Dr. Robert Malenka: How Your Brain’s Reward Circuits Drive Your Choices
02:47:29 Share

Welcome to the huberman lab podcast, where we discuss science and science space tools for everyday life. I'm ander huberman and i'm a professor of neurobiology and opened ology at stanford school of medicine today. My guest is doctor Robert milena.

Doctor Robert millikan is a professor, psychiatry behavioral sciences at stanford university school of medicine. He is both a medical doctor in md and a researcher, A P. H.

D. His laboratory is famous for having discovered some of the key components allowing neuroplasticity, that is, the neutral systems ability to change in response to experience. In addition, dr. MOlina's research is considered central to the textbook knowledge about how reward systems in the brain are organized in function. Indeed, documents like this research over the last ten or fifteen years has merged what was want two disperate fields, the first being the study of neuroplasticity, again, the other systems ability to change in response to experience, the other field being the field of doping.

As IT relates to pleasure and addiction, his labatt has shown, for instance, that when we seek out particular forms of pleasure, regardless of whether or not they are healthy for us, that changes the way that our reward circuitry works and actually changes the way that dopamine is released and how IT impacts the brain. And his work has also informed how we seek out healthy pleasures, including healthy food and social connection. Today's discussion explores all of these topics, and by the end of today's discussion, you will have a rich understanding of how neurochemicals, like dopamine and serotonin, work in parallel.

To reinforce that is, to increase the probability that we will engage in certain types of thinking and behaviors. So if you are somebody interested in neuroplasticity, that is how the other system can change in response to experience, and or you are interested in reward systems, what motivates us and what we are likely to pursue in the future, given our choices of past. And if you are interested in things like social connection and empathy or lack there of today's discussion encompasses all of those topics.

IT is worth mentioning that doctor, a link up, is a true luminary in all of the fields I just mentioned as well as several other fields. In fact, when you look out on the landscape of modern neuroscience, what you'll discover is that a very large percentage of the top laboratory studying neuroplasticity and reward systems and so on all stemmed from having trained in document anchors laboratory. So it's a real honor and pleasure to be able to host him today.

And i'm sure that our discussion is going to greatly enriching way that you think about brain function, neuroplasticity and reward. Before you begin, i'd like to emphasize that this podcast is separate from my teaching and researchers at stanford. IT is, however, part of my desired effort to bring zero cost to consumer information about science and science related tools to the general public.

In keeping with that theme, i'd like to thank the sponsors of today's podd cast. Our first sponsor is element. Element is an electoral light drink with everything you need and nothing you don't.

That means plenty of salt magnesium in peason, the so called electronic and no sugar. Now salt magnesium um in patashie are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. In fact, in order for your neurons to function properly, all three electro lights need to be present in the proper ratios.

And we now know that even slight reductions in electoral light concentrations or dehydration of the body can lead to deficits. And cognitive and physical performance element contains a science back electronic ratio of one thousand milligrams, that one gram of sodium, two hundred milligrams of plastic and sixty milligrams of magnesium. I typically drink element first thing in the morning when I wake up in order to hydrates my body and make sure I have enough electrical lites.

And while I do any kind of physical training and after physical training as well, especially if i've been sweating a lot, if you'd like to try element, you can go to drink element, that element dot com slash huberman to claim a free element sample pack with your purchase. Again, that drink element L M T dot com slash human. Today's episode is also brought to us by waking up, waking up as a meditation APP that includes hundreds of meditation programs, mindfulness trainings, yoga eda sessions and n sdr non sleep depressed protocols.

I started using the waking up up a few years ago because even though i've been doing regular meditation since my teens and I started doing yoga edra about a decade ago, my dad mentioned to me that he had found an APP, turned out to be the waking up APP, which could teach you meditations of different durations. And they had a lot of different types of meditations to place, to bring your body into different states, and that he liked IT very much. So I gave the waking up up a try.

And I too found IT to be extremely useful, because sometimes I only have a few minutes to meditate, other times have longer to meditate. And indeed, I love the fact that I can explore different types of meditation to bring about different levels of understanding about consciousness, but also to place my brain body into lots of different kinds of states, depending on which meditation I do. I also love that the waking up up has lots of different types of yoga eja sessions.

Those you don't know, yogananda a is a process of lying very still, but keeping an active mind. It's very different than most meditations. And there is excEllent scientific data to show that yogananda. And something similar to IT called non sleep deep breath or nsd r can greatly restore levels of cognitive and physical energy, even which is a short ten minute session.

If you would like to try the waking up, you can go to waking up 点 com slash huberman and access a free thirty day trial。 Again, that's waking up dot com slash huberman to access a free thirty day trial. And now for my discussion with doctor Robert milena. Doctor milena. Robert, welcome.

yeah. Thanks for having me .

delighted to have you here both for the sake of your medical knowledge and training as a psychosis and of course, as a luminary in the field of neuroplasticity dopamine and reward systems, social systems, your knowledge of auto m social interactions, a newer interest in or perhaps old interest in psychodeviant s and what they're doing in potential for mental health. There are just so many things that you've done in this field.

I've been a long, long time fan of your work since your days as an assistant professor. I've tracked your career. I've learned a tremendous amount from you by observing you and from being your colleague. So really delighted to have you here.

You're making me blessing. I don't blush easily. Well.

it's all true. And and I will say as well, you've also trained an enormous number of incredible scientists um coral dive the coral don a emphatic always speaks incredibly highly of you as a mentor and somebody she's learning to tremendous out from and pretty much anyone that worked on neural plasticity on doping and reward systems addiction and now in the fields of autism and soon psychiatric s as well.

References as you often and you've been mention many times before in this podcast, if not by named by work. So again, thank you for being here. I'd love to kick off the conversation by talking about something which is very fundamental to everything we're going to talk about, but certainly fundamental to our daily lives, which is dopamine. We hear so much about dopamine, people think about doping hits. People think about dopiness pleasure, depine reward for the novice.

How would you frame the dopamine and system? I mean, does a bunch of different things in different areas of the brain and body, but to you, what what does dopa mean represent as its major function in the brain? And could you give us a kind of general country of the neural circuits that allow this chemical to more or less put value on our experiences?

Yeah, that's very well put. Um as you point out, doping is one of the major what we term neuromodulators in the brain, a chemical signal messenger that the brain uses to mediate a complex array of actions on its best well known function is in what we call the brain reward circuitry. So this is a circuit in the brain.

When we use the term circuit, what we really mean is one part of the brain communicating with another part of the brain, because the brain is this very complex, it's the most complex organ is organ in the universe um with lots of different nerve cells talking to each other simultaneously. And as neuroscientists, we try to pass what different brain areas are doing and what different neuromodulators might be doing. And chopine was discovered oh I should know this many decades ago um and it's it's, as I said, the major chemical messenger molecule in the so called brain reward circuitry and when you're talking about so what is the brain's reward circuitry? This is a part of the brain that tells us something is reinforcing in our environment.

Some or in quotes is rewarding, makes us feel Better or good, although that's a gross over simplification. And before getting into the details of dopamine and its function in the reward circuitry, I think it's useful to talk about why do we need a reward circuitry? Why do we need something in our brain that tells us this feels good or this feels bad? And IT goes back to evolution.

I I am a biological scientists, that means I believe in the evolution. Um and if you think about the evolution of our species, um everything is driven by developing mechanisms that increase our survival and it's really useful. You need something in your nervous system that tells you some stimuli in your environment is important for your survival or some stimulus in your environment is dangerous.

So it's not magic that sugary, high fat laden foods are highly reinforcing and rewarding, rewarding. It's not an accent that there has to be a mechanism in the brain that tells us that it's not an accident, that most of the time, for most of us, a sexual experience is pretty reinforcing, is pretty rewarding. It's not an accident that warm feels really good when you're cold.

That water taste much Better when you're really thirsty. There have what evolved is a mechanism to tell our nervous systems and tell our brains this feels pretty good. I should repeat the behavior that leads to that rewarding experience.

And similarly, IT was really important when you know there is an adventure in your life that's highly dangerous for some mechanism mean your brain to say, wow, I don't want to go back to where that line was and we can get into that. So this was a long run that wave saying what the reward circuitry tells us is this event, this stimulus that could be an external stimulus. Like I said, you know, a crispy cream donor, which I happened to love and I have to be very disciplined so I don't eat too many of them.

Um IT could be a drug of abuse, and maybe we'll talk about that a little bit. All of these stimuli m to activate and cause the release of dopamine in this brain reward circuitry. So now we need to get into a little bit of detail.

Um nth scientists uses. Very unfriendly terms to describe dib different brain regions. So the home of dopamine cells or brain cells are called neurons. So the home of doping neurons um are in a part of the brain, sort of what we call the lower mid brain. Um the top miner answer, a part of the reward circuitry are found in this area called the ventures tegmental ary, which i'm sorry to have to use such technical jargon and we call IT the vta.

That's the akron. I think the roof of the middle in is the team that means roof and the base of the the brain IT means floor, which is tegmental. I think that so there's a rationale, but IT doesn't help much at all to know the names.

And in fact, you are absolutely correct and I always forget. So thank you for pointing .

that it's it's a side effect .

of teaching neuro that and then which I once did back in the early eighties, but i've forgotten everything I taught. So anyhow so these doper minerals and we can talk about other types of doper miners, they send messages, what we call projections um using telegraph wires that we call actions.

They send projections to many different brain regions, the key ones in the brain, reward circuitry being an area, again, with a very complicated name called the nucleus a cumbers. And maybe after you know, I actually don't know how that name evolve the nuclei. Sure, I should know, because i've been studying for thirty years, but I have never looked up the genesis of that name.

Well, the fortunate thing about this podcast is it's both on audio platforms like spotify and apple, but also on youtube. And so now we can be absolutely sure that somebody has put IT into the youtube comments underneath this episode and therefore everyone will learn, including us. So I don't know the origins that there .

were nuclear comms and it's a gross over simplification, but it's the activity of these dopy irons in the venture al tegmental area um that then cause the release of this powerful neuromodulation neuromodulator dupine in the nucleus a cumbes which has is part of another brain structure with a tough to remember name called the ventures stride. Um and then magic happens.

And when I say magic happens even though we've been studying how dopamine modifies the properties of cells in this nuclear occupants, the truth is we don't have a deep mechanistic understanding why when dopamine is released in the nucleus a cubs, we experience that. As i'm being very cautious here, the simple way would be to say as highly rewarding, but it's a little more complicated than that. What what IT tells us is that there's something really important happening in our environment.

So and could we say that accused the arousal .

system IT gets the arousal system going. There's close ties to our memory systems, which hopefully intuitively makes some sense if something really important is happening in your environment. Because again, we I think what's helpful for your audiences to always be thinking about how these systems evolved from an evolutionary perspective.

And if depine is signaling something really important and silicate is happening in your environment, you want to remember that I could be a highly rewarding experience like a source of food for me. It's a critic I, I, I like, all done. So I don't want to, I do, to emphasize any one manufactured of one donor versus the other.

I like sugar laden, that eden food. Ds, that's why I never eat them because I like them so much. And I use that as an example, but because that was an important event for my survival of this reward circuitry.

Yes, IT stimulates my arouse the system IT gets me to pay attention. Um IT also has very close ties to memory systems. I mean, to go off and a little bit of attention, I think the one. Um I don't want to say it's a mistake. I think perhaps somewhere over simplification of how people conceptualize dopamine role in the brain is even though it's a major important role is for IT to be active and released during highly reinforcing experiences like sex, like really good food, like drugs of abuse and also can get activated subdivisions of the system during painful stimuli and during aversive stimuli um which again are really important for you to be aware of to say, oh my god, that's really bad for me and so the dopamine system is reward circuitry and its sub components that may be perhaps signal more saillant or aversion aversion in the environment are closely tied to arousal systems and memory systems. Um again, hopefully for somewhat obvious reasons you want to remember powerfully reinforcing events in your life as well as powerful emotionally or physically painful events in your life so I hope I answered your question to a modest degree no far Better than .

a modesty that that's an excEllent description of the dopamine in system from a true expert um and the question I have is about some of the context and nuance of the system but in in sort of world terms, how should I think about this? Even in my training is a neuroscientist, I know neurons can be a little active, a lot active, everything in between. They could be actually over long periods of time and short periods of time.

But let's use the example of the donor. I like a glazed old fashion donate. I actually don't have craving for sweet things, but donut is an exception.

I like the glaze old fashion donor, but if I were to see just a little piece of a glaze old fashion versus a full glazed fashion donor, could I expect that more dopamine released to the anticipation of the complete donor? And then the other question is, how does context influence the diploma in in system? For instance, if i'm very full, a glazed fashion dona might be aversive to me or as I am just a little bit hungry um or if I actually more on a schedule rewarding myself for obtaining from sweet fatty foods, then abstaining from the food might be your own form of reward yeah I mean and so to me, the dopamine system seems incredibly simple and yet incredibly prone to immediate context and the kinds of nuance that, I mean, we're constantly juggling.

