Welcome to the huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew huberman and I'm a professor of neurobiology and Ophthalmology at Stanford school of medicine. Today, my guest is dr. Robert milenka dr. Robert milanka is a, professor of Psychiatry and Behavioral Sciences at Stanford University, School of Medicine. He is both a medical doctor, an m.d. and a researcher, a PhD his laboratory.
Is famous for having discovered, some of, the key components, allowing neuroplasticity, that is the nervous. Systems ability to change in response to experience in addition. Dr. Malenko's research is considered Central to the textbook knowledge about how reward systems in the brain are organized and function. Indeed, doctor malenko's research over the last 10 or 15 years has merged. What was once two, disparate Fields? The first being the study of neuroplasticity. Again, the nervous systems ability to change in response to experience and
Other field, being the field of dopamine as it relates to pleasure an addiction. His laboratory is 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,
Russian. You will have a rich understanding of how neurochemicals like dopamine and serotonin work in parallel to reinforce that is to increase the probability that we will engage in certain types of thinking and behaviors. So if you are somebody interested in neuroplasticity, that is how the nervous system can change in response to experience and or you are interested in reward systems. What motivates us and what we are likely to pursue in the future given our choices of past. And if you are interested in things like
Social connection and empathy or lack thereof, today's discussion encompasses, all of those topics. It is worth mentioning that doctor milenka 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 neural, plasticity, and reward systems and so on all stemmed from having trained in doctrinal 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 enrich the way that you think about brain function neuroplasticity and reward. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to Consumer information about science and science related tools to the general public in keeping with that theme. I'd like to thank the sponsors of today's podcast. Our first sponsor is rokka rokka makes eyeglasses and sunglasses that are the absolute highest quality.
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Yeah. Thanks for having me,
delighted to have you here both for sake of your medical knowledge and training.
Raining as a psychiatrist and of course, as a luminary in the field of neuroplasticity dopamine, reward systems social systems, your knowledge of autism and social interactions, a newer interest in or perhaps old interest in psychedelics, and what they're doing and potential for mental health. They're 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 blush and I don't blush easily. Well,
it's all, it's all true, and I will say as well. You've also trained an enormous number of incredible scientists. Carl dicer off the Carl dicer off on a Lemke. Always speaks incredibly highly of you as a mentor and somebody she's learned a tremendous amount from and pretty much anyone that's worked on neural.
Plasticity on dopamine and reward systems addiction. And now in the field of autism and soon psychedelics as well references as you often. And you've been mentioned many times before, in this podcast, if not, by name 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. Yeah, we hear so much about dopamine people talk about dopamine hits people think about
Amina's pleasure, dopamine reward for the novice. How would you frame the dopamine system? I mean it but does a bunch of different things in different areas of the brain and body. But to you, what, what is dopamine represent as its major function in the brain and could you give us a general Contour of the neural circuits that allow this chemical to more or less put value on our experiences?
Yeah, that's very well put
As you point out, dopamine is one of the major. What we term neuromodulators in the brain, a chemical signaling messenger that, the brain uses to mediate a complex array of actions its best. Well, known function is in what we call the brain's reward circuitry. So, this is a circuit in the brain. And when we use the term circuit, what we really mean is one part of the brain communicating with the
Other part of the brain because the brain is this very complex. You know, it's the most complex organism organ in the universe with lots of different nerve cells, talking to each other simultaneously and is neuroscientist, we try to parse what different brain areas are doing. And what different neuromodulators might be doing and dopamine was discovered, oh, I should know this many decades ago and it's
It's as I said, the major chemical messenger molecule in the so-called brain's reward circuitry and when you're talking about. So what is the brain's reward circuitry? This is a part of the brain that tells us something is reinforcing in our environment. Some stimuli or is in quotes, is rewarding, makes us feel better.
Better or good although that's a gross oversimplification and 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 am a biological scientist. That means I believe in evolution and if you think about
Out the evolution of our species. 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 accident. There has to be a mechanism in the brain that tells us that it's not an accident that most of the time for most of us. A sexual experience is pretty reinforcing is pretty rewarding. It's not an accident that warmth feels really good when you're cold that water taste much better when you're
Thirsty there hath. What evolved? As 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's really important when you, you know, there is an event in your life that's highly dangerous for some mechanism, in your brain to say, whoa, I don't want to go back to where that line was and
we can get into that. So this was a long-winded way of saying what the reward circuitry tells us is this events this stimulus. It could be an external stimulus, like I said, you know, a Krispy Kreme doughnut which I happen to love, and I have to be very disciplined. So I don't eat too many of them. It could be a drug of abuse and maybe we'll talk about that a little bit. All of these stimuli seem to activate and
cause the release of dopamine in this brain's reward circuitry. So, now we need to get into a little bit of detail Neuroscience just use these
Very unfriendly terms to describe different brain regions. So the home of dopamine cells or brain cells are called neurons. So the home of dopamine neurons are in a part of the brain, sort of what we call the lower midbrain. The dopamine neurons are part of the reward circuitry or found in this area called the ventral tegmental area.
Which I'm sorry to have to use, such technical jargon, and we call it the VTA, that's the acronym. And the roof of the midbrain is the tectum. It means roof and the base of the midbrain, it means floor which is tegmentum. I think that's the so there's a rationale but it doesn't help much at all to know the names. And in fact, you were absolutely correct and I always forget that so thank you for pointing that out. It's a it's a side effect of teaching your own at and then which I once did.
Back in the early 80s but I've forgotten everything. I taught so come anyhow. So these dopamine neurons and we can talk about other types of dopamine neurons. They send messages what we call projections, using Telegraph wires that we call axons, they send projections to many different brain regions. The key. One in the brain's reward circuitry being an area again with a very complicated name called the nucleus accumbens
And and maybe Andrew, you know I actually don't know how that name evolve the nucleus accumbens. I don't I'm sure I should know because I've been studying it for 30 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
So, I don't know the origins of the word nucleus
and it's a gross oversimplification but it's the activity of these dopamine neurons in the ventral tegmental area that then cause the release of this powerful neuromodulator to my neuromodulator, dopamine in the nucleus accumbens, which has a is part of an another brain structure with a tough to remember name.
I'm called the ventral striatum and then magic happens. And when I say magic happens, even though we've been studying how dopamine, modifies the properties of cells in this, nucleus accumbens the truth is, we don't have a deep mechanistic understanding why when dopamine is released in the nucleus accumbens, we experience that as I'm being very cautious.
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 Dan, could we say that? It cues the arousal
system. It it gets the arousal system going, there's close ties to our memory systems which hopefully intuitively makes some sense. If something really important is happening in your environment. Because again, we
we at, I think what's helpful for your audience is to always be thinking about how these systems evolved from an evolutionary perspective. And if dopamine is signaling something really important and Salient is happening in your environment. You want to remember that? It could be a highly rewarding experience like a source of food for me. It's a Chris. I like all Donuts so I don't want to I do to emphasize anyone.
Picture of one donut versus the other. I like sugar-laden fat-laden Foods, that's why I never eat them. Because I like them so much and I use that as an example, but because that was an important event for my survival. This reward circuitry. Yes, it stimulates my arousal system, it gets me to pay attention. It also has very close ties to memory systems and to go off and a little bit of a tangent. I think the one
I don't want to say it's a mistake. I think perhaps somewhat over simplification of how people conceptualize dopamines 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 this system during pain.
Awful stimuli. And during aversive stimuli 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 this reward circuitry and its subcomponents that maybe perhaps signal more salience or a version of version in the environment are closely tied to arousal systems and memory systems again. Hopefully,
Are
somewhat obvious reasons you want to remember powerfully reinforcing events in your life as well as powerfully emotionally, or physically painful events in your life. So I hope I answered your question to a modest
degree. Know far better than a monastery that that's an excellent description of the dopamine system from a true expert. And the question I have is about some of the context.
