is, you know, let's pick a drug like cocaine.

00:31:31.880 | I've never done cocaine, but people who have done cocaine

00:31:36.080 | tell me that it feels very good.

00:31:38.220 | And one of the more salient features of the cocaine high

00:31:42.580 | is that it comes on very fast

00:31:44.700 | and it ends pretty quickly too.

00:31:46.580 | Is the rate of dopamine increase related

00:31:51.400 | to the addictive property of a drug or behavior

00:31:55.600 | as much as how much dopamine is released?

00:31:59.360 | - And that's a very sophisticated question.

00:32:01.380 | And the answer is yes.

00:32:03.180 | And that's usually the lecture I give.

00:32:07.260 | The way I think about addiction,

00:32:09.540 | and obviously my friend and colleague Ana Lemki

00:32:12.460 | is one of the world's experts in terms of the understanding,

00:32:16.000 | the human experience of addiction.

00:32:18.040 | I have studied it as a cellular molecular neuroscientist

00:32:22.820 | trying to understand how addictive substances

00:32:27.920 | modify reward circuitry, modify the connections

00:32:31.560 | in the reward circuitry, modify how dopamine neurons act.

00:32:35.400 | And the way I, you know, like any,

00:32:38.340 | what appears to be a simple term,

00:32:41.720 | it's layered with complexity.

00:32:43.760 | Addiction is somewhat of a continuum.

00:32:47.340 | And I like to think about whether you're talking

00:32:49.620 | about substances like cocaine,

00:32:52.080 | and I will explicitly answer your question soon,

00:32:55.460 | or opioids, as you know, we're going in this country,

00:32:59.740 | there is an opioid epidemic.

00:33:03.040 | I do like to think about addictive liability.

00:33:06.800 | And it is, in my view, it is pretty clear

00:33:10.280 | that when we're talking about drugs,

00:33:12.620 | they have different degrees of addictive liability.

00:33:16.900 | I mean, I had a cup of coffee this morning.

00:33:19.300 | And many of us listening to this podcast,

00:33:24.640 | it's really hard to start our day

00:33:26.300 | without getting that hit of caffeine.

00:33:28.620 | But are we addicted to caffeine?

00:33:31.200 | That's a tricky question,

00:33:32.640 | because I've never heard of anybody robbing a bank

00:33:35.260 | to get caffeine, destroying their personal life

00:33:40.260 | to get caffeine.

00:33:41.740 | So I would say caffeine causes tolerance,

00:33:46.520 | but I would not say it has a particularly

00:33:48.600 | high addictive liability.

00:33:51.180 | Whereas drugs like psychosimulants, like cocaine,

00:33:55.520 | have a very, or opioids,

00:33:56.940 | have a very high addictive liability.

00:33:58.760 | So to answer your mechanistic question,

00:34:01.620 | there have been some famous studies done

00:34:04.620 | by the director of the National Institute on Drug Abuse,

00:34:08.620 | Nora Volkoff.

00:34:09.840 | Simultaneously, there have been studies

00:34:13.360 | in animal models of addiction where you nailed it.

00:34:18.980 | In a rough way, the addictive liability of a substance

00:34:23.620 | is directly correlated with two aspects of dopamine,

00:34:28.620 | how much dopamine is released in the accumbens

00:34:31.180 | and the kinetics of the dopamine release, as you said,

00:34:34.140 | how rapidly it's released.

00:34:36.520 | To get a little technical,

00:34:38.060 | even with a drug like cocaine or opioids,

00:34:41.140 | it's not only the drug itself,

00:34:43.900 | it's the root of administration,

00:34:46.180 | because the root of administration influences the kinetics,

00:34:50.640 | meaning how fast that drugs gets into your brain,

00:34:54.280 | influences the reward circuitry

00:34:57.160 | and how fast it causes a big rapid release of dopamine.

00:35:01.840 | And some of your podcast listeners may be old enough

00:35:06.200 | to remember the crack cocaine epidemic or freebase cocaine.

00:35:11.200 | And cocaine does have, like methamphetamine,

00:35:14.580 | a very high addictive liability.

00:35:17.780 | I give lectures to students at Stanford

00:35:22.660 | about neurobiology of addiction

00:35:24.300 | as part of a team-taught course.

00:35:28.860 | I have kids who I had to deal with.

00:35:31.800 | And what I always say is,

00:35:33.900 | it's not that if you use this drug,

00:35:36.820 | you're automatically gonna become an addict,

00:35:39.660 | but you're taking that risk.

00:35:43.320 | And it is impossible to become addicted to a substance

00:35:46.300 | if you've never used it, by definition.

00:35:48.220 | But back to the root of administration.

00:35:49.940 | So I went off on a tangent there.

00:35:51.780 | - Well, that's actually an interesting statement.

00:35:53.540 | Because I think we may have heard that in high school,

00:35:55.740 | although I, to be honest,

00:35:57.980 | wasn't the most attentive high school student,

00:35:59.620 | and I regret that high school students pay attention.

00:36:01.660 | - You did okay for yourself.

00:36:02.500 | - Eventually I came around,

00:36:03.860 | but it was an uphill battle there.

00:36:06.360 | But that you can't become addicted

00:36:08.100 | to something that you've never done,

00:36:10.100 | which I just wanna earmark that,

00:36:12.620 | because I think it's a profound statement,

00:36:14.640 | because it points to the importance of the memory system,

00:36:18.820 | but also plasticity.

00:36:20.300 | And so I wanna make sure that eventually we get around

00:36:22.640 | to talking about how the amount of dopamine released

00:36:26.160 | and the kinetics, how that might influence plasticity.

00:36:28.860 | Basically what I'm asking here,

00:36:30.200 | queuing up in the back of your mind,

00:36:32.420 | is whether or not addiction is just related

00:36:37.340 | to the sensation that we have when we indulge in a behavior,

00:36:41.380 | or when we are under the influence of a drug,

00:36:44.340 | or whether or not it actually modifies neural circuitry

00:36:48.060 | in a way that makes a broader range of drugs

00:36:53.060 | or experiences attractive to us.

00:36:56.200 | - It's probably the latter.

00:36:57.860 | But so let me get back,

00:36:59.460 | and I will answer that in a second,

00:37:00.960 | to the point I was making.

00:37:02.140 | So it's not only the substance,

00:37:03.960 | it's the root of administration.

00:37:08.540 | As I said, you can't develop a problem with a substance

00:37:12.640 | and develop a substance abuse problem if you never take it.

00:37:16.500 | But snorting cocaine is a different experience

00:37:21.500 | than smoking it or injecting it.

00:37:24.300 | And one of the reasons the crack cocaine epidemic

00:37:27.820 | was so powerful is it gets into,

00:37:34.660 | when you're smoking it or injecting it,

00:37:36.500 | and people do this now with methamphetamine,

00:37:40.260 | I mean, meth addicts, most of them,

00:37:42.360 | and that is another epidemic in our country,

00:37:45.580 | most of them smoke it.

00:37:47.140 | And the danger of that is the drug,

00:37:50.380 | whether it's cocaine, methamphetamine,

00:37:51.900 | gets into your brain almost instantaneously,

00:37:55.880 | causes a very rapid, powerful surge of dopamine

00:38:00.880 | in the accumbens, in this reward circuitry,

00:38:04.440 | and that the feeling you get,

00:38:06.500 | which, and we're gonna get into this,

00:38:07.940 | is not necessarily a happy feeling.

00:38:11.380 | And it only lasts, it can last for tens of seconds

00:38:16.380 | or a few minutes.

00:38:18.180 | And it's a feeling that gives you

00:38:22.740 | this overwhelming compulsion and urge,

00:38:27.660 | I wanna do it again.

00:38:29.460 | So even though it may not actually feel all that good,

00:38:34.460 | and again, this gets into,

00:38:38.260 | we didn't have an addiction problem

00:38:41.360 | for any substance other than alcohol

00:38:44.600 | for most of humanity's existence,

00:38:49.800 | because these substances like cocaine,

00:38:52.620 | methamphetamine, synthetic opioids like fentanyl,

00:38:56.080 | they didn't exist.

00:38:57.700 | And the truth is our brains are not designed

00:39:02.700 | to handle those kinds of very powerful substances.

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00:40:04.760 | - So where do you want to go from here?

00:40:05.820 | You asked a question about, you know,

00:40:07.740 | the neural mechanisms of what we call addiction.

00:40:12.660 | - Yeah, I'd like to know about the role

00:40:13.900 | of neuroplasticity in addiction.

00:40:15.740 | I do want to highlight something you said,

00:40:17.220 | and I apologize for interrupting a moment ago.

00:40:20.300 | - No, absolutely not. - But it was an interruption

00:40:22.420 | based on real excitement because a person I know quite well

00:40:27.420 | who is a recovered cocaine addict told me,

00:40:32.120 | and by the way, folks, this isn't I have a friend

00:40:34.340 | and I'm actually, you know, I truly have never tried cocaine.

00:40:37.680 | And this person said that the first time they did cocaine,

00:40:41.280 | his thought was I hate this and I can't wait to do it again.

00:40:47.140 | And that's exactly how you described it.

00:40:49.540 | And I think that is a fairly common experience

00:40:54.540 | with people suffering from an addiction disorder.

00:40:59.580 | We're not supposed to use the word addicts anymore

00:41:02.140 | because that's a little bit judgmental.

00:41:04.440 | - That's the new nomenclature.

00:41:06.460 | - Something along those lines.

00:41:07.660 | - Got it, calling someone an addict

00:41:09.820 | as opposed to being addicted.

00:41:10.980 | - Yeah, being, and that is a beautiful description.

00:41:15.980 | I hate it, but I want to do it again.

00:41:19.380 | And again, it just shows the power of this system,

00:41:23.460 | which remember, evolved for our survival.

00:41:27.040 | So a very simple way of thinking about it

00:41:28.860 | is these drugs are tricking the reward circuitry

00:41:32.740 | to say this stimulus, this experience

00:41:36.780 | is really important for my survival.

00:41:38.860 | I have to go do it again and again.

00:41:41.180 | And again, a side question is the huge question

00:41:44.180 | is why does some people develop an addiction problem

00:41:48.900 | and others who have used this substance just don't?

00:41:53.380 | And again, as a world-class neuroscientist yourself,

00:41:57.300 | you know the answer.

00:41:58.260 | It's always a complex combination of underlying genetics,

00:42:03.220 | the environment in which they find themselves,

00:42:06.040 | the environment in which they grew up

00:42:08.340 | and how that modified their reward circuitry.

00:42:12.500 | So to get at your question,

00:42:16.500 | one set of experiments my lab did,

00:42:19.820 | which other labs did too,

00:42:21.780 | I don't deserve the sole credit for this,

00:42:24.140 | is showing that drugs of abuse cause powerful plasticity

00:42:29.140 | in the neurons that make up the cells

00:42:33.140 | that make up the reward circuitry.

00:42:35.180 | And in fact, drugs of abuse like cocaine, methamphetamine,

00:42:39.580 | opioids like morphine, heroin,

00:42:44.180 | change the synapses.

00:42:46.740 | The synapses are the connections from other nerve cells

00:42:51.560 | onto dopamine neurons,

00:42:53.300 | onto the nerve cells in the accumbens

00:42:55.740 | and these connections, these synapses can change

00:42:59.100 | and drugs of abuse cause powerful changes

00:43:03.200 | in those connections and therefore powerful changes

00:43:06.900 | in the activity of the dopamine neurons

00:43:09.940 | and the neurons in the ventral, in the nucleus accumbens.

00:43:13.780 | And in fact, the types of changes that occur

00:43:16.980 | appear to be similar to the types of changes

00:43:21.000 | that have evolved for good uses,

00:43:24.540 | for adaptive forms of learning and memory.

00:43:27.580 | So again, this is an example

00:43:30.460 | that this superficially simple dopamine reward circuitry

00:43:35.460 | is changing all the time.

00:43:40.500 | It is highly plastic and can become more sensitive

00:43:45.060 | to certain experiences, et cetera, et cetera.

00:43:48.620 | - Well, could I ask you a question

00:43:49.660 | about some of the general contours of the plasticity

00:43:52.220 | in the dopamine system?

00:43:53.860 | You said before, and I love this statement,

00:43:56.820 | even though it's very simple,

00:43:58.380 | but in its simplicity, it's really elegant

00:44:00.340 | that we can't become addicted to a substance

00:44:02.560 | or a behavior that we haven't taken or partaken in.

00:44:07.220 | So is there data to support the idea

00:44:12.020 | that just one exposure to cocaine

00:44:15.820 | or one exposure to some sort of behavior

00:44:19.300 | can lead to a lasting change in the dopamine system

00:44:23.580 | such that one's propensity to be addicted to that substance,

00:44:28.580 | again, if one were to indulge in the future

00:44:31.620 | or behavior again in the future is increased.

00:44:34.820 | And I have a very particular reason for asking this,

00:44:36.880 | but I'm very curious what the answer is.

00:44:38.600 | - I mean, in the work my lab and other labs have done

00:44:43.600 | in preclinical rodent models, the answer is yes,

00:44:48.760 | a single administration of a drug of abuse like cocaine,

00:44:54.300 | like morphine, can cause relatively several days,

00:45:00.220 | several weeks of changes in the connections

00:45:05.060 | onto dopamine neurons and onto the neurons

00:45:09.500 | in the nucleus accumbens.

00:45:11.080 | Those changes, that does not mean these changes

00:45:14.480 | are permanent or irreversible,

00:45:19.120 | but the changes last a long time.

00:45:21.460 | And again, the big question for understanding

00:45:25.820 | the neurobiology of addiction is,

00:45:28.260 | those changes are probably happening

00:45:30.760 | in most people who take the drug in this case,

00:45:33.720 | and we can talk about other stimuli,

00:45:36.720 | non-drug stimuli that can become, in quotes, addictive.

00:45:40.640 | Again, why in certain individuals?

00:45:43.600 | To be honest, it's not a big deal.

00:45:46.300 | Yeah, I did cocaine at this party.

00:45:48.560 | It was nice, but I don't feel any craving

00:45:51.200 | or urge to do it again, whereas other individuals,

00:45:55.080 | it sets them down a very bad path

00:45:59.440 | and really badly affects their life.

00:46:02.000 | And that's a huge question in the research field,

00:46:05.560 | because obviously if we could make predictions

00:46:08.280 | on which individuals are more susceptible,

00:46:12.880 | and not to get too political here,

00:46:16.000 | but whether you develop a problem with addiction or not

00:46:22.040 | is influenced by the other parts of your life.

00:46:28.880 | - Do you have other ways of getting reinforcing stimuli,

00:46:32.640 | getting satisfaction, having an outlet,

00:46:35.760 | that other ways of activating your reward

00:46:38.240 | or dopamine circuitry?

00:46:39.840 | - Healthy ways. - Healthy ways.

00:46:41.720 | Like as you have articulated, I think, in your podcast,

00:46:46.040 | getting exercise.

00:46:47.960 | You and I both like to get exercise.

00:46:50.420 | I feel really good.

00:46:52.300 | Sometimes it's painful during the exercise,

00:46:54.300 | but afterwards I feel great.

00:46:57.680 | - Almost the inverse of the cocaine response.

00:47:00.000 | The desire and then the I hate this,

00:47:03.360 | but I can't wait to do it again.

00:47:04.420 | It seems like exercise is often the opposite.

00:47:07.160 | It's I hate this, I don't want to do this.

00:47:08.700 | And then afterwards, gosh, I always feel better

00:47:11.440 | and I'd be happy to do it again.

00:47:12.880 | - I mean, yes.

00:47:14.500 | I mean, I like to exercise chasing a ball

00:47:17.240 | because that gets me off thinking about this hurts.

00:47:20.800 | So anyhow, back to addiction.

00:47:25.080 | So yes, these drugs can cause,

00:47:28.440 | I don't want to, definitely not permanent changes

00:47:30.960 | from a single exposure.

00:47:32.680 | And the types of studies I'm talking about

00:47:36.360 | were all done in experimental animals.

00:47:41.280 | So how that relates to what happens in our brains,

00:47:46.280 | in human subjects' brains is not completely clear,

00:47:50.380 | but I think there are parallels.

00:47:52.040 | So the changes might last a few days, a week or two,

00:47:57.000 | but one can see if somebody,

00:47:59.080 | there have been studies done where in an animal model,

00:48:04.000 | if you give repeated administration of a drug like cocaine,

00:48:09.000 | the changes get stronger and they last longer,

00:48:12.960 | which is kind of intuitively obvious.

00:48:15.240 | But again, the big question is why in human subjects,

00:48:22.200 | there are people who can use these substances

00:48:25.080 | and not develop a serious problem

00:48:27.300 | and there are others where they're very, very damaging.

00:48:30.620 | And then that's why I still make the point,

00:48:34.840 | if you're a young person, do you want to take that risk?

00:48:39.080 | Is it worth it to have that experience?

00:48:42.180 | And that's an individual decision.

00:48:44.920 | - We've done some podcast episodes

00:48:46.600 | about alcohol, cannabis, et cetera,

00:48:48.200 | and there does seem to be a pretty wide variation

00:48:50.640 | in people's response to the information.

00:48:52.640 | I think because there are people out there who,

00:48:55.040 | well, I've got friends who are recovered alcoholics,

00:48:58.200 | who will tell me the first drink they took,

00:49:01.800 | they use language like,

00:49:03.400 | it combined with the chemistry of my body

00:49:08.600 | in a way that nothing before ever had

00:49:12.000 | and they felt like it was like this magic elixir, right?

00:49:14.960 | That has not been my experience with alcohol.

00:49:18.360 | - And I've heard the same stories

00:49:20.360 | and it's hard for me to relate because like you,

00:49:22.600 | alcohol does not have that effect on me.

00:49:26.200 | And that's where, it's hard to believe

00:49:29.520 | that kind of immediate response to alcohol

00:49:33.800 | is due to the environment in which they grew up,

00:49:38.160 | although that can have an influence.

00:49:39.740 | That just feels almost more genetically encoded.

00:49:43.400 | And there is evidence that issues with the use of alcohol

00:49:49.000 | in developing alcohol use disorder does run in families.

00:49:53.560 | And obviously if it runs in family,

00:49:55.160 | you have to worry about how the environment

00:49:56.960 | of that family influences.

00:49:58.360 | There's a lot of studies saying there is a genetic component.

00:50:01.760 | Maybe like you, if I have a drink or two in the afternoon,

00:50:05.500 | I just fall asleep.

00:50:06.840 | And it does not have that effect on me.

00:50:09.360 | And anyone could imagine similar things

00:50:14.240 | for other drugs of abuse.

00:50:16.600 | There are people who have used cocaine,

00:50:19.040 | have used methamphetamine,

00:50:20.840 | who find it modestly enjoyable,

00:50:23.640 | but it's not the be all or end all.

00:50:28.080 | It isn't this incredibly powerful experience.