I enter up myself to say that we're constantly juggling a bunch of different reward contingencies. We want to you have good health metrics and maybe have a certain esthetic qualities, our body, but we also want to donate. And so how does A A system as simple as a one neuron dullah system in the V. T. A to nuclear accumbens with some connections to the memory? How does IT baLance all of that information in real time to me, that just like staging ly complex, but also incredibly interesting.

I think you beautifully put, very eloquent description. You just said that it's staggering, simple, simultaneously, staggeringly complex, and you ask several different questions. So context makes an enormous importance.

And that's one of the reasons I became interested in the dopamine reward circuitry is, as you know, as a colleague in the academic in our science world. But your listeners probably don't. I started out my career studying very basic mechanisms of plasticity.

How does the brain modify itself and what makes the brain different than computer computer hardware is are the physical connections in the brain are constantly changing. The strength of the communication similarly for the dopamine reward circuitry is highly plastic and it's highly contextual ly dependent. Um and so you gave the example of donuts and feeding, and i'll answer you your question about the cues.

Um yes, it's I I used to give the example of thanksgiving. So let me give that example. You know in the morning of thanksgiving, all for most of us in in the united states, the morning of thanksgiving, if you are at home visiting your parents, the smells of the apple pie, the smells of the turkey cooking are highly competitive, highly reinforcing.

You're anticipating that fun event, your anticipating uncle joe coming to visit you for thanksgiving. And that's all because these cues, the smells, the anticipation of uncle joes your previous experiences are part, are part of your memory system, sort of talking to, in a simple way, your rewards or countries. So you're building up the same anticipation.

One can almost say this craving, which maybe we'll talk about in the context of addiction. And then make a long story short, think about that evening at the end of thanksgiving, those exact same cues, the exact same smell of the apple pie, turkey and uncle joe himself, at the very least, there are no longer competitive, meaning they might actually be aversive. The last thing you want is a piece of apple pie you can't wait for uncle do to leave your thanksgiving dinner.

And I always argue that just not happened magically. That happens because your brain has been modified by the context in which IT sits. And this very important modulator system, this reward circuitry, is responding to the exact same stimulated a very different response so that i'm just telling you, i'm repeating what you said the phenomenology and and again, my other favorite example is any of us who have been in an intimate relationship knows that the love of your life can turn to the pain of your existence in twenty seconds.

And again, that doesn't happen magically. This person who you crave, who you love, does something. And two minutes later you're brain is saying, oh my god, you know, I may have to break up with this person or this is an incredibly painful emotional experience.

And what fascinates me about the brain is how does the brain mediate that rapid change? So now back to so, yes, context makes is everything about how this powerful neuman dual choice system that uses doping works. And the truth is, we don't know.

It's because the inputs onto these documents irons the other nerve cells that are driving the activity of the document neurons. And i've actually studied this in my lab at stanford universe city with a colleague, you know well leach on lavo, who's a world class neuroscientist. Um we're studied the complexity of the neuroanatomy of the dopy system and these dopy neurons in the venture al tegmental area.

The source of the reward circuitry doping are receiving inputs from all over the brain. They're receiving you know indirectly or directly inputs from visual areas, from SATA sensory areas. Um and i'm not giving you a really good answer because that's one of the goals of my research to try to understand how context, how the history that you've had with these cues, which we're going to get back to of the donor or of a drug.

How is that modified, how this neuromodulator system response um similarly the the nucleus accused the the target of this powerful of modulator doping is receiving communications and what what we call inputs from all sorts of brain regions that you know about. Andrew, your audience may not that IT receives inputs. Feminine area called the hip campus, which you may have covered in previous podcast, which is very powerfully, very morant for memories, both establishing new memories.

And again, remember, that makes sense. You want this system, the doping reward circuitry, to be very connected to memory systems. So the nuclear circumvent the activity in the nuclear succumbs is modulated by dopamine, while IT is receiving information from the hip campus, which helps encode new memories, while it's receiving information from a brain area called the amygdala, which tells is a part of the brain involved in our emotional experiences.

The accompts also receives inputs from the prefrontal cortex, which is this brain area, as you know Better than me. And true um is important for decision making, for planning our activity. And I could go on .

and on we talk about pref cortex a moment because um IT always .

was surprising .

to me that prefrontal cortex is talked about is this higher executive functions area. But then when you look at the neuron atomy, it's as we say monos optically as you I know when one connection um away from structure like a mig, one connection away from structures like the the nuclear to comment in other words, prefrontal cortex to me is every bit as ancient um as some of these other structures that we think of as more ancient.

And really the whole ancient evolve thing gets a little bit dc because certain areas are not like the prevent the cortex are more elaborated in humans. But but to me, that prevented cortex seems to be especially important in the context of this thing of scaling the reward response or context of the reward response because IT can set rules IT IT seems to know. Um okay, we're recording a podcast now and there are certain rules are certain things we're going to not do.

But what's fascinating about, and i'm so glad you gave a bunch of different examples because what's fast in, for instance, about the the relationship example is that yes, at one moment um we can adore somebody. In another moment later, if they do something or don't do something, we can be incredibly frustrate with them. They can even become versions to us. Hopefully that doesn't happen too frequently.

But I think we've all had the experience of a donate an event or a person actually looking different to us and you know from one moment to the next, hopefully not at random right? And so to me that seems like um the prefrontal cortex is uniquely positioned to really say, okay, right now we are in a mode of, for a Better word, love and loving like we in the verb tense of loving being, the verb tense of arguing we're now arguing or in the verb tense of of of reconciliation of or between or something of that sort and how a structure in a circuit as simple as the dopamine system, right one molecule, could suddenly say so you know, now getting over my anger is rewarding where five minutes ago being right and being the most angry was rewarding and then five minutes before that, again, we're accelerating this movie. But five minutes or five days or five years before that this person could do no wrong and the dopamine system is just crack acting out doping said, whatever you do, i'm just delighted incredible like to me I can't think of a more interesting system .

in the I mean that was eloquently put um I agree with pretty much everything you said. I don't have much to add because you what your pointing out is the chAllenges of studying these systems, the importance of studying these systems and the chAllenge of presenting how the brain works to this podcast audience because on the one hand, you have done a mark in a fantastic job over the last few years in your podcast of making complex subjects accessible to a lay audience um and get them to be thinking about how our modern view of how the brain work may could be used to enhance health, could enhance mental well being.

But as neuroscientists, academic neuroscientists ourselves, we we know you know you are oversimplifying things and the actual functioning of a system like the dopamine reward secretary, as you just eloquently point out, is so much more complex. Um it's modified by these prefrontal inputs which are simultaneously. Telling our memory systems you know pay attention here um i'm repeating what you just said.

The context makes a big difference. The history you have with the person or stimulate with whom you're interacting like to bring this back to you you know which I never. The initial question is a small piece of a dona activate the q that that small piece of a dona activate the rewards architect and caused release of dopamine to the same extent as the full donet depends on your experience with donor.

I mean, I think for you and me, because we seem to both you know White donuts, they're highly competitive for us. Um probably doesn't matter of because we have learned even a little piece of a donor act. They talk about our memory system saying, man, that's an old fashioned laze, donate.

I want to eat that, I want to get one or I want to have the discipline not to eat IT. Um so I hope to make you question IT in. I'm shifting topics completely, but that's why addiction is so chAllenging. Let's talk about that.

Let's talk about because you've done a turn of important work in this area of addiction. I mean, one of the basic questions I have about addiction is now we hear that certain drugs are more addicting than other drugs or certain behaviors. We also hear that that we can become addicted anything. When on olympe was on this podcast, I said, what's the most unusual addiction you've ever seen and he talked about a patient who sadly committed suicide at some point later that he told us had been addicted to water to drinking of any kind first alcohol but then water eventually um and so so my question about addiction in the dopamine system is for let to pick a drug like cocaine. I've never done cocaine um but people who have done cocaine tell me that IT feels very good um and one of the more salient features of the cocaine highs that IT comes on very fast and IT ends pretty quickly too is the rate of dopamine an increase related to the addictive property of a drug or behavior as much as how much doping is released?

That's a very sophisticated a question and the answer is yes. And that usually the the lecture I give, the way I think about addiction, and obviously my friend and colleague on olympics is one of the world's experts in terms of the understanding, the human experience of addiction. I have studied IT as a cellar.

Molecular neuroscience is trying to understand how addictive substances modify reward circuitry, modify the connections in the reward circuitry, modify how doping neons act and the way I like any what appears to be a simple term. It's layered with complexity. Um addiction is somewhat of a continuum, and I like to think about whether you're talking about substances like cocaine and I who will explicitly answer your questions soon or ops as we you know, we're going in this country, there is an option ID epidemic.

Um I do like to think about addictive liability. And IT is in my view, IT is pretty clear that when we're talking about drugs, they have different degrees of addictive liability. I mean, I had a cup of coffee this morning and I and many of us listening to this podcast, it's really hard to start our day without getting that hit of caffeine.

But are we addicted to caffeine? That's a tRicky question because i've never heard of anybody robbing a bank to get casting, destroying their personal life to get caffeine. Um so I would say caffeine causes tolerance, but I would not say IT has a particularly high addictive liability. Whereas drugs like psychostimulants, like cocaine um have a very or oppos have a very high addictive liability.

So to answer your mechanistic question, there have been some famous studies done um by the director of the national suit on drug abuse s nor vocab um similar anew sly they're been studies in animal models of addiction where you nailed the in a rough way the addictive liability of a substance is directly correlated with two aspects of dopamine how much dopamine is releasing the combine and the connect s of the dopa as you said, how rapidly it's released to get a little technical even with the drug like cocaine or opioid, it's not only the drug itself, is the root of administration. Because the root of administration influences the connected s meaning how fast that drugs gets into your brain influences the reward circuitry and how fast IT causes a big rapid release of depine. And some of your podcast listeners may be old enough to remember the crack cocaine epidemic, or free base cocaine.

And cocaine does have, like meth ampt mine, a very high addictive liability. I teach the nearby, I give lectures to students at stanford about nearby ology addiction as part of a team course. Team taught course. I have kids um who I have to deal with them what you know what I always say. It's not that if you use the drug you automatically onna become an addict, but you're taking that risk and IT is impossible to become addicted to a substance if you've never used IT by a definition. And but back to the root .

of administration. So an interest know because I think we may have heard that in high school, though I, to be honest, wasn't the most attentive high school too. And I regret that high students eventually I came around but there was an but there um but you that you can't become addicted to something that you've never done which um I just wanted remark that because I think it's a profound statement because IT points to the importance of the memory system but also plasticity.

And so I want to make sure they eventually we get around to talking about how um the amount of document released on the connect ics, how that might influences plasticity. basic. What i'm asking here, queuing up in the back your mind is whether not addiction is just related to the sensation that we have when we indulge in a behavior or when we are under the influence of a drug or whether or not IT actually modifies neural circuitry in a way that makes a brougher range of uh, drugs or experiences attractive to us.

It's probably the latter. But so let me get back and I will answer that in the second to the point I was making. So it's not only the substance, it's the root of administration. So and you know, as I said, you can't develop a problem with a substance and develop substance abuse problem if you never take IT. But snorting cocaine is a different experience than smoking IT or injecting IT.

And one of the reasons the crack cocaine epidemic was so powerful is IT gets into when you're smoking IT or injecting IT, IT gets in and people do this now with, I mean math, add s most of them, and that is another epidemic in our country. Most of them smoke in. And that the danger of that is the drug, whether it's cocaine, theremin gets into your brain almost instantaneously, causes a very rapid, powerful surge of depine in the accompts in this reward circuitry.

And that the feeling you get, which and we're going to get into this, is not necessarily a happy feeling. And IT only last IT can last for tens of seconds or a few minutes. And it's a feeling that for gives you this overwhelming compulsion and urge. I wanna do IT again so even though I may not actually we feel all that good it's written and again, this gets into you know we didn't have an addiction problem for any substance other than alcohol um you know for most of human in these existence because these substances like cocaine, meth therein, synthetic opioid like center, they didn't exist. And our brain, you know the truth is our brains are were not are not designed to handle those kinds of very powerful substances.

I'd like to take a quick break and acknowledge one of our sponsors, athletic Greens. Athletic Greens, now called ag one, is a vitamin mineral probiotic c drink that covers all of your foundational nutritional needs. I've been taking athletic Greens since two thousand and twelve, so i'm delighted that they're sponsoring the podcast.

The reason I started taking athletic Greens, and the reason I still take athletic Greens once, are usually twice a day, is that IT gets to be the probiotics that I need for god. Health, our god is very important, is populated by got microbial to that, communicate with the brain, the immune system and basically all the biological systems of our body strongly impact our immediate and long term health. And those probiotic tics and athletic Greens are optimal and vital for microbiota health. In addition, athletic Greens contains a number of adaptations, vitamin minerals, that make sure that all of my foundational nutritional needs are met and IT tastes great. If you'd like to try athletic Greens, you can go to athletic Greens dot com slash huberman and theyll give you five free travel packs that make IT really easy to mix up athletic Greens while you're on the road, in the car, on the plane, at sea, and they'll you a year supply of vitamin d 3k two again， that's athletic Greenstock comes slash huberman en to get the five free travel packs and the year supply of vitamin d three k two.