East and Nuance of the system, but in in sort of real world terms, how should I think about this even in my training as a neuroscientist? I know neurons can be a little active, a lot active, everything in between that could be active over long periods of time or short period of time. But let's use the example of the donut. I'm I like a glazed old-fashioned donut. I actually don't have a craving for sweet things, but Donuts is an exception. I like the glaze old-fashioned donut, but if I were to see, just a little piece of a glaze,
Fashion donut versus a full glazed old-fashioned donut. Could I expect that more dopamine is released to the anticipation of the complete donut? And then the other question is, how does context influence the dopamine system? For instance, if I'm very full. Yep. A glazed old-fashioned donut, might be aversive to me. Yeah. Whereas, if I'm just a little bit hungry, or if I'm actually more on a schedule of rewarding myself or abstaining from sweet,
Eat fatty foods then abstaining from the food might be its 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'll interrupt myself to say that we're constantly juggling a bunch of different reward, contingencies. We want to, you know, have good health metrics, and maybe have a certain aesthetic qualities to our body but we also want the donut. And so, how does a simple?
System as simple as a one neuromodulator system and the VTA to nucleus accumbens and with some connections to the memory area. How does it balance? All of that information in real-time to me? That's just like staggeringly complex but also incredibly
interesting. I think you beautifully put viewed very eloquent description. You just said it, it's staggeringly simple simultaneously, staggeringly complex, and
You asked several different questions. So context makes an enormous importance and that's one of the reasons I became interested in the dopamine reward circuitry is as, you know, as a colleague in the academic Neuroscience 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 compute the computer?
Computer hardware is are the physical Connections in the brain are constantly changing the strengths of the communication.
Similarly, for the dopamine reward circuitry. It's highly plastic, and it's highly contextually dependent. And so you gave the example of donuts and feeding and I'll answer your question about the cues. Yes, it's 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 the United States, the morning of Thanksgiving. If you're at home,
Home visiting your parents. The smells of the apple pie. The smells of the turkey, cooking are highly appetitive, highly reinforcing. You're anticipating that fun event. You're anticipating Uncle, Joe coming to visit you for Thanksgiving and that's all because these cues, the smells the anticipation of Uncle Joe's your previous experiences are part are part of your memory system sort of talking to
In a simple way you reward circuitry. So you're building up this anticipation. One could almost say this craving, which maybe we'll talk about in the context of addiction. And then make a long story short think about that evening. At the end of Thanksgiving, those exact same cues, the exact same smell of the apple pie turkey and Uncle Joe himself at the very least, they're no longer appetitive. Meaning they might actually
Be a versa. The last thing you want is a piece of apple pie. You can't wait for Uncle Joe to leave your Thanksgiving dinner. And I always argue that just not happen, magically that happens because your brain has been modified by the context in which it sits, and this very important module ettore system. This reward circuitry is responding to the exact same stimuli with a very different response so that I'm just telling you, I'm repeating what you said.
The phenomenology. And and again my other favorite example is any of us who have been in an intimate relationship knows that the love of your life can turn to the bane of your existence in 20 seconds. And again, that doesn't happen magically this person who you crave, who you love does something and two minutes later, your brain is saying, oh my God, you know, I may have to break up with this person or this is an incredibly painful
experiment tional 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 neuro module Choice system that uses dopamine works. And the truth is we don't know it's because the inputs on to these dopamine neurons the other nerve cells that are driving the activity of the dopamine neurons and I've actually
This in my lab at Stanford University, with a colleague, you know, well leech on luo who's a world-class neuroscientist with studied the complexity of the neuroanatomy of the dopamine system and these dopamine neurons in the ventral tegmental area. This the source of the reward circuitry dopamine are receiving inputs from all over the brain. They're receiving you know, indirectly or directly inputs from
All areas from somatosensory areas 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 queues, which we're going to get back to, of the donut or of a drug. How is that modified? How this neuromodulatory system responds? Similarly, the the nucleus accumbens the
Target of this, powerful modulator dopamine is receiving.
Communications. What we call inputs from all sorts of brain regions that, you know, about Andrew, your audience, may not, they receives inputs from an area called the hippocampus which you may have covered in previous podcast which is very powerfully. Very important for memories, both establishing new memories. And again, remember that makes sense. You want this system. This dopamine reward circuitry to be very connected to memory.
Systems. So the nucleus accumbens the activity in the nucleus accumbens is modulated by dopamine. While it is receiving information from the hippocampus which helps encode new memories while that's receiving information from a brain area called the amygdala, which tells is a part of the brain involved in our emotional experiences. The accumbens also receives inputs from the prefrontal
It'll cortex which is this brain area. As you know, better than me, Drew is important for decision-making for planning, our activity and I could go on and on what could we talk about? Prefrontal cortex. You're a moment because always
Was surprising to me, that prefrontal cortex is talked about, is this higher executive function area. But then, when you look at the neuroanatomy, it's as we say, monosynaptic Lee, as you, and I know when one connection away from structures, like the amygdala one connection away from structures, like the the nucleus accumbens in other words, prefrontal cortex to me is every bit as ancient as some of these other structures that we think of as more ancient and really the whole a
ancient evolved thing gets a little bit dicey because certain areas are like the prefrontal cortex are more elaborated in humans but but to me the prefrontal cortex seems to be especially important in the context of this thing of scaling, the reward response or context of the reward response because it can set rules. It seems to know. Okay we're recording a podcast now and there are certain rules are certain things we're going to do and not do. But what's fascinating about the
And I'm so glad you gave a bunch of different examples because what's fascinating, for instance, about the relationship example, is that? Yes, at one moment, we can adore somebody in another moment later, they do something or don't do something. We can be incredibly frustrated with them. They can even become inversive to us. Hopefully, that doesn't happen too frequently, but I think we've all had, the experience of a donut, an event or a person actually looking different.
To us in a, you know, from one moment to the next. Hopefully not at random right. And so to me, it seems like the prefrontal cortex is uniquely positioned to really say, okay, right now, we are in a mode of, for lack of a better word love, and loving like the in the in the verb tense of loving being the verb tense of arguing. We're now arguing, you know, we're in the verb tense of reconciliation, you know kind of somewhere in between or something of that sort and how
Us structure in a circuit as simple as the dopamine system, right? One molecule could suddenly say, oh, you know what? Now getting over my anger is rewarding whereas five minutes ago, being, right? And being the most angry was rewarding, and then five minutes before that, again, we're accelerating this movie, but five minutes or five days, or five years before that, this person could do no wrong and the dopamine system is just cranking out. Dopamine said whatever you do. I'm just delighted by incredible. Like to me, I
I can't think of a more interesting system in Neuroscience.
Well, I mean, that was eloquently. Put, I agree with pretty much everything you said, I don't have much to add because what you're 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 I'm 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 and get them to be thinking about how our modern view of how the brain works. May could be used to enhance Health could enhance mental well-being. But as neuroscientists
Scientists academic neuroscientist ourselves. We know, you know, you are oversimplifying things and the actual functioning of a system like the dopamine reward circuitry, as you just eloquently point out, is so much more complex. It's Modified by these. Prefrontal inputs, which are simultaneously telling our memory systems. You know, pay attention. Here, I'm repeating.
What you just said, the context makes a big difference, the history you have with the person or stimuli with whom you're interacting like to bring this back to urine. You know, which I never the initial question is a small piece of a doughnut activate, the queue that that small piece of adone and activate the reward circuitry and cause release of dopamine to the same extent as the full donut. Depends on your experience with doughnuts.
I mean, I think for you and me because we seem to both have, you know, like donuts. They're highly appetitive for us probably doesn't matter because we have learned even a little piece of a donut activates all of our memory system saying man that's an old-fashioned glazed doughnut. I want to eat that. I want to get one or I want to have the discipline not to eat it. So I hope I'm answering your question. It's and I'm shifting topics completely but
That's why addiction is so
challenging. Well, let's talk about that. Let's talk about that because you've done a ton of important work in this area of addiction. I mean, one of the basic questions I have about addiction is we hear that certain drugs are more addicting than other drugs or certain behaviors. We also hear that we can become addicted to anything. When on a Lemke was on this podcast. I said, what's the most unusual addiction you've ever seen? And she talked about a patient who sadly committed suicide at some point later that
She told us had been addicted to water to drinking of any kind, first, alcohol. But then water eventually. And so. So my question about addiction in the dopamine system is, you know, for let's pick a drug like cocaine. Mmm, I've never done cocaine. But people who have done cocaine, tell me that, it feels very good. And one of the more Salient features of the cocaine high, is that it comes on very fast and it
This pretty quickly too, is the rate of dopamine increase related to The Addictive property of a drug or behavior as much as how much dopamine is
released. And that's a very sophisticated question and the answer is yes. And that's usually the lecture. I give the way I think about addiction. And obviously my friend and colleague on the Lemke is one of the world's experts in terms of the
Understanding The Human Experience of addiction. I have studied it as a cellular molecular Neuroscience is trying to understand how addictive substances modify reward, circuitry modify the connections in the reward. Circuitry modify how dopamine neurons Act and the way I like any what appears to be a simple term it's layered with complexity.