00:50:31.000 | And you just talked about, I think, a friend or a colleague

00:50:34.440 | who said, "I hate it, I hate that,

00:50:36.280 | "but I wanna do it again."

00:50:37.880 | And that's fascinating.

00:50:39.320 | - Yeah, they're now a recovered alcoholic and cocaine addict

00:50:42.360 | and they've abstained for many years,

00:50:44.020 | but still get a little bit of a gleam in their eye

00:50:46.580 | when they talk about alcohol or cocaine

00:50:49.140 | in a way that I just can't relate to.

00:50:51.580 | - I can relate, I mean, can I tell you a little vignette

00:50:53.780 | about me, which I love to tell?

00:50:55.480 | - Sure, sure.

00:50:56.580 | - And it gets into how the reward circuitry

00:50:59.900 | is so closely associated with memory systems

00:51:04.900 | and how cues associated with powerful experiences

00:51:11.400 | develop their own reinforcing or aversive quality.

00:51:15.780 | So long story short, when I was a young kid,

00:51:18.820 | in, I can't remember, in my 20s, maybe 20,

00:51:21.960 | I spent a few weeks in Paris.

00:51:24.300 | I started smoking cigarettes.

00:51:25.840 | I mean, this is a long time ago.

00:51:28.580 | And I got, cigarettes are very interesting.

00:51:31.220 | Nicotine is highly addictive,

00:51:34.180 | as the tobacco companies were fully aware of.

00:51:37.380 | - High addictive liability?

00:51:38.780 | - Very high addictive liability.

00:51:40.220 | - People will rob people for the money to buy cigarettes?

00:51:43.020 | - They may not rob because,

00:51:48.440 | although my understanding is they've become quite expensive,

00:51:52.580 | but counterfeit cigarettes are a huge market

00:51:57.580 | for organized crime.

00:51:59.880 | There are parts of our, in the world,

00:52:04.200 | third world countries where organized crime

00:52:07.720 | produce counterfeit cigarettes

00:52:10.360 | and are making hundreds of millions or billions of dollars.

00:52:14.020 | And so I think nicotine as it is delivered in cigarettes,

00:52:20.180 | as you know, I mean, tobacco companies put in a lot of work

00:52:24.460 | to figure out the exact dose of nicotine

00:52:28.060 | that will make you get that kind of feeling

00:52:31.980 | that only lasts for a few minutes.

00:52:34.680 | So you wanna do it again and again.

00:52:37.500 | So we can talk about, and nicotine, you know,

00:52:41.140 | what becomes a problem in a specific society with addiction

00:52:46.140 | is not only based on the neurobiological actions,

00:52:52.320 | if we're talking still about drugs

00:52:53.960 | or substances of that substance,

00:52:56.000 | it's heavily influenced by the availability

00:52:58.260 | of the substance too.

00:52:59.440 | But my little story is I smoked some cigarettes in Paris.

00:53:02.580 | I learned why people like to smoke.

00:53:06.800 | It was very satisfying to have a cigarette

00:53:09.980 | in a Parisian cafe.

00:53:11.460 | It just, you know, and it's very interesting

00:53:13.480 | because the first few times you inhale tobacco,

00:53:16.160 | you get dizzy, it's kind of aversive,

00:53:18.340 | and it's exactly what you articulated.

00:53:20.940 | Despite that, you wanna do it again.

00:53:23.360 | So it was just a lot of fun for me.

00:53:26.260 | I enjoyed it.

00:53:27.300 | And I was disciplined, you know, at some point,

00:53:30.300 | whenever this was, I came back to the United States.

00:53:32.240 | I didn't smoke because I knew it was bad for you.

00:53:36.020 | But to this day, 40 years later,

00:53:39.760 | every time I go back to Paris, I get cravings.

00:53:43.640 | I actually just wanna get a pack of cigarettes.

00:53:47.580 | I want to have that feeling again of inhaling the smoke.

00:53:52.060 | But the point is of how powerful

00:53:55.940 | these rewarding experiences can be

00:53:58.020 | or reinforcing experiences.

00:54:00.180 | And for your audience, technically, you know,

00:54:03.660 | what I have been taught by some of my psychology colleagues

00:54:08.260 | is we use the term reinforcing

00:54:10.380 | in a very behaviorally defined way.

00:54:14.860 | Something is reinforcing is if the behavior

00:54:19.660 | that led to that stimuli,

00:54:22.240 | it makes you wanna do that behavior again.

00:54:24.780 | Rewarding means it actually felt, in quotes, good.

00:54:29.340 | - No, it's an important distinction.

00:54:31.340 | - They actually can be different.

00:54:33.100 | Again, as you defined by your friend who,

00:54:37.300 | I forget, I think it was cocaine.

00:54:38.780 | Cocaine was highly reinforcing,

00:54:41.420 | but it was not necessarily enjoyable or rewarding.

00:54:45.100 | And isn't that fascinating?

00:54:46.620 | I have some colleagues in the addiction field.

00:54:50.660 | One of them is retired now,

00:54:53.660 | Kent Barrage and Terry Robinson.

00:54:56.080 | They distinguish between the terms wanting and liking.

00:55:01.440 | Wanting and liking.

00:55:03.620 | And think about that.

00:55:05.400 | Liking something means it's something you like, you enjoy.

00:55:10.400 | Wanting means you want it,

00:55:15.420 | but you don't necessarily like it or enjoy it.

00:55:19.480 | And that's a description

00:55:21.360 | of your friend's experience with cocaine.

00:55:24.080 | Some of us have been in destructive relationships

00:55:27.800 | where you want that individual,

00:55:30.040 | but you're not sure you necessarily like that individual.

00:55:32.880 | - Sometimes people will be in relationships

00:55:34.360 | where they actively dislike the other person,

00:55:37.400 | which is a bit foreign of a concept to me,

00:55:39.840 | but it's interesting this separation

00:55:42.040 | of reinforcing and rewarding, wanting and liking,

00:55:44.220 | because one of the things that's very prominent

00:55:47.340 | in 12-step programs is to create rewards

00:55:51.000 | around abstaining from the drug or behavior.

00:55:54.160 | And I should mention that programs like 12-step,

00:55:56.360 | when followed, seem to have very high success rates.

00:55:58.680 | At least that's what Anna Lemke tells me.

00:56:00.720 | That in some ways they are modifying

00:56:05.840 | the wanting and liking.

00:56:07.560 | They're splitting the wanting and liking of alcohol,

00:56:11.000 | for instance, creating a liking of sobriety

00:56:14.480 | more than the wanting of alcohol, for instance.

00:56:17.040 | - That's beautifully put.

00:56:19.260 | And I think that's right.

00:56:20.560 | How that plays out in the neural mechanisms,

00:56:24.680 | that as a neuroscientist, I'm interested in it.

00:56:27.320 | Man, that's a tough one.

00:56:28.920 | But I think that's why those programs

00:56:35.220 | are pretty successful.

00:56:37.480 | It's helping the person make those dissociations.

00:56:41.640 | And I don't know that much about those programs,

00:56:45.580 | because I have not seen patients myself

00:56:49.200 | for whatever, it's been 27, 28 years,

00:56:52.520 | but I think part of them are to help that individual

00:56:56.960 | find both other sources of liking and reward,

00:57:01.960 | getting some satisfaction and reward

00:57:08.360 | from the actual abstinence,

00:57:10.800 | being able to cognitively teach themselves

00:57:14.220 | that I deserve a pat on the back, I deserve credit,

00:57:17.480 | I feel good that I did not take a drink at that party,

00:57:22.480 | that I did not use that substance again.

00:57:26.160 | And how that plays out in our brains is a really tough one.

00:57:30.160 | - Yeah, those are, the way you described it

00:57:32.200 | is exactly right, those programs are highly reinforcing

00:57:35.200 | for abstinence behaviors,

00:57:37.080 | everything from the social connection,

00:57:38.600 | which we're gonna get to social connection, as you know,

00:57:42.060 | to the way that people start to conceptualize

00:57:44.980 | their addict self versus other self.

00:57:46.900 | It actually involves a splitting of the self

00:57:48.880 | in interesting ways.

00:57:50.200 | As long as we're talking about donuts, cigarettes,

00:57:54.880 | alcohol, cocaine, I'm curious before we move

00:57:58.640 | to a bit more on neuroplasticity,

00:58:01.260 | is there anything that people ought to know

00:58:05.560 | about how different substances and behaviors

00:58:09.060 | that are addicting might impact

00:58:10.560 | the dopamine reward circuitry differently?

00:58:13.480 | So for instance, we talked about cocaine

00:58:15.420 | as having this very rapid onset,

00:58:16.900 | big increase in dopamine, then a crash, as we know,

00:58:19.720 | a certain pattern of kinetics, as you describe it,

00:58:23.860 | the opioid crisis is incredibly serious problem right now,

00:58:28.860 | as is methamphetamine, but it sounds like methamphetamine

00:58:32.300 | functions a bit like cocaine and in terms of its kinetics.

00:58:35.860 | So an opioid is a very different chemical than cocaine,

00:58:40.860 | but it sounds like it impacts the dopamine system.

00:58:45.580 | Is the dopaminergic activity caused by opioids

00:58:51.540 | responsible for the addictive properties of opioids?

00:58:53.860 | Or do people also like the feeling of being under opioids?

00:58:57.540 | I personally hate it coming out of surgery,

00:58:59.260 | like they gave me Vicodin once and I hated it.

00:59:03.100 | I'd rather have the pain, post-operative pain,

00:59:06.440 | than take something like Vicodin or a Valium or fentanyl

00:59:11.440 | or anything like that to me is just completely aversive.

00:59:14.820 | But I realized that there are many millions of people

00:59:16.920 | that feel quite differently.

00:59:18.460 | - It's a great question.

00:59:19.540 | So I think all the studies, both in human beings

00:59:23.720 | and preclinical animal models, yes, would suggest

00:59:28.720 | that the addictive liability of opioids

00:59:35.020 | and psychostimulants, which are cocaine and methamphetamine,

00:59:39.160 | have the common final action of causing massive release

00:59:43.820 | of dopamine in this target of the dopamine neurons,

00:59:48.540 | the nucleus accumbens.

00:59:50.580 | They do it, if we wanna get a little scientifically

00:59:54.100 | technical here, via very different mechanisms.

00:59:59.000 | So cocaine and methamphetamine,

01:00:02.300 | the drugs known as psychostimulants,

01:00:05.380 | actually bind to a protein in the brain

01:00:09.320 | or a molecule in the brain that is responsible

01:00:12.440 | for sucking up, it's a vacuum cleaner,

01:00:17.020 | sucking up the dopamine after it's been released.

01:00:20.260 | And cocaine prevents that dopamine from being vacuumed up

01:00:24.500 | so the cocaine hangs around longer.

01:00:27.060 | Meth not only prevents the dopamine from being vacuumed up,

01:00:31.860 | it actually causes the reverse.

01:00:35.020 | It actually causes the direct release of dopamine

01:00:38.400 | from what we call nerve terminals,

01:00:41.460 | from the site where dopamine's released.

01:00:44.060 | Opioids work very differently.

01:00:46.100 | They actually primarily, not solely,

01:00:49.140 | work where the dopamine neurons live.

01:00:53.300 | And it's a little complicated if it's not that critical,

01:00:57.020 | but they indirectly increase the activity

01:01:02.020 | within the dopamine neurons themselves,

01:01:05.000 | causing a big massive,

01:01:07.260 | bigger than normal release of dopamine.

01:01:09.840 | So that's one commonality.

01:01:13.280 | But anybody who has used these drugs or read about

01:01:16.120 | these drugs, the subjective experience of the drugs

01:01:19.720 | are dramatically different.

01:01:21.520 | And that's because of the actions they're having,

01:01:24.360 | not only in the reward circuitry, but throughout the brain.

01:01:27.960 | So, and it's interesting you talked about Vicodin.

01:01:30.560 | I've taken Vicodin because I've had several knee surgeries

01:01:33.800 | and things, like you, I didn't like it.

01:01:36.760 | I've gotten other opioids for pain relief

01:01:40.920 | that were great.

01:01:44.280 | I mean, they took away a lot of pain

01:01:46.720 | after my ligament repair.

01:01:49.340 | And that's a different question,

01:01:52.720 | that even when you're talking about opioids,

01:01:55.360 | all drugs are not, they're not identical.

01:01:58.720 | Fentanyl has a much larger addictive liability

01:02:03.720 | because of its molecular properties

01:02:06.520 | and how it's interacting with the opioid system

01:02:10.720 | in our brains and the receptors,

01:02:13.120 | the actual proteins in the brain that it interacts with.

01:02:17.460 | But the subjective experience of opioids,

01:02:20.580 | I mean, it's interesting.

01:02:22.100 | Some people love it.

01:02:24.200 | That's, you know, if we go back in history, as you know,

01:02:27.380 | there were the opium dens throughout

01:02:30.680 | Asia.

01:02:33.880 | There were wars about opioids,

01:02:37.040 | the famous opioid wars between China

01:02:39.480 | and the United Kingdom.

01:02:41.300 | I mean, showing you how powerful

01:02:43.680 | the availability of a substance like an opioid can be.

01:02:48.080 | So I'm going off on a tangent, I apologize.

01:02:51.040 | But commonality is dopamine release in the accumbens.

01:02:54.660 | But it's a, if you remember what a Venn diagram is,

01:02:58.680 | all these drugs have some common actions,

01:03:01.220 | usually on directly or indirectly

01:03:03.960 | causing the massive release of dopamine in the accumbens.

01:03:06.680 | But then they have their own individual actions

01:03:10.000 | because obviously when you take cocaine or methamphetamine,

01:03:13.320 | it's a stimulator, you know,

01:03:15.560 | people are grinding their teeth, they're hyped up.

01:03:18.480 | For most people, opioids are the exact opposite.

01:03:22.120 | I mean, in opium dens from the movies I watched

01:03:26.480 | and watching Narcos and all those TV shows,

01:03:29.560 | you're often, you're lying down,

01:03:32.440 | you're kind of in almost a dreamlike state.

01:03:35.440 | So very different subjective experiences.

01:03:38.560 | - I'd like to just take a brief break

01:03:40.140 | and thank one of our sponsors, which is Element.

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01:03:44.440 | that has everything you need and nothing you don't.

01:03:46.660 | That means plenty of salt, sodium, magnesium, and potassium,

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01:03:53.100 | Now, salt, magnesium, and potassium are critical

01:03:55.960 | to the function of all the cells in your body,

01:03:57.800 | in particular to the function of your nerve cells,

01:04:00.440 | also called neurons.

01:04:01.640 | And we now know that even slight reductions

01:04:04.260 | in electrolyte concentrations or dehydration of the body

01:04:07.480 | can lead to deficits in cognitive and physical performance.

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01:04:13.580 | of 1,000 milligrams, that's one gram, of sodium,

01:04:16.680 | 200 milligrams of potassium, and 60 milligrams of magnesium.

01:04:20.200 | I typically drink Element first thing in the morning

01:04:22.260 | when I wake up in order to hydrate my body

01:04:24.400 | and make sure I have enough electrolytes.

01:04:26.160 | And while I do any kind of physical training

01:04:28.440 | and after physical training as well,

01:04:29.940 | especially if I've been sweating a lot,

01:04:31.740 | and certainly I drink Element in my water

01:04:34.560 | when I'm in the sauna and after going in the sauna,

01:04:37.040 | because that causes quite a lot of sweating.

01:04:38.720 | If you'd like to try Element,

01:04:39.800 | you can go to drink element, that's lmnt.com/huberman

01:04:44.280 | to claim a free Element sample pack with your purchase.

01:04:46.600 | Again, that's drink element lmnt.com/huberman.

01:04:50.800 | - Yeah, I had an experience with opioid recently,

01:04:53.640 | not voluntarily over the Christmas holiday.

01:04:57.080 | We went to visit friends and before going to sleep,

01:05:00.580 | I wanted some tea.

01:05:02.080 | And I asked if they had any non-caffeinated tea.

01:05:04.720 | So they gave me this tea.

01:05:06.680 | And that night I had the most bizarre dreams I've ever had.

01:05:10.720 | And I slept for 14 hours.

01:05:13.280 | The next morning I was like, what was that tea?

01:05:16.200 | And I felt off in the morning.

01:05:18.240 | And I went, it was actually a blue lotus flower tea

01:05:21.420 | that is actually illegal in the United States,

01:05:23.580 | but it is sold and it has morphine-like compounds in it.

01:05:27.860 | And I am one of those people that's very susceptible

01:05:31.200 | to even low doses of any kind of novel drug.

01:05:34.340 | - So interesting, have you ever taken cough syrup

01:05:36.900 | with dextromethorphan?

01:05:38.480 | - No, I avoid that stuff.

01:05:40.400 | - Well, I have a tendency when I get a cold,

01:05:44.560 | it gets into my lungs, I cough a lot.

01:05:47.260 | And I think this has been reported.

01:05:49.480 | This is my anecdotal experience.

01:05:51.280 | I'm confirming what you said.

01:05:52.960 | Dextromethorphan is a different sort of opioid.

01:05:56.900 | And actually some people develop a problem with it.

01:06:00.220 | For me, it gives me really bizarre dreams,

01:06:03.420 | really similar to what you were describing.

01:06:05.020 | - Yeah, it was a very unusual experience.

01:06:06.220 | - And that's a whole different conversation

01:06:08.180 | about what makes us dream

01:06:09.800 | and what are the meaning of dreams.

01:06:12.160 | Fascinating, I hope you've covered,

01:06:13.920 | maybe you've covered that.

01:06:14.760 | - We have not yet, but we are intending

01:06:16.460 | to do a whole series on sleep and dreaming.

01:06:18.120 | - Yeah, I think that would be wonderful.

01:06:19.240 | - We will definitely get into it.

01:06:20.080 | - I started out in sleep research,

01:06:21.760 | so I have a fondness for it.

01:06:23.240 | - Well, drug research and sleep research

01:06:24.720 | have a long history of overlap with Alan Hobson's work

01:06:27.680 | on LSD. - I worked with Alan Hobson.

01:06:29.380 | - Okay, by the way, folks, if you're interested

01:06:31.260 | in the relationship between hallucinations and dreaming,

01:06:34.420 | Alan Hobson is a good name to start your rabbit hole.

01:06:37.940 | - In 19, oh my God, I'm dating myself.

01:06:41.700 | 19, oh, 70, I can't remember if it was 76 or 77,

01:06:46.700 | I worked with Alan Hobson as an undergraduate.

01:06:50.140 | - At Harvard Medical School.

01:06:51.040 | - No, as an undergraduate at Harvard.

01:06:52.860 | - He was at Harvard Medical School, yeah.

01:06:54.920 | - Amazing, I love his writing and I learned a lot from it.

01:06:57.360 | He was really ahead of his time.