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

Yeah, i'd like to know about the role of neuroplasticity and addiction. I do want to highlights something. I said I apologized for interrupting A A moment ago and was an interruption based on real excitement a um uh a person I know quite well who is a recovered cocaine added told me and that, by the way, folks, this isn't.

I have a friend and I matter. I truly have never tried coking and this person said that the first time they did cocaine, his thought was, I hate this and I can't wait to do IT again. And and that's exactly how .

you described. And I think that is a fairly common experience with people suffering from an addiction disorder. We're not supposed to use the word add s anymore because that's .

a little bit judgmental and a new in something long dict um and .

um that is a beautiful description. I hate IT but I want to do IT again um and again IT just shows the the power of the system which remember evolved for our survival so a very simple way thinking about IT is these drugs are tricking the reward circuitry to say this stimulus, this experience is really important for my survival I have to go do IT again and again and again.

A side question is the huge question is why does some people develop an addiction problem and others who have used the substance just don't. And is, again, as a world class in our scientists yourself, you know, the answer is always a complex combination of underlying genetics, the environment in which they find themselves, the environment in which they grew up and how that modified their reward circuit train. So to get at your question um one set of experiments my lab did, which other labs did too I don't deserve the sole credit for this is showing that drugs of abuse cause powerful plasticity in.

The neurons that make up the cells that make up the reward circuitry, and in fact, drugs of abuse like cocaine, meth, meth, amine, opioids like morphine, heroin change the the synapse ses. The synapse ses are the connections from other nerve cells on to top minerals on to the nerve cells in the accumbens. And these connections, these synapses, can change.

And drugs of abuse cause powerful changes in most connections, and therefore powerful changes in the activity of the dopa neurons and neurons in the the ventures, in the, in the nuclear. And in fact, the types of changes that occur appear to be similar to the types of changes that have evolved for good uses for adaptive forms of learning and memory. Um so again, this is an example that this, a superficially simple dopamine reward circuitry is changing all the time, is is highly plastic and can become more sensitive to certain experiences. Setter IT setter.

Could I ask a question about some of the general controls of the plasticity in the dopamine system? Um you said before and I love this statement, even though it's very simple, but in its simplicity is really elegant that we can become addicted to a substance behavior that we haven't taken or part taken in so is there data to support the idea that just one exposure to cocaine or one exposure to some sort of behavior can lead to a lasting change in the dopamine in system such that once propensity to be addicted to that substance again, if one were to indulge in the future, or behavior again in the future is increased? And I have a very particular reason for asking this, but i'm very curious with the answer.

I mean, in in the work my lab and other labs have done in preclinical rodent models, I want to the answer is yes.

A single administration of a drug of abuse, like cocaine, like IT morphine, can cause relatively several days, several weeks of changes in the connections onto doping and onto the neurons in the nuclear occupants those changes that does not mean these changes are permanent or um or irreversible but the change is last the long time um and again, the big question for understanding the news biology of addiction is what you know those changes are probably happening in most people who take the drug in this case and we can talk about other stimulants on drug stimuli that can become in quotes addictive you again, why in certain individuals, to be honest, it's it's not a big deal. Yeah, I did cocaine at this party. IT was nice, but I don't feel any craving or urge to do IT again.

Um whereas other individuals that sets them down you know A A very bad path and really badly affects their life. And that's a huge question in the research field is obviously if we could make predictions on which individuals are more accept ble um and you know not to get to political here um but it's also you know whether you become develop a problem with addiction or not is influenced the other parts of your life. Do you have other ways of getting reinforcing stimulus unsatisfaction having an outlet that other ways of activating your reward or dopamine e circuitry? Hey, you healthy ways like, you know, as you have articulated, I think in in your podcast getting exercise.

You know, you and I both like to get exercise. I feel really good. Sometimes it's painful during the exercise, but afterwards I feel .

great um very almost the inverse .

of the cocaine responsive.

And I hate this, but I can't wait to do IT again. I M like because IT I hate this. I don't want to do this. And then afterwards, gosh, I always feel Better and i'd be happy to do IT again.

I mean yes, I mean i'd like to exercise chasing a ball because that gets me off thinking about this hurts but um so anyhow back to addiction um so yes, these drugs can cause I don't want definitely not permanent changes from a single exposure, you know. And the types of studies i'm talking about, we're all done in experimental animals.

So how that relates to what happens in our brains and human subjects s brains is not completely clear, but I think there are parallels. So the changes might last a few days, a week or two but when can see if somebody there have been studies done where in an animal model, if you give repeated administration of a drug like cocaine, the changes gets stronger and they last longer, which is kind of intuitively obvious. Um but I getting the big question is why um in human subjects there are people who can use these substances are not develop a serious problem and there are others where they're they're very, very damaging. Um and yeah then that's why I still make the point. If you a Young person, if you you're do you want to take that risk is IT worth um to have that experience and that's an individual decision.

We we've done some pod test epo alcohol can of and seem to be a pretty wide variation in people's response to the information. I think because there are people out there who, well, i've i've got friends who are recovered alcoholics who will tell me the first drink they took. Yes, they use language like, you know, IT combined with the chemistry of my body in a way that nothing before ever had. And they felt like I was like this magical lizer, right? That has not been my experience and .

I I ve heard the same stories and it's it's hard for me to relate because like you, alcohol does not have that effect on me and that's where that is. Hard to believe that kind of immediate response to alcohol is due to their the environment in which they grew up, although that can have an influence that just feels almost more genetically encoded.

And there is evidence that issues with the use of alcohol and developing alcohol use disorder does run in families. And obviously, if IT runs in family, you have to worry about how the environment of that family influences. There's a lot of money saying there is a genetic component.

Maybe like you, if I have a drink creature in the afternoon, I just fall a sleep. Yeah, and IT does not have that effect on me. And and anyone could imagine similar things for other drugs of abuse. There are people who have used cocaine, have used methods amine, you know, who find IT modestly enjoyable IT, oh, you know, the ball or and dollar isn't this incredibly powerful experience. And you just talked about, I think, a friend or a colleague who said, I hate you, I hate that, but I want to do IT again, that's fascinating.

They're now a recovered alcohol and cocaine act, and they've ve obtained for many years, but still get a little bit of a gleam in their eye when they talk about alcohol, cocaine, in a way that I just can't relate to.

I like, I mean, I can I tell you a little than yet about me, which I love to tell. sure. And IT gets into how the reward circuitry is so closely associated with memory systems and how cues associated with powerful experiences develop their own reinforcing reverse of quality.

So, long story short, when I was a Young kid, and I can't remember, in my twice, maybe twenty, I spent a few weeks in paris, I started smoking cigarette. Me, this is a long time ago, and I got its cigarettes. Very interesting. Nickel is highly addictive, as as the tobacco companies were fully aware.

high addictive liability.

very high addictive liable.

People rob people for the money to buy cigarette.

They may not rob because although they are, my understanding is have become quite expensive. But counterfeit cigarettes are a huge market for organized. There are third parts of our of our in the world, third world countries where organized crime produce counterfeit cigarettes and are making hundreds of millions or billions of dollars um and so I think nicotine as IT is delivered in cigarettes, as you know.

I mean tobacco companies put in a lot of work to figure out the exact dose of nicotine that will make you get that kind of feeling that only last for a few minutes. So you want to do IT again and again um so we can talk about the nick you know what becomes an an a problem in a specific society with addiction is not only based on the neurobiological actions. If we're talking still about drugs or substances of that substance, it's heavily influenced by the availability of the substance to but my little story is I smoke some cigarettes in paris.

I I learned why people like to smoke IT was very satisfying to have a cigarette in a parian cafe. Just very interesting is the first few times you in hill tobacco, if you get dizzy, kind of adversities, and it's exactly what you articulated despite that you want to do IT again. So I IT was just a lot of fun for me.

I enjoyed IT, and I was disciplined. You know, at some point, whenever this was, I came back in states I didn't smoke um because I knew I was bad for you. But to this day, forty years later, every time I go back to paris, I get cravings. I actually just when I get a pack of cigarettes, I want to um have that feeling again of inhaling the smoke. But the point is of how no powerful these rewarding experiences can be. Or reinforcing experiences and for your audience is technically, you know what I have been taught by some of my psychology colleagues is we use the term reinforcing in a very behaviorally to find way something is reinforcing is, if in the behavior that LED to that stimulates IT makes you want to do that behavior here, again, rewarding means IT actually felt in quotes good. It's an .

important.

can be different. Again, as you defined by your friend, who is, I forget, I think that was cocaine. Cocaine was highly reinforcing, but I was not necessarily enjoyable or rewarding. And isn't that fascinating? I have a some colleagues in the addiction field.

Um I one of them is retired now can berge and Terry Robinson they they coin they distinguish between the terms at wanting and liking and think about that liking something means it's something you like you enjoy wanting means you wanted but you don't necessarily like IT or enjoy IT. And that's a description of your friend's experience with cocaine. Some of us have been in destructive relationships where you want that individual, but you're not sure you necessarily like that.

And sometimes people be in relationship. They actively dislike the other thing, which forging of a concept to me. But well, it's interesting this the separation of reinforcing and rewarding, wanting and liking because one of the things that very prominent in twelve p programs is to create rewards around obtaining from the drug behavior.

yes. And I should mention that programs like twelve p when followed seem to have very high successor ies at what oneyman pko tells me that in some ways they are modifying the wanting and liking. They're splitting the wanting and liking of you know alcohol, for instance, creating A A liking of the priority more than the wanting of alcohol .

for that's beautifully put um and I think that's right. How that plays out in the neural mechanisms that is a neuroscientist of interest and may I that's a tough one, but I think that's why those programs are pretty successful. It's helping the person make those associations. Um and I I don't know that much about those programs because I have not seen patients myself for whenever it's been twenty seven and twenty eight years.

But I think part of them are to help that individual find as you both other sources of lighting and reward um getting some sad satisfaction and reward from the actual abstinence being able to cognitively teach themselves that I deserve a pat on the back, I deserve credit. I feel good that I did not take a drink at that party, that I did not use that substance again. And how that plays out in our brains is a really tough one and those .

are um the way you described that is exactly right. Those those programs are highly reinforcing for absence behaviors. Everything from the social connection which we we're going to get to social connection as you know, um to the way that people start to conceptualize their added self forces others it's actually involves a splitting of the self in in interesting ways.

Um as long as we're talking about donuts, cigarettes, alcohol, cocaine, i'm curious before we move to um a bit more on neuroplasticity, is there anything that people ought to know about how different substances and behaviors that are addicting might impact the dopamine reward circuitry differently? So for instance, we talk about cocaine is having this a very rapid onset big increase until then a crash as we know um a certain pattern of connections as you describe IT. The obeid crisis is is you know incredibly serious problem right now as is matthee fedewa.

But that sounds like method to my functions, a bit like cocaine in in terms of its connect. So an opposite is a very different chemical and cope cocaine um but that sounds like IT impacts the dopamine in system um is the dopa energia activity caused by opioids responsible for the addictive properties of oppos? Or do people also like the feeling of being under oppos?

I personally hate IT coming out a surging like that game they gave me vacate and once and I hated IT. I'd rather have the pain post Operative pain, then take something like, you know, via in or or a volume or fenty or or anything like that, to me is just completely aversive. But I realized that there are many millions of people that feel quite differently.

It's a great question. So I think all the studies, both in human beings and preclinical animal models, yes, would suggest that the kind the addictive liability of opioid and cycle stimulus, which are cocaine and methamphetamine, have the common final action of causing massive release of depine in this target of the dope minerals and nuclear occupants. They do IT.

If we want to get a little scientifically technical here, the a very different mechanisms. So cocaine and methamphetamine drugs known as psychostimulants um actually bind to a protein in the brain, or a molecule in the brain that is responsible for sucking up. It's a vacuum cleaner sucking up the dopamine after it's been released.

And cocaine prevents that chopine from being vacuum up. So the cocaine hangs around longer. Mn only prevents the dopamine from being vacuum up.

IT actually causes the reverse and actually causes the direct release of dopamine from what we call nerve terminals from the site where dopamine released opp O S. Work very differently. They actually primarily, not solely work where the dopy neurons live.

And it's a little complicated. It's not that critical. But they indirectly in increased the activity within the dopy neurons themselves, causing a big, massive bigger than Normal release of dopy. So that's one comment.

Um but anybody who has used these drugs or read about these drugs to the subjective experience of the drugs are dramatically different and that's because of the actions they're having, none only in the reward circuitry but throughout the brain. So and it's it's interesting you talked about Victor, i've taken vacation because i've had several ne surgeries and things like you. I didn't like IT.

I've i've gotten other option ids for pain relief that were great. I mean, they took they took away a lot of pain after my ligament repair. Um and that's a different question that even when you're talking about opioid, all drugs are not create. They are not identical, has a much a big larger um addictive liability because of its molecular properties and how it's interacting with the opioid system in our brains and the receptors, the actual proteins in the brain that that interacts with. But the subjective experience of opiates, I mean it's interesting as some people love IT that you know if we go back in history, as you know there were the um O P M dense throughout um asia um there were wars about opposite thing.