And is somewhat of a Continuum. And I like to think about, whether you're talking about substances, like cocaine. And I will explicitly. Answer your question soon or opioids. As we, as you know, we're going in this country, there is an opioid epidemic. 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. Am 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 caffeine destroying their personal life to get caffeine. 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 have a very or opioids, have a very high addictive liability. So, to answer your mechanistic question, there have been some famous studies done by the director of the National Institute on drug abuse norvo, cough simultaneously. There have been studies in animal
Models of addiction where you nailed it. The in a rough way, The Addictive liability of a substance is directly correlated with two aspects of dopamine. How much dopamine is released in the accumbens and the kinetics of the dopamine release. As you said how rapidly, its released to get a little technical, even with the drug like cocaine or opioids, it's not only the drug itself, it's the route of administration,
Station, because the route of administration influences the kinetics meaning, how fast that drugs gets into your brain influences, the reward circuitry, and how fast it causes a big Rapid Release of dopamine. And some of your podcast listeners may be old enough to remember the crack cocaine epidemic or freebase cocaine. And cocaine does have like methamphetamine a very
A high addictive liability, I teach the naropa. I give lectures to students at Stanford about neurobiology of addiction as part of a team course. Team taught course, I have kids who I had to deal with and what, you know what I always say is, you know, you it's not that if you use this drug, you're automatically going to 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 definition but back to the route of administration. So I went
off, that's actually an interesting statement. Yeah, you know, because I think we may have heard that in high school although I to be honest, wasn't the most attentive high school student and I regret that high school students page, okay? For yourself ventually, I came around but it was an uphill battle there but you that you can't become addicted to something that you've never done. Which?
I just want to earmark that because I think it's a profound statement because it points to the importance of the memory system, but also plasticity. Yeah. And so I want to make sure that eventually we get around to talking about how the amount of dopamine released in the kinetics, how that might influence plasticity. And basically what I'm asking here are queuing up in the back of your mind is whether or not addiction is just related to The Sensation that we have when we indulge in a
savior 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 broader range of drugs or experiences attractive to
us. It's probably the latter but so let me get back and I will answer that in a second to the point I was making. So it's not only the substance. It's the route of administration so and you know, as I said, you can't develop a problem.
Mm with the substance and develop a 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 gets in and the and people do this. Now with methamphetamine, I mean meth addicts, most of them. And that is another epidemic in our country, most of them, smoke it. And that the danger of that is the drug, whether it's cocaine, methamphetamine gets into your brain. Almost instantaneously causes a very rapid powerful surge of dopamine in the accumbens 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 lasts it can last for tens of seconds or a few minutes and it's a feeling that for give you this overwhelming compulsion and urge, I want to do it again, but so even though it may not actually
All that good, it's real. And again, this gets into, you know, we didn't have an addiction problem for any substance other than alcohol. You know, for most of you manatees existence because these substances Like Cocaine, methamphetamine, synthetic, opioids, like ventral they didn't exist and our brain. You know, the truth is our brains aren't were not are not
Signed to handle those kinds of very powerful substances.
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So where do you want to go from here? You asked a question about, you know the the neural mechanisms of the of what we call
addiction. Yeah. I'd like to know about the role of neuroplasticity and addiction. I do want to highlight something you said and I apologize for interrupting a moment ago, you know? And then everything but it was an interruption based on real excitement because a person I know quite well who is a recovered cocaine addict told me and that, by the way, folks,
Isn't I have a friend and I'm actually I truly have never tried cocaine. 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 addicts anymore because that's a little
a bit judgmental. And that's a new nomenclature as something along those lines. God I'm calling
somebody an addict, you know, as
opposed to being addicted. Yeah. Being and that is a beautiful description. I hate it. But I want to do it again. And again, it just shows the power, the power of this system which remember evolved for our survival. So a very simple way of thinking about it is these drugs are tricking the reward circuitry to
A 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 this substance just don't and as again as a world-class neuroscientist yourself, you know the answer, it's always a complex combination of underlying genetics.
It's the environment in which they find themselves the environment in which they grew up and how that modified their reward circuitry. So to get at your question,
one set of experiments, my lab did, which other labs did to. 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, methamphetamine, opioids like morphine heroin.
Change the, what the synapse is. The synapses are the connections from other nerve cells on to dopamine neurons. On to the nerve cells in the accumbens and these connections, these synapses can change and drugs of abuse, cause powerful changes in those connections and therefore, powerful changes in the activity of the dopamine neurons, and the neurons in the ventral, in the, in the nucleus accumbens.
And in fact, the types of changes that occur appear to be similar to the types of changes that have evolved for good uses for adaptive forms of learning and memory. So again, this is an example that this
Superficially simple, dopamine reward. Circuitry is changing all the time is highly plastic and can become more sensitive to certain experiences. You know, etc, etc. Well, could I ask a question about some of the general Contours of the plasticity in the dopamine system? The you said before and I love this statement even though it's very simple but in its Simplicity it's really elegant that we can't become addicted to a substance.
Or a behavior that we haven't taken or partake 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 system, such that one's 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 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 on to dopamine neurons and onto the
On to the nucleus accumbens those changes that does not mean these changes are permanent or or irreversible. But the change is last a long time. And again, the big question for understanding the neurobiology of addiction is, you know, those changes are probably happening in most people who take the drug in this case and we can talk about other stimuli non-drug stimuli that can become in.
In quotes. Addictive again. Why in certain individuals.
To be honest, 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. Whereas other individuals that sets them down, you know, a very bad path and really badly affects their life. And that's a huge question in the research field because obviously if we could make predictions on which individuals are more susceptible and you know not to get too,
To political here. But it's also you know, whether you become a developer problem with addiction or not is influenced by the other.
Parts of your life. Do you have other ways of getting reinforcing stimuli getting satisfaction, having an outlet? That other ways of activating your reward or dopamine circuitry? How is it you know, healthy ways like you know, as you have articulated I think 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.
Very almost the inverse of the cocaine
response. Yeah,
that desire. And then the I hate this but I can't wait to do it again. It seems like exercise is often the opposite. As I hate this, I don't want to do this. And then at afterwards, gosh, I always feel better, and I'd be happy to do it again.
I mean, yes. I mean, I like to exercise chasing a ball that could because that gets me off thinking about this hurts, but so, anyhow back to addiction. So, yes, these drugs can
Cause I don't want to definitely not permanent changes from a single exposure and, you know, and and the types of studies I'm talking about were all done in, you know, experimental animals. So, how that relates to what happens in our brains, and human subjects Brains. It's not completely clear but I think there are parallels. So the changes might last, you know, a few days a week or two.
But one 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. But again, the big question is why in human subjects. There are people who can use these substances and not develop a serious problem. And there are others where they're very, very
Jing. And, you know, and then that's why I still make the point. If you're a young person, if you're do, you want to take that risk? Is it worth it to have that experience? And that's an individual decision.
We've got we've done some podcast episodes about alcohol, cannabis etcetera and they just seemed 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 got friends, who are recovered alcoholics. Who do I, who will tell me the
The first drink, they took yep. They use language like, you know, the it combined with the chemistry of my body in a way that nothing before ever had. And they felt like it was like this magic Elixir, right? That is not been my experience. Not and
I and I've heard the same stories and it's hard for me to relate because like you alcohol, does not have that effect on me and that's where that's. It's hard to believe that.
Kind of immediate response to alcohol is due to their in the environments in which they grew up although that can have an influence that's 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 families, you have to worry about how the environments of that family influences, it. But there's a lot of studies saying there is,
A genetic component. Maybe like you, if I have a drink or two in the afternoon, I just fall asleep. Yeah, and it does not have that effect on and and and, and one could imagine similar things for other drugs of abuse. There are people who have used cocaine of used methamphetamine, you know, who find it modestly enjoyable, but it's not, you know, the be all and end. All it is in this incredibly powerful
Experience and you just talked about, I think I friend, or a colleague who said I hate it. I hate that, but I want to do it again. And that's fascinating,
they're now a recovered alcoholic and cocaine addict. And they've, they've abstained for many years, but still get a little bit of a gleam in their eye when they talk about alcohol or cocaine in a way that I just can't relate to
her. Like, I mean, can I tell you a little vignette 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 or aversive quality. So, long story short, when I was a young kid and I can't remember in my 20s, maybe 20. I spent a few weeks in Paris. I started smoking cigarettes. I mean, this is a long time ago and I got it. Cigarettes.