01:06:58.960 | - Yes, he was.

01:06:59.800 | Anybody who knows me won't believe this,

01:07:03.840 | but back then, I was a very shy, insecure,

01:07:08.080 | 20-year-old kid. - I would not have guessed.

01:07:09.960 | - Oh, and even in medical school,

01:07:12.960 | I literally was not confident of my opinions at all.

01:07:16.680 | I was very shy, thought all of the ideas I had

01:07:21.040 | must be obvious and I should never say them out loud.

01:07:23.780 | - Do you mind if I ask, since you raised this,

01:07:25.960 | I think it's really important.

01:07:27.340 | I mean, you have this incredible career track record.

01:07:31.740 | You're adored by your colleagues, you're highly respected.

01:07:35.580 | You've won just about every award there is

01:07:37.820 | to win in neuroscience.

01:07:38.900 | So was there something in particular

01:07:40.440 | that was in an overnight thing where one day you woke up

01:07:43.420 | and thought, I actually believe in myself.

01:07:46.540 | But if you wouldn't mind sharing that,

01:07:48.040 | 'cause I think before we get back into some of the science,

01:07:50.800 | I, you know, science is a human endeavor

01:07:53.240 | and most people listening are probably not scientists,

01:07:55.780 | but I think everybody deals with these issues of self-doubt

01:07:59.640 | and people appear to have varying levels of confidence,

01:08:02.780 | but what happened?

01:08:05.700 | - So thank you for asking.

01:08:07.140 | No, for me, it was a very gradual process

01:08:11.920 | and I'm not, as an undergraduate, as a medical student,

01:08:15.900 | even as a postdoc, yeah, I was very unsure

01:08:20.640 | of my ideas, of my intellectual abilities,

01:08:24.700 | of whether what I was thinking was really worthwhile.

01:08:29.700 | So it was a very gradual process.

01:08:32.980 | I think the increase in my confidence, I think,

01:08:36.520 | began when I was a postdoc, which is a training period

01:08:41.260 | after you've received a PhD or an MD

01:08:44.700 | where you get additional research training.

01:08:47.480 | And I worked with a guy named Roger Nicollet, UCSF,

01:08:50.140 | and Roger was a very intellectually intense,

01:08:54.040 | very forceful individual.

01:08:57.480 | And I got involved in a field where,

01:09:01.480 | I mean, people, a little bit of a tangent.

01:09:04.400 | Your listeners may think that scientists

01:09:08.420 | are these geeky individuals wearing white coats

01:09:13.260 | with no passion or emotion

01:09:15.880 | and nothing could be further from the truth.

01:09:18.840 | The most successful scientists that I know

01:09:21.960 | are pretty passionate and pretty intense

01:09:25.360 | about what they're working on and driven.

01:09:29.080 | I mean, and this is a gross generalization.

01:09:32.100 | So anyhow, during my postdoc, I started getting involved

01:09:35.760 | in a topic where there were vigorous arguments

01:09:40.220 | about phenomenology we were studying.

01:09:43.940 | So I had to develop a tougher and thicker skin.

01:09:48.360 | I had to be able to argue my side

01:09:51.160 | of the hypotheses we were generating.

01:09:55.080 | So it started developing as a postdoc

01:09:57.320 | and then it slowly evolved as an assistant professor.

01:10:01.240 | And for your listeners who don't know,

01:10:03.860 | I don't like to admit this, but I'm in my late 60s.

01:10:08.800 | I have been running my own lab for almost 40 years.

01:10:12.900 | So I have been, so gradually as an assistant professor,

01:10:17.400 | I realized, hey, I can do this.

01:10:20.040 | I can do science.

01:10:21.280 | I can write papers that my colleagues

01:10:23.280 | seem to be interested in.

01:10:25.360 | And then gradually, over then the next 10, 20, 30 years,

01:10:29.580 | I gained more and more confidence.

01:10:33.720 | So for me, it was this very gradual buildup

01:10:38.720 | of many different experiences

01:10:44.160 | where I developed some confidence that not all of my ideas

01:10:49.160 | are great, of course they're not,

01:10:51.800 | but it's okay to voice my opinion.

01:10:55.760 | It's okay to state my ideas and why I believe this

01:10:59.640 | and why I don't believe that.

01:11:01.600 | So that was my experience.

01:11:03.600 | - Thank you for sharing that because I think

01:11:06.400 | people struggle with that very issue.

01:11:08.940 | And clearly showing up again and again

01:11:12.000 | over a long period of time is helpful.

01:11:13.580 | But as you said, learning to trust one's ideas,

01:11:16.400 | just a brief anecdote when I was coming up in neuroscience,

01:11:21.120 | a few years behind you.

01:11:23.000 | - 20 years behind me.

01:11:24.880 | - Not too many, I mean, but I recall the incredible number

01:11:29.880 | of high profile papers on neuroplasticity

01:11:34.400 | and long-term potentiation, long-term depression.

01:11:36.120 | These are terms related to the modification of synapses

01:11:40.360 | that Rob Malenka and Roger Nicole pioneered

01:11:44.180 | a big segment to that work.

01:11:45.580 | And I remember seeing your names on papers

01:11:47.420 | and I thought Roger worked for you.

01:11:50.020 | Sorry, Roger.

01:11:50.840 | - I'd love to hear that, I'd love to hear that.

01:11:53.500 | - I was under the impression he worked for you

01:11:55.700 | and only later did I learn that you were his postdoc.

01:11:58.620 | - And then we collaborated as equals.

01:12:01.020 | - You became peers very quickly.

01:12:02.340 | - Very quickly.

01:12:03.180 | - Yeah, so you've had a-

01:12:04.220 | - And Roger, you know, I-

01:12:05.620 | - Roger's wonderful.

01:12:06.460 | - I did have the confidence even as a postdoc

01:12:09.980 | and he actually, even as a grad student,

01:12:11.640 | even though I was a little insecure about my ideas,

01:12:14.780 | I wanted to be treated as an equal.

01:12:16.800 | That's the one thing I did have.

01:12:18.180 | I never felt that I was working for somebody else.

01:12:21.560 | I always felt that I was working for myself

01:12:24.460 | and that we were colleagues,

01:12:26.640 | even though my mentors had more experience

01:12:29.880 | and I could learn from them, but-

01:12:31.600 | - I like that you're working for yourself

01:12:33.260 | even though you have mentors.

01:12:34.860 | I think there's some real gems in what you just described.

01:12:38.240 | So thank you for taking the time to do that.

01:12:40.360 | - Sure.

01:12:41.260 | - I'd like to discuss one aspect of reward circuitry

01:12:45.520 | that I don't think most people think about, right?

01:12:48.680 | Fairly straightforward nowadays.

01:12:50.520 | I like to think more people know what dopamine is

01:12:52.800 | and understand it thanks to your work and Ana's work

01:12:56.000 | and some discussions have taken place on our podcasts,

01:12:58.240 | other podcasts, but, you know, all too often we think

01:13:01.600 | dopamine, reward, wanting, liking, drugs.

01:13:04.440 | Okay, all of that is great.

01:13:07.020 | But what about the truly adaptive stuff, right?

01:13:10.080 | Because it's easy to fall into a discussion around dopamine

01:13:13.980 | of, you know, the things that are bad for us.

01:13:16.060 | But what I'm thinking about here is social interaction.

01:13:19.400 | Clearly we are a social species and a lot of your work

01:13:24.600 | in the last decade and a half or so

01:13:27.960 | has focused on the relationship

01:13:30.680 | between the reward circuitry,

01:13:32.160 | which you beautifully described for us,

01:13:34.240 | and social interaction and connection.

01:13:37.880 | And where I'm going with this is ultimately

01:13:40.140 | this has huge implications for autism

01:13:43.780 | and autism spectrum disorders.

01:13:45.940 | I don't know if nowadays, is it okay?

01:13:47.740 | You're not supposed to call autism a disease.

01:13:49.360 | Is that right?

01:13:50.200 | You hear about neuro-typical and neuro-atypical,

01:13:52.720 | but I have friends who have children

01:13:55.660 | who are severely autistic.

01:13:57.540 | And I don't know many parents who would elect

01:14:00.580 | to have a severely autistic kid.

01:14:03.100 | And so those people often will talk about it as autism

01:14:07.360 | or a child having autism.

01:14:08.940 | So first of all, before we get into the social piece,

01:14:11.640 | maybe because I just tabled it,

01:14:13.300 | how are we supposed to talk about autism nowadays?

01:14:17.140 | - I am very interested in the pathophysiology

01:14:23.020 | of what the medical profession

01:14:26.160 | terms autism spectrum disorder.

01:14:28.900 | As you pointed out, the individuals living

01:14:33.580 | with an autism spectrum disorder are quite heterogeneous.

01:14:38.340 | And it can range from individuals

01:14:42.200 | with severe intellectual impairments

01:14:45.960 | and quite severe impairments in social interactions,

01:14:50.960 | impairments in sensory processing,

01:14:54.080 | impairments in lots of different aspects of our behaviors

01:14:58.600 | that are important.

01:14:59.860 | And I think nobody would say,

01:15:02.300 | would argue those individuals on the severe spectrum

01:15:05.240 | do not have some sort of, in quotes, disorder.

01:15:09.780 | The issue we have to be sensitive to

01:15:13.480 | is it's a heterogeneous disorder like many brain issues

01:15:18.480 | that psychiatrists deal with, like depression.

01:15:22.000 | We all like obsessive compulsive disorder,

01:15:25.360 | like various anxiety disorders.

01:15:26.800 | It's always on a continuum and a spectrum.

01:15:30.340 | So for autism spectrum disorder,

01:15:34.060 | there are individuals who are high functioning,

01:15:37.260 | who one could argue have a different style

01:15:42.260 | of interacting socially,

01:15:44.020 | may have a different way of processing sensory information,

01:15:47.820 | but who would prefer not to be viewed as having an illness,

01:15:54.140 | but rather would be viewed as having a different style

01:15:58.380 | of living and interaction.

01:16:00.080 | And I think we need to respect that.

01:16:02.180 | So the challenge is, again,

01:16:05.520 | not oversimplifying a complex heterogeneous disorder

01:16:10.520 | and both being respectful of the people

01:16:17.440 | who don't wanna be defined as having

01:16:19.460 | a neuropsychiatric or brain disorder,

01:16:22.240 | while equally being respectful of people like your friends

01:16:25.800 | with severely impaired children who deserve help,

01:16:30.640 | who deserve research.

01:16:32.400 | And it's a tough one because my understanding from,

01:16:35.760 | to be honest, just reading articles in the lay press

01:16:39.000 | and going to websites from organizations

01:16:42.600 | that philanthropically support research related to autism,

01:16:46.940 | within that community of individuals

01:16:50.240 | who are not researchers,

01:16:52.400 | but who have family members or are themselves

01:16:56.800 | dealing with some degree of autism spectrum disorder,

01:17:01.280 | there's disagreements about what terminology to use,

01:17:06.160 | how to deal with them.

01:17:07.200 | And it's complicated.

01:17:08.620 | I think we just have to respect everybody.

01:17:10.560 | And if you're interacting with individuals,

01:17:15.240 | I think it's appropriate.

01:17:16.320 | What do you prefer?

01:17:18.360 | - I do know as a medical professional,

01:17:22.020 | and especially when you're dealing with children,

01:17:25.000 | there are children who need help.

01:17:28.960 | And we're not doing them a service

01:17:32.020 | by saying they don't have an issue

01:17:34.560 | that we should be helping them with and working on.

01:17:36.720 | So I hope that answers your question.

01:17:38.520 | - Beautifully, I think it beautifully answers it

01:17:40.880 | and encompasses all sides so that we can move forward.

01:17:44.800 | And I think, so as we use the term autism

01:17:47.500 | or children or people with autism,

01:17:49.520 | that's what we're referring to.

01:17:51.720 | - I think people are very sensitive,

01:17:53.220 | especially those individuals who are neuro-atypical,

01:17:57.960 | who previously might be diagnosed

01:18:00.000 | as autism spectrum disorder,

01:18:01.760 | but would prefer to not be labeled

01:18:05.320 | as having a brain illness, that's fine.

01:18:08.980 | It's kind of, once you are an adult,

01:18:11.860 | you can make that decision for yourself.

01:18:14.340 | - We certainly have colleagues at Stanford and elsewhere

01:18:16.640 | who, at least by my non-clinical assessment,

01:18:19.360 | seem to fall somewhere on that spectrum.

01:18:21.360 | - And again, it's a continuum,

01:18:22.640 | just like the experience of depression is a continuum.

01:18:26.280 | - And as with depression,

01:18:28.400 | you wouldn't love a child or an adult any less

01:18:30.360 | because they have depression,

01:18:31.380 | nor would you love a child or adult any less

01:18:34.200 | because of expression of some autism symptoms.

01:18:37.400 | - I know the point.

01:18:38.500 | People don't, you know.

01:18:39.600 | And so we are being trained in the medical profession

01:18:43.920 | to be very, and our society is going this way too,

01:18:48.040 | very careful with the terms we use

01:18:52.560 | and the labeling of individuals.

01:18:54.920 | So I've been taught you can say individuals

01:18:59.160 | living with an autism spectrum disorder,

01:19:02.200 | some people don't like using a term,

01:19:05.300 | oh, that individual is autistic,

01:19:07.580 | because that has some, can have some,

01:19:11.300 | I don't wanna say derogatory meaning,

01:19:13.360 | but some labeling kind of,

01:19:15.200 | but you know, sometimes this gets out of control too,

01:19:17.960 | as we both know.

01:19:18.800 | - Well, for sake of fluid conversation,

01:19:20.480 | we will do our best,

01:19:21.520 | but we will acknowledge from the outset

01:19:23.820 | that we are well-meaning,

01:19:24.880 | but far from perfect in how we'll handle this.

01:19:27.320 | - Well put, well put.

01:19:29.000 | - So in thinking about social interactions

01:19:30.400 | and leaving aside anything related to autism for the moment,

01:19:33.400 | it appears that the circuits in the brain

01:19:36.720 | that mediate the desire to spend time

01:19:38.900 | with others of the same species,

01:19:40.840 | maybe even with other species like a dog,

01:19:43.300 | are fairly hardwired, but modifiable.

01:19:48.160 | We were born with the capacity to build them up

01:19:51.320 | and that social behavior is highly rewarded.

01:19:56.820 | Is it rewarded through the dopamine system?

01:20:00.080 | And what, if any, involvement is there

01:20:03.080 | of the serotonergic system?

01:20:05.040 | And we haven't talked about serotonin yet,

01:20:06.600 | but I'd love to bring up serotonin at this point.

01:20:08.760 | Maybe you could educate us a little bit about serotonin

01:20:11.240 | because, gosh, if dopamine is fascinating,

01:20:14.660 | serotonin is at least as incredible.

01:20:18.420 | - Yeah, great question.

01:20:19.520 | So I think for me, the easiest way for me to answer it

01:20:22.840 | is actually just tell you my research history

01:20:27.320 | and how a lab like mine at Stanford

01:20:30.720 | that at one point was studying

01:20:33.200 | what you and I would call

01:20:35.560 | fairly hardcore molecular mechanisms of neuroplasticity.

01:20:40.560 | How do connections between nerve cells change

01:20:44.880 | and what molecules are changing

01:20:47.160 | and pretty hardcore molecular stuff.

01:20:50.540 | How did I end up studying social behaviors in mice

01:20:54.080 | and what I hope we'll end up talking about,

01:20:56.380 | even developing behavioral models

01:20:58.520 | of what I will define as empathy in mice?

01:21:02.080 | The answer is very simple.

01:21:03.600 | My lab was working on roles

01:21:07.360 | of classic dopamine reward circuitry

01:21:10.200 | and how it changes in models of addiction.

01:21:14.000 | We haven't talked about depression, models of depression,

01:21:16.960 | because just intuitively,

01:21:18.380 | hopefully your listeners can understand

01:21:20.840 | if one component of depression is what we call anhedonia,

01:21:25.800 | the inability to experience reward.

01:21:29.720 | Eating a donut is no longer satisfying.

01:21:32.100 | Having sex is no longer that much fun,

01:21:34.760 | which is a component of depression.

01:21:36.920 | If there's a mechanism in the brain

01:21:39.160 | that tells you something is rewarding,

01:21:41.180 | by definition, that's not functioning normally

01:21:43.780 | in severe depression.

01:21:45.380 | So we were doing models of depression

01:21:47.360 | to figure out how the dopamine reward circuitry

01:21:50.280 | was changing, as were many other labs.

01:21:52.960 | We were studying addiction.

01:21:54.420 | Those were the obvious ones.

01:21:56.180 | And I mean, it might be entertaining to your audience

01:21:59.840 | to learn how academic scientists think.

01:22:02.480 | I was thinking, those are fascinating topics.

01:22:05.160 | They're pretty competitive.

01:22:07.300 | Lots of other labs were working on it.

01:22:09.920 | And I started thinking, what other experiences

01:22:14.600 | might be modifying the reward circuitry?

01:22:17.440 | I actually made some attempts to look at feeding behavior,

01:22:20.560 | but I don't wanna, I mean,

01:22:21.800 | we actually never pursued that for a variety of reasons.

01:22:25.320 | And that's obviously important because of,

01:22:27.880 | there is an obesity epidemic in this country.

01:22:32.160 | And we can talk about how the reward circuitry

01:22:36.280 | and some of the things we've learned

01:22:37.960 | from our studies of addiction may be helpful

01:22:41.560 | to understanding obesity.

01:22:42.960 | But back to social interaction, I started thinking,

01:22:46.480 | well, for most of us, what I call a prosocial,

01:22:51.480 | non-sexual experience is highly reinforcing.

01:22:56.280 | Andrew, you're a pretty social guy.

01:22:58.160 | I'm a pretty social guy.

01:22:59.880 | Most of the time, I'd rather go to a movie,

01:23:03.040 | a sporting event, a dinner with friends.

01:23:06.500 | Actually, for me, the most meaningful component of my life,

01:23:12.000 | other than spending time with my children,

01:23:14.520 | is spending time with my close friends.

01:23:17.100 | And I started thinking, well, why is that?

01:23:19.440 | Why do I have such a good time going to a ball game

01:23:22.940 | with my best friend or going out to dinner

01:23:25.220 | with another couple and interacting?

01:23:28.980 | It's because, well, it's highly reinforcing.

01:23:31.080 | And if it's highly reinforcing,

01:23:32.760 | it must involve the reward circuitry.

01:23:35.380 | And then I started thinking evolutionarily,

01:23:37.700 | it makes a lot of sense because if you are part

01:23:41.000 | of a social species, there's a lot of evolutionarily,

01:23:45.820 | a lot of advantages for your survival to be hanging out

01:23:52.820 | with other members of your species in a non-aggressive way.

01:23:57.040 | It can increase your likelihood

01:23:59.800 | to find a mate and reproduce.