There is the famous opposite wars between china and the united kingdom I mean showing you how powerful um the availability of a substance like an oppoa can be so i'm going off and a no commonality is dopa released in the economies but it's if you remember what I then diagram is all these drugs have some common action, usually on directly or indirectly causing the massive release of dopamine in the accompany but then they have their own individual actions because obviously when you take cocaine or method to mean it's a stimulator, you know, people are grounding their teeth. They're hype up. For most people, opioid are the exact opposite. You, I mean, in opp m dense from the movies I watched in watching arcos and all those T, V shows, you are often you're lying down your your kind of in almost a dream like state s so a very different subjective experiences.

Yeah I had an experience with the opp o ID recently, uh not voluntarily.

Over the Christmas holiday we went to visit friends and before um going to sleep I wanted some tea and I asked if they had any non caffeine tea so they gave me this tea and um that night I had the most bizarre dreams i've ever had and I slept for fourteen hours the next morning was like what was that tea and I felt off in the morning and I went IT was actually a blue lotus flower tea that is actually illegal in the united states but IT is sold and IT has morphine like compounds in IT. Um I am one of those people. It's very sumptious to even low doses of any .

kind of novel drug, yes, of serve with dextra mothering.

I boy that stuff.

Well, I I have a tendency when I get a cold, IT gets into my lungs. I cove a lot. And I think this has been reported.

This is my anette confirming what you said, dexter, with thorns and is a different sort of oppoa, and actually some people develop a problem with that for me. IT gives me really bizarre dreams, really similar to what you, I was very new. And that's a whole different conversation about what makes us dream and what they are.

What are the meaning of dreams? fascinating. And I hope you have covered, maybe you have covered that.

We not yet, but we are intending to do a whole is on sleep.

And dreaming would only get, I started out in sleep research. So I have a fun this .

drug research and sleep research have a long history of overnight with Allan homes. Work on okay.

by the way, folks.

if you're the relationship between hu cino and dreaming, Allan hobson is a good name to start your your rabbit .

nineteen of my god, i'm dating myself. Nineteen h. seventy.

I can't remember that was seventy six or seventy seven. I worked with Allan hobson as an undergraduate. No undergraduate harder. He was harvard medical.

amazing. I love his writing. And I made a lot from IT was really ahead of his time that I was like nobody.

anybody who knows me won't believe this. But I back that I was a very shy, insecure, know twenty years old. And oh, I and even in medical school, I I literally was not confident of my opinions at all. I was very shy, was thought all of the ideas I had must be obvious, and I should never save them out.

Do since you raises, I think it's really important. I mean you have this incredible career track record um you know you are doing by your college here highly respected you one just every war there is to when in neuroscience so something in particular that um was in an overnight or one day you woke up and that you know I actually believe in myself. But if you wouldn't mind sharing that because I think before we get back into some of the science, I this is scientists, a human endeavor, and and most people listen, you probably not scientists, but I think everybody deals with these issues of self out in people appeared at varying levels of confidence. But uh.

what what happened? So thank you for asking. IT was enough for me. That was a very gradual process.

And i'm i'm not as as an undergraduate, as a medical student even as a post stock. Yeah I was very unsure of my ideas, of my intellectual abilities, of weather. What I was thinking was really worthwhile.

So was a very gradual process. I think IT, the increase in my confidence, I think, began when I was a post stock, which is a training period after you've received A P, H. D.

And md, where you get additional research training. And I worked with a guy named Roger Nicholas ucsf. And Roger was a very for intellectual intense, he very forceful individual.

And I got involved in a field where, I mean, people, a little bit of attention. Your your listeners may think that scientists are these kiki individuals wearing White coats with no passionate emotion, and nothing could be further from the truth. The most successful scientists I know are pretty passionate and pretty intense about what they're working on and driven um and this is a great journalizing.

So anyhow, during my post stock, I started getting involved in a topic where there were vigorous arguments about phenomenology we were studying. So I had to develop a tougher and thicker skin. I had to be able to argue my side of of the hypotheses we were generating. So I started developing as a post dog, and then IT slowly evolved as an assistant professor.

And for your listeners who don't know, I don't like to admit this, but i'm in my late sixties I ve been running my own lab for almost forty years um so I have been it's so gradually as an assistant professor, I realized, hey, I can do this. I can do science, I can write papers that my colleagues seem to be interested in. And then gradually you know over them the next ten, twenty, thirty years, I I gained more and more confidence.

So for me I was this very gradual um build up of many different experiences where I developed some confidence that yeah not all of my ideas are great. Of course they're not. But it's okay to voice my opinion. It's okay to state my ideas and why I believe this and why I don't believe that. So that was my experience.

Thank you for sharing that because I think, you know people struggle with the that very issue and clearly showing up again and again over a long period time is helpful. But as you said, you know, learning to trust one's ideas, just a brief anette when I was um coming up in neuroscience a few years behind you.

Not too not too not .

too many I mean but I .

recall the incredible .

number of high profile papers on oral plasticity and long term long term depression terms related to the modification of synapse. Is um that rob, lana and Roger and pioneer a big segment to that work. And I remember seeing your named on labor's and I thought Roger worked for you.

Sorry, I I I love to hear that .

I was a learning pressure. He work for you, and only later did I learn that you were his postdoc.

And then, and then we collaborated as .

you became peers. Very quick, very quick.

You ve had Roger I Rogers wonder. I did have the confidence, and even as supposed stock, and actually even as a grad student, even though I was a little insecure about my ideas, I wanted to be treated as an equal. That's the one thing I did have.

I never felt that I was working for somebody else. I always felt that I was working for myself and that we were colleagues. And even though my mentors, I had more experience and I could learn from them.

but I like that that you're working for yourself even though you have mentors said, I think there there are some real gems in what you just describes. So thank you for taking the time to do that. I'd like to discuss one aspect of reward circuitry that I don't think most people think about, right? It's IT fairly straight forward.

I know that is I like to think more. More people know what dopamine is and understand IT. Thanks to your work and honors work and some discussions have taken place on our podcast other podcast.

But all too often we think doping reward, wanting, liking drugs. Okay, all of that is great. But what about the truly adaptive stuff, right? Because it's it's um easy to fall into a discussion around dopa. You know the things that are bad for us but what i'm thinking about here is social interaction.

Um clearly, we are a social species and a lot of your work in the last decade and a half or so has focused on the relationship between the reward circuitry which you beautifully described for us and social interaction and connection. And where i'm going with this is ultimately this has huge implications for autism and autism spectrum disorders. I don't know nowa ys is okay.

You're not posc autism a disease. Is that right? You hear about neurotypical and neurotic typical but is, but I have friends who have children who are severely autistic, and I don't know many parents who would elect to have a severely autistic kid. And so those people often talk about IT as autism or a child having autism. So first, all before we get into the social piece, maybe because I just table that what how are we supposed to talk about .

autism nowadays? I, I, I am very interested in the path of physiology, of what the medical profession terms. Autism spectrum disorder. As you pointed that out, the individuals living with an autism spectrum disorder are quite heterogeneous and IT can range from individuals with severe intellectual impairments and quite severe impairments in social interactions, impairments in century processing, impairments and in lots of different aspects of our behaviors that are important.

And I think nobody would say would argue those individuals on the severe spectrum do not have some sort of in quotes disorder. The issue we have to be sensitive to is is it's a hearty ious disorder. Like many brain issues that psychiatrists deal with, like depression, we are like obsessive compulsive order. Like various things. I I disorder is is always on a continue in a spectrum.

So for autism spectrum disorder, there are individuals who are high function ing, who, one could argue, have a different style of interacting socially, may have a different way of processing century information, but who have who would prefer not to be viewed as having an illness but rather would be viewed as having a different style of living and interaction and I think we need to respect that so the chAllenge is again, not oversimplifying a complex degenerous disorder um and both being respectful of the people who don't want to be defined as having a nth psychic, a brain disorder, while equally being respectful of people like your friends with severely impaired children who deserve help, who deserve research. And it's a tough one because my understanding from to beyond st reading articles in the lay press and going to websites from organizations that philanthropic ally support research related to autism within that community of individuals who are not researchers but who are have family members who are themselves dealing with some degree of autism struction resort. There's disagreements about how to what terminology to use, how to deal with them in.

It's complicated. I think we just have to respect everybody. And if you're interacting with individuals, you you know I think it's appropriate.

What do you prefer? Um I do know as a medical professional they are and especially when you're dealing with children, there are children who need help and I I I were not doing them a service by saying they don't have an issue that we should be helping them with work. So I hope that answers .

your question beautifully. I think that beautifully answers IT and encompasses all sides um so that we can move forward. And I think so as we use the term autism or children or people with autism um that's what we're referring.

I think people are very sensitive of, especially those individuals who are neuro a typical who in previously might be diagnosed as autism spectrum disorder but would prefer to not be labelled as having a brain illness that that's fine. Um it's kind of once you are an adult, you can make that decision for yourself.

We certain we have colleagues at stanford and elsewhere who at least by my non clinical course somewhere .

and again continue like you know, the experience of depression is an a but .

with depression, you love a child or an adult any less because they have depression, nor would you love a child, adult any less a because of, uh.

expression of some autism. I know the people don't, you know and so we we are being trained in the medical profession to be very for you know in our society is going this way to very careful with the terms we use and the labelling of the individuals um so you know i've been taught, you can say individuals living with an autism spectrum disorder. Um some people don't like using a term of that individual is autistic because that has some can have some I don't want to say derogatory meaning but some labelling a kind of but you know sometimes this gets out of control too as we well .

for sake of fluid conversation, we will do our best. But we will acknowledge from the outset that we are well meaning but far from perfect.

And how will handle this?

So when thinking about social interactions and leaving aside anything relate to autism for the moment, IT appears that the circuits in the brain that mediate the desire to spend time with others of the same species, maybe even with other species like a dog, um are fairly hardwired, but modifiable that we were born with the capacity to build them up. And that social behavior is highly rewarded, is IT rewarded through the dolph in system.

And what, if any, involvement is there of the serra egil system. And we have been talked about certa ia yet, but i'd love to bring up serotonin. This point maybe could educate us a little bit about serotonin because um gosh, if dopamine is fascinating, serotonin is at least as incredible.

Yeah great question.

So I I think for me these this way for me to answer IT is actually just tell you my research history and how a lab like mine at stand for that at one point was studying I, you and I would call, fairly core molecular mechanisms of neuroplasticity, how do connections between nerve cells change and what molecules are changing? And pretty hard corn molecular stuff, how do I end up studying social behaviors in mice? And what I hope we'll end up talking about even developing behavioral models of what I will define as empathy in mice, the answer is very simple.

My lab was working on the roles of classic dopamine reward circuitry and how IT changes in models of addiction. We haven't talked about depression models of depression, because just intuitively, hopefully your listeners can understand if one component of depression is what we call antonia, the inability to experience reward. You know, eating a donate is no longer satisfying.

Having sex is no longer in that much fun, which is a component of depression. If there is a mechanism in the brain that tells you something is rewarding, by definition, that's not functioning Normally. And severe depression.

So we were doing models of depression to figure out how the dopamine reward circuitry was changing. As were many other labs. We were studying addiction.

Those were the obvious ones. And I mean, that might be entertaining to do to your audience that that learn how academic scientists think. I was thinking those are fascinating topics.

They're pretty competitive. Um lots of other labs were working on IT and I started thinking what other experiences might be modifying the reward circuit? true. I actually made some attempts to look at feeding behavior, but I don't want to mean we actually never pursued that variety reasons. And that's obviously important because of there is an obesity epidemic in this country.

Um and we can talk about how the reward circuitry and some of the things we've learned from our studies of addiction may be helpful to understanding or be city bit back to social interaction. I started thinking, well, for most of us, uh, what I call a prosocial non sexual experience is highly reinforcing. Um Andrew, you're a pretty social guy.

I'm a pretty social guy most of the time. I rather go to a movie, a sporting event, a dinner with friends. Um it's you know actually for me, the most meaningful component of my life, other than spending time with my children, is spending time with my close friends.

And I started thinking, what why is that? Why do I have such a good time going to a ball game with my best friend? Are going out to dinner with another couple? Um and interacting it's because, well, it's highly reinforcing and if its highly reinforcing, IT must involve the reward circuitry.

And then I started thinking evolutionary and makes a lot of sense because if you are part of their social species, there is a lot of evolutionary, uh uh A A lot of advantages for your survival to be hanging out with other members of your species in a non aggressive way. IT can increase your likelihood to find a mate and reproduce. IT can protect you from predators.

I mean, that's why any of your listeners who ever watch, you know, wild life shows or national geographic shows, there's a reason all these animals hanging out together, it's for. Protection from predators. So there are all these reasons. So about whenever I was thirteen or fourteen years ago, my lab decided to start looking at how the reward circuitry may play a role and when I am going to call positive, pro social, non aggressive interactions um another word we use is just sociability um and for a variety reasons that back then this is got this is at least thirteen years ago, maybe fifteen years ago, a postdoc joined my lab named gold dolen.