Are very interesting. Nicotine is highly addictive. As are as the tobacco companies were fully aware of high addictive liability, very high, addictive liable, Rob people for the money to buy cigarettes.
They may not robbed because although there be my understanding is to become quite expensive, but I guess that's a vote significant. Counterfeit cigarettes are a huge market for organized crime. There are 30 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.
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 lasts for a few minutes. So you want to do it again and again, so we can talk about the and nicotine you know what becomes 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 do. But my little story is I smoke some cigarettes in Paris. I, I, I learned why people like to smoke. It was very, satisfying to have a cigarette in a Parisian Cafe. It's just, you know, it's very interesting because the first few times,
As you inhale, tobacco, if you get dizzy, it's kind of a versiv and it's exactly what you articulated despite that you want to do it again. So, I was just a lot of fun for me and I enjoyed it. And I was disciplined, you know, at some point, whenever this was, I came back United States, I didn't smoke because I knew it was bad for you. But to this day, 40 years later. Every time I go back to Paris, I get Cravings. I actually
I just want to get a pack of cigarettes. I want to have that feeling again of inhaling the smoke, but the point is of how powerful these rewarding experiences can be or reinforcing experiences and for your audience. Technically, you know what, I have been taught by some of my psychology colleagues is we use the term reinforcing in a very behaviourally defined.
Way. Something is reinforcing is if the behavior that led to that stimuli, it makes you want to do that behavior again. Rewarding means it actually felt in quotes good. It's an important day actually can be different again as you defined by your friend who his? I forget it. I think it was cocaine. Cocaine was highly reinforcing, but it was not necessarily enjoyable or
Warding. And isn't that fascinating, I have a, some colleagues in the addiction field. One of them is retired. Now, Kent barrage and terrie Robinson. They coined, they distinguish between the terms wanting and liking. And think about that liking. Something means it's something you like you enjoy.
Wanting means you want it.
But you don't necessarily like it or enjoy it. And that's a description of your friends 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 it is sometimes people will be in relationships where they actively dislike the other person, which is that, which is a bit foreign of a concept to me. But, well, it's interesting this, this separation of reinforcing and rewarding wanting and liking, because one of the things
It's very prominent in 12-step programs is to create rewards around abstaining from the drug user behavior. And I should mention that programs like 12-step. When followed seem to have very high success rates, at least that's what on Olympic. He 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 liking of sobriety more than the wanting of
Prince. That's beautifully. Put and I think that's right. How that plays out in the neural mechanisms? That is a neuroscientist. I'm interest in it, man. That's a tough one. But I think that's why those programs are pretty successful. It's helping the person make those dissociations. And I don't know that much about those programs because
I have not seen patients myself for whatever. It's been 27 28 years but I think part of them are to help that individual find as you both other sources of liking and reward getting some satisfaction 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.
Yeah those are the way you described it is exactly right. Those those programs are highly reinforcing for abstinence behaviors everything from the social connection which we're going to get to social connection as you know to the way that people start to conceptualize their addicts self versus
Our other self, it's actually involves a splitting of the self and interesting ways. As long as we're talking about, Donuts, cigarettes, alcohol, cocaine. I'm curious before we move to 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 talked about cocaine is having this very
But on said, big increase in dopamine. Then a crash as we know a certain pattern of kinetics, as you described it. The opioid crisis is, you know, incredibly serious problem right now as is methamphetamine, but it sounds like methamphetamine functions a bit like cocaine and in terms of its kinetics. Yes. So an opioid is very different chemical than cope cocaine, but it sounds like it impacts. The dopamine system is the do.
Opium energetic, activity caused by opioids, responsible for the addictive properties of opioids, or do people also, like, the feeling of being under opioids. I personally hate it coming out of surgery, like they gave me, they gave me Vicodin once and I hated it. I'd rather have the pain post-operative pain, then take something like, you know, Vicodin or a valium or fentanyl 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, which suggests that the, The Addictive liability of opioids, and psychostimulants, which are cocaine and methamphetamine have the common final action of causing massive release of dopamine in this.
Target of the dopamine neurons. The nucleus accumbens, they do it. If we want to get a little scientifically technical here, the very different mechanisms. So cocaine and methamphetamine what the drugs known as psychostimulants 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 dopamine from being vacuumed up. So the cocaine hangs around longer method. Not only prevents the dopamine from being vacuumed up. It actually causes the reverse. It actually causes the direct release of dopamine from what we call nerve terminals from the site where dopamine is released opioids work very differently than
They actually primarily not solely work, where the dopamine neurons live, and it's a little complicated, it's not that critical, but they indirectly increase the activity within the dopamine neurons themselves. Causing a big massive bigger than normal release of dopamine. So that's one commonality. But anybody who has used these drugs or read about these.
Drugs to the subjective experience of the drugs are dramatically different. And that's because of the actions, they're having not only in the reward circuitry, but throughout the brain. So and it's interesting, you talked about Vicodin, I've taken Vicodin because I've had several knee surgeries and things like you, I didn't like it. I've I've gotten other opioids for pain relief that were great. I mean they took they took away a lot.
Of pain after my ligament repair and that's a different question. That even when you're talking about opioids, all drugs are not create, they're not identical. Then to know, has a much bigger larger addictive liability because of its molecular properties and how its interacting with the opioid system in our brains and The receptors. The actual proteins in the brain that it
Tracks with, but the subjective experience of opioids. I mean, it's interesting, some people love it. That's, you know, if we go back in history, as you know, there were the Opium dens throughout Asia. There were Wars about opioids, thing. The the famous opioid Wars between China and the United Kingdom, it's showing you how powerful the availability.
E of a substance like an opioid can be so I'm going off in a tangent know, he's alright but commonality is dopamine release in the accumbens but it's a if you remember what a Venn diagram is all these drugs, have some common actions, usually on directly or indirectly causing the massive release of dopamine in the accumbens. But then they have their own individual actions. Because obviously, when you take cocaine or Methamphetamine, it's a stimulator your, you know, people are
Ending, their teeth are hyped up for most people opioids or the exact opposite. Your, I mean, in opium dens from the movies, I watched and watching narcos and all those TV shows your often you're lying down, you're kind of in almost a dreamlike state. So very different subjective experiences.
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Your purchase again. That drink element LMN t.com hubermann. Yeah, I had an experience with opioid recently, not voluntarily over the Christmas holiday. We went to visit friends and before going to sleep, I wanted some tea and I asked if they had any non-caffeinated T. So they gave me this tea and, and that night, I had the most bizarre dreams I've ever had. And I slept for 14 hours the next morning, I 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. And I am one of those people that's very susceptible to even low doses of any kind of Novel drug, you know. So
interested you ever taken cough syrup with
dextromethorphan know? So I avoid that stuff.
Well I you know I have my can I have a tendency when I get a cold? It gets into my lungs, I cough.
If a lot and I think this has been reported. This is my anecdotal experience, I'm confirming. What you said, dextromethorphan, an is a different sort of opioid, and actually, some people develop a problem with it. For me, it gives me really bizarre dreams, really busy similar to what you were. It was a very unusual. That's a whole different conversation about what makes us dream and what their, what are the meaning of dreams fascinating and I hope you covered. Maybe you've covered
that you have not yet but we are
intending to do a whole series on sleep and
dreaming and I believe that would be able to get into. I started out and sleep research. So I have a fondness for drug research in sleep, research have a
long history of overlap with Alan Hobson's, work on Li worked with Alan Hobson, okay? By the way, folks, if you're interested in the relationship between hallucinations and dreaming, Alan Hobson is a good name to start your your rabbit 19 Rabbit Hole, Brad 19. Oh my God, I'm dating myself, 19.