01:24:02.040 | It can protect you from predators.

01:24:05.000 | I mean, that's why any of your listeners

01:24:07.760 | who ever watch wildlife shows or National Geographic shows,

01:24:12.760 | there's a reason all these animals hang out together.

01:24:17.320 | It's for protection from predators.

01:24:19.680 | So there are all these reasons.

01:24:21.400 | So about whenever it was, 13 or 14 years ago,

01:24:26.400 | my lab decided to start looking at how the reward circuitry

01:24:31.180 | may play a role in what I am gonna call

01:24:34.840 | positive prosocial non-aggressive interactions.

01:24:39.840 | Another word we use is just sociability.

01:24:43.520 | And for a variety of reasons back then,

01:24:48.120 | this is at least 13 years ago, maybe 15 years ago,

01:24:53.120 | a postdoc joined my lab named Gul Dolan.

01:24:56.180 | She's now a professor at Johns Hopkins.

01:24:58.560 | And she had an interest in oxytocin.

01:25:02.100 | And as your listeners know,

01:25:05.440 | oxytocin is this evolutionarily conserved neuropeptide

01:25:11.040 | that's very important for parturition,

01:25:15.540 | having a baby born, for milk being produced.

01:25:18.940 | And it's gotten a lot of attention

01:25:20.500 | as a potential love neuropeptide

01:25:23.540 | is something that is released in our brains

01:25:26.660 | during a positive social interaction.

01:25:29.140 | There's a well-known researcher in social behavior

01:25:34.140 | and bonding research called Larry Young.

01:25:37.840 | And he did some very important,

01:25:39.440 | now somewhat classic work studying a species called the vole

01:25:44.300 | in particular the prairie vole.

01:25:46.400 | And prairie voles are a species where they mate for life.

01:25:51.260 | It's called pair bonding.

01:25:53.080 | So one vole will find another vole.

01:25:55.220 | They basically get married, they have kids,

01:25:58.260 | and they hang out together for the rest of their life.

01:26:01.920 | - No divorce, no 50% divorce rate.

01:26:03.780 | - No 50% divorce rate.

01:26:06.480 | And what Larry elegantly showed in part,

01:26:10.080 | in early days in collaboration with a guy named Tom Insull,

01:26:13.520 | who is a famous academic psychiatrist,

01:26:16.400 | they showed that oxytocin action

01:26:20.300 | within the nucleus accumbens, within this reward circuitry

01:26:23.520 | was required and really important

01:26:26.660 | for this monogamous pair bonding.

01:26:29.880 | Having said that, there was just a paper

01:26:32.820 | that called into question that, but that's--

01:26:36.500 | - But there's 30 years of research prior to that.

01:26:39.140 | I'm glad you brought that up

01:26:40.100 | because we'll keep this contemporary

01:26:41.780 | and the reality is that that recent paper

01:26:44.720 | got a lot of attention.

01:26:45.740 | - You know the paper I'm talking about.

01:26:46.580 | - Yeah, that maybe oxytocin isn't playing

01:26:48.060 | as prominent a role in pair bonding as people had thought.

01:26:50.460 | And yet, folks, that could be true.

01:26:54.860 | We have to be scientific about this and be open-minded.

01:26:57.060 | But there's three decades of the work

01:26:59.820 | that speaks to the contrary.

01:27:01.480 | So I think we wanna weigh the evidence.

01:27:04.620 | - Yeah, exactly.

01:27:05.460 | And again, the investigators who presented the work

01:27:08.760 | saying oxytocin may not be as important,

01:27:10.920 | there are limitations to the manipulations they did,

01:27:13.560 | which they would agree with.

01:27:14.780 | So I'm just telling you,

01:27:16.600 | so Guldolin was a postdoc in my lab

01:27:19.680 | and we formulated a project to look at the actions

01:27:22.820 | of oxytocin in the nucleus accumbens in mice.

01:27:27.540 | And the reason we study mice is they're what are known

01:27:32.460 | as a genetically tractable organism.

01:27:35.620 | We have all sorts of really cool

01:27:38.920 | and sophisticated tricks we can do

01:27:42.620 | to probe brain circuitry,

01:27:45.780 | the actions of neuromodulators like dopamine and serotonin

01:27:49.300 | and oxytocin in ways that we can't do in other species.

01:27:54.300 | And I'm gonna get back to dopamine in a second.

01:27:58.940 | And what we found was that oxytocin action

01:28:03.380 | in the nucleus accumbens was indeed important

01:28:07.480 | for promoting sociability,

01:28:10.760 | probably for promoting the reinforcing component

01:28:15.760 | of a social interaction.

01:28:17.980 | And that surprised us.

01:28:20.100 | It was like, wow, it's oxytocin seems to be causing,

01:28:24.800 | enhancing the release of serotonin in the nucleus accumbens.

01:28:29.180 | And that, perhaps we'll get to this,

01:28:31.920 | that led me off on a whole series of experiments

01:28:35.580 | trying to figure out how serotonin works,

01:28:38.040 | studying this drug we may talk about called MDMA,

01:28:41.340 | which is ecstasy or molly,

01:28:43.340 | which actually causes release of serotonin.

01:28:46.100 | So we did that work and that got us working in serotonin.

01:28:49.340 | Simultaneously, there were some other papers reporting

01:28:53.580 | that dopamine release in the accumbens,

01:28:56.180 | that dopamine is released in the accumbens

01:28:58.900 | during a social interaction,

01:29:00.560 | a positive non-aggressive social interaction.

01:29:03.220 | Truth be told, it may also be released

01:29:05.780 | during an aggressive interaction.

01:29:08.820 | - Some people like to fight.

01:29:10.020 | - Some people like to fight.

01:29:11.500 | And the difference here is the dopamine release

01:29:16.280 | and its role in social interactions,

01:29:18.160 | it's not specific only for social interaction,

01:29:20.740 | as we have talked about.

01:29:22.180 | But nevertheless, that led my lab and other labs

01:29:26.320 | to do a series of papers.

01:29:29.140 | I'm talking about the field now showing that,

01:29:32.700 | and I'm giving you a lot of information here.

01:29:34.780 | So how might dopamine release happen

01:29:38.500 | during a non-aggressive social interaction?

01:29:42.020 | It turns out that oxytocin is not only released

01:29:46.080 | in the nucleus accumbens,

01:29:47.740 | it's released in the home of the dopamine neurons in the VTA.

01:29:52.060 | So my lab and another lab from Northwestern

01:29:55.140 | showed that oxytocin can actually modulate

01:29:59.260 | dopamine neuron activity in the ventral tegmental area.

01:30:03.100 | So I hope I'm making sense here.

01:30:04.620 | I don't wanna get too technical.

01:30:06.060 | But it just shows how we discuss these neuromodulators

01:30:11.060 | like dopamine, I just brought in oxytocin.

01:30:14.620 | We're gonna talk about serotonin in a second.

01:30:17.300 | Unfortunately for your listeners,

01:30:19.540 | they don't work in isolation.

01:30:21.420 | They influence each other in ways

01:30:25.700 | that I think it's important for us

01:30:27.500 | to understand and elucidate.

01:30:29.340 | - That is not too much technical detail.

01:30:33.100 | And I think it's wonderfully rich

01:30:34.300 | with areas for us to discuss.

01:30:36.180 | And I'm so very glad that you brought up

01:30:38.900 | that neither dopamine nor serotonin nor oxytocin

01:30:42.100 | work in isolation because all too often,

01:30:44.140 | and admittedly, sometimes even on my podcast,

01:30:47.940 | I'll talk about these things in isolation

01:30:49.520 | as a way to try and simplify them a bit.

01:30:51.180 | But there's just no way that the brain works that way.

01:30:54.960 | For instance, turning on dopamine and turning off serotonin,

01:30:57.420 | it's a weighting of inputs.

01:30:59.660 | And I think that serotonin, perhaps I should frame it

01:31:02.900 | this way, just as often as dopamine is framed

01:31:05.580 | as this reward molecule and pleasure and dopamine hits,

01:31:08.980 | all too often, I think, in the popular press,

01:31:11.780 | serotonin is discussed, and oxytocin too, for that matter,

01:31:16.540 | as this kind of warm, feel good, everything's mellow,

01:31:20.140 | not really associated with a reward and reinforcement.

01:31:24.020 | And of course, it's not that simple.

01:31:26.220 | So when it comes to social interactions,

01:31:28.780 | it sounds like oxytocin and serotonin

01:31:30.980 | are playing a prominent role, also in the accumbens,

01:31:34.680 | and that dopamine is activated too, have that right?

01:31:39.180 | Okay, so I don't want to take us too far down

01:31:42.700 | the rabbit hole of neural circuit function,

01:31:45.180 | but that to me makes at least a brief discussion

01:31:49.020 | about the nucleus accumbens itself.

01:31:51.180 | Interestingly, okay, so I'm thinking nucleus,

01:31:53.020 | I know that means a pile of neurons,

01:31:55.060 | an aggregation of neurons,

01:31:56.220 | it's talking to this ventral striatum.

01:31:58.580 | So we got a bunch of neurons--

01:31:59.420 | - It's a part of the ventral striatum.

01:32:00.620 | It's a subdivision of it.

01:32:02.260 | - Excuse me, I misspoke.

01:32:04.000 | Yeah, it's part of the ventral striatum,

01:32:05.820 | and the neurons there can be active

01:32:09.500 | and communicate with other brain areas,

01:32:10.960 | but we're talking about a lot of nuance of function.

01:32:13.620 | - Oh man, I'm smiling.

01:32:15.940 | I don't know if your audiences can see me smiling,

01:32:17.900 | because it's so, I sometimes go to bed feeling,

01:32:21.060 | it's so complicated, oh my God.

01:32:23.100 | - It is, and yet, could we say

01:32:25.100 | that within the nucleus accumbens,

01:32:26.740 | there are neurons that are acting

01:32:28.220 | as accelerators and breaks?

01:32:32.020 | Is there a simple analogy that perhaps,

01:32:34.620 | while not exhaustive, can still be true?

01:32:37.140 | 'Cause that's always the goal on this podcast.

01:32:38.940 | There's no way we can be exhaustive,

01:32:40.280 | but we want to be as accurate as possible.

01:32:42.500 | - So a very influential hypothesis,

01:32:45.380 | which has guided my thinking,

01:32:47.420 | and again, the trick, I mean,

01:32:50.140 | you have done a wonderful job of communicating

01:32:54.220 | complex scientific topics to your podcast audience,

01:32:58.900 | and I congratulate you on that.

01:33:00.860 | And it's a really important role.

01:33:04.220 | But as you know, it's always more complicated

01:33:09.860 | than we want it to be as scientists,

01:33:12.260 | especially when you're dealing with brain activity issues

01:33:16.280 | and how the brain mediates all its amazing functions.

01:33:20.500 | So historically, we have thought about

01:33:24.020 | the nucleus accumbens and other components

01:33:28.680 | of this ventral striatal brain area

01:33:33.140 | as primarily being composed to two different cell types.

01:33:38.140 | And as you pointed out, one being sort of an accelerator,

01:33:42.820 | something that promotes certain behaviors,

01:33:46.060 | and then the other cell type somewhat being a break,

01:33:51.060 | saying don't do that behavior,

01:33:53.140 | don't perform that motor action.

01:33:55.100 | And it is true that there are these different cell types.

01:34:01.060 | It is true that they are modulated by these modulators,

01:34:06.140 | like dopamine and serotonin, in different ways.

01:34:10.900 | And that simplistic hypothesis,

01:34:15.460 | or heuristic we call it, has been very useful

01:34:18.860 | in making models about how the accumbens

01:34:22.040 | does all its wonderful things.

01:34:23.980 | What I'm leading up to is,

01:34:25.560 | unfortunately, it's a little more complicated.

01:34:28.140 | But yes, there are two different cell types.

01:34:31.440 | And at least for your audience,

01:34:33.080 | we can think about dopamine driving the activity of one,

01:34:38.080 | promoting certain behaviors,

01:34:40.700 | and inhibiting the activity of the other cell type,

01:34:43.620 | and being a sort of break on certain behaviors.

01:34:47.700 | As long as you and I as scientists appreciate,

01:34:50.820 | it's not quite that simple.

01:34:52.380 | It's a little more complicated.

01:34:54.020 | - So using that as a framework

01:34:55.940 | to think about social behavior, as you said,

01:34:59.260 | pro-social, non-aggressive, non-sexual interactions

01:35:04.260 | involve the choice of a lot of behaviors,

01:35:08.100 | but also the suppression of a lot of behaviors.

01:35:10.700 | And so maybe you're starting to sense what I'm doing here.

01:35:14.180 | I think for people to understand how a single structure

01:35:18.340 | like the accumbens could mediate social interaction

01:35:20.440 | and reward it, what it sounds like it's doing

01:35:22.960 | is rewarding a certain category

01:35:25.940 | and catalog of behavioral options

01:35:28.700 | and punishing, or at least reducing the probability

01:35:31.800 | of the occurrence of other behavioral actions.

01:35:34.100 | 'Cause when I go to dinner with friends,

01:35:35.580 | if I know them really well, I might hug them.

01:35:38.140 | I might even say something mildly inappropriate.

01:35:41.700 | If I know the context to be safe, right?

01:35:44.220 | But at a dinner interview or discussion with somebody

01:35:48.060 | I barely know, I might watch my words a little bit more,

01:35:51.780 | for instance.

01:35:52.620 | - And I think the accumbens and its associated circuit,

01:35:55.620 | I love the way you just put that, probabilities.

01:35:58.540 | It's my probability of having this behavior

01:36:01.460 | in a certain context is increase the probabilities

01:36:05.220 | of not doing certain behaviors.

01:36:07.400 | And I think there's little doubt that this brain area

01:36:11.660 | called the nucleus accumbens and all of its associated

01:36:14.880 | circuitry play a very important role

01:36:18.680 | in what behaviors you choose to do, pursue,

01:36:22.980 | play a very important role in these making the decision

01:36:26.940 | and performing these pro-social, non-aggressive,

01:36:30.680 | non-sexual interactions.

01:36:32.740 | I actually also think it plays a role in empathy

01:36:35.740 | and I'm leading you there.

01:36:37.420 | I wanna have a discussion about that.

01:36:39.500 | - Please.

01:36:40.900 | - Again, as a mechanistically driven neuroscientist,

01:36:45.480 | what is frustrating for me is I know a lot of the connections

01:36:49.740 | it's making and the other brain areas

01:36:51.800 | it's communicating with, but I can't give you

01:36:55.060 | a coherent hypothesis or diagram of how it all happens.

01:37:00.060 | - Yet, yet, you're still going.

01:37:03.860 | - What I can say is even at our current level

01:37:07.780 | of understanding, it is leading to novel hypotheses

01:37:12.780 | that are allowing the, if we bring it back to autism,

01:37:19.160 | that are allowing the development of novel at the moment,

01:37:25.420 | pharmacologic therapeutics that might be helpful

01:37:30.180 | for people who are not having normal pro-social interactions

01:37:35.180 | and would like to have them, would like to be able

01:37:39.260 | to function in that domain in a more adaptive

01:37:44.260 | and productive and meaningful way.

01:37:47.080 | And that's the importance in my view

01:37:49.780 | of the kind of mechanistic work my lab

01:37:51.980 | and many other labs around the country are doing.

01:37:54.360 | Even if we don't have a detailed understanding

01:37:58.320 | of how it's all happening, we can identify drugs

01:38:02.400 | and druggable targets or even behavioral interventions

01:38:06.140 | that might actually help people.

01:38:08.420 | For example, suffering from autism spectrum disorder

01:38:13.420 | of the sort that they actually want and need therapeutic help.

01:38:19.100 | - I think looking at the social connection circuitry

01:38:25.380 | through the lens of autism is going to be very interesting

01:38:27.620 | for us to do.

01:38:28.460 | I do have a question about what is being selected for

01:38:31.980 | in rewarding social interactions?

01:38:34.400 | Because obviously we are living in a time

01:38:37.340 | where we don't have to aggregate in groups necessarily

01:38:40.980 | to protect ourselves physically.

01:38:43.580 | It helps in certain ways and certain circumstances,

01:38:46.980 | but certainly to support ourselves and each other emotionally

01:38:51.980 | having people that we can call on when we're not feeling

01:38:54.180 | so well that we can look to for resources

01:38:57.700 | and that they can look to us.

01:38:59.380 | But when we go out to dinner with friends

01:39:00.980 | or we go to a ball game with friends

01:39:02.220 | or we interact with friends, I'm very familiar

01:39:03.980 | with the feeling of like, well, that felt really good.

01:39:05.860 | It just felt good.

01:39:06.700 | It gives me energy.

01:39:07.800 | It actually gives me energy to go back and do other things

01:39:10.300 | like spend four days alone with a bunch of papers

01:39:13.580 | and lectures preparing for a podcast,

01:39:15.180 | which I also really enjoy.

01:39:16.720 | But when I do that, when I go out to dinner with friends

01:39:20.700 | or see friends, I'm not thinking about buffering myself

01:39:23.180 | against loneliness when I do it.

01:39:24.820 | I just like the interaction.

01:39:26.980 | So what sorts of evolutionary hypotheses

01:39:31.980 | can we come up with as to why the human brain

01:39:36.540 | is so tuned for these social interactions?

01:39:39.540 | Why it's rewarded by not just one dopamine, but also--

01:39:43.300 | - Serotonin. - Serotonin and oxytocin.

01:39:45.500 | Three prominent neuromodulatory chemicals in the brain

01:39:50.200 | are devoted at one site in the brain and others

01:39:53.500 | that it's connected to, of course,

01:39:54.640 | but to making sure that we do this as often as possible

01:39:59.060 | without giving up the rest of our lives.

01:40:01.180 | - Well, I mean, again, I think the answer

01:40:03.300 | I'm gonna be able to give, I hope it's not trite

01:40:06.080 | and it may be a little bit obvious, is,

01:40:09.080 | and in some ways, it's analogous

01:40:12.580 | to why drugs of abuse and addiction

01:40:18.940 | are also a problem is that the circuitry

01:40:22.880 | that is telling us a prosocial positive interaction

01:40:27.720 | is so highly reinforcing evolved over millions of years

01:40:32.520 | or hundreds of thousands of years, whatever that is.

01:40:36.060 | And the only hypothesis I can come up with,

01:40:38.680 | and Andrew, you may be able to come up with better ones,

01:40:41.260 | is what I alluded to earlier is that it was very adaptive

01:40:46.020 | when we were more primitive organisms,

01:40:47.980 | nevermind non-human primates,

01:40:49.740 | but when we were whatever we were to be a social species

01:40:54.740 | for basically primarily two reasons.

01:41:00.100 | For reproductive purposes, it increased your likelihood

01:41:05.100 | of reproducing if you were hanging out

01:41:08.260 | with other members of your species in a non-aggressive way

01:41:12.780 | and for protection against predators.