She's now professor john's hopkins um and SHE have an interest in oxytocin um and as your listeners know, um oxy chosen is this evolutionary conserved neural petite that's very important for partition the having a baby born for milk being produced and it's gotten a lot of attention as a potential love. Neuro peptide is something that is released in our brains during a positive social interaction. There is a well known researcher in social behavior and bonding research called Larry Young, and he did some very important, now somewhat classic, work studying a species called the wall.

In particular, the prayer wall, and praise walls are a species where they made for life. It's called peer bonding. So one vote will find another wall. They basically get married. They have kids and are they hang out together for the rest of their life no dior percent divorce rate. And what Larry elemental showed um in part in an early days in collaboration with a guy in tom and soul who is a famous academic psychiatrist um they showed that oxytocin action within the nuclear circus, within this reward circuitry was required and really important for this monograms pair bonding. Having said that, there was just a paper that called into question that but that but .

there's thirty years glad you brought that up because will keep this contemporary the the reality that recent paper got a lot of attention yeah that maybe oxytocin isn't playing as prominent role in airbender as people who thought and yet folks uh, that could be true. We have to be scientific about, doesn't be open minded. But there is, you know, three decades of work that that speaks to the contrary. So I think we want to be a we want to .

weigh the evidence exactly. And again, the investigators who present the work saying oxytocin may not be as important. There are limitations to the manipulations they did, which they would agree with. So i'm just telling you so gold dolen was a post socket in my lab. And we decide we formulated a project to look at the actions of oxytocin in the nucleus, ecumenical in mice.

And the reason we study mice is you there, whether known as a genetically tractable organism? We have all sorts of really cool and sophisticated tricks we can do to probe brain circuitry, the actions of neuromodulators like dopamine in seattle, and an oxide in ways that we can do in other species um and i'm going to get back to dopamine and a second. And what we found was that oxytocin action in the nuclear circus was indeed important for promoting sociability, probably for promoting the reinforcing component of a social interaction.

And that surprised us. You know, I was like, wow, it's it's oxx y toast on seems to be causing enhancing the release of serotonin in the nucleus succumbs. And that will i'm perhaps we'll get to this that let me off on a whole series of experiments trying to figure out how serotonin works.

Studying this drug we may talk about called m dma, which is ecstasy or malley, which actually causes release of serotonin. So we did that work. And actors working in seattle, a simultaneously, there were some other papers reporting that dopamine e released in the comments that dopamine is released in the accumulating through a social interaction, a positive nonaggressive social interaction.

Truth be told, IT may also be released during an aggressive interaction. Some people like to fight. Some people like to fight. And the difference here is the dopamine released and its role in social attractions. It's not specific only for a social interaction, as we have talked about, but nevertheless, that LED my lab and other labs to do a series of papers. I'm talking about the field now showing that, and i'm giving you a lot of information here.

So how might dopa mean release happen during a non aggressive social interaction? IT turns out that oxy chosen is not only released in the nucleus occur baLance, it's released in the home of the doping unions in the vta. So my lab and another lab from northwestern showed that oxytocin can actually module dopy neuron activity in the venture al tegmental area.

So I hope of making sensor. I don't want to get to think, but this just shows how, you know, we discuss these neuromodulators like doping. I just brought an oxytocin.

We're gona talk about Sarah toner in a second. Unfortunately for your listeners, they don't work in isolation. They community influence each each other in ways that I think it's important for us to understand an elusive that .

is not too much technical detail, and I think it's wonderfully rich with areas for us to discuss. And i'm so very glad that you brought up that neither dopy nor sir tony, nor oxytocin in isolation because all too often and sometimes even on my podcast, i'll talk about these things in isolation as a way to try and simplify them a bit. But there is just no way that the brain works that way.

You know, france is turning on doping and turning off a tony. It's a waiting of of inputs. And I think that certain an IT, perhaps I should frame IT this way just as often as doping is framed as this reward molecule and pleasure and dopamine hits all too often.

I think in the popular press serotonin is discussed in oxytocin, two for that matter, as this kind of warm feel good, everything is smell um you know not really associate a reward and reinforcement and of course it's not that simple. So when IT comes to social interactions, IT sounds like oxytocin and serotonin are playing a prominent role also in the a cubans. Um and the dog in is is activated too.

You have that right? okay. So um I don't want to take us too far down the rabbit hole of neural circuit function but that to me um makes at least a brief discussion about the nuclear comment itself interesting ly OK, i'm thinking nuclear as I know that means a pilot neurons, an aggregation of neurons. It's talking to the ventures stride so we got .

to punching part of the ventures subdivision .

cuse me I miss book. Yes, it's part of the ventures strategy and it's um and in the neurons there can be active and communicate with other rain areas. But we're talking about .

a lot of nuances of function. I sometimes go to bed feeling it's so complicated.

Oh my god, IT is and and yet could we say that within the nucleus accumbens are neurons that are acting as um accelerators and breaks? Um is there a simple analogy that perhaps well, not exhaustive can be true because that's always the goal on this podcast. Knowing can be exhaustive, but we want to be as accurate as possible.

So a very influential hypothesis, which is guide at my thinking. And again, the trick, I mean, you know you have done a wonderful job of communicating complex scientists topics to your podcast audience, and I can graduate you on that and it's a really it's a really important role. But as you know, it's always more complicated than we wanted to be a scientist, especially when you're dealing with brain activity issues and how the brain media it's all its amazing functions.

Um so historical we have thought about the nucleus a cubans and other components of this ventures stride brain area as primarily being composed of two different cell types and as you pointed out, one being sort of an accelerator, something that promote certain behaviors um and the other cell type somewhat being a break saying don't do that behavior, don't perform that motor action. And that IT IT is true that there are these different sell types, IT is true that they are modulated by these modulators like dopamine and serotonin in different ways. And that simplistic hypothesis, or eristic we call IT, has been very useful in making models about how the accountant does all it's wonderful things.

What i'm leading up to is it's unfortunately, it's a little more complicated. But yes, it's there are two different sell types. And at least for your audience, we can think about job amine drive the activity of one, promoting certain behaviors and inhibiting the activity of the other, sot type and being a sort of break on certain behaviors, as long as you and I as scientists, appreciate it's not quite bad. Simple, it's a little plant.

So using that as a framework to think about social behavior, as you said, social nonaggressive non sexual interactions involve the choice of a lot of behaviors, but also the suppression of a lot of behaviors. And um and so maybe you're starting a sense what i'm doing here and I I think for people to understand how a single structure like the comments could mediate social interaction and reward IT IT sounds like it's doing is rewarding a certain category or and cateau gue of behavior options and punishing or at least reducing the probability of the occurrence of other behavioral actions. Because when I go to dinner with friends, if I know them really well, yeah, I might hug them.

I might even say something mildly and appropriate if I know the context to be safe, right? But at a dinner interview or discussion with somebody you know, I barely know, I might watch my words a little bit more. Yes, for instance.

and I think the accumbens it's associated circle. I love the way you just put that probabilities. It's my probability of having this behavior in the certain context is increase my the probabilities of not doing certain behaviors.

And I think there's little doubt that this brain area called the nucleus accumbens, all of its associated, play a very important role in what behaviors you choose to do, pursue, play a very important role in these making the decision and performing these prosocial, nonaggressive non sexual interactions. I actually also think that plays a role in empathy and leading you there. I want to have a discussion about that again.

The as a mechanistically driven neuroscientist, what is frustrating for me is I know a lot of the connections it's making and the other brain areas it's communicating with. But I can give you a coherent hypothesis or diagram of how IT all happens. Yes, you know, yes, you're still go.

What I can say is even at our current level of understanding, IT is leading to novel hypotheses that are allowing the developer hat know if we bring you back to autism, that are allowing the development of novel at at the moment, pharma logic therapeutics. That might be helpful for people who are not having Normal pro social contract and would like to have them, would like to be a about A N function in that domain and a more adaptive and productive and meaningful way. And that's the important of the the importance, in my view, of the kind of mechanistic work my lab and many other lives around the country are doing, even if we don't have a detailed. Understanding of how it's all happening. We can identify drugs and drug able targets, or even behavioral interventions that might actually help people for, for example, suffering from autism spectrum disorder of the sort that they actually want and need, interact, need the appeal to help.

I think looking at the social connection circuitry a through the lens of autism is going to be very interesting for us to do. I do have a question about what is being selected for in rewarding social interactions because obviously um we are living in a time where we don't have to aggregating groups necessarily to protect ourselves physically IT helps in certain ways in certain circumstances, but certainly to support ourselves in each other emotionally.

You know having people that we can call on when we're not feeling so well that we can look to for resources and that they can look to us um but when we go out to dinner with friends, we go to a ball game with friends and we interact with friends, i'm very familiar with the people like, well, that felt really good. I just felt good to give me energy IT actually gives me an energy to go back and do other things like spend four days alone with a bunch of papers and lectures repairing for a podcast which I also really enjoy. Um but when I do that, when I go out to dinner with friends or see friends, i'm not thinking about buffering myself against lonely ess. When I do, is I just likely interaction? So what sorts of evolutionary hypotheses can we come up with as to why the human brain is so tuned for the social interactions, why it's rewarded by not just one doping .

but .

also on in? And three prominent neuromodulation chemicals in the brain are devoted at one site in the brain and others that is connected to a course, but to making sure that we do this as often as possible without giving up the rest of our lives.

Well, I mean, again, I I think the answer i'm going to be able to give, I hope it's not tried and IT maybe a little bit obvious is and in some ways, it's it's it's it's analogous to why drugs of abuse and addiction are also a problem. Is that the circuitry that is telling us a prosocial positive interaction is so highly reinforcing evolved over, you know, millions of years or hundreds of thousands of years, whatever that that is. And I the only hypothesis I can come up with an Andrew, you may be able to come up with Better ones is what I eluded to earlier is IT was very adaptive when we were more primitive organisms, never mind non human primates, but when we were whatever we were to be a social species um for basically primarily two reasons for reproductive purposes, IT increases your likelihood of reproducing if you were hanging out with other members of your species in a non aggressive way and for protection against predators and there maybe other .

reasons party child wearing your absence, you trusted friends to .

your off thank very good point. So the circuits, the modulator we use that evolved over millennia and as you point IT out, um you know eventually i'm independent on the society in which you live.

You didn't need those social interactions for protection against predators um although you know if we look at our world now, one can make arguments both ways if you're in a war zone is a Better to be off by yourself, is a Better to be with a group of people but so they the mechanisms evolved for one purpose and they don't just disappear because there's no disadvantage to having this mechanism that tells us the social interaction is reinforcing. And I would still argue there's benefit for reproductive purposes. You can have kids if you're buy yourself all the time.

Well, this is actually think it's possible, aren't. And you can find a partner with whom to have if you're socially isolating, what makes IT much harder. So I hope I am answers your question and I think um and then and then as you pointed out, you know for many of us there's a lot of positive aspects to having friendships and hanging with your friends, emotional support, emotional buffering and .

feeling connected, something that this notion feeling connected and and later we will talk about psychiatric but yeah this notion of feeling connected um has a lot to do with buffering lonely ess when we are alone the memories and the and the energy for lack of a Better word that we feel in recalling social experiences and anticipating social experiences is really powerful. You mention um that you know that people can have children if they spend all their time alone. It's actually I realize you're not on social media and more more power to you, but this is actually a prominent discussion on social media.

You know there's an entire culture of Young people, in particular Young men these days, who, at least from what I understand in the the research literary about this, are socially isolated, spending other time online, maybe not even on social media, but are spending a lot of time online video games, hiding in electronic landscapes, digital landscapes and concern about mental health issues. There are eta concerned about porn over use in addiction there, etta. But social media itself is an incredible phenomenon to consider in light of everything we're talking about.

I can't say even though I am on social social media platforms and I you know quite active there, I can't say that i've never been on social media and experience the kind of delight and thrilling and persistent energy uh, increase that I experience within personal interaction. And yet social media, I have to assume, is capitalizing on some of the same reward mechanisms in presumably the nuclear accumbens. Um are there any data I realize this, the hard experiment to do, maybe impossible. Are there are any data that you're are aware of that that shows that social media has a high addictive liability? Or do we even need experiment?

I am not sure we need an experiment. I think IT clearly does. I agree with the point you're making. Although your podcast audience probably doesn't know who I am, I am in my late sixties.

I grew up well.

They know who you are. And I grew up before computers, before cell phones. Um so I still am a believer perhaps in an old fashion way that physical, interpersonal reactions are really important.

Obviously, there are advantages to being able to interact over social media. And I I mean, for all sorts of reasons, there's a lot of positive and good from that. But back to your question, can we get addicted? I I can't speak to social media, can speak an analyst. Icy, you know I think is much more able to eloquently describe the issues around here. I can just talk for my own experience that my cell phone is um and check you this is in social media but checking my email messages, checking my text, my text messages has a for me has a compulsive addictive equality .

of s it's like .

a lever press for a mouse and I am part of that is my own personality part of that is the immediate feedback so you get from a social media post, from seeing your name, mention, getting a message from one of your friends sure, you know i'd like getting messages for my friends. That means they're thinking about me. That means i'm part of their world.