O 7D. I can't remember who was 76 or 77 I worked with Alan Hopson as an undergraduate at Harvard Med know as an undergraduate at Harvard. He was at Harvard Medical School near
amazing. I love his writing and I had a lot from it. Very really ahead of his time. Yes he was I will get I
wish I could nobody would anybody? Who knows, me won't believe this, but I back then I was a very shy insecure. You know, 20 year old would not have guessed who and even in medical school I all
All 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 that I should never say them out loud. Do you mind? If I ask you, since you
raised us, I think it's really important. I mean, you, you have this incredible career, track record, you know, your adored by your colleagues, your highly respected. You won just about every award award there is to win a neuroscience. So, whatever something in particular, that was in an overnight thing or one day, you woke up.
Up and thought, you know, I actually believe in myself. But if you wouldn't mind sharing that because I can before we get back into some of the the science I you know this science is a human endeavor and most people listen, you're probably not scientist but I think everybody deals with these issues of self-doubt and people appear to have varying levels of confidence. But what what
happened? It's a thank you for asking.
For me, it was a very gradual process and I'm not as an undergraduate as a medical student, even as a postdoc. Yeah, I was very unsure of my ideas of my intellectual abilities of whether what I was thinking was really, you know, worthwhile. So it's a very gradual process. I think it the increase in my confidence, I think began when I was a post.
Doc, which is a training period after you've received a PhD or an MD where you get additional research training and I worked with a guy named Roger, nickel at UCSF. And Rodger was a very for intellectually intense, very forceful individual. And I got involved in a field where I mean, people a little bit of a tangent. Your your your listeners may think that science to
Are these geeky individuals wearing white coats with no passion or emotion and nothing could be further from the truth. The most successful scientist, I know, are pretty passionate, and pretty intense about what they're working on and driven, and this is a gross generalization. So, any out during my postdoc, 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, it started developing as a postdoc, 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 60s.
I've been running my own lab for almost 40 years so I have been 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 then the next 10, 20, 30 years
I gained more and more confidence. So, for me, it was this very gradual buildup 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 of time is helpful. But as you said, you know, learning to trust one's ideas, just a brief anecdote when I was coming up in Neuroscience, a few years behind you,
not two years. Now I know that's not too many. I mean but but but recall the
Credible number of high-profile papers on neuroplasticity and long-term potentiation long-term, depression. These are terms related to the modification of synapses that Rob milenka and Roger, Nicole pioneered a big segment to that work. And I remember seeing your names on papers and I thought, Roger worked for you. Yeah,
sorry, Roger. I'd love to hear that. I was here for you and only later, did I
learn that you were his postdoc. So, and
then and then we collaborate
It
as he became a very quick very quickly so you've had
and Roger, you know, I Rogers wonder I did have the confidence even as a postdoc and he 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 even though my mentors are like had more experience and I
Learn from them but I
like it that you're working for yourself even though you have a mentor. So I think there's some there's some real gems in what you just described. So thank you for sure, taking the time to do that. Sure. I'd like to discuss one aspect of reward circuitry that I don't think most people think about right, see, fairly straightforward. I nowadays, I like to think more people know what dopamine is and understand it. Thanks to your work and on has work and some discussions have taken place on our podcast other podcast, but, you know,
All too, often we think dopamine reward wanting liking drugs. Okay, all of that is great. But what about the truly adaptive stuff, right? Because it's easy to fall into a discussion around, dopamine of, you know, the things that are bad for us. But what I'm thinking about here is social interaction. Yeah. 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
Should 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 if nowadays is it, okay, I you're not supposed to call autism a disease. Is that right? You hear about neurotypical and neuroatypical but is but I have friends who have children who are severely autistic and I don't know many parents who would allow
elect to have a severely autistic kid. And so, those people often will talk about it as autism or a child having autism. So first of all, before we get into the social piece maybe because I just tabled it. What it, how are we supposed to talk about autism, nowadays? I am very interested in the path of physiology of what the medical profession terms autism, spectrum disorder, as you pointed out.
They're individuals living with an Autism Spectrum Disorder are quite heterogeneous and it can range from individuals with severe intellectual impairment and quite severe impairments in social interactions impairments and sensory processing impairments and lots of different aspects of our behaviors that are important. And I think
I think nobody would say would argue those individuals on the severe Spectrum do not have some sort of in quotes disorder. The issue we have to be sensitive to is it's a heterogeneous disorder like many brain issues that psychiatrists deal with like depression. We all like obsessive compulsive disorder like various anxiety disorders, it's always on a Continuum in a spectrum.
So for autism, spectrum disorder, there are individuals who are high functioning who
One could argue have a different style of interacting. Socially may have a different way of processing, sensory information. But who have who would prefer not to be viewed as having an illness but rather would be viewed as having a different style of living an interaction and I think we need to respect that. So the challenge is again, not oversimplifying a complex
X heterogeneous, disorder and both being respectful of the people who don't want to be defined as having a Neuropsychiatric or brain disorder. While equally being respectful of people like your friends with severely impaired children who deserve help, who deserve research and it's a tough one. Because my understanding from, to be honest, just reading articles in the lay press
And going to websites from organizations that philanthropic. Lee support research related to autism within that community of individuals who are not researchers, but who are have family members or are themselves dealing with some degree of autism spectrum disorder. There's disagreements about how to what terminology to use. How to deal with them. And it's complicated, I think
We just have to respect everybody and if you're interacting with individuals, you know I think it's appropriate. What do you prefer? I dunno as a medical professional there and especially when you're dealing with children, there are children who need help and I we're not doing them a service by saying. They don't have an issue that we should be helping them with and working on. So I hope that answers your
question.
I think it beautifully answers it and encompasses all sides so that we can move forward. And I think we'll, so as we use the term autism or children or people with Autism, that's what we're
referring to. I think, people are very sensitive, especially those individuals who are neuro a typical whom previously might be diagnosed as autism spectrum disorder, but would prefer to not be labeled as having a brain illness that that's fine.
It's kind of once you are an adult, you can make that decision for
yourself. We certainly have colleagues at Stanford and elsewhere who at least by my non clinical assessment, some tourists somewhere on that
spectrum. And again, it's a Continuum just like, you know, the experience of depression is in a Continuum, but
are they as with depression, you would love a child or an adult, any less because they have depression, or would you love a child or adult any less because of expression of some
autism effective. I know the pointer people.
Don't, you know?
And so we have been, we are being trained in the medical profession to be very, you know, in our society is going this way to very careful with the terms we use and the labeling of the individuals. So, you know, I've been taught, you can say, individuals living with an Autism Spectrum Disorder. 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 labeling kind of but, you know, sometimes this gets out of control to as we both know,
they're in for sake of fluid conversation, we will do our best. We will acknowledge from the outset that we are well-meaning but far from perfect and how handle this
well, put well put.
So in think about social interactions and leaving aside anything related to autism for the moment,
It appears that the circuits in the brain that mediate the desire to spend time with others of the same species, maybe even with other species, like a dog are fairly hard wired, but modifiable they, we were born with the capacity to build them up and that social behavior is highly rewarded. Is it rewarded through the dopamine system? And what if any involvement is there of the serotonergic?
System and we haven't talked about serotonin yet, but I'd love to bring up serotonin at this point. Maybe you could educate us a little bit about serotonin because gosh, if dopamine is fascinating serotonin is at least as
incredible. Yeah. Great question. So I think for me, the easiest way for me to answer it is actually just tell you my research history and how a lab like mine at Stanford that at one point was studying what?
What you and I would call fairly hardcore molecular mechanisms of neuroplasticity. How do connections between nerve cells change and what molecules are changing and pretty hardcore molecular stuff. How did I end up? Studying? Social behaviors in mice and what I hope will 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
King 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 anhedonia the inability to experience reward. You know, eating a donut is no longer satisfying, having sex is no longer that much fun.
One, which is a component of depression. If there's a mechanism in the brain that tells you something is rewarding by definition. That's not functioning normally and severe depression. So are we were doing models of depression to figure out how the dopamine reward circuitry was changing as were many other labs. We were studying addiction. Those were the obvious ones. And I mean, it might be entertaining to do to your audience, to learn how academic scientists think. I was thinking those are fascinating.