01:41:16.100 | And there may be other reasons.

01:41:18.300 | - Probably child-rearing, too.

01:41:19.500 | - Oh yeah, thank you.

01:41:20.340 | - In your absence, you want trusted friends

01:41:22.760 | that can watch your offspring.

01:41:24.020 | - Thank you, very good point.

01:41:26.420 | So the circuits, the modulators we use,

01:41:29.460 | that evolved over millennia, and as you pointed out,

01:41:32.800 | eventually, I mean, depending on the society

01:41:38.960 | in which you live, you didn't need those social interactions

01:41:43.820 | for protection against predators, although, you know,

01:41:48.340 | if we look at our world now,

01:41:49.980 | one can make arguments both ways.

01:41:52.060 | If you're in a war zone, is it better to be off by yourself?

01:41:54.900 | Is it better to be with a group of people?

01:41:57.780 | But so the mechanisms evolved for one purpose,

01:42:02.940 | and they don't just disappear,

01:42:05.120 | because there's no disadvantage to having this mechanism

01:42:09.620 | that tells us a social interaction is reinforcing.

01:42:12.660 | And I would still argue there's benefit

01:42:14.500 | for reproductive purposes.

01:42:17.060 | You can't have kids if you're by yourself all the time.

01:42:20.700 | - Well, and this is actually--

01:42:21.540 | - I think it's impossible, at least currently,

01:42:23.660 | and you can't find a partner with whom to have kids

01:42:27.300 | if you're socially isolated, or it makes it much harder.

01:42:30.480 | So I hope I'm answering your question.

01:42:32.020 | I think, and then as you pointed out,

01:42:39.380 | for many of us, there's a lot of positive aspects

01:42:43.340 | to having friendships and hanging out with your friends.

01:42:46.420 | Emotional support, emotional buffering.

01:42:49.540 | - And feeling connected.

01:42:50.620 | There's something about this notion of feeling connected,

01:42:54.080 | and later we'll talk about psychedelics,

01:42:55.620 | but this notion of feeling connected has a lot to do

01:42:59.580 | with buffering loneliness when we are alone.

01:43:02.700 | The memories and the energy, for lack of a better word,

01:43:06.620 | that we feel in recalling social experiences

01:43:10.220 | and anticipating social experiences is really powerful.

01:43:13.620 | You mentioned that people can't have children

01:43:18.040 | if they spend all their time alone.

01:43:19.220 | It's actually, I realize you're not on social media

01:43:21.500 | and more power to you,

01:43:23.300 | but this is actually a prominent discussion on social media.

01:43:25.940 | There's an entire culture of young people,

01:43:29.200 | in particular young men these days,

01:43:30.720 | who, at least from what I understand

01:43:33.220 | in the research literature about this,

01:43:35.600 | are socially isolated, spending all their time online,

01:43:39.660 | maybe not even on social media,

01:43:41.380 | but are spending a lot of time online,

01:43:42.860 | video games hiding in electronic landscapes,

01:43:46.860 | digital landscapes.

01:43:48.060 | And concern about mental health issues there, et cetera.

01:43:53.520 | Concern about porn overuse and addiction there, et cetera.

01:43:57.140 | But social media itself is an incredible phenomenon

01:44:01.420 | to consider in light of everything we're talking about.

01:44:05.320 | I can't say, even though I am on all social media platforms

01:44:09.860 | and I'm quite active there,

01:44:11.960 | I can't say that I've ever been on social media

01:44:15.380 | and experienced the kind of delight and thrill

01:44:18.780 | and persistent energy increase

01:44:22.420 | that I experienced with in-person interaction.

01:44:24.420 | And yet social media, I have to assume,

01:44:27.040 | is capitalizing on some of these same reward mechanisms

01:44:30.420 | in presumably the nucleus accumbens.

01:44:32.900 | So are there any data,

01:44:34.660 | I realize this is a hard experiment to do in mice,

01:44:36.680 | maybe impossible.

01:44:37.880 | Are there any data that you're aware of

01:44:39.580 | that shows that social media has a high addictive liability

01:44:44.580 | or do we even need an experiment?

01:44:46.580 | - I'm not sure we need an experiment.

01:44:49.560 | I think it clearly does.

01:44:52.360 | I agree with the point you're making,

01:44:54.040 | although your podcast audience probably

01:44:57.360 | doesn't know who I am.

01:44:58.680 | I am in my late sixties.

01:45:00.660 | I grew up--

01:45:01.500 | - Well, they know who you are now.

01:45:02.400 | - I grew up before computers, before cell phones.

01:45:07.400 | So I still am a believer, perhaps in an old fashioned way,

01:45:13.320 | that physical interpersonal reactions are really important.

01:45:18.660 | Obviously there are advantages to being able to interact

01:45:23.660 | over social media.

01:45:25.700 | And I mean, for all sorts of reasons,

01:45:28.760 | there's a lot of positive and good from that.

01:45:31.420 | But back to your question, can we get addicted?

01:45:33.740 | I can't speak to social media.

01:45:36.140 | I can speak, and Anna Lemke, I think is much more able

01:45:41.140 | to eloquently describe the issues around here.

01:45:44.140 | I can just talk from my own experience

01:45:46.540 | that my cell phone is,

01:45:50.020 | this isn't social media, but checking my email messages,

01:45:54.860 | checking my text messages,

01:45:59.480 | for me has a compulsive addictive quality to it.

01:46:03.020 | - It's like a lever press.

01:46:03.900 | - It's like a lever press for a mouse.

01:46:06.240 | And part of that is my own personality.

01:46:10.460 | Part of that is the immediate feedback.

01:46:14.860 | So you get from a social media post,

01:46:18.980 | from seeing your name mentioned,

01:46:20.600 | getting a message from one of your friends.

01:46:23.260 | Sure, I like getting messages from my friends.

01:46:26.900 | It means they're thinking about me.

01:46:28.600 | It means I'm part of their world.

01:46:31.860 | I have no doubt it's activating my reward circuitry,

01:46:36.100 | not nearly to the degree that a hit of cocaine

01:46:40.180 | or an opioid would do.

01:46:42.240 | So I don't know what else to say about it.

01:46:48.540 | I think as a society, we have to be aware of these issues,

01:46:56.580 | and it's really complicated how we manage,

01:46:59.760 | especially once you're an adult,

01:47:01.780 | you make your own decisions for better or worse,

01:47:04.780 | but it's a huge issue obviously for anybody

01:47:08.260 | who has children or is planning to have children.

01:47:11.320 | - And it halts on social media.

01:47:13.180 | I see lots of accounts of people that are 18 and older

01:47:16.940 | who they spent a lot of time on there.

01:47:19.220 | And I'm not necessarily saying that's a bad thing.

01:47:21.420 | A lot of people have entire careers

01:47:22.660 | that exist on social media.

01:47:23.820 | It just seems to me that Instagram, Facebook,

01:47:27.820 | LinkedIn, Twitter have capitalized

01:47:30.260 | on this hardwired circuitry.

01:47:33.740 | The release of, I mean, to make it really reductionist,

01:47:35.940 | the release of serotonin, dopamine, and oxytocin

01:47:38.700 | by virtue of someone saying something to us,

01:47:41.380 | maybe not even a positive thing.

01:47:43.340 | Maybe it's a negative thing.

01:47:45.740 | As you said, they're thinking of us.

01:47:47.180 | There's something about being recognized by others.

01:47:49.940 | And maybe this is a good segue,

01:47:51.100 | we're heading towards empathy here,

01:47:52.820 | a discussion about empathy.

01:47:53.900 | - I think that's very well put.

01:47:57.160 | It is capitalizing on these more primitive

01:48:01.120 | neurobiological mechanisms that evolved

01:48:03.900 | for purposes of reproduction and survival.

01:48:07.460 | I think that certainly has to be the case.

01:48:11.060 | And I think it's important,

01:48:13.860 | I mean, thank you for bringing that up,

01:48:15.120 | for us as a society to be at least aware of this.

01:48:20.120 | And it doesn't mean, it's like many things.

01:48:22.340 | It's not all good, it's not all bad.

01:48:24.780 | It has, there are positive uses of social media, I can see.

01:48:28.840 | But mostly we read about the dangers of it.

01:48:33.420 | We read about these kids who are socially isolated,

01:48:37.020 | who make bad decisions based on what they're seeing

01:48:39.820 | with social media.

01:48:41.340 | But anyhow, back to the neuroscience,

01:48:43.860 | you're absolutely correct.

01:48:45.980 | It's capitalizing on these mechanisms

01:48:49.800 | that evolved for physical interpersonal interactions,

01:48:54.800 | because our evolution didn't anticipate it.

01:48:58.540 | - Right, just as pornography is capitalizing

01:49:01.020 | on the sexual arousal reward circuit,

01:49:03.180 | associated reward circuit.

01:49:04.020 | - No question about it, just as the gambling industry does.

01:49:07.980 | I mean, as you know, the Vegas casinos

01:49:11.340 | have full-time people developing algorithms

01:49:15.340 | for how frequently should a slot machine pay off?

01:49:19.920 | What's the perfect amount of payoff

01:49:22.320 | to keep certain individuals coming back?

01:49:25.800 | - So pernicious, someone, you could tell

01:49:28.800 | I've been spending a lot of time around addicts

01:49:30.880 | and former addicts.

01:49:31.720 | I've been researching some things for the podcast.

01:49:34.960 | And a gambling addict told me something interesting.

01:49:38.680 | They said, the real stinger with being a gambling addict

01:49:42.320 | is that the next time really could change everything.

01:49:45.600 | Whereas no alcoholic says that,

01:49:47.180 | that the next drink could change everything for the better.

01:49:49.520 | Or the cocaine addict doesn't think,

01:49:51.980 | oh, the next line of cocaine

01:49:53.820 | could make all of life better now and forever.

01:49:56.480 | Whereas the gambling addict actually holds in mind

01:49:59.180 | the infinitesimally small and yet real potential

01:50:04.000 | that the next time really could wipe out their debt

01:50:06.700 | and perhaps wipe out their,

01:50:08.520 | and yet we know they would lose that too, right?

01:50:10.640 | Whatever winnings they have.

01:50:11.480 | And casinos are fully aware of this.

01:50:14.360 | I have been told by friends who know,

01:50:16.680 | they employ full-time quantitative,

01:50:21.680 | for lack of a better term,

01:50:25.020 | well, I was gonna say computer geek.

01:50:27.360 | I don't mean to that be an innate derogator.

01:50:30.040 | - And probably neuroscientists too.

01:50:32.120 | - I would be amazed if they don't have neuroscientists

01:50:34.720 | who have expertise in what's called neuroeconomics

01:50:37.960 | or behavioral economics.

01:50:39.840 | I'm 95% sure that has to be the case.

01:50:44.840 | - I occasionally sit down to the roulette table

01:50:47.360 | 'cause I just, it's so passive and easy.

01:50:49.180 | And not long ago, actually,

01:50:51.160 | I had the experience of winning a fairly,

01:50:54.000 | not a large sum, but a meaningful sum of money.

01:50:56.960 | And I'll tell you, my sole mission at that point

01:51:00.000 | was to get up and go back to my room

01:51:02.480 | and not stop at another table.

01:51:04.500 | And I confess, I pulled one brief stop at another table,

01:51:07.540 | played it one hand and then lost it.

01:51:09.360 | And then just got back to my room as quickly as possible

01:51:11.400 | and then left Las Vegas as quickly as possible.

01:51:14.260 | - Gambling is fascinating.

01:51:15.100 | - But they'll probably get me the next time.

01:51:16.840 | - Gambling is, again, it all gets back

01:51:19.720 | to this reward circuitry.

01:51:21.480 | And the intermittent rewards are very, very powerful.

01:51:26.480 | - Well, and you mentioned earlier

01:51:28.400 | that the reward system is powerfully tuned to remember

01:51:30.920 | what were the behaviors that led up

01:51:32.360 | to the rewarding experience.

01:51:34.040 | And nobody ever won at the roulette or craps table

01:51:38.080 | or poker table by getting up and leaving, right?

01:51:41.920 | And so I guess my brain was just thinking,

01:51:43.720 | well, how did I win?

01:51:44.560 | I won by sitting down and putting chips on the table,

01:51:47.560 | not by going back to my room.

01:51:49.020 | - Exactly, exactly.

01:51:50.280 | - And yet I have a fair number of degrees

01:51:53.340 | and I like to think my prefrontal cortex is working

01:51:55.440 | and yet it was still challenging in that moment.

01:51:58.160 | - Gambling is really, I mean, yeah,

01:52:00.720 | another human activity that's quite complicated.

01:52:06.600 | It can be enjoyable or it can be incredibly damaging.

01:52:09.880 | - And now people are gonna think I was that gambling addict

01:52:12.240 | that I was referring to, but I swear I'm not.

01:52:13.880 | Fortunately, I feel very blessed that that's not my addiction.

01:52:16.920 | I'd like to talk about empathy and use that as a framework

01:52:21.920 | for eventually returning to our discussion of autism.

01:52:24.120 | But you have this perhaps longstanding interest,

01:52:27.580 | but recent research interest in empathy.

01:52:31.560 | Tell me about this work.

01:52:32.400 | I'm not familiar with it yet.

01:52:33.320 | - Okay, so I'm gonna, I hope it's okay,

01:52:37.840 | drag in some work I've done on this drug called MDMA

01:52:41.320 | because it is related.

01:52:42.720 | So we were working on in my lab, social behaviors,

01:52:48.520 | positive pro-social behaviors that stimulated me

01:52:53.520 | to start thinking about what are components

01:52:56.440 | of a positive pro-social non-aggressive interaction.

01:53:01.320 | A common key component of that is having some empathy

01:53:06.320 | and compassion for the individuals you're hanging out with.

01:53:13.000 | And it is a topic I've been interested in

01:53:15.260 | for many, many decades.

01:53:17.300 | I was once a psychiatrist and to get on my,

01:53:22.080 | whatever the word is, hobby horse, I look at the world today.

01:53:26.680 | I try to be optimistic.

01:53:29.440 | Again, I am a child of the '60s and '70s.

01:53:32.440 | When I look at the world, and I actually just did a trip

01:53:37.080 | to Israel to give a series of lectures,

01:53:39.320 | and I look at the Israeli-Palestinian conflict,

01:53:42.200 | what always enters my mind,

01:53:43.680 | and I've felt this way for decades,

01:53:45.800 | is what is more important for the survival

01:53:48.920 | of the human species than empathy and compassion,

01:53:52.720 | than actually being able to look at another human being,

01:53:56.760 | even if they look different than you,

01:53:58.880 | even if they have a different belief system than you?

01:54:02.520 | What is more important than actually understanding

01:54:05.720 | that 98% of your life is very similar?

01:54:10.720 | You have some differences in how you look

01:54:15.380 | and the beliefs you have, but there's so much in common.

01:54:18.380 | So what's more important than understanding

01:54:20.600 | that when another person is suffering,

01:54:23.480 | they're suffering, it's the same as your suffering,

01:54:27.700 | and having compassion for somebody.

01:54:29.440 | So I started thinking, what is more important?

01:54:31.720 | And I'm not a politician.

01:54:33.400 | As you know, Andrew, I have no social media presence.

01:54:36.760 | I figured the only way I might be able to contribute

01:54:39.840 | to efforts that might help the human species

01:54:46.120 | enhance empathy and compassion

01:54:48.380 | is by studying the neurobiological underpinnings of it.

01:54:53.120 | And I didn't realize I might be able to do that

01:54:55.880 | until I started studying sociability

01:54:59.640 | or prosocial behaviors in mice.

01:55:02.500 | And then I was able to have a young woman scientist,

01:55:07.500 | and I want to give her credit, Monique Smith.

01:55:14.940 | You might want to have Monique on your podcast.

01:55:16.900 | She's a dynamo.

01:55:18.220 | She's now an assistant professor at UCSD,

01:55:22.040 | where you once was.

01:55:23.160 | And Monique introduced me to a series of behavioral assays

01:55:28.160 | that I like to use the phrase,

01:55:33.240 | they are measurements,

01:55:34.240 | they are behavioral antecedents of empathy.

01:55:38.080 | Because in the world of psychologists

01:55:41.420 | and people who use the term empathy,

01:55:43.360 | it has a lot of different meanings to different people.

01:55:46.680 | I'm using it basically to mean one member of a species

01:55:52.020 | manifests some behavior that indicates

01:55:55.900 | it is being influenced by the emotional state

01:56:00.500 | or what we call the affective state,

01:56:02.860 | affective with an A,

01:56:04.360 | of another member of that species

01:56:07.360 | in its immediate environment.

01:56:09.080 | For human interactions, I just think of,

01:56:14.000 | we were talking about friendships.

01:56:17.080 | Any of us who watch a close friend suffer, it's hard.

01:56:21.880 | You want to do anything you can to help them.

01:56:24.020 | That's empathy.

01:56:25.240 | A mother with their child, a good mother, hopefully.

01:56:28.680 | When you have a kid who is sick,

01:56:31.320 | there's nothing worse as a parent.

01:56:33.040 | You just want to take that pain and suffering away.

01:56:36.000 | That's how I'm defining empathy.

01:56:37.900 | So it's my belief that like any complex human behavior,

01:56:42.900 | there are evolutionary reasons why that has been adaptive

01:56:48.020 | and important and maintained.

01:56:49.860 | And if it's evolutionarily evolved,

01:56:54.480 | there are ways of studying it

01:56:55.800 | in more primitive organisms like mice.

01:56:59.220 | So I'll tell you some of the behavioral assays we're doing.

01:57:02.640 | One is, and I get a kick out of this,

01:57:06.420 | because it's pretty new for me.

01:57:09.720 | So one assay, and we published a paper

01:57:11.820 | in a journal called Science about this,

01:57:15.480 | which is if you take one mouse and in a ethical way,

01:57:20.420 | you put it in pain, you make its hind paw,

01:57:23.660 | one of its paws, one of its feet hurt a modest amount,

01:57:27.780 | and you take another mouse and you let that,

01:57:29.960 | what's known as the bystander mouse,

01:57:32.100 | just hang out with the mouse that's in pain for one hour,

01:57:36.140 | just one hour, the bystander mouse,

01:57:38.740 | who has experienced no physical injury whatsoever,

01:57:43.060 | will manifest behaviors indicating it is now in pain.

01:57:47.840 | And it lasts maybe four to 20 hours.

01:57:50.620 | But think about that.

01:57:51.900 | A mouse that is normal,

01:57:54.920 | hanging out with another mouse in pain,

01:57:56.940 | starts feeling pain itself.

01:57:59.700 | - And the mice are able to see one another

01:58:04.200 | and hear one another?

01:58:05.360 | - Good point.

01:58:06.200 | So you're getting to how is that communication happening?

01:58:10.260 | And a lot more work needs to be done on it.