I have no doubt it's activating my reward circuitry, not nearly to the degree that ahead of cocaine or an opp what I would do. Um so I I know what else to say about that. I I I think as a society, we we have to be aware of these issues and it's really complicated how we man, especially you know, once you an adult t you make your own decisions for Better or worse. But you know it's a huge issue obviously for anybody who has children or is .

planning to have children and on. And I see lots of accounts of people that are eighteen and older who they spend a lot of time on there. And and i'm not necessarily saying that's a bad thing.

A lot of people have entire careers that exist on social media IT just seems to me that um in syrian, facebook, linton, twitter have capitalized on this hardwired circuitry the release of ox I mean to make him really reductions as the sera and dopamine in and oxytocin virtue of someone saying something to us maybe not even a positive thing. Maybe it's A A negative thing. As you said, they're thinking of us.

There's something about being recognized by others. And this is a good seat. We're heading towards empathy here.

a discussion about empathy. I think that's very well put, that IT is capitalizing on these more primitive neurobiological mechanisms that evolved for purposes of reproduction and survival. I think that's certainly has to be the case um and I think it's important.

I mean, thank you for bringing that up for I says, the society to be at least to aware of this and IT doesn't mean it's it's like many things, it's not all good. It's not all bad IT has there are positive uses of social media, I can see. But you know, mostly we read about the the dangers of IT. We read about these kids who are socially isolated, who make bad decisions based on what they're seeing with social media. Um but and back to the nearabout neuroscience, you are absolutely correct um it's capitalizing on these mechanisms um that evolved for physical interpersonal reinterview tions because that our evolution didn't anticipate .

right just as pornography is capable zing on the sexual rose .

notion just as the gambling industry does I mean, as you know that the veggies casinos have full time people developing algorithms for how frequently should a smart machine pay off? You know what's the perfect amount of payoff ff, to keep certain individuals coming back?

Precious when you can tell I been spending a lot time around addix and former addix i've been researching things for the podcast um and a gambling addict told me something interesting they said, you know the real stinger with a gambling added is that the next time really could change every there has no alcohol lic says that that the next drink could change everything for the Better or you know that the coca tic doesn't think you know the next line cocaine could could make all of life Better now and forever where's the gambling attic actually holds in mind the infantile small ah and yet a real potential that the next time really could wipe out their debt and the wipe out and yet we know they would lose that too right?

Whatever winning say and casinos are fully aware of this. I have been told by friends who know they they employee and full time quantitative you for lack of a Better term. I was gonna computer gig.

I don't mean to that. The the and no, I would be amazed if they don't have neuroscientists to have expertise and what's called neuroeconomics or behavioral economics um I ninety five percent and sure that has to be the case. I occasionally sit down .

to the relected table because I just. So have an easy. And not long ago, actually, I had the experience of winning very little, not a large time, but but a meaningful some of money. And i'll tell you, my soul mission at that point was to get up and go back to my room and not stop at another table. And I confess, I pull one brief stop at another table, play to one here and then, and lost IT, and then just got back to my room as ickle was, and then left.

lost vegas as quickly as possible. And you probably, yes, gambling is that now again, it's all gets back to this reward circuitry. And the inter mining rewards are very, very powerful. Well, you mentioned earlier that .

the the reward system is powerfully tend to remember what were the behaviors that LED up to the rewarding experience. And and nobody nobody ever want on the at the rules tor crafts table or poker table by getting up and leaving. Yeah yeah.

So I guess my brain was just think, how did I win I one by sitting down and putting chips on the table, not by going back to my room. Exactly, exactly. And yet, I have fair number of degrees. And i'd like to think my preventive cortex is working. And yet IT was still chAllenging that moment.

The ambling is really, really you, another human activity that's quite complicated. IT can be enjoyable and where can be incredibly damaging and now are .

going to think I was that gambling ada, I was really but I swear i'm not fortunately feel very blush. That's not my addiction. I'd like to talk about empathy and you use that as a framework for eventually returning to our discussion of autism. But um you have this perhaps lang standing interest but recent research interest in empathy tell me about this work. I'm not .

familiar with IT OK. So I am gna. I'm gonna. I hope it's okay. Drag in the some work i've done on this drug called m dma because that is related um so we were working on in my lab social behaviors, positive for social behaviors um that stimulated me to start thinking about what are components of a positive prosocial nonaggressive interaction um AAAA common key component of that is having some empathy and compassion for the individuals you're hanging out with and IT is the topic of been interested in for many, many decades I was once a psychiatrist um and to get on my whatever the word is hobbyhorse um I look at the world today.

I try to be optimistic um again I am a child of the sixties and seventies when I look at the world and I actually just did a trip to israel to give a series of lectures and I look at the israeli palestinian conflict when always entered my mind. I've felt this way for decades is what is more important for the survival of the human species, then empathy and compassion, then actually being able to look at another human being, even if they look different than you, even if they have a different belief system menu. What is more important than actually understanding that ninety eight percent of your life is very is very similar.

You know if you have some differences in how you look in the beliefs you have but there's so much in common. So what's more important than understanding that when another person is suffering, they're suffering is the same as you're suffering with um and having compassion for somebody? So I started thinking, what is more important? And i'm not a politician as you know, Andrew, I have no social media present.

I figured the only way I might be able to contribute to efforts that might help you, the human species enhance empathy and compassion, is by studying the neurobiological underpinnings of IT. And I didn't realize I might be able to do that until I started studying sociability or prosocial behaviors in mice. And then I was.

Am able to t have a Young woman scientist and I want to give her credit month smith, um you might want to have moque on your podcast. She's she's a dynamo. She's now in a system professor at ucsd where you was was and moni introduced me to a series of behavioral essays that i'd like to use, that i'd like to use the phrase they are measurements, they are behavioral and thd of empathy.

Because in the world of psychologists and people who use the term empathy, IT has a lot of different meanings to different people. I'm using IT basically to mean one member of a species manius some behavior that indicates IT is being influenced by the emotional state or what we call the effective state, effective with an a of another member of that species in its immediate environment um in for human interactions. I just think of you know any of you were talking about friendships.

Any of us who had watch a close friend suffer. It's hard you want to do anything you can to help the match. Empathy, a mother with their child, a good mother, hopefully you know, when you have a kid who is sick, there's nothing worse as a parent, you just want to take that pain and suffering away.

That how i'm defining everything. So it's my belief that like any complex human behavior, there are our evolutionary reasons why that has been adapt of an important and maintained and if its evolutionary evolved, their ways of studying and more primitive organisms like mice. So i'll tell you some of the behavioral assays we're doing, one is and I get a kick out of this because it's it's pretty new for me.

So one ask what we published a paper in the journal called science about this um which is if you take one mouse and in an ethical way, you put IT in pain, you make IT time pause. One of its pause, one of its feet hurt a modest amount, and you take another mouse and you'd let that, what's known as the bystander mouse, just hang out with the mouse that is in pain for one hour, just one hour, the bystander mouse, who has experienced no physical injury whatsoever, will manifest behaviors indicating IT is now in pain. And at last, maybe four to twenty hours. But think about that, a house just hang a mouse that is Normal hanging out with another mouse in pain starts feeling and met pain itself.

And the and the mice are able to see one another and hear one another.

Good point. So you're getting to how is that communication happening and a lot more work needs to be done on IT. Most can her previous colleagues and others. One component of that is probably an a factory queue or what we call a pheromone.

The massing is creating probable .

probably because you can take betting from mice in pain and exposed the bystander mice. So that's one thing. And I ve never heard of these behavior lasses. We developed our and this is pretty cool.

Then i'll tell you two others and then i'll tell you how a connected reward circuitry um we developed ed, a novel assay which is the social transfer of pain relief. Pain relief is called analgesia. And I thought this was pretty cool.

So you take, and this is in this paper that was published in science a year ago, you take two mice and they're both in pain, modest pain. I don't want your listening ers to get upset. We are not hurting these mice too badly.

Um and IT is a tRicky issue is you know is that okay to put a mouse in pain so you can the goal is to develop Better treatments for human beings and pain obviously. Um so you have two mice and modest pain. You give one mice mouse morphine so it's now analgesic.

IT is no longer experiencing pain. You take another mouse that's in pain and you just let IT hang out with the mouse that is no longer in pain, and the mouse let is in pain will show behaviors indicating IT IT is experiencing analgesia IT is no longer in as much pain. Now think about that.

And there's actually evidence from human studies that I can tell speak to in any comprehensive way where, I mean, it's called social buffing of pain, if you are. I mean, to be honest, i've been having some neck pain just because i'm an old guy and I woke up on the right side of the bed. And if I buy myself, I focus on that pain and that bothers me more if i'm in a social socially engage. I I think it's not only that i'm not paying as much attention to the pain, but I think there's actually some relief from what's known as the social refrain of paint. So well.

i'm not happy but I actually think that um all species including humans are eating molecules mainly ordinance that are perhaps even acting directly as as analysis s and I can make that statement without ordering too much that people think i'm completely crazy because we had a known sober on the podcast from the wise men who shared with us, you know not one, not two, but at least a dozen ways in which humans are making molecules typically and communicating those to one another to powerfully impact their testosterone levels, their face of present levels, their mother and and of course no one works on all the actions that is going to be back told that system, just one slice of the sensory array. Mean, what about the the way that somebody can look at us in a way that that makes us feel good on a Normal day, one more in pain, just even the touch to a shoulder. I mean going to meetings when I was early neuroscientist and I I would probably at that point of of um you know not been the types to just walk up and say hello to because I wasn't in your field and you're the illuminate itself but I remember .

as I start my good very good I always .

say hide every .

I know you are and that .

state was a reflection on me, not a reflection on you but as I advanced through my career, what I found was you'd give a talk or something, and someone in your field more senior to you, who you respected, would give a nod or something. Those nod's mean a lot, and those nodes could Carry you along distance. I mean, obviously want to be intrinsically driven to do the work we do. But but the social communication.

social service, I think .

there's a whole landscape of things. So what you're describing um is incredible, but I think makes a tonal sense.

yes. So we have the social transfer pain of analysts here. We're working on and there's a little bit of evidence in the literature suggesting this might work. And then i'll talk about reward circuitry and maybe m dma.

And is that an impatient or not and how that might influence therapeutic efforts for autism? We're working on behavioral models where we're asking the question, will one mouse behave to give another mouse a reward? So it's the mouse that's behaving that has to press bar, nose poke or even experience a shock.

Will the mouse do that simply to get give one of its buddies a reward? Pure l and ah it's pure. It's what we call a generosity, a generosity essay and early days that looks like IT might be working. I don't um and that's a generosity essay. We can also ask a question, will amounts work so another mouse doesn't get a shock, doesn't get hurt, which is compassion.

And I think these things are gone to be working and whether you want to call that empathy, I would call that those of behaviors i'd like to use to turn behavioral antecedents of how we define empathy in human beings and the connection to reward circuitry. And in the little bit of work we have done on this is we presented evidence that these behaviors we call the social transfer of pain, one mouse experiencing pain just because it's hanging out with another mouse, the social transfer vanel gensia a mouse pain, getting some pain relief from hanging out with another mouse in pain. Whose has that pain relief? IT seems to involve one component of the complex brain mechanisms, seems to involve a part of the brain called the entire singular cortex, which human brain imaging studies suggest are is activated during empathic c.

Human responses and the projections of that area into the nucleus accumbens the connection. And we're interested in whether neuromodulators like dopamine and serotonin may influence these circuitry, these connections that are involved in these in quotes empathic behaviors um it's Better and Better um and we think drugs can be used as probes of those kinds of neo modulator mechanism. And I hope this is all making sense.

ExcEllent sentence is fascinating. Um i'm not want to suggest experiments to uh, colleagues in areas where I don't work, but I am going to anyway, when you're really smart.

that well would value your suggestions. Well, you know I love .

the the motivational backbone to what you're describing here, because I agree the world has a lot of issues. And what IT could be more important than to increase the amount of empathy and compassion in the world? But one thing that we know inhibits empathy and compassion is one's own chAllenges and struggles.

And so i'm wondering if there's a way to introduce something to this behavioral such that the working to provide another animal relief from pain, one animal working to provide relief of another animal in pain, or a animal working to provide pleasure reward for another animal. You know, if I could be scaled with how inconvenient that work is, i'm very hungry. I mean, we all taught to put our own oxygen mask on first way too, so that we don't all die, so to speak.

But you know, I grew up, for instance, with the one pair of my mother was the kind of person who would see at that time there were far fewer homeless people on the street maybe they were all institutionalize, I don't know um but if he saw a homeless person on the street of the town we lived and he would literally pull over, give them money, find hotels SHE had homeless people living in hotels all over the town we lived in IT was crazy and we couldn't get anywhere. That was the problem. We will never arrive anywhere on time.

And that's my excuse for always being late. I believe in enforce are being late. I always run late and I always run incredible, right? Just a very strong sense of a social connection, that kind of thing. But in any case, some people are like that, like he could not experience any even more come of inconvenience for helping others whereas I think most of us feel like if i'm rushing to catch a flight and I see someone who's struggling, i'm probably gone to help them if they're in a cute pain or IT seems like a dire circumstance.