Books, they're pretty competitive. Lots of other labs were working on it and I started thinking what other experiences might be modifying the reward circuitry. I actually made some attempts to look at feeding Behavior, but I don't want to, I mean, we actually never pursued that for a variety of reasons. And that's obviously important because of there is an obesity epidemic in this country and we can talk about how
The reward circuitry. And some of the things we've learned from our studies of addiction may be helpful to understanding obesity, but back to social interaction, I started thinking well for most of us, what I call a pro-social non sexual experience is highly reinforcing Andrew. You're a pretty social guy. I'm a pretty social guy. Most of the time I'd rather go to a movie, a sporting event.
Dinner with friends. 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, well, why is that? Why do I have such a good time? Going to a ball game with my best friend or going out to dinner with another couple and interacting, it's because, well, it's highly reinforcing. And if it's highly reinforcing, it must involve the rewards.
Circuitry. And then I started thinking evolutionarily and makes a lot of sense. Because if you are part of a social species, there's a lot of evolutionarily, 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, Wildlife shows, or National Geographic shows, there's a reason, all these animals hang out together, it's for protection from predators. So there are all these reasons so about whenever it was 13 or 14 years ago, my lab decided to start looking at how the reward circuitry may play a role in what I am going to call.
All positive pro-social non aggressive interactions. Another word we use is just so she ability and for a variety of reasons that back then this is got this is at least 13 years ago, maybe 15 years ago, a postdoc joined my lab named Gould Dolan. She's now a professor at Johns Hopkins and she had an interest in oxytocin, and as your listeners,
No, oxytocin is this evolutionarily? Conserved neuropeptide, that's very important for parturition the having a baby born for milk being produced and it's gotten a lot of attention. As a potential love neuropeptide is something that is released in our brains during a positive social interaction. There's a well-known researcher in social behavior and
and bonding research called Larry young and he did some very important. Now somewhat classic work, studying a species called the vole in particular, the Prairie vole and Prairie voles are a species where they mate for life. It's called pair bonding. So one vowel will find another Vol. They basically get married. They have kids and their they hang out together for the rest of their life. No
divorce, no 15 of the worst
50.
Percent divorce rate. And what Larry elegantly showed in part in early days in collaboration with the guy named Tom. And so who is a famous academic psychiatrist, they showed that oxytocin action within the nucleus accumbens within this reward, circuitry was required in really important for this. Monogamous pair bonding having said that there was just a paper that called into question.
That. But that's,
but there's 30 years of research prior to that and and I'm glad you brought that up because I will keep this contemporary in the the reality is that that recent paper got a lot of attention, you know, their paper. Um yeah that maybe oxytocin isn't playing as prominent as a bonding as people had thought. And yet folks, that could be true. We have to be scientific about this and be open-minded, but there's, you know, three decades of work that that speaks to the contrary. So I think we want to be a little. We want to weigh the
evidence. We were
Exactly. And again, the, the investigators Who present it 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, Google Dolan was a postdoc in my lab and we decide, we formulated a project to look at the actions of oxytocin, in the nucleus accumbens in mice. And the reason we study mice is there what are known as a genetic genetically tractable?
Bilal organism, we have all sorts of really cool and sophisticated tricks we can do to probe brain circuitry, the actions of neuromodulators like, dopamine and serotonin and oxytocin in ways that we can't do in other species. And I'm going to get back to dopamine in a second and what we found was that oxytocin action in the
The Cummins was indeed important for promoting sociability. Probably for promoting the reinforcing component of a social interaction. And that surprised us, you know, it was like, wow, it's oxytocin seems to be causing enhancing the release of serotonin in the nucleus accumbens and that will perhaps we'll get you this. That led me off on a whole series of
Are immense trying to figure out how serotonin Works studying this drug. We may talk about called MDMA, which is ecstasy or Molly, which actually causes release of Serotonin. So we did that work and that got us working in serotonin simultaneously. There were some other papers reporting that dopamine release in the comments that dopamine is released in the accumbens during a social interaction, a positive non-aggressive, social interaction. Truth be told it may.
So be released during an aggressive interaction,
some people like to fight
some people like to fight. And the difference here is the dopamine release and its role in social interactions. It's not specific only for social interaction as we have talked about. But nevertheless that led my lab and other labs to do a series of papers. I'm talking about the field now showing that and I'm giving you a lot of information.
Here. So, how might dopamine release happened during a non-aggressive social interaction? It turns out that oxytocin is not only released in the nucleus accumbens, it's released in the home of the dopamine neurons in the VTA. So, my lab and another lab from Northwestern showed that oxytocin can actually modulate. Dopamine neuron activity in the ventral tegmental area. So, I hope I'm making sense here.
Don't want to get too technical. I think it's just shows how you know we discuss these neuromodulators like dopamine. I just brought in oxytocin. We're going to talk about serotonin a second. Unfortunately for your listeners they don't work in isolation. They Community. They influence each other in ways that I think it's important for us to understand and elucidate.
That is not too much technical detail and I think it's wonderfully rich with air.
Areas for us to discuss. And I'm so very glad that you brought up that neither dopamine or serotonin, or oxytocin work in isolation because all too often and admittedly 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's just no way that the brain works that way. You know, for instance, turning on dopamine, and turning off serotonin, it's a weighting of of inputs. And I think that serotonin, perhaps, I should frame it this way just as often as
Dopamine is framed as this reward molecule and pleasure and dopamine hits all too often. I think in the popular press
Serotonin is discussed and oxytocin to for that matter as this kind of warm feel good, everything's mellow, you know, not really associate with 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 accumbens and that dopamine is is activated to just have that, right? Okay, so I don't want to take us too far.
Down the rabbit hole of neural circuit function, but that to me makes at least a brief discussion about the nucleus accumbens itself. Interestingly, okay, so I'm thinking nucleus, I know that means a pile of neurons and aggregation of neurons is talking to this ventral striatum. So we got a bunch of
part of the ventral striatum part of the subdivision,
he's me. Yeah, I misspoke. Yeah, it's part of the ventral striatum and it's and the neurons there can be active and communicate with other brain areas, but we're talking about a lot.
Nuance of
function, man. So so I'm not smiling. I don't know if your audience is just see me so because it's so I sometimes go to bed feeling, it's so complicated. Oh my God. It is
yeah. Could we say that within the nucleus accumbens? There are neurons that are acting as accelerators and brakes? I mean, is there a simple analogy that perhaps while not exhaustive can still be true? Should that's always the goal on this podcast. There's no way he can be exhaustive but we want to be as accurate as
possible.
So a very influential hypothesis, which has guided my thinking and again the trick. I mean, you know, you have done a wonderful job of communicating, complex scientific topics to your podcast audience and I congratulate 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 as
Actually, when you're dealing with brain activity issues and how the brain mediates all it's amazing functions. So, historically we have thought about the nucleus accumbens and other components of this ventral, striatum brain area, as primarily being composed of two different cell types and as you pointed out, one being sort of an accelerator
Order something that promotes certain behaviors and the other cell type somewhat being a break saying, don't do that behavior, don't perform that motor action. And it it is true that there are these different cell types. It is true that they are modulated by. These modulator is like dopamine and serotonin in different ways and that
Simplistic hypothesis or your ristic. We call. It has been very useful in making models about how the accumbens does. All its 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 cell types and at least for your audience, we can think about dopamine driving the activity of one promoting certain behaviors and inhibiting the activity.
He of the other cell type and being a sort of break on certain behaviors as long as you and I a scientist. Appreciate it's not quite that simple. Sure, it's a little more
complicated. So using that as a framework to think about social behavior, as you said, you know, pro-social non-aggressive non sexual interactions involve the choice of a lot of behaviors but also the suppression of a lot of behaviors and and so maybe you
You're starting to sense what I'm doing here. I'm I think for people to understand how a single structure like the accumbens could mediate social interaction and reward at what it sounds like it's doing is rewarding a certain category or and catalog of Behavioral 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 inappropriate if I know.
Oh, 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. Yep, for
instance, and I think the accumbens and its Associated circuit. I love the way you. Just put that probabilities. It's my probability of having this behavior in this certain context is increase my profit, the probabilities of not doing certain behaviors. And I think there's little doubt that this brain area called the
Lisa Cummins and all of its Associated, circuitry 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 pro-social non-aggressive, non sexual interactions. I actually also think it plays a role in empathy and leading you there. I want to have a discussion about that please again there.
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't give you a coherent.