01:58:14.780 | Monique and her previous colleagues and others,

01:58:17.440 | one component of it is probably an olfactory cue

01:58:22.540 | or what we call a pheromone.

01:58:24.220 | - So the mouse that's in pain is secreting an ovary?

01:58:26.580 | - Probably, probably,

01:58:27.780 | because you can take bedding from mice in pain

01:58:31.580 | and expose the bystander mice.

01:58:33.740 | So that's one thing.

01:58:34.580 | And I had never heard of these behavioral assays.

01:58:37.420 | We developed our, and this is pretty cool,

01:58:39.420 | and then I'll tell you two others,

01:58:40.580 | and then I'll tell you how it connects to reward circuitry.

01:58:43.420 | We developed a novel assay,

01:58:46.700 | which is the social transfer of pain relief.

01:58:51.100 | Pain relief is called analgesia.

01:58:54.120 | And I thought this was pretty cool.

01:58:56.040 | So you take, and this is in this paper

01:58:59.200 | that was published in Science a year ago,

01:59:01.900 | you take two mice and they're both in pain, modest pain.

01:59:06.580 | I don't want your listeners to get upset.

01:59:08.560 | We are not hurting these mice too badly.

01:59:12.340 | And it is a tricky issue.

01:59:13.620 | Is it okay to put a mouse in pain so you can,

01:59:17.100 | the goal is to develop better treatments

01:59:19.000 | for human beings in pain, obviously.

01:59:22.340 | So you have two mice in modest pain.

01:59:24.760 | You give one mouse morphine, so it's now analgesic.

01:59:29.760 | It is no longer experiencing pain.

01:59:32.720 | You take another mouse that's in pain

01:59:35.420 | and you just let it hang out with the mouse

01:59:39.000 | that is no longer in pain.

01:59:40.940 | And the mouse that is in pain will show behaviors

01:59:44.620 | indicating it is experiencing analgesia.

01:59:48.180 | It is no longer in as much pain.

01:59:50.340 | Now think about that.

01:59:51.440 | And there's actually evidence from human studies

01:59:54.260 | that I can't speak to in any comprehensive way

01:59:59.260 | where, I mean, it's called social buffering of pain.

02:00:02.920 | If you are, I mean, to be honest,

02:00:05.140 | I've been having some neck pain just because I'm an old guy

02:00:08.860 | and I woke up on the wrong side of the bed.

02:00:11.500 | And if I'm by myself, I focus on that pain

02:00:15.940 | and it bothers me more.

02:00:17.260 | If I'm in a socially engaged, I think it's not only that,

02:00:21.940 | I'm not paying as much attention to the pain,

02:00:23.820 | but I think there's actually some relief

02:00:26.740 | from what's known as the social buffering of pain.

02:00:29.700 | - Well, I'm no hippie, but I actually think that

02:00:33.500 | all species, including humans, are secreting molecules,

02:00:37.060 | mainly odorants that are perhaps even acting

02:00:40.860 | directly as analgesics.

02:00:43.140 | And I can make that statement without ordering too much

02:00:46.880 | that people think I'm completely crazy

02:00:49.040 | because we had a Noam Sobol on the podcast

02:00:51.940 | from the Weizmann who shared with us, you know,

02:00:55.260 | not one, not two, but at least a dozen ways

02:00:58.220 | in which humans are making molecules, typically odors,

02:01:03.460 | and communicating those to one another

02:01:05.460 | to powerfully impact their testosterone levels,

02:01:09.060 | their vasopressin levels, their immune molecules, you know?

02:01:12.740 | And of course, Noam works on olfaction,

02:01:15.020 | so he's going to be biased toward that system,

02:01:16.580 | but that's just one slice of the sensory array.

02:01:19.420 | I mean, what about the way that somebody can look at us

02:01:22.700 | in a way that makes us feel good on a normal day?

02:01:25.020 | Well, when we're in pain,

02:01:26.300 | just even the touch to a shoulder can mean a lot.

02:01:28.540 | I remember going to meetings

02:01:29.620 | when I was a early neuroscientist

02:01:31.940 | and I would probably at that point have, you know,

02:01:36.940 | not been the type to just walk up and say hello to you

02:01:39.520 | 'cause I wasn't in your field

02:01:40.580 | and you're this luminary and stuff.

02:01:41.900 | But I remember as I started-

02:01:43.180 | - I'm a good guy, by the way.

02:01:44.220 | - You are, very, very good.

02:01:46.620 | - I always say hi to everybody.

02:01:48.020 | - I know you are.

02:01:48.940 | And that statement was a reflection on me,

02:01:51.300 | not a reflection on you.

02:01:52.540 | But as I advanced through my career,

02:01:53.960 | what I found was, you know, you'd give a talk or something

02:01:56.060 | and someone in your field more senior to you

02:01:58.060 | who you respected would give a nod or something.

02:02:00.740 | Those nods meant a lot.

02:02:02.300 | - Yeah, absolutely.

02:02:03.140 | - I mean, those nods could carry you a long distance.

02:02:05.260 | I mean, obviously we wanna be intrinsically driven

02:02:07.140 | to do the work we do, but the social communication stuff-

02:02:09.820 | - We're social species.

02:02:10.740 | - I think there's a whole landscape of things.

02:02:13.740 | So what you're describing is incredible,

02:02:16.660 | but I think makes a ton of sense.

02:02:18.940 | - Yeah, so we have these social transfer pain

02:02:20.860 | of analogies here.

02:02:22.020 | We're working on, and there's a little bit of evidence

02:02:25.380 | in the literature suggesting this might work.

02:02:28.860 | And then I'll talk about reward circuitry

02:02:31.300 | and maybe MDMA and is it an empathogen or not

02:02:35.220 | and how that might influence therapeutic efforts for autism.

02:02:39.220 | We're working on behavioral models.

02:02:41.300 | We're asking the question, will one mouse behave

02:02:46.300 | to give another mouse a reward?

02:02:49.180 | So it's the mouse that's behaving,

02:02:50.960 | that has to press a bar or nose poke

02:02:53.880 | or even experience a shock.

02:02:55.740 | Will the mouse do that simply to give one

02:02:58.820 | of its buddies a reward?

02:03:00.780 | - Pure altruism.

02:03:01.840 | - And yeah, it's pure, it's what we call a generosity,

02:03:05.060 | a generosity assay.

02:03:07.020 | In early days, it looks like it might be working.

02:03:09.640 | And that's a generosity assay.

02:03:13.740 | We can also ask the question, will a mouse work

02:03:16.540 | so another mouse doesn't get a shock, doesn't get hurt,

02:03:20.220 | which is compassion.

02:03:21.820 | And I think these things are gonna be working.

02:03:24.000 | And whether you wanna call that empathy,

02:03:27.580 | I would call that, those are behaviors,

02:03:29.800 | I like to use the term behavioral antecedents

02:03:32.600 | of how we define empathy in human beings

02:03:35.820 | and the connection to reward circuitry.

02:03:37.660 | And in the little bit of work we have done on this

02:03:42.660 | is we presented evidence that these behaviors,

02:03:47.780 | we call the social transfer of pain,

02:03:50.740 | one mouse experiencing pain just because it's hanging out

02:03:53.500 | with another mouse, the social transfer of analgesia,

02:03:57.460 | a mouse in pain getting some pain relief

02:04:00.260 | from hanging out with another mouse in pain

02:04:03.780 | who has that pain relief.

02:04:05.900 | It seems to involve one component

02:04:08.660 | of the complex brain mechanisms,

02:04:11.140 | seems to involve a part of the brain

02:04:14.760 | called the anterior cingulate cortex,

02:04:17.540 | which human brain imaging studies suggest is activated

02:04:22.540 | during empathic human responses.

02:04:26.220 | And the projections of that area into the nucleus accumbens,

02:04:30.340 | that's the connection.

02:04:31.580 | And we're interested in whether neuromodulators

02:04:37.380 | like dopamine and serotonin may influence these circuitry,

02:04:42.380 | these connections that are involved in these,

02:04:47.500 | in quotes, empathic behaviors, et cetera, et cetera.

02:04:51.880 | And we think drugs can be used as probes

02:04:54.540 | of those kinds of neuromodulatory mechanisms.

02:04:57.020 | I hope this is all making sense.

02:04:58.360 | - Yeah, it makes excellent sense and it's fascinating.

02:05:01.380 | I'm not one to suggest experiments to colleagues

02:05:05.020 | in areas where I don't work, but I'm going to anyway.

02:05:07.700 | - Yeah, please, you're a really smart guy,

02:05:10.780 | so I will value your suggestions.

02:05:13.900 | - You know, I love the motivational backbone

02:05:16.280 | to what you're describing here because I agree,

02:05:18.360 | the world has a lot of issues

02:05:20.060 | and what could be more important

02:05:21.480 | than to increase the amount of empathy and compassion

02:05:24.500 | in the world.

02:05:25.880 | But one thing that we know inhibits empathy and compassion

02:05:29.800 | is one's own challenges and struggles.

02:05:32.740 | And so I'm wondering if there's a way to introduce something

02:05:34.860 | to this behavioral paradigm such that the working

02:05:39.820 | to provide another animal relief from pain,

02:05:42.460 | one animal working to provide relief

02:05:44.500 | of another animal in pain or a animal working

02:05:47.860 | to provide pleasure, reward for another animal.

02:05:51.000 | You know, if it could be scaled

02:05:52.580 | with how inconvenient that work is, right?

02:05:55.420 | Like if I'm very hungry, I mean, we're all taught

02:05:57.440 | to put our own oxygen mask on first in some way too,

02:06:00.720 | so that we don't all die, so to speak.

02:06:03.340 | But you know, I grew up, for instance, with one parent.

02:06:07.060 | My mother was the kind of person who would see,

02:06:09.300 | at that time, there were far fewer homeless people

02:06:11.540 | on the street.

02:06:12.380 | Maybe they were all institutionalized, I don't know.

02:06:15.200 | But if she saw a homeless person on the street

02:06:18.740 | of the town we lived in, she would literally pull over,

02:06:21.780 | give them money, find hotels.

02:06:23.860 | She had homeless people living in hotels

02:06:25.940 | all over the town we lived in.

02:06:27.460 | It was crazy.

02:06:28.460 | I mean, we couldn't get anywhere.

02:06:29.700 | That was the problem, is we would never arrive anywhere

02:06:31.580 | on time, and that's my excuse for always being late.

02:06:33.580 | I would positively reinforce her being late.

02:06:35.460 | I always run late and I always run, incredible, right?

02:06:37.980 | Just a very strong sense of social connection,

02:06:41.060 | that kind of thing.

02:06:42.060 | But in any case, you know, some people are like that.

02:06:44.380 | Like she could not experience any even modicum

02:06:48.740 | of inconvenience for helping others.

02:06:51.960 | Whereas I think most of us feel like if I'm rushing

02:06:54.340 | to catch a flight and I see someone who's struggling,

02:06:56.820 | I'm probably gonna help them if they're in acute pain

02:06:58.880 | or it seems like a dire circumstance.

02:07:00.900 | But let's be honest.

02:07:02.100 | Most people are probably gonna prioritize

02:07:06.020 | their own stress and priorities, for lack of a better word,

02:07:11.020 | when the situation often calls for us to set those aside

02:07:15.620 | and tend to people that are suffering.

02:07:17.500 | So if there was a way to introduce a probe

02:07:21.360 | of the interplay of circuitries that involve

02:07:24.060 | how convenient or inconvenient it is,

02:07:25.780 | like if we're well fed, it's pretty easy to go out

02:07:28.120 | and gather and distribute food for others.

02:07:30.300 | But if we're hungry, we tend to focus on our own hunger.

02:07:33.820 | - So first, you know, in full disclosure,

02:07:38.220 | even though I'm studying empathy and compassion,

02:07:40.380 | I can look in the mirror and say,

02:07:42.160 | I probably don't practice it nearly as much as I should.

02:07:45.360 | I'm thinking of your example.

02:07:46.680 | If I was late for a plane,

02:07:48.980 | I'm not sure I would stop and help somebody.

02:07:51.180 | And I'm not saying that--

02:07:52.020 | - I guess it depends on what sort of suffering.

02:07:53.500 | - Yeah, exactly.

02:07:54.340 | - I mean, if they're hemorrhaging on the side of the road,

02:07:56.180 | we all would. - Of course, of course.

02:07:57.020 | - But if I'm tired, right, you might think,

02:07:58.940 | oh goodness, like, do I have time for this?

02:08:00.740 | - Yeah, yeah, exactly.

02:08:01.580 | And so I'm not proud of that statement.

02:08:03.520 | But back to your question.

02:08:05.040 | Yes, I think absolutely we can design experiments

02:08:09.640 | where after we've established the basic phenomenology,

02:08:13.640 | then we can take our subject, animal or mouse,

02:08:17.880 | and put it into certain circumstances.

02:08:21.360 | If it's hungry itself,

02:08:23.240 | will it work as hard to give another animal?

02:08:25.600 | I mean, it's a good question

02:08:26.920 | because I'm not sure what the outcome will be.

02:08:28.900 | One could predict it might work harder

02:08:30.800 | because it understands the hunger, in quotes, more.

02:08:34.160 | - I love that answer. - Or it could be,

02:08:36.540 | of course it's not gonna work hard for another animal

02:08:39.480 | to get a food reward because it's starving itself

02:08:42.680 | and it needs to take care of itself first.

02:08:45.040 | It's a great question.

02:08:46.040 | We're also asking questions about,

02:08:48.220 | do you have to know your buddy mouse, right?

02:08:50.920 | Do you, is it, are you more likely to behave

02:08:53.740 | in a generous or compassionate way

02:08:56.400 | if you grew up with that mouse, you know,

02:08:59.260 | in the way our mice grow up in academic environments?

02:09:03.960 | And if it's a stranger, how will you behave?

02:09:07.300 | How will you behave if you had a fight

02:09:09.200 | with that mouse previously?

02:09:11.360 | And what if you had, and it also matters,

02:09:14.960 | did you win the fight or did you lose the fight, right?

02:09:18.760 | Intuitively, as we probably would all guess,

02:09:21.760 | I'm more likely to help somebody

02:09:23.520 | I defeated in a fight previously

02:09:26.840 | because I'm the, in the hierarchy, I'm the dominant one.

02:09:31.400 | I'm probably less likely if that person beat me up.

02:09:34.920 | So all these are great questions.

02:09:37.160 | I think we can study them.

02:09:39.480 | I also think there are ways we can study

02:09:41.720 | these kinds of interactions in human subjects.

02:09:45.260 | Not that I am gonna do that myself.

02:09:47.120 | - But someone at Stanford will.

02:09:48.220 | - Yeah, yeah.

02:09:49.080 | So I think there's also an opportunity,

02:09:51.120 | and I'm happy to discuss how neuromodulators,

02:09:53.920 | like in particular serotonin,

02:09:56.080 | but also perhaps dopamine and oxytocin

02:09:59.000 | may influence the brain, the circuitry

02:10:01.960 | and the brain mechanisms that are mediating

02:10:04.760 | what I term empathic behaviors.

02:10:07.680 | - Let's return to autism.

02:10:09.040 | - Right.

02:10:09.880 | - Does autism involve a lack of empathy?

02:10:14.760 | Does autism involve a restructuring of the reward system

02:10:18.900 | around social interactions?

02:10:21.260 | Maybe considering the second question first,

02:10:24.160 | I could imagine, for instance,

02:10:25.880 | that there are variations in brain wiring

02:10:28.480 | that would make it such that a kid

02:10:31.840 | who then becomes an adult gets a tremendous amount of reward

02:10:35.520 | from, I don't know, math, designing mugs,

02:10:40.240 | any number of activities,

02:10:43.040 | but that through some variation in brain wiring,

02:10:46.740 | social interaction, spending time with friends

02:10:49.640 | is just not as socially rewarding.

02:10:51.480 | It just doesn't feel good in the moment,

02:10:54.360 | doesn't necessarily feel bad,

02:10:56.240 | but it's not selected for.

02:10:59.040 | And is there any evidence that that's the case

02:11:01.840 | in children who are classified as autistic

02:11:06.120 | or having autism?

02:11:07.120 | - I wanna be clear.

02:11:10.000 | I am not a world expert on pathophysiology

02:11:14.080 | of individuals with autism spectrum disorder.

02:11:17.200 | I have read some of the literature.

02:11:18.920 | I do study mouse models

02:11:23.200 | of genetically-based autism spectrum disorder.

02:11:26.600 | So the answer is yes.

02:11:28.200 | There have been imaging studies.

02:11:31.120 | And again, so your audience,

02:11:34.320 | certain members of your audience, don't get mad.

02:11:37.100 | Remember our earlier conversation,

02:11:39.200 | we made the point that autism spectrum disorder

02:11:42.720 | is a highly heterogeneous set of behavioral symptoms

02:11:47.720 | with wide variation in how these symptoms manifest

02:11:53.160 | in each individual.

02:11:54.560 | So we cannot make blanket statements

02:11:58.040 | that individuals with autism spectrum disorder

02:12:03.040 | are this or that.

02:12:04.720 | But there are studies, both in human beings and mice,

02:12:08.600 | that suggest that the reinforcing component

02:12:12.400 | of a social interaction is much less or lacking

02:12:17.400 | in our models of autism spectrum disorder

02:12:22.280 | and certain individuals.

02:12:24.280 | An important point is, is that just genetically wired?

02:12:29.280 | Was that because in their early experiences,

02:12:34.620 | they weren't able to get the sensory stimuli

02:12:38.000 | that tell them this is a reinforcing social experience?

02:12:42.100 | Unknown, or at least those are topics

02:12:44.960 | that I think are worthy of investigation.

02:12:47.260 | Do individuals or mice with autism spectrum disorder

02:12:54.200 | lack or do not have the capacity

02:12:57.320 | or the same experience of empathy?

02:13:00.640 | Again, a very complex topic in question.

02:13:03.960 | And it's very likely for some individuals,

02:13:08.760 | the answer is yes, meaning they do lack

02:13:13.080 | some of the neuro mechanisms that allow them,

02:13:15.540 | but that probably doesn't apply to everybody.

02:13:18.120 | I can say in our mouse models of social mechanisms,

02:13:23.760 | of social interactions, and our mouse models

02:13:26.680 | of in quotes, empathy, in these are mice show deficits.

02:13:31.680 | And those deficits can be rescued, meaning improved upon,

02:13:40.140 | by manipulations of certain neuromodulatory systems,

02:13:44.440 | in this case, the serotonin system,

02:13:47.060 | by giving drugs, including a drug called MDMA or ecstasy,

02:13:53.020 | so I hope I'm answering your question.

02:13:56.280 | I think these are worthwhile subjects for investigation.

02:14:01.280 | I think there's a lot of value in studying them.

02:14:08.680 | - Let's go back to serotonin in the nucleus accumbens.