But let's be honest, most people are probably going to prioritize their own stress and and priorities for lack Better word when the situation often calls for us to set those aside and intended people that are suffering. So if there was a way to introduce the um the probe of the interplay of circuit ries that are involved, how convenient or inconvenient is like a welfare is pretty easy to go out and gather and distribute food for others. But if were hungry, we tend to focus on our own hungry.

I K, so first, in full disclosure, even though i'm studying empathy and compassion, I can look in the mirror and say, I probably don't practice IT nearly as much as I should. I'm thinking of your example. If I was late for a plane, i'm not sure I would stop and help somebody.

And I just on exactly and emerging on the retire, right? You might think, goodness like, do I have time?

Yeah, exact. And so i'm proud of that statement. But back to your question, yes, I think absolutely. We can design experiments, wear afterwards, established the basic phenomenology, then we can take our subject animal or mouse and put IT in just two certain circumstances. If it's hungry itself, what IT work is hard to give another animal.

I mean, it's a good question, is i'm not sure what the outcome will be in one could predict that might work harder because that understands the hunger. In quotes, more could be, of course, it's not gonna work hard for another animal to get a food reward because it's starving itself and IT needs to take care of itself first. It's a great question.

We're also asking questions about, do you have to know your buddy mouse, right? Do you is that are you more likely to behave in a generous or compassionate way if you grew up with that mouth, you know, in the way our mice grow up in academic environments? And if it's a stranger, how will you behave? How would you behave if you had a fight with that most previously? And what if you had and and IT also matters.

Did you win the fighter? Did you lose the fight, right? You're prot, you know intuitively, is we probably would all guess, are more unlikely to help somebody I defeated in a fight previously because i'm the sun and the high archy, the dominant one, and probably less likely if that person beat me up well.

So all these are great questions. I think we can study them. And I also think there are ways we can study these kinds of interactions in human subjects, not that I am going to do that myself, someone to stand for the well, yeah yeah. So I think there is also an opportunity. And i'm happy to discuss how no modulators, like in particular serotonin, but hall, so perhaps dopamine, oxytocin may influence the brain, the circuitry and the brain mechanisms that are mediating what I term empathic behaviors.

Let's return to autism. alright.

Does autism involve a lack of empathy? Does autism involve a restructuring of the reward system around social interactions? Um maybe considering the second question first, I could imagine for instance that there are variations in brain wiring that would make IT such that um a kid who then becomes an adult gets a tremendous amount of reward from um I don't know math of designing mugs um any number of activities but that through some variation of brain wiring social interaction spending time with friends is just not a socially rewarding IT just doesn't feel good in the in the moment doesn't surly feel bad but it's not selected for and um is there any evidence that that's the case in children who are classified as autistics or having autism?

Um I I am I want to be clear I am not a world expert on path of physiology of individuals with auto s inspections disorder. I have read some of the literature. I do study mouse models of genetically based auto inspector disorder.

So the answer is yes. There there have been imaging studies. And again, so your audience, certain members, your audience, don't get mad. We remember our earlier conversation. We we made the point that autism spector disorder is a highly hearing ious set of behavioral symptoms with wide variation in how these symptoms manifest in each individual. So we cannot make blanket statements that individuals with autism and spectrum disorder are this or that. But there are studies both in human beings and mice that suggests that the reinforcing component of a social interaction is much less or lacking in our models of autism spectrum spectrum disorder and certain individuals. An important point is, is that just genetically wired was that because in their early experiences, they weren't able to get the century stimuli that tell them this is a reinforcing social experience unknown um at least those are topics that I think there are worthy investigation.

Do individuals or mice with autism spectrum disorder lack or do not have the capacity or the same experience of empathy? Again, a very complex topic and question um and it's very likely for some individuals answers yes meaning they they they do lack some of the neuroses 又 isms that allow them but that probably doesn't apply to everybody I can say in our mouse models of social interactions and our mouse models of in quotes empathy in these um are my are my show deficits um and those deficits can be rescued， meaning improved upon by manipulations of certain modulator system, in this case the serotonin system, by giving drugs including a drug called md mr ecstasy. Um so I hope I am entering your question.

I think these are worthwhile subjects for investigation. I think there's a lot of value in studying them. Let's go back to serotonin .

in the nucleus a combines. Um we will get into this in a bit more detail when we discuss m dma, but i've now spent a lot of time with a recent paper of years that .

really one the yeah part of one yeah .

the that passed the relative roles of doping in the nucleus comments versus one nucleus and by the way, um book by time this episode comes out in episode all about m dma itself and its a mode of action will have already aid and you can find that. But even if you haven't heard that um md amazing amazing molecule because IT profoundness increases um dopamine and that's why the word method femme is actually in m dma.

Um still a surprise to many people to hear that, but IT also robustly increases a tone and transmission. And what I love about the paper from your lab, that explorer this is that at least by my read of the data IT showed very convincingly that is serotonin released in the nucleus ments that's responsible for the prosocial effects of M D M A, where as oxytocin thing we talked about earlier, that everyone assumes is the carbonic molecule, the molecule of love, both in humans. Now there's a study in humans and and the mouse work that you've done doesn't seem to play as prominent a role in the social uh enhancement that M D M A causes.

And the reason i'm asking this in the context of autism is that for a long time there was excitement about the idea that oxytocin nasal spray might make autistic kids more excited about social interactions, more tuned to social interactions. First question is, is there any evidence that increasing oxytocin in a child, adult with autism makes them somehow more social or desire more social connections? I'm not aware .

of any I don't think the I think IT is IT is a worth. Wa IT has been studied. I I don't think we can close the door on the potential therapeutic c uses of oxy token from the people I know who are much more expert in this than I am.

I think most of the clinical trials have been pretty disappointing without know a lot of hope that intranasal oxytocin would promote more positive prosocial experiences. I don't think the door is shut yet. There may be different ways of administering, administering IT.

There may be ways of making a different type of oxytocin that might be beneficial. Al, I have a colleague at stanford who's actually looking at a related neuropace tide called lazo person, and she's finding some potential benefit from mat and VISA president and oxytocin closely related to each other. They can even activate some of the same, what we call receptors in the brain.

So I don't think the door is closed on the possibility of oxytocin or related therapeutic agents having some therapeutic potential. The evidence, as far as I know, where is not there yet in terms of m dma. Um again, complicated story.

Um as you pointed out, M G M A it's major molecular targets don't want to get too technical. Here are the the serotonin vacuum cleaner, the molecule that vacuum up serotonin and the dopamine vacuum cleaner, the molecule that vacuum up and excuse my language sucks up doping when it's released um because it's an unfit mean derivative. Um as you point correctly pointed out, IT natly prevents these proteins. We call them these molecules, these vacuum cleaners from vacuum up the document in sera and went to release IT actually causes IT. How do I don't want to use the the the terminals to bomb IT .

out to of me that's .

what I say on the release i'm .

known for when I my solar opposites, when I talk about some after release, i'll say that they they bombed out.

So what when i'm fin deriving .

transit's an insult .

does is IT actually calls what's known as a reverse transport. IT actually causes IT. None only prevents the vacuum cleaners from sucking up the dopa.

And serotonin IT causes IT to spew out dopamine and serious. So or imagine if you're vacuum cleaner started the pressure, your vacation cleaner reverse, and all the dirt you collected started being spewed out. Now, the one difference for m dma and is a fascinating and topic I hope we have time to talk about is why is M G M A. Quality tatis ly for most people, give give human subjects a different experience, then cocaine or mEthane are especially matthee theta.

presumably the fact that they're .

so much serota exactly. And so if you actually, again, and this is why for your audiences, this is why hard core molecular science can actually teach us something about complex human behavioral phenomena, such as social interactions and addiction, at least the hypothesis we propose and others in the field. It's not just science is not done in isolation.

So I want to give credit where creditors do. We did not define the following that M G M A IT affects the share a toning system more than the joplin's system. So it's not equal.

It's not fifty, fifty. Maybe it's seventy, thirty, eighty, twenty. And that's because the molecule itself of M D M A, again, i'm trying not to use language hazard if bind to IT has a higher ethical IT likes to bind to an influence. The serotonin vacuum cleaner more than the dope me vacuum cleaner. It's still affecting both but it's not fifty fifty. It's more whatever seventy seventy percent seaton, thirty percent dopamine um and then IT does the influence oxytocin in very complex ways um which is a further technology discussion um IT was just a nice paper that came out that reported that serotonin release in a hypothetical mic structure which again the hype of Thomas.

you can explain your marbles size structure above the roof, your mouth responsible for a sex temperature control uh feeding and society and a bunch of other things critical um and yeah .

and it's the home of neurons that produce socks y to you so this paper reported that when serotonin is released in the hypothalamic, IT activate and causes the release of oxytocin that's in hypothenuse. Our work in the reward circuitry suggested oxytocin so that's serao an upstream of oxytocin. The hypothalamic and the where we were looking in the accumbens was the opposite caused the release of satan.

So at the point to your listeners is the brains, unfortunately, complicated, know what we like, traction. But we like to come up with general hypothesis and principles, but sometimes the devils in the details, and we really need to probe deeper. So back to your question about our previous paper, and dopamine and serotonin, so what we are what we proposed, which is far from nail down, is that M D M A, because IT is an epitome derivative, does influence depine release and depine the dopamine system.

And some of my colleagues in the m dma field, who I respect enormously, don't like me to say this, but i'm going to say at anyhow. Remember earlier in the podcast, we talked about different substances. Having addictive liabilities doesn't mean a substances automatically addictive, doesn't mean it's automatically not.

It's a continuum. And I would argue that M, G, M A does have a some addictive liability because IT is an epitome derivative. IT feel good and IT feels good.

And so there are individuals that especially you know your listeners may know and dma has gotten a lot of attention because it's in a therapist trial that looks very promising for as an adjunct to psychotherapy for post dramatic stress disorder. And the the F D A, the part of our government that approves or disapproves the legal distribution of thai ative drugs, mind up approving M D M A for certain uses. Um the point being is that once if IT gets approved, my personal feeling is that will have some addictive liability.

IT also has this very powerful what you and I my term and drew a prosocial effect. Um some people even call IT an impatience en that's a little controversial meaning that enhances your capacity for empathy to to experience the emotional state of another individual to want to understand that persons experiences and emotional state um and are what we've suggested is that the addictive liability is mostly, although not solely being mediated by its actions on the dopamine e system. Whether it's positive, more prosocial effects and perhaps it's in pathogenic effects are more likely to be mediated by its interactions with the serotonin system in in in this reward circuitry.

And we're actually doing a lot of work to test that hypothesis. We're actually testing m dma in these behavioral models of empathy in mice um and IT looks like our hypothesis being supported. The other thing just to drive your your listeners crazy about, sorry, listeners, how complex the brain is.

if you think I was neither you nor I were consulted the design phase and so boxy because .

I don't trust me as a sciences, I wish I could keep things simple as possible. That's what good science is. IT turns out the satan, satan in is produced by neurons in another part of the brain, with this wonderful name called the doors, or rafa nucleus.

And IT turns out the serotonin neons talk to the dopy neurons. That is an influence dopy neurons. And um so it's again the point we made earlier in your podcast, even though it's fun and useful both for your listeners and as scientists to think about these powerful chemical messengers in isolation because that's how we can make progress scientifically.

It's how your audience can understand some of the concepts that have been elucidate from brain research over the decades. But they don't work in isolation. They influence each other, they communicate with each other. We're actually doing studies showing that serotonin release and the incomes actually modules stop in release.

So I gets crazy complicated, but you can still develop symbolistic hypotheses, like, as I was saying about M D M A, where, you know, abuse, addictive liability and some of its reinforcing qualities, which you just mention, M D M A, A lot of people find IT fun to take. IT is probably mostly being media to be of the doping system and some of the social effects of and are being mediated by the serotonin stem. We're actually doing studies to figure out whether the reinforcing component of a social experience requires that dopamine release probably does.

That's what i'm most interested really in the context of md ma. And we should just mention because we do like to mention these caveats. yes. And I can say this because I participated in a trial with dma. IT is a very pleasant experience.

It's certainly not for everybody is still is a schedule one drug at this moment as so so you can go to for possessing and or selling. In fact, there was a big bus recently in canada and another one in brussels. A large amount md may collect to those people are probably going to go to prison for a long period of time. So you you you don't want to take IT or position that is illegal. Um we're talking about clinical trials here, but also um the fentener issue.

There's a lot of feminine.

So we be nice if we did. A lot of people are dying thinking that they're taking one drug when they are taking another. So so we are not encouraging the use of these. But I will say that the objective experience of M D M A, provided it's done in the appropriate clinical setting, it's actually M D M A doesn't contain other things those correctly at sea um is a pleasant one for sure. And my sense is that um the dopamine release uh is reinforcing the experience that the context that salton's is providing with a social context and and the word context there becomes important when we think about back to the nineties when raves and people were also you know getting um I guess positive feedback from the interactions they were having dancing all night party with friends. That said, I mean I think that um returning to the issue of autism in the roller seat onan, so in autism there seems to be less of A A reinforcement pathway for certain kinds of social interactions um in some individuals with autism um and i'm aware that there are some prescription treatments for autism that capital on the system and open ming system.