Hypothesis or diagram of how it all happens, you know? Yeah, you're still going. What I can say is even at our current level of understanding,
it is leading to novel hypotheses that are allowing the devel. You know, perhaps, you know, if we bring it back to Oz Schism that are allowing the development of Novel at the, at the moment, pharmacologic Therapeutics, that might be helpful for people who are not having normal Pro social interactions and would like to have them would like to be able to
Func function in that domain in 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 labs 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 about targets or even behavioral interventions that might actually help people. For example,
Suffering from autism spectrum, disorder of the sort that they actually want and need interact need therapeutic.
Help. I think, looking at the social connection circuitry 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, we are living in a time where, you know, we don't have to aggregating,
Oops, necessarily to protect ourselves physically, it helps in certain ways and certain circumstances, but certainly to support our selves 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. But when we go out to dinner with friends, or we go to a ball game with friends or we interact with friends. I'm very familiar with the feeling of like, well, that felt really good, it just felt good. It gives me energy. It actually gives me energy to go back and do other things.
Things like spend four days alone with a bunch of papers and lectures preparing for a podcast, which I also really enjoy. But when I do that, when I go out to dinner with friends or see friends, I'm not thinking about buffering myself against loneliness, when I do it, I just liked the interaction. So what sorts of evolutionary hypotheses can we come up with as to why the human brain is so tuned for these social interactions? Why it?
Rewarded by not just one dopamine, but also
serotonin and
oxytocin, three prominent, neuromodulatory chemicals in the brain are devoted at one site in the brain and others that it's connected to of 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 think the answer I'm going to be able to give. I hope it's not tried and it may be a little bit. Obvious is and it
In some ways it's analogous to why drugs of abuse and addiction are also a problem is that the circuitry that is telling us a pro-social. Positive interaction is so highly reinforcing evolved over you know millions of years or hundreds of thousands of years. Whatever that is and I the only hypothesis I can come up with and Andrew you may be able
To come up with better ones is what I alluded to earlier is that it was very adaptive when we were more primitive organisms, nevermind non-human primates. But when we were whatever we were to be a social species for basically, primarily two reasons for Reproductive purposes, it increased your likelihood of reproducing. If you were hanging out with other members of your
PCS and a non-aggressive way, and for protection against predators. And there may be other reasons,
probably child-rearing to do ya Thang in your absence, you want trusted friends that can watch your
offspring thank you very very good point. So there's circuits the modulated to use that evolved over Millennia. And as you pointed out, you know, eventually I mean depending on the society in which you live
You didn't need those social interactions for protection against predators. Although you know if we look at our world, now one can make arguments both ways. If you're in a war zone, is the better to be off by yourself? Is it better to be with the group of people? But so they the mechanisms involved 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't have kids if you're by yourself all the time. Well, and this is actually think it's impossible, right? At least currently. And yeah, can't find a partner with whom to have kids. If you're socially isolated, makes it much harder. So, I hope I'm answering your question, I think. And then, and then, as you point it out.
You know, for many of us there's a lot of positive aspects to having friendships and hanging out with your friends. Emotional, support, emotional buffering and feeling connected. There's something about connect, is no shaft feeling connected. I'm and later we'll talk about psychedelics, but this notion of feeling connected has a lot to do with buffering loneliness. When we are alone, the memories and the and the energy for lack of a better word that we
In recalling Social experiences and anticipating social experiences is really powerful. You mentioned that, you know, that people can't have children. If they spend all their time alone. It's actually, I realize you're not on social media and more and 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 research literature about this are socially isolated.
spending their 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, Etc, concern about porn overuse in addiction their etcetera, 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 all social media platforms and I, you know, quite active there. I can't say that I've ever been on social media and experience the kind of delight and thrill and persistent energy increase that I experienced with in-person interaction. And yet social media, I have to assume is capitalizing
Some of the same reward mechanisms in presumably the nucleus accumbens so are there any data I realize this hard experiment to do in mice? May be impossible. Are there any data that you're aware of that? It shows that social media has a high addictive liability, or do we even need an
experiment? I-i'm 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, I am in my late 60s. I grew
up. Well, they know who you are. Now, I drew
up before computers before cell phones. So, I still am a believer. Perhaps, in an old fashioned way that physical interpersonal reactions are really important. Obviously, there
are
advantages to being able to interact over social media and I'd, I mean, for all sorts of reasons.
Reasons. There's a lot of positive and good from that, but back to your question, can we get addicted? I can't speak to social media. I can speak in an olympic, you know, I think can is much more able to eloquently described the issues around your, I can just talk from my own experience that
My cell phone is and chat, you know this isn't social media, but checking my email messages, checking my texting, my text messages has a for me, has a compulsive addictive quality because I never pressed. It's like a lever press for a mouse and it 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 mentioned, getting a message from one of your friends. Sure. You know, I like getting messages from my friends, it means they're thinking about me, it means I'm part of their world, I have no doubt. It's activating my reward, circuitry, not nearly to the degree that a hit of cocaine or an opioid would do. So
I don't know what else to say about it. I
I think as a society we have to be aware of these issues and it's really complicated how we manage, especially, you know, once you're an adult, you make your own decisions for better or worse. But you know, it's a huge issue obviously for anybody who has children or as planning to have
children and adults on social media. And I see lots of accounts of people that are 18 and older, who they spent 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 Instagram, Facebook LinkedIn, Twitter have capitalized on this hardwired circuitry
app, the release of oxygen to make him really
reductionist the release of Serotonin dopamine and oxytocin by virtue of someone saying something to us, maybe not even a positive thing, maybe it's a - bye. As you said, they're thinking of us, there's something about being recognized by others.
Maybe this is a good Segway. We're heading towards empathy hear 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 and I think it's important. I mean thank you for bringing that up for
Us as a society, to be, at least aware of this. And it doesn't mean 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 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? But anyhow back to the new robot Neuroscience. You're absolutely correct.
Capitalizing on these mechanisms, that have evolved for physical interpersonal, react interactions because our Evolution didn't anticipate, right? Just as
pornography is got lysing on the sexual arousal, a reward circuit Associated
reward. No question about it and he just has the gambling industry does. I mean as you know the you know, the Vegas casinos.
Have full-time people developing algorithms for how frequently should a slot machine. Pay off what, you know, what's the perfect amount of payoff to keep certain individuals coming back so pernicious? Yeah, someone you can tell, I've been spending a lot of time around addicts and former addicts. I've been researching some some things for the podcast and a gambling addict. Told me something interesting, they said that the real Stinger with being a gambling
Is that the next time really could change everything res. No alcoholic says that the next drink could change everything for the better. Or, you know, the the cocaine addict doesn't think, oh, you know, the next line of cocaine could could make all of life better now and forever. Whereas the gambling addict actually holds in mind the infant issam only small. Yeah. And yet real potential that the next time really could wipe out their debt and
perhaps what about the and yet we know
they would lose that to write whatever winnings
they and because
Casinos are fully aware of this? I have been told by friends who know they they employ, you know, full-time quantitative, you know, for lack of a better term. Well, I was going to say computer geek, I don't mean to that the and derogatory sorts and Narada. I would be amazed if they don't have neuroscientist who have expertise in what's called neuro economics or behavioral economics.
95% sure that has to be the case. I occasionally
sit down to the roulette table because I just don't pass. Have an easy and not long ago. Actually, I had the experience of winning fairly not a large sum but a meaningful sum of money. Fun. And I'll tell you my soul Mission at that point was to get up and go back to my room and and not stop at another table. And I confess, I pulled one brief stop, another table played one hand, and then lost it. And then just got back to my room as quickly as possible. And then,
Las Vegas as quickly as
possible. Yeah. Gambling is but
they'll probably get me the next time.
Yeah. Gambling is a, you know, it again and it's all gets back to this reward circuitry and the intermittent, real intermittent rewards are very, very
powerful. Well, and you mentioned earlier that the the reward system is powerfully tuned to remember what were the behaviors that led up to the rewarding experience and and nobody? Nobody ever won on the at the roulette or craps table or poker table by getting up and leaving. Yeah.
So, I guess my brain was just thinking, well, how did I win? I won by sitting down and putting chips on the table, not by going back to my
room. Exactly, exactly. And
yet, I have, you know, their number of degrees, and I like to think my prefrontal cortex is working and yet it was still challenging in that moment.
Gambling is really enjoy having? Yeah. Another human activity that's quite complicated. It can be enjoyable at work, can be incredibly damaging
and now people are going to think. I was that
gambling.