02:14:11.920 | We will get into this in a bit more detail

02:14:13.920 | when we discuss MDMA, but I've now spent a lot of time

02:14:16.600 | with a recent paper of yours that really parsed--

02:14:19.200 | - Really, which one, the MDMA paper?

02:14:21.200 | The Boris Heifetz one?

02:14:22.960 | - Yeah, that parsed the relative roles of dopamine

02:14:26.960 | in the nucleus accumbens versus serotonin

02:14:28.880 | in the nucleus accumbens.

02:14:29.720 | By the way, folks, by the time this episode comes out,

02:14:33.280 | an episode all about MDMA itself and its modes of action

02:14:36.820 | will have already aired, and you can find that,

02:14:39.600 | but even if you haven't heard that,

02:14:41.500 | MDMA is an amazing molecule

02:14:44.000 | because it profoundly increases dopamine,

02:14:47.400 | and that's why the word methamphetamine

02:14:50.320 | is actually in MDMA.

02:14:52.500 | Still a surprise to many people to hear that,

02:14:55.220 | but it also robustly increases serotonin transmission,

02:14:59.640 | and what I love about the paper from your lab

02:15:02.520 | that explored this is that, at least by my read of the data,

02:15:06.300 | it showed very convincingly that it's serotonin released

02:15:10.400 | in the nucleus accumbens that's responsible

02:15:12.160 | for the prosocial effects of MDMA,

02:15:14.340 | whereas oxytocin, this thing we talked about earlier

02:15:17.360 | that everyone assumes is the pair bonding molecule,

02:15:19.560 | the molecule of love, both in humans now,

02:15:22.640 | there's a study in humans,

02:15:23.600 | and in the mouse work that you've done,

02:15:25.760 | doesn't seem to play as prominent a role

02:15:28.240 | in the social enhancement that MDMA causes,

02:15:32.800 | and the reason I'm asking this in the context of autism

02:15:35.440 | is that, for a long time, there was excitement

02:15:38.800 | about the idea that oxytocin nasal sprays

02:15:41.280 | might make autistic kids more excited

02:15:43.720 | about social interactions,

02:15:45.580 | more tuned to social interactions.

02:15:48.040 | First question is, is there any evidence

02:15:50.340 | that increasing oxytocin in a child or adult with autism

02:15:54.200 | makes them somehow more social

02:15:55.960 | or desiring more social connections?

02:15:59.080 | I'm not aware of any.

02:16:00.320 | - I don't think the, I think it is a worthwhile,

02:16:05.320 | it has been studied, I don't think we can close the door

02:16:10.080 | on the potential therapeutic uses of oxytocin.

02:16:14.200 | From the people I know who are much more expert in this

02:16:17.720 | than I am, I think most of the clinical trials

02:16:21.040 | have been pretty disappointing,

02:16:23.020 | with a lot of hope that intranasal oxytocin

02:16:27.080 | would promote more positive prosocial experiences.

02:16:32.080 | I don't think the door is shut yet.

02:16:33.900 | There may be different ways of administering it.

02:16:38.900 | There may be ways of making a different type of oxytocin

02:16:43.760 | that might be beneficial.

02:16:45.880 | I have a colleague at Stanford

02:16:48.240 | who's actually looking at a related neuropeptide

02:16:50.980 | called vasopressin,

02:16:52.640 | and she's finding some potential benefit from that.

02:16:57.280 | And vasopressin and oxytocin

02:16:59.040 | are closely related to each other.

02:17:01.280 | They can even activate some of the same,

02:17:04.360 | what we call receptors in the brain.

02:17:06.680 | So I don't think the door is closed on the possibility

02:17:10.840 | of oxytocin or related therapeutic agents.

02:17:16.600 | Having some therapeutic potential.

02:17:19.440 | The evidence, as far as I'm aware, is not there yet.

02:17:22.760 | In terms of MDMA, again, complicated story.

02:17:27.760 | As you pointed out, MDMA,

02:17:32.320 | it's major molecular targets,

02:17:36.920 | don't wanna get too technical here,

02:17:39.160 | are the serotonin vacuum cleaner,

02:17:43.160 | the molecule that vacuums up serotonin,

02:17:47.600 | and the dopamine vacuum cleaner,

02:17:50.640 | the molecule that vacuums up and, excuse my language,

02:17:55.640 | sucks up dopamine when it's released.

02:17:59.240 | And because it's an amphetamine derivative,

02:18:04.180 | as you correctly pointed out,

02:18:06.680 | it not only prevents these proteins, we call them,

02:18:10.380 | these molecules, these vacuum cleaners,

02:18:12.900 | from vacuuming up the dopamine and serotonin

02:18:16.300 | when it's released, it actually causes it,

02:18:19.620 | I don't wanna use the term,

02:18:21.020 | the terminals to vomit out dopamine and serotonin.

02:18:23.840 | - That's what I say on the--

02:18:25.200 | - All right, is that, am I allowed to say that?

02:18:26.040 | - When I talk about synaptic release,

02:18:27.520 | I'm known for, in my solo episodes,

02:18:29.800 | when I talk about synaptic release,

02:18:31.240 | I'll say that they, bleh, they vomited out.

02:18:34.180 | - So what amphetamine derivative--

02:18:35.780 | - But you worked on synaptic transmission,

02:18:37.220 | so that's almost an insult to a biologist

02:18:38.960 | that works on synaptic transmission.

02:18:39.800 | - No, no, not at all.

02:18:40.620 | What MDMA does is it actually calls

02:18:41.780 | what's known as a reverse transport.

02:18:43.500 | It actually causes, it not only prevents

02:18:45.940 | the vacuum cleaners from sucking up

02:18:49.080 | the dopamine and serotonin,

02:18:50.840 | it causes it to spew out dopamine and serotonin.

02:18:53.960 | So imagine if your vacuum cleaner started,

02:18:56.620 | the pressure in your vacuum cleaner reversed

02:18:58.960 | and all the dirt you collected started being spewed out.

02:19:02.360 | Now the one difference for MDMA,

02:19:04.400 | and it's a fascinating topic I hope we have time

02:19:08.500 | to talk about, is why does MDMA qualitatively for most people

02:19:13.500 | give human subjects a different experience

02:19:19.120 | than cocaine or meth, or especially methamphetamine?

02:19:22.080 | - Presumably it's the fact that there's so much serotonin.

02:19:24.440 | - Exactly.

02:19:25.280 | And so if you actually get, and this is why,

02:19:29.000 | for your audiences, this is why hardcore molecular science

02:19:32.840 | can actually teach us something about

02:19:36.580 | complex human behavioral phenomena,

02:19:39.280 | such as social interactions and addiction.

02:19:43.780 | At least the hypothesis we propose,

02:19:46.080 | and others in the field, it's not just,

02:19:48.800 | science is not done in isolation.

02:19:51.040 | So I wanna give credit where credit is due.

02:19:53.060 | We did not define the following,

02:19:54.880 | that MDMA affects the serotonin system

02:19:59.880 | more than the dopamine system.

02:20:03.000 | So it's not 50/50.

02:20:05.640 | Maybe it's 70/30, 80/20,

02:20:08.500 | and that's because the molecule itself of MDMA,

02:20:12.480 | again, I'm trying not to use language,

02:20:15.100 | it binds to, it has a higher affinity.

02:20:18.280 | It likes to bind to and influence

02:20:20.820 | the serotonin vacuum cleaner

02:20:22.880 | more than the dopamine vacuum cleaner.

02:20:25.160 | It's still affecting both, but it's not 50/50.

02:20:28.460 | It's more, whatever, 70% serotonin, 30% dopamine.

02:20:34.980 | And then it does influence oxytocin in very complex ways,

02:20:39.980 | which is a further technical discussion.

02:20:44.860 | It was just a nice paper that came out

02:20:48.860 | that reported that serotonin release

02:20:51.560 | in a hypothalamic structure,

02:20:53.760 | which again, the hypothalamus,

02:20:55.540 | you can explain to your listeners.

02:20:58.160 | - Marble-ish size structure above the roof of your mouth,

02:21:00.960 | responsible for sex temperature control,

02:21:04.040 | feeding and satiety, and a bunch of other things critical.

02:21:07.040 | - And it's a home of neurons that produce oxytocin.

02:21:12.680 | So this paper reported that when serotonin is released

02:21:16.280 | in the hypothalamus, it activates

02:21:18.040 | and causes the release of oxytocin.

02:21:20.420 | That's in the hypothalamus.

02:21:21.620 | Our work in the reward circuitry suggested oxytocin,

02:21:26.620 | so that's serotonin upstream of oxytocin

02:21:30.060 | in the hypothalamus, where we were looking

02:21:33.100 | in the accumbens, it was the opposite.

02:21:35.500 | Oxytocin caused the release of serotonin.

02:21:38.740 | So the point to your listeners is,

02:21:40.480 | the brain's unfortunately complicated.

02:21:42.640 | - It's tractable.

02:21:43.840 | - It's tractable.

02:21:45.240 | We like to come up with general hypotheses and principles,

02:21:49.140 | but sometimes the devil's in the details

02:21:51.380 | and we really need to probe deeper.

02:21:53.620 | So back to your question about our previous paper

02:21:57.620 | and dopamine and serotonin.

02:21:59.620 | So what we proposed, which is far from nailed down,

02:22:04.620 | is that MDMA, because it is an amphetamine derivative,

02:22:10.440 | does influence dopamine release

02:22:12.840 | and the dopamine system.

02:22:15.900 | And some of my colleagues in the MDMA field,

02:22:20.060 | who I respect enormously, don't like me to say this,

02:22:23.260 | but I'm gonna say it anyhow.

02:22:24.980 | Remember earlier in the podcast,

02:22:29.340 | we talked about different substances

02:22:31.300 | having addictive liabilities.

02:22:33.580 | It doesn't mean a substance is automatically addictive,

02:22:36.640 | doesn't mean it's automatically not, it's a continuum.

02:22:40.300 | And I would argue that MDMA does have

02:22:44.700 | some addictive liability,

02:22:47.220 | because it is an amphetamine derivative.

02:22:49.460 | - It feels good.

02:22:50.300 | - And it feels good.

02:22:51.260 | And so there are individuals that especially,

02:22:55.260 | as your listeners may know,

02:22:56.860 | MDMA has gotten a lot of attention

02:22:59.700 | because it's in a therapeutic trial

02:23:01.560 | that looks very promising as an adjunct to psychotherapy

02:23:06.380 | for post-traumatic stress disorder.

02:23:08.500 | And the FDA, the part of our government

02:23:11.620 | that approves or disapproves the legal distribution

02:23:16.500 | of therapeutic drugs,

02:23:18.180 | may end up approving MDMA for certain uses.

02:23:21.880 | The point being is that if it gets approved,

02:23:26.620 | my personal feeling is it will have some addictive liability.

02:23:30.340 | It also has this very powerful,

02:23:35.100 | what you and I might term, Andrew, a prosocial effect.

02:23:38.840 | Some people even call it an empathogen.

02:23:42.860 | That's a little controversial,

02:23:44.340 | meaning it enhances your capacity for empathy,

02:23:48.120 | to experience the emotional state of another individual,

02:23:53.100 | to want to understand that person's experiences

02:23:56.720 | and emotional state.

02:23:58.060 | And what we've suggested is that the addictive liability

02:24:02.740 | is mostly, although not solely,

02:24:04.700 | being mediated by its actions on the dopamine system,

02:24:08.340 | whereas its positive, more prosocial effects,

02:24:11.920 | and perhaps its empathogenic effects,

02:24:14.980 | are more likely to be mediated by its interactions

02:24:18.980 | with the serotonin system in this reward circuitry.

02:24:23.340 | And we're actually doing a lot of work

02:24:25.840 | to test that hypothesis.

02:24:28.080 | We're actually testing MDMA

02:24:31.180 | in these behavioral models of empathy in mice.

02:24:35.380 | And it looks like our hypothesis is being supported.

02:24:39.920 | The other thing, just to drive your listeners crazy

02:24:44.020 | about, sorry, listeners, how complex the brain is,

02:24:47.860 | if you think--

02:24:48.700 | - Well, neither you nor I were consulted

02:24:50.580 | at the design phase, and so we don't have to apologize

02:24:53.220 | for the brain's complexity.

02:24:54.460 | - Because I don't, trust me, as a scientist,

02:24:56.960 | I wish I could keep things as simple as possible.

02:24:59.740 | That's what good science is.

02:25:01.480 | It turns out the serotonin is produced by neurons

02:25:05.780 | in another part of the brain,

02:25:07.780 | with this wonderful name called the dorsoraphane nucleus.

02:25:11.920 | And it turns out the serotonin neurons

02:25:15.140 | talk to the dopamine neurons.

02:25:18.260 | And influence the dopamine neurons.

02:25:20.820 | And so it's, again, the point we made earlier

02:25:24.880 | in your podcast, even though it's fun and useful,

02:25:28.700 | both for your listeners and as scientists,

02:25:32.020 | to think about these powerful chemical messengers

02:25:35.600 | in isolation, because that's how we can make progress

02:25:39.440 | scientifically, it's how your audience can understand

02:25:43.500 | some of the concepts that have been elucidated

02:25:46.660 | from brain research over the decades.

02:25:50.580 | But they don't work in isolation.

02:25:52.860 | They influence each other,

02:25:54.260 | they communicate with each other.

02:25:56.280 | We're actually doing studies showing that

02:25:59.260 | serotonin release in the accumbens

02:26:01.100 | actually modulates dopamine release,

02:26:03.220 | so it gets crazy complicated.

02:26:06.120 | But you can still develop simplistic hypotheses,

02:26:09.440 | like as I was saying about MDMA,

02:26:12.020 | where, you know, abuse, addictive liability,

02:26:14.800 | and some of its reinforcing qualities,

02:26:17.960 | which you just mentioned, MDMA,

02:26:19.600 | a lot of people find it fun to take it,

02:26:22.200 | is probably mostly being mediated via the dopamine system,

02:26:26.560 | and some of its social effects

02:26:28.560 | are being mediated by the serotonin system.

02:26:32.800 | We're actually doing studies to figure out

02:26:34.600 | whether the reinforcing component of a social experience

02:26:39.360 | requires that dopamine release, probably does.

02:26:42.860 | - That's what I'm most interested in, really,

02:26:44.620 | in the context of MDMA.

02:26:45.940 | And we should just mention,

02:26:46.920 | 'cause we do like to mention these caveats,

02:26:51.060 | yes, and I can say this 'cause I participated

02:26:53.340 | in a trial with MDMA, it is a very pleasant experience.

02:26:56.420 | It's certainly not for everybody.

02:26:57.820 | It still is a schedule one drug at this moment.

02:27:00.340 | - Absolutely.

02:27:01.260 | - So you can go to jail for possessing or selling it.

02:27:04.420 | In fact, there was a big bust recently in Canada

02:27:07.060 | and another one in Brussels.

02:27:08.760 | Large amounts of MDMA collected.

02:27:11.580 | Those people are probably gonna go to prison

02:27:13.340 | for a long period of time.

02:27:14.520 | So you don't want to take it or possess it.

02:27:17.860 | It's illegal.

02:27:19.160 | We're talking about clinical trials here,

02:27:20.460 | but also the fentanyl issue.

02:27:23.040 | There's a lot of fentanyl contamination.

02:27:24.880 | - And I was just gonna mention to your listeners-

02:27:25.720 | - So we'd be remiss if we didn't mention.

02:27:27.460 | A lot of people are dying thinking

02:27:28.920 | that they're taking one drug when they're taking another.

02:27:30.820 | So we are not encouraging the use of these,

02:27:33.260 | but I will say that the subjective experience

02:27:36.620 | of MDMA provided it's done

02:27:38.660 | in the appropriate clinical setting,

02:27:40.320 | it's actually MDMA, doesn't contain other things,

02:27:43.060 | dosed correctly, et cetera,

02:27:44.560 | is a pleasant one for sure.

02:27:47.940 | And my sense is that the dopamine release

02:27:52.180 | is reinforcing the experience that,

02:27:56.540 | the context that serotonin is providing

02:27:58.720 | with the social context.

02:28:00.240 | And the word context there becomes important

02:28:02.300 | when we think about back to the '90s

02:28:04.080 | when there were a lot of raves

02:28:05.420 | and people were also getting, I guess,

02:28:09.060 | positive feedback from the interactions they were having,

02:28:11.280 | dancing all night, partying with friends, et cetera.

02:28:13.460 | I mean, I think that returning to the issue of autism

02:28:17.060 | and the role of serotonin,

02:28:18.580 | so in autism, there seems to be less

02:28:22.860 | of a reinforcement pathway

02:28:25.220 | for certain kinds of social interactions

02:28:27.680 | in some individuals with autism.

02:28:29.980 | And I'm aware that there are some prescription treatments

02:28:33.700 | for autism that capitalize on the serotonergic system

02:28:36.620 | and dopamine system.

02:28:37.740 | So is it fentamine?

02:28:39.420 | To my knowledge, the only FDA approved

02:28:43.920 | pharmacologic therapeutic for individuals

02:28:47.900 | with autism spectrum disorder is actually,

02:28:51.380 | oh God, I'm just blanking.

02:28:53.320 | It's not a serotonergic drug.

02:28:55.960 | I have to look it up.

02:28:59.020 | I wanna say resperidone for agitation.

02:29:02.740 | There is no drug for,

02:29:08.300 | for lack of a better term, the social deficits.

02:29:12.700 | There's no FDA approved drug.

02:29:14.740 | If you look at the literature,

02:29:16.860 | psychiatrists and individuals with good intention

02:29:21.180 | have tested the utility of traditional serotonergic drugs

02:29:26.180 | like Prozac, SSRIs.

02:29:29.100 | There are drugs known as SNRIs,

02:29:31.580 | drugs that influence serotonin release

02:29:33.460 | and another neuromodulator that you know well,

02:29:35.940 | norepinephrine and at least well done clinical trials,

02:29:40.940 | which in my view as an academic are very important.

02:29:44.340 | None of them have showed efficacy.

02:29:46.820 | Having said that, there are several companies

02:29:49.620 | and full disclosure here,

02:29:51.780 | I am the founder of a small biotech

02:29:55.660 | called Map Light Therapeutics.

02:29:57.600 | And I'm not advertising for Map Light.

02:29:59.880 | I'm just doing a full disclosure.

02:30:02.060 | It was founded with Karl Deisseroth,

02:30:04.220 | who you've had on your podcast

02:30:06.500 | and an entrepreneur in San Francisco

02:30:09.580 | named Caroline Nickolich.

02:30:11.040 | And we have the phase two trial.

02:30:15.220 | Phase two trial means it's a safe drug.

02:30:18.340 | We've done all the safety work

02:30:22.380 | and it's a drug that targets a subtype

02:30:27.380 | of receptor for serotonin.