So is IT fentiman to my knowledge, the only fda approved pharmacologic therapeutic for individuals with auction and spectrum disorder is actually god, i'm just blank king. It's not a cerritos gic drug. I have to look at up.

I want to say we spare on for agitation. There is no drug for for lack of a Better terms, the social deficits. There is no fda approved drug. If you look at the literature, psychiatrists and individuals with with good intention have tested the utility of traditional theatre tric drugs like prosaic assize.

There are drugs known as S N R S, drugs that influence saton release and another neuromodulator that you know well, nor benin and at least well done clinical trials, which in my view, as an academic, are very important. None of them have showed ethical acy. Having said that, there are several companies and full disclosure here.

Here I am the founder of a small biotech called map light therapeutics and i'm not advertising for map light. I'm just during a full disclosure IT was found IT with carl day, who you've had on your podcast um in an entrepreneur in sanford going to entirely Nicolet. Um and we have the phase to trial.

Phase to trial means it's a safe drug. We ve done all the safety work um and it's a drug that targets a subtype of receptor for saton's. Serotonin works on many different I know what word can I use other than receptor?

No, this this podcast probably be familiar with the substance of parking spots for for you. Yes, that the paper you I was refreshing earlier from your lab IT talked about the tone and one b recept being particularly important.

And the point being is, you know, I do have an interest in this on, can you use the type of discoveries we ve made in mice might not actually have any relevance to human, sub human beings, in particular those who some of which have some sort of sociability deficits. Other companies are pursuing this too. So m dma itself, there has been I don't know if it's ongoing. There is a well known organization.

I don't if you've ever had anybody from maps in this, the multi disciplinary association for psychiatric studies, a map deserves a lot of credit for being a pioneer in saying, in particular with M, D, A, promoting the idea that you know, this drug deserves rigorous, an ethical study that at least my view in maps, which was founded by uh individual name rip dbl in, has deserves enormous credit for their thirty year effort to make IT allowed illegal to actually study mda the point of making, as I know, maps and perhaps others have done some small trials studying md ma in individuals, high functioning individuals with some form of social anxiety. Um i'm saying this because this is public. There's another company called mine made which is one of the publicly traded psychiatric companies and this is on their website full disclosure.

I am on their scientific advisory board um they are gearing up to do a trial of A I don't want to get too technical of a certain form of m dma. There are two different types of m gma that they have these horrible names called in nantillons. Um so the M D M A that is used for clinical trials that maps M D M A is a molecule and IT has mirror images of itself.

And one one has the name R M G M A and one has the name S M G M A. And there they're called this heart in nanjing as because they are mirror images of each other and other labs over the years, not my lab. I deserve no credit for this.

Have done some studies to suggest that the S N. Antimachus the one that has a higher interaction with the dopamine e system and the r in antimachus a higher interaction with the serotonin system. Um if if you look at the the literature on autism spectrum disorder in human subjects, there's a bunch of paper suggesting seery c systems are malfunctioning in individuals with autism spectrum disorder. And if you look at reviews have written early of my papers, we probably cite some of the reviews.

It's clear that certa a is playing some role in social interactions, at least in my son, almost certainly in humans as well. It's hard to imagine, based on data from everything from accessorize to neo toxic lesion of the human brain eta, that it's not also playing at .

least a similar role. And I fully agree with that. And as we were discussing, there's there's a modestly extensive clinical literature, meaning literature from human subjects suggesting that some aspects of brain systems, say, utilize serotonin, and as one of their signal molecules, one of their neuromodulators ory mechanisms may not be functioning in some populations of individuals with auction and spectrum disorder.

So based on that, based on my life's work on the role of satan in in modifying reward circuitry, its role, role in pro social behaviors. And the biggest clue, which I think you would agree with, Andrew, is this drug, M D M A. I mean, this is why I am not a juggling myself.

I am a child of the sixties and seventies, so I did, which means some twenty years older than you, Andrew. I did experiment like everybody of my generation with psychoactive substances in the seventies. So I don't want to lie about my experiences. I also would say, like many neuroscientists, my experiences with psychoactive substances stimulated my interest in neuroscience.

How do these substances work? why? When I get, when I was a Young kid, the first time I got drunk on beer, why is that happening? But more seriously, I use drugs in my research as powerful probes of brain function, with the advantage that are now talking scientist to scientist with you, Andrew.

They have molecular targets that we can manipulate in rigorous ways. We can figure out where in the brain they act using the modern tools of neuroscience with. Your audience may not know about, i'm saying this to you, conditional knock out mice. Rescue experiments, we can do all those fancy stuff and we can use drugs to study even things as complicated as empathy.

And I really do believe that it's why i've been interested in an m dma for decades is there's a clue there how does a drug that has molecular targets in the dopy nero dulichium stem in the serotonin neo modulator system have such a powerful effect, which is relatively specific on social interactions? IT doesn't make you want to go eat more donuts. IT doesn't um I don't know for me, there's a clue there. There's something really important from that phenomenal logical observation in the human experiences that we can learn from.

I completely agree about md ma. And we've done a couple podcast about Sullivan and by extension, elsy because even though there are differences, there are so as far as we understand, largely work through um you know activation of the certain ones and two a recept broadening network connectivity. So again, that's serotonin, serotonin, serotonin.

But different receptors, very different subjective experience. And I guess perhaps the best way to describe IT IT is that lsd and Sullivan was always considered mystic in in their subjective effects where as um M D M A can be an impatient an activity um and so serita in acting to three different receptor or systems impacting and creating very different subjective experience. I also agree, I think M D M is particularly interesting for the neuroscientist um perhaps also because at least to mind knowledge there is no substance in nature, no plant, no mushroom, no got, no um any mode um that creates this increase in dopamine, serotonin, sii, multi evensen.

M D M A is a sympathized molecule and so IT may be one of the again, highlighting all the safety issues and things we talked about before. IT may be one of the great at least experimental probes of the brain that humans have developed and IT may be one of the great therapeutic probes um that folks like maps of are now doing such fantastic work on. So I am very excited about what's happening with the research on M D.

M. A. So glad that your laboratory is passed that some of the relative rules of serotonin and the receptors involved IT since we mentioned serotonin two a for solicited and lt. We'd be remiss if we didn't say that this wonderful paper that we will provide a link to in the shown of captions by the way folks um that uh rob lana here's laz focus on the sir tony one b receptor so IT even just differences in receptor subtypes leading to profoundly different subjective outcomes. I find that to be just one of the most important areas that one could even think about little long work on.

Thank you. I appreciate the compliment. I will also say unlike everything we're finding, it's not all about only saton in one bee, but as you know, there are again pointing to the the amazing and powerful complexity of the human brain or the a million brain.

There are sixteen different serotonin parking spots or receptors that are distributed in different brain areas in complex ways. And so that's daunting. But IT also offers possibilities for developing very novel of the reputed agents that that activate or inhibit these in complex ways, hopefully for therapists benefit.

So before we conclude, i'm very curious to get your opinion on what you see is the landscape of the work on psychiatrically and m dma, which shish really a classic psychiatric. But all these drugs that, as you point IT out during your youth, we're used recreational and for mind exploration and expansion, and are now being as potential theraputics for various mental health chAllenges, as well as potentially expanding consciousness, empathy in all all of that.

I mean, not getting into the details of the the legal issues that have to be overcome, not even necessary talking about the clinical trials of the people doing the work in different laboratory, which have to imagine this is must amuse ticket surprise you. I mean, how do you feel about what you're seeing now? Because this is a very exciting time .

for these compound. Um IT tickles me and excites me with the appropriate caution. Um so I do think drugs are very powerful robes of brain function. I think this class of drug, which, as you correctly pointed out, people use the term psychodeviant scientifically when pursuing their understanding, their therapy tic potential, their mechanism of action, is more useful to divide them up into different categories.

The classic allusions, which are all else, and suicide ban, the intact or and pathogen which is M D M A which is really equalisation vely different drug there are other substances which we we don't time to talk about like I began an iowa a which are very complex peyote but nevertheless I am tickled and excited as a child of the sixties and seventies um but I am also not even Angelical about their you use and their therapy peut c potential so as you can imagine what i'm gna say I think they should be the subject of rigorous, sophisticated and most importantly ethical research. Um I think we could learn a lot about how the brain works and its amazing capabilities. I think we could I think they may notice, I say may have therapeutic potential, but I do not think they're gonna miracle cures. And I do worry.

As somebody who lived through the sixties and seventies and watched because of the Larry the history with Timothy leary and his colleagues and the political landscape of how they were being used and promote IT, I am cautious that these substances need to be studied scientifically and rigorously um and I hope that the case and I want to caution your audience that not everybody should take these substances they are not miracle cures and while they certainly may be be of benefit to certain individuals who are suffering and they certainly may provide unusual and in quotes mythical experiences from certain individuals, I am very concerned that there are individuals out there that will gain access to these substances and have very bad experiences because is anybody who group in the sixties and seventies knows all about bad trips and truth be told, I have had a bad trip or two in the seventies and i'm glad I did because I made me I have no idea what a suicidal depression feels like where you are experiencing such a darkness, such a lack of hope, that a rational decision is to end one's life. But and I think the closest I ever came to that experience is a bad trip on L. D.

And I do have concerns that if you look at the clinical trials that have been done, the world had done, not the anecdotal. I went and saw some psychiatric therapies that a friend commended and IT did wonders forming, but the well controlled clinical trials that are being done by certain biotech ks, some academic institutions, they have very strict what are known as inclusion, ary and exclusionary criteria about who is allowed to participate in the subject and may rule out a lot of people. So I don't mean to be overly cautious, but I do worry that if some people take these substances and bad things happen, IT will slow down the excitement that's currently happening and IT will make IT more difficult for serious human subjects, researchers, preclinical researchers, to study these substances in the way they deserve to be studied. Um so I hope that um articulates like you point to I think IT does and thank you for that .

viewpoint is an important counterbaLance on a lot of the excitement that we hear about these days. I think the state of kentucky just recently decided to give forty two million dollars from the opioid lawsuit settled with reduce pharmacy euros to the study of I begin. So there's a lot happening. I just to be clear.

I think there is no problem with that. And I actually would support that as long as the studies of ibogaine are done, thought fully, carefully and ethically uh, I see no problem with testing its efficency in certain mental illnesses and addiction and it's it's actually a topic I know a little bit about that will save that for another time, right?

Well, first off, I wanted thank you for coming here and sharing your knowledge with all of us. For me, it's been a real thrill and I also just want to thank you for the incredible amount of work that you've done over the years. I know it's still ongoing here by no means retiring, and I certainly hope not but um i'm sure the listeners have um now a nuclear picture of the enormous number of contributions in areas you've worked everywhere from, as I mentioned earlier, neo plus to of the cellar level molecular level addiction work with ling to social cognition and social interactions rather um as IT pertains to autism models and now psychedelics and empathy and on and on and again trained so many prominent scientists in our field and to take time out of your schedule to come out here with us and share some of that knowledge and stimulate or our thinking and as you mention, raise still more questions that need to be resolved is a real privilege so thank you ever so much. And indeed, as you just mention, we'd love to have you back again .

for another conversation I wanted. Thank you for having me I wasn't little hasn't into nervous about coming here and now I want to come back so that was a blast when I just stood with you, and I be happy to continue this conversation anytime. Ah so thank you for your very sophisticated and thoughtful questions to be continue to be continued.

Thank you for joining me for today's discussion all about neuroplasticity reward systems, social connection and empathy with doctor Robert millikan. If you're learning from and or enjoying this podcast, please subscribe to our youtube channel. That's a terrific zero cost way to support us.

In addition, please subscribed to the podcast on spotify and apple. And on most spotify and apple, you can leave us up to a five star review. If you have questions for me or comments about the podcast, or guess that you like me to consider hosting on the huberman lab podcast, please put those in the comments section on youtube.

I do read all the comments. In addition, please check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast.

Not so much on today's episode, but on many previous episode of the huberman in law podcast, we discuss supplements. While supplements are not necessary for everybody, many people derive from men is benefit from them for things like enhancing sleep hormones, ort and focus and much more. The huberman lab podcast is partner with momentous supplement.

If you're interested in learning more about the supplements discussed on the huberman and lab podcast, please go to live momentous spelt O U S. That's live momentous dot com slash huberman. If you're not already following me on social media, I am huberman lab on all social media platform.

So that means instagram, twitter, facebook and linton on all those platforms. I post content, some of which over lapse with the content of the human woman lab podcast, but much of which is distinct from the content on the huberman lab podcast. If you haven't already sub ribes to the humane lab podcast, neural network newsletter, the neural network newsletter is a monthly newsletter.

IT is completely zero cost, and IT includes protocols or what we call tool kits that you can download. So for instance, tool kits for enhancing sleep, a tool kit for learning a neuroplasticity tools, ds for fitness, and for much more, to sign up for the neural network newsletter, simply go to huberman lab dot com, go to the menu and scroll down to newsletter. You sign up by providing your email.

But I want to be clear that we do not share your email with anybody. Thank you once again for joining me for today's discussion with doctor Robert meana. And last but certainly not least, thank you for your interest in science.