02:30:30.220 | Serotonin works on many different,

02:30:32.160 | I don't know, what word can I use other than receptor?

02:30:35.100 | - No, listeners of this podcast

02:30:37.340 | probably be familiar with receptors.

02:30:38.640 | It's sort of parking spots for molecules.

02:30:41.340 | Yes, the paper I was referencing earlier from your lab,

02:30:45.900 | it talked about serotonin 1B receptors

02:30:48.580 | being particularly important.

02:30:50.020 | - And so the point being is,

02:30:52.640 | I do have an interest in this

02:30:54.940 | on can you use the type of discoveries we've made in mice?

02:30:59.900 | Might it actually have any relevance to human beings,

02:31:04.900 | in particular those who,

02:31:07.940 | some of which have some sort of sociability deficits?

02:31:11.900 | Other companies are pursuing this too.

02:31:16.080 | So MDMA itself, there has been,

02:31:20.040 | I don't know if it's ongoing.

02:31:21.380 | There's a well-known organization.

02:31:23.280 | I don't know if you've ever had anybody from MAPS on this.

02:31:27.300 | The Multidisciplinary Association for Psychedelic Studies.

02:31:31.140 | MAPS deserves a lot of credit for being a pioneer

02:31:34.660 | in saying, in particular with MDMA,

02:31:38.020 | promoting the idea that this drug deserves

02:31:42.300 | rigorous and ethical study.

02:31:45.880 | That's at least my view.

02:31:48.800 | And MAPS, which was founded by a individual

02:31:53.980 | named Rick Doblin, deserves enormous credit

02:31:57.260 | for their 30-year effort to make it allowed and legal

02:32:02.160 | to actually study MDMA.

02:32:03.580 | The point I'm making is I know MAPS and perhaps others

02:32:06.900 | have done some small trials studying MDMA

02:32:10.940 | in individuals, high-functioning individuals

02:32:15.140 | with some form of social anxiety.

02:32:18.520 | I'm saying this because this is public.

02:32:21.500 | There's another company called MindMed,

02:32:24.500 | which is one of the publicly traded psychedelic companies,

02:32:28.380 | and this is on their website.

02:32:30.280 | Full disclosure, I am on their scientific advisory board.

02:32:34.200 | They are gearing up to do a trial of a,

02:32:40.140 | I don't wanna get too technical, of a certain form of MDMA.

02:32:44.700 | There are two different types of MDMA.

02:32:47.020 | They have these horrible names called enantiomers.

02:32:51.940 | So the MDMA that is used for clinical trials at MAPS,

02:32:56.940 | MDMA is a molecule and it has mirror images of itself.

02:33:01.540 | And one has the name R-MDMA and one has the name S-MDMA.

02:33:06.540 | And they're called the enantiomers

02:33:09.660 | because they're mirror images of each other.

02:33:12.300 | And other labs over the years, not my lab,

02:33:15.580 | I deserve no credit for this, have done some studies

02:33:19.660 | to suggest that the S enantiomer

02:33:23.780 | is the one that has a higher interaction

02:33:27.460 | with the dopamine system.

02:33:29.260 | And the R enantiomer has a higher interaction

02:33:33.300 | with the serotonin system.

02:33:35.060 | - Interesting.

02:33:36.500 | - If you look at the literature on autism spectrum disorder

02:33:40.740 | in human subjects, there's a bunch of papers suggesting

02:33:47.380 | serotonergic systems are malfunctioning

02:33:52.180 | in individuals with autism spectrum disorder.

02:33:56.260 | And if you look at reviews I've written or any of my papers,

02:34:01.260 | we probably cite some of the reviews.

02:34:03.340 | - It's clear that serotonin is playing some role

02:34:06.020 | in social interactions, at least in mice

02:34:09.220 | and almost certainly in humans as well.

02:34:11.420 | It's hard to imagine based on data from everything

02:34:14.180 | from SSRIs to neurotoxic lesions of the human brain,

02:34:16.900 | et cetera, that it's not also playing

02:34:18.660 | at least a similar role in humans.

02:34:19.980 | - Right, and I fully agree with that.

02:34:22.380 | And as we were discussing, there's a modestly extensive

02:34:27.380 | clinical literature, meaning literature from human subjects

02:34:30.780 | suggesting that some aspects of brain systems

02:34:35.780 | that utilize serotonin as one of their signaling molecules,

02:34:41.180 | one of their neuromodulatory mechanisms

02:34:44.060 | may not be functioning in some populations

02:34:47.740 | of individuals with autism spectrum disorder.

02:34:50.260 | So based on that, based on my lab's work

02:34:53.500 | on the role of serotonin in modifying reward circuitry,

02:34:57.900 | its role in pro-social behaviors.

02:35:00.940 | And the biggest clue, which I think you would agree

02:35:04.860 | with, Andrew, is this drug, MDMA.

02:35:08.180 | I mean, this is why I am not a druggie myself.

02:35:11.500 | I am a child of the '60s and '70s.

02:35:14.180 | So I did, which means I'm 20 years older than you, Andrew,

02:35:17.540 | I did experiment like everybody of my generation

02:35:22.100 | with psychoactive substances in the '70s.

02:35:25.540 | So I don't wanna lie about my experiences.

02:35:29.020 | I also would say like many neuroscientists,

02:35:32.180 | my experiences with psychoactive substances

02:35:35.460 | stimulated my interest in neuroscience.

02:35:39.540 | How do these substances work?

02:35:41.660 | Why, when I was a young kid,

02:35:45.620 | the first time I got drunk on beer, why is that happening?

02:35:49.980 | But more seriously, I use drugs in my research

02:35:54.980 | as powerful probes of brain function

02:35:59.220 | with the advantage that,

02:36:01.180 | and now I'm talking scientist to scientist with you, Andrew,

02:36:05.540 | they have molecular targets that we can manipulate

02:36:09.740 | in rigorous ways.

02:36:11.260 | We can figure out where in the brain they act

02:36:14.580 | using the modern tools of neuroscience,

02:36:17.160 | which your audience may not know about.

02:36:20.260 | I'm saying this to you, conditional knockout mice,

02:36:23.700 | rescue experiments.

02:36:24.900 | We can do all those fancy stuff.

02:36:27.420 | And we can use drugs to study even things

02:36:31.140 | as complicated as empathy.

02:36:34.300 | And I really do believe that it's why I've been interested

02:36:37.820 | in MDMA for decades is there's a clue there.

02:36:41.780 | How does a drug that has molecular targets

02:36:46.020 | in the dopamine neuromodulatory system,

02:36:48.660 | in the serotonin neuromodulatory system

02:36:51.420 | have such a powerful effect,

02:36:54.620 | which is relatively specific on social interactions.

02:36:59.620 | It doesn't make you wanna go eat more donuts.

02:37:03.620 | It doesn't, I don't know, for me, there's a clue there.

02:37:08.620 | There's something really important

02:37:11.420 | from that phenomenological observation

02:37:14.840 | in the human experiences that we can learn from.

02:37:18.140 | - I completely agree about MDMA.

02:37:20.260 | And we've done a couple podcasts about psilocybin

02:37:23.620 | and by extension LSD,

02:37:25.380 | because even though there are differences there,

02:37:27.660 | psilocybin LSD, as far as we understand,

02:37:30.700 | largely work through activation of the serotonin 2A receptor,

02:37:35.060 | broadening of a brain network connectivity.

02:37:37.340 | So again, it's serotonin, serotonin, serotonin,

02:37:40.260 | but different receptors,

02:37:42.140 | very different subjective experience.

02:37:45.840 | And I guess perhaps the best way to describe it

02:37:48.100 | is that LSD and psilocybin are almost always considered

02:37:51.420 | mystical in their subjective effects,

02:37:54.140 | whereas MDMA can be an empathogen, an actogen.

02:37:58.740 | And so serotonin acting through different receptor systems

02:38:03.700 | impacting and creating

02:38:04.980 | very different subjective experiences.

02:38:06.540 | I also agree, I think MDMA is particularly interesting

02:38:09.380 | for the neuroscientist,

02:38:10.860 | perhaps also because at least to my knowledge,

02:38:14.120 | there is no substance in nature, no plant, no mushroom,

02:38:18.140 | no ergot, no mold that creates this increase

02:38:23.140 | in dopamine and serotonin simultaneously.

02:38:27.700 | MDMA is a synthesized molecule.

02:38:30.060 | And so it may be one of the, again,

02:38:32.460 | highlighting all the safety issues

02:38:33.880 | and things we talked about before,

02:38:34.900 | it may be one of the great, at least experimental probes

02:38:38.680 | of the brain that humans have developed.

02:38:40.900 | And it may be one of the great therapeutic probes

02:38:44.260 | that folks like MAPS are now doing such fantastic work on.

02:38:47.900 | So I'm very excited about what's happening

02:38:50.260 | with the research on MDMA.

02:38:51.500 | And I'm so glad that your laboratory

02:38:53.500 | has parsed some of the relative roles of serotonin

02:38:56.820 | in the receptors involved.

02:38:58.980 | Since we mentioned serotonin 2A for psilocybin and LSD,

02:39:02.040 | we'd be remiss if we didn't say that this wonderful paper

02:39:04.620 | that we will provide a link to in the show note captions,

02:39:06.500 | by the way, folks,

02:39:08.020 | that Rob Malenka here's lab,

02:39:10.500 | it's focused on the serotonin 1B receptor.

02:39:13.540 | So it even just differences in receptor subtypes

02:39:16.620 | leading to profoundly different subjective outcomes.

02:39:19.340 | I find that to be just one of the most important areas

02:39:24.040 | that one could even think about, let alone work on.

02:39:27.860 | - Thank you, I appreciate the compliment.

02:39:30.060 | I will also say, like everything we're finding,

02:39:33.520 | it's not all about only serotonin 1B,

02:39:36.020 | but that's, as you know, there are, again,

02:39:38.780 | pointing to the amazing and powerful complexity

02:39:43.780 | of the human brain or the mammalian brain.

02:39:47.460 | There are 16 different serotonin parking spots or receptors

02:39:53.300 | that are distributed in different brain areas

02:39:57.240 | in complex ways, and so that's daunting,

02:40:00.480 | but it also offers possibilities

02:40:04.340 | for developing very novel therapeutic agents

02:40:07.620 | that activate or inhibit these in complex ways,

02:40:12.620 | hopefully for therapeutic benefit.

02:40:14.740 | - So before we conclude, I'm very curious

02:40:17.980 | to get your opinion on what you see as the landscape

02:40:22.140 | of the work on psychedelics and MDMA,

02:40:26.040 | which isn't really a classic psychedelic,

02:40:27.860 | but all these drugs that, as you pointed out,

02:40:30.800 | during your youth were used recreationally

02:40:33.320 | and for mind exploration and expansion

02:40:35.300 | and are now being probed as potential therapeutics

02:40:39.100 | for various mental health challenges,

02:40:41.580 | as well as potentially expanding consciousness,

02:40:44.780 | empathy, and all of that.

02:40:46.540 | I mean, not getting into the details of the legal issues

02:40:50.420 | that have to be overcome, not even necessarily

02:40:52.820 | talking about the clinical trials

02:40:54.360 | or the people doing the work in different laboratories,

02:40:56.500 | but just, I have to imagine this must amuse,

02:41:01.260 | tickle, surprise you.

02:41:02.640 | I mean, how do you feel about what you're seeing now?

02:41:05.220 | Because it is a very exciting time for these compounds.

02:41:08.980 | - It tickles me and excites me

02:41:11.340 | with the appropriate caution.

02:41:14.380 | So I do think drugs are very powerful probes

02:41:18.380 | of brain function.

02:41:19.780 | I think this class of drug,

02:41:21.780 | which as you correctly pointed out,

02:41:23.300 | people use the term psychedelics scientifically

02:41:27.660 | when pursuing their understanding,

02:41:32.420 | their therapeutic potential, their mechanism of action,

02:41:35.940 | it's more useful to divide them up into different categories,

02:41:39.560 | the classic hallucinogens, which are LSD and psilocybin,

02:41:43.780 | the intact or empathogens, which is MDMA,

02:41:47.020 | which is really a qualitatively different drug.

02:41:50.340 | There are other substances,

02:41:51.740 | which we don't have time to talk about,

02:41:53.540 | like Ibogaine and ayahuasca,

02:41:55.180 | which are very complex, and peyote.

02:41:58.160 | But nevertheless, I am tickled and excited

02:42:00.980 | as a child of the '60s and '70s,

02:42:03.580 | but I am also not evangelical

02:42:08.460 | about their use and their therapeutic potential.

02:42:13.060 | So as you can imagine what I'm gonna say,

02:42:15.780 | I think they should be the subject of rigorous,

02:42:19.620 | sophisticated, and most importantly, ethical research.

02:42:24.620 | I think we could learn a lot about how the brain works

02:42:29.020 | and its amazing capabilities.

02:42:32.780 | I think we could, I think they may, notice I say may,

02:42:36.900 | have therapeutic potential,

02:42:39.340 | but I do not think they're gonna be miracle cures.

02:42:43.680 | And I do worry, as somebody who lived through

02:42:47.720 | the '60s and '70s and watched, because of the Leary,

02:42:52.240 | the history with Timothy Leary and his colleagues,

02:42:57.540 | and the political landscape of how

02:43:00.780 | they were being used and promoted,

02:43:03.860 | I am cautious that these substances

02:43:08.380 | need to be studied scientifically and rigorously.

02:43:12.700 | And I hope that's the case.

02:43:14.520 | And I wanna caution your audience

02:43:17.720 | that not everybody should take these substances.

02:43:20.560 | They are not miracle cures.

02:43:22.440 | And while they certainly may be of benefit

02:43:25.760 | to certain individuals who are suffering,

02:43:27.880 | and they certainly may provide unusual

02:43:32.880 | and in quotes, mystical experiences

02:43:35.680 | for certain individuals,

02:43:38.560 | I am very concerned that there are individuals out there

02:43:43.160 | that will gain access to these substances

02:43:46.320 | and have very bad experiences.

02:43:48.800 | Because anybody who grew up in the '60s and '70s

02:43:50.900 | knows all about bad trips.

02:43:53.500 | And truth be told, I have had a bad trip or two in the '70s.

02:43:58.500 | And I'm glad I did, because it made me,

02:44:02.740 | I have no idea what a suicidal depression feels like,

02:44:07.600 | where you are experiencing such a darkness,

02:44:11.000 | such a lack of hope that a rational decision

02:44:15.580 | is to end one's life.

02:44:18.120 | And I think the closest I ever came to that experience

02:44:21.360 | is a bad trip on LSD.

02:44:23.820 | And I do have concerns that if you look

02:44:26.940 | at the clinical trials that have been done,

02:44:29.520 | the well could be done, not the anecdotal.

02:44:32.680 | I went and saw some psychedelic therapist

02:44:35.640 | that a friend recommended.

02:44:37.400 | And it did wonders for me.

02:44:39.900 | But the well-controlled clinical trials

02:44:42.200 | that are being done by certain biotechs,

02:44:44.640 | some academic institutions, they have very strict

02:44:48.920 | what are known as inclusionary and exclusionary criteria

02:44:54.240 | about who is allowed to participate in the subject.

02:44:57.600 | And they rule out a lot of people.

02:45:00.440 | So I don't mean to be overly cautious,

02:45:02.840 | but I do worry that if some people

02:45:07.840 | take these substances and bad things happen,

02:45:11.360 | it will slow down the excitement that's currently happening.

02:45:15.600 | And it will make it more difficult

02:45:17.980 | for serious human subjects researchers,

02:45:21.700 | preclinical researchers, to study these substances

02:45:25.040 | in the way they deserve to be studied.

02:45:28.500 | So I hope that articulates my viewpoint.

02:45:33.500 | - I think it does.

02:45:36.140 | And thank you for that viewpoint.

02:45:37.620 | It's an important counterbalance

02:45:39.460 | on a lot of the excitement that we hear about these days.

02:45:42.060 | I think the state of Kentucky just recently decided

02:45:46.220 | to give $42 million from the opioid lawsuit settlement

02:45:51.000 | with Purdue Pharmaceuticals to the study of Ibogaine.

02:45:55.020 | So there's a lot happening here.

02:45:57.660 | Just to be clear, I think there's no problem with that.

02:46:00.860 | And I actually would support that

02:46:03.080 | as long as the studies of Ibogaine

02:46:07.420 | are done thoughtfully, carefully, and ethically.

02:46:12.180 | I see no problem with testing its efficacy

02:46:15.220 | in certain mental illnesses and addiction.

02:46:20.140 | And it's actually a topic I know a little bit about

02:46:23.500 | that we'll save that for another time.

02:46:25.860 | - Right, well, first off, I want to thank you

02:46:29.580 | for coming here and sharing your knowledge with all of us.

02:46:32.900 | For me, it's been a real thrill.

02:46:35.380 | And I also just want to thank you

02:46:37.660 | for the incredible amount of work

02:46:39.260 | that you've done over the years.

02:46:40.300 | I know it's still ongoing.

02:46:41.620 | You're by no means retiring.

02:46:43.860 | - Who knows, who knows?

02:46:44.820 | - I certainly hope not.

02:46:45.960 | But I'm sure the listeners have now a clear picture

02:46:50.380 | of the enormous number of contributions

02:46:52.500 | and areas you've worked everywhere from,

02:46:54.220 | as I mentioned earlier, neuroplasticity

02:46:56.420 | at the cellular level, molecular level, addiction,

02:46:59.780 | work relating to social cognition and social interactions,

02:47:02.800 | rather as it pertains to autism models

02:47:06.740 | and now psychedelics and empathy and on and on.

02:47:10.140 | And again, trained so many prominent scientists

02:47:12.300 | in our field and to take time out of your schedule

02:47:14.680 | to come sit here with us and share some of that knowledge

02:47:17.780 | and stimulate our thinking.

02:47:19.020 | And as you mentioned, raise still more questions

02:47:22.020 | that need to be resolved is a real privilege.

02:47:25.280 | So thank you ever so much.

02:47:26.980 | And indeed, as you just mentioned,

02:47:28.200 | we'd love to have you back again for another conversation.

02:47:30.380 | - All I can say is I want to thank you for having me.

02:47:34.240 | I was a little hesitant or nervous about coming here

02:47:39.080 | and now I want to come back.

02:47:40.860 | So that was a blast when I just did with you

02:47:45.460 | and I'd be happy to continue this conversation anytime.

02:47:49.180 | So thank you for your very sophisticated

02:47:51.860 | and thoughtful questions.

02:47:54.520 | - To be continued. - Yeah, to be continued.

02:47:57.120 | - Thank you for joining me for today's discussion,

02:47:59.260 | all about neuroplasticity, reward systems,

02:48:01.980 | social connection and empathy with Dr. Robert Malanka.

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Dr. Robert Malenka: How Your Brain’s Reward Circuits Drive Your Choices | Huberman Lab Podcast

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