Out of that, I was referring to, but I swear, I'm
not. Fortunately, a very blessing, that's not my addiction. I'd like to talk about empathy and use that as a framework for eventually returning to our discussion of autism. But you have this, perhaps long-standing interest but Recent research interest in empathy. Tell me about this work, I'm not familiar
with it, okay? So, I am going to, I'm gonna, I hope it's okay, Dragon. The some work I've done on this drug called MDMA because it is
Laid it. So we were working on in my lab, social behaviors positive pro-social behaviors that stimulated me to start thinking about what are components of a positive pro-social, non-aggressive interaction. A common key component of that is having some empathy and compassion for the individuals, your
Hanging out with and it is a topic. I've been interested in for many, many decades. I was once a psychiatrist and to get on my whatever the word is hobbyhorse. I look at the world today, I try to be optimistic again. I am a child of the 60s and 70s 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 enters my mind and I felt this way for decades is, what is more important for the survival of the human species than empathy and compassion than actually being able to look at another human being even if they look different than you even if they have a different belief system than you, what is more important than actually understanding that 98% of your life is very is, is very similar
You know, if you have some differences in how you look and the beliefs you have, but there's so much in common, so what's more important than understanding? That when another person is suffering, their suffering is the same as your suffering, we 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 presence, I figured the only way I might be able to contribute
Two 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. So she ability or pro-social behaviors in mice and then I was
Able to ha have a young woman scientist and I want to give her credit Monique Smith. You might want to have Monique on your podcast. She says, she's a Dynamo. She's now an assistant professor at UCSD. We're you one was and Monique introduced me to a series of Behavioral assays that I like to use that. I like to use the phrase, they are measurements, they are behavioral antecedents.
It's 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 manifest, 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 and for human interactions. I just think of you know, any other we were talking about friendships, any of us who had to watch a close friend suffer, it's hard. You want to do anything, you can to help them. That's 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's how I
I'm defining apathy. So it's my belief that like any complex human behavior. There are evolutionary reasons why that has been adaptive and important in maintained. And if its evolutionarily
Evolved, there are ways of studying it in 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 pretty new for me. So, one asset and we published a paper in a journal called science about this which is if you take one Mouse and in a ethical way, you put it in pain, you make its hind paw
One of its paws, one of its feet hurt, a modest amount and you take another mouse and you let that what's known as the bystander Mouse, just hang out with the mouse. That's in pain for one hour, just one hour, the bystander Mouse who has had experience. No physical injury whatsoever will manifest behaviors indicating. It is now in pain and it lasts maybe four to 20 hours, but think about that a mouse, just hang on.
A mouse that is normal hanging out with another mouse in pain starts feeling and pain
itself and the, the mice are able to see one another and here, 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 Monique, and her previous colleagues and others. One component of, it is probably an olfactory Q or what. We
All
of pheromone. So there's a sense in pain is secreting, an old
probably probably because you can take bedding from mice and pain and expose the bystander mice. So that's one thing and I had never heard of these behavioral assays. We developed our and this is pretty cool, and then I'll tell you to others and then I'll tell you how it connects to reward. Circuitry, we developed a novel assay, which is the social transfer of Pain Relief. Pain relief is called analgesia
Asia 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 listeners to get upset. We are not hurting these mice too badly and it is a tricky issue. Is it, you know, is it okay to put a mouse in pain so you can the goal is to develop better treatments for human beings in pain obviously. So you have to
Ice 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 that is in pain will show behaviors indicating. 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't speak to in any comprehensive way where I mean it's called social buffering 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 wrong side of the bed and if I'm by myself, I focus on that pain and it bothers me more if I'm in a social socially engaged, I think it's not only that I'm not paying as much attention.
Ancient of the pain but I think there's actually some relief from what's known as the social buffering of pain. So,
well, I'm no hippie but I actually think that all species including humans are secreting molecules mainly odorants that are perhaps even acting directly is as analgesics and I can make that statement with without worrying too much. That people think I'm completely crazy because we had known Sobel on the podcast from the Wiseman who
Who shared with us, you know, not one, not two, but at least a dozen ways in which humans are making molecules, typically, odors and communicating. Those to one another, to powerfully impact their testosterone levels, their face oppression levels, their
immune molecules that, you know,
and and of course gnome works on olfaction. So he's going to be biased toward that system, but that's just one slice of the sensory array. I mean, what about the the the way that somebody can look at us in a way that
It makes us feel good on a normal day will, when we're in pain, just even the touch to a shoulder, can mean a lot. I remember going to meetings when I was a curly neuroscientist and I would probably at that point of, you know, not been the type to just walk up and say hello to you because I wasn't in your field and your this luminary and stuff. But but I remember as I start
my good guy by, you are very very good. I always say hi to every. I know you are an idiot. That
statement was a reflection, a reflection on you, but as I
Advance through my career, what I found was, you know, you'd give a talk or something and someone in your field, more senior, to you, who you were respected, would give a nod or something. Those nods
me a lot. Absolutely
nods. Could carry you a long distance. I mean, obviously, we want to be intrinsically driven to do the work we do but but there's social communication, social speak. I think there's a whole landscape of thing. So what you're describing is incredible but I think makes a ton of sense.
Yeah. So we have these social transfer paint available G's here. We're working on
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 MDMA and is it a name pathogen or not? And how that might influence therapeutic efforts for autism? We're working on behavioral models. 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 a bar know.
Nose poked or even experience the shock will the mouse do that simply to get give one of its buddies. A reward pure altruism. And yeah, it's pure. It's what we call it generosity a generosity assay and early days. It looks like it might be working. We have. And that's a generosity. A say, we can. Also, ask the question will a mouse work. So, another mouse doesn't get a shock, doesn't get hurt, which is compassion and I think these things are
Going to be working. And whether you want to call that empathy, I would call that those are behaviors. I like to use the term 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
Hanging out with another mouse, the social transfer of analgesia a mouse in pain. Getting some pain relief from hanging out with another mouse in pain who 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 anterior cingulate cortex which human brain Imaging studies. Suggest our is activated.
During empathic human responses and the projections of that area into the nucleus accumbens. That's the connection and we're interested in weather.
Neuromodulators like dopamine and serotonin made influence these circuitry. These connections that are involved in these in quotes, empathic behaviors, etc, etc. And we think drugs can be used as probes of those kinds of neuromodulatory mechanisms. I hope this is all making
sense of excellence and is fascinating. I'm not one to suggest experiments to colleagues.
In areas where I don't work but I am going to anyway up please um One You're a really smart guy,
your suggestions,
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 Paradigm 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. Yeah you know if it could be scaled with how inconvenient that work is a brightly if I'm very hungry. I mean we're all taught to put our own oxygen mask on first, don't wait too so that we don't all die so to speak but you know I grew up.
Up for instance, with a one pair of my mother, it was the kind of person who would see at that time, there were far fewer homeless people on the street, maybe they were all institutionalized, I don't know. But if she saw a homeless person on the street of the town, we lived in, she would literally pull over. Give them money. Find hotels, she had homeless people living, in hotels all over the town. We lived it, it was crazy. I mean, we couldn't get anywhere. That was the problem is we never arrive anywhere on time and that's my excuse for always being late, possibly The Enforcer.
Labeled you always run late and I always run incredible, right? Just a very strong sense of social fantastic connection, that kind of thing, but in any case, you know, some people are like that, like she could not experience any even modicum of inconvenience for helping others good. 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 going to help them if they're an acute pain or it seems like a dire circumstance but let's be honest. Yeah, most people are probably going.
To prioritize their own stress and priorities for lack of a better word when the situation often calls for us to set those aside and intend to people that are suffering. So if there was a way to introduce the the internal probe of the interplay of circuitry's that involve how convenient or inconvenient it is like if we're well fed. It's pretty easy to go out and gather and distribute food for others. But if we're hungry we tend to focus on our own hunger.
We 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'm not saying
that ends on the on what sort of
stuff. Yeah. Exactly. I
mean, I am urging on the south course of we all would of course I'm Tire. Right. You might think oh, goodness, like do I have time for? Yeah,
exactly. And so I'm not proud of that statement, but back to your question.
Yes, I think absolutely we can design experiments where after we've established the basic phenomenology then we can take our subject animal or Mouse and put it in just to certain circumstances. If it's hungry itself, will it work is hard to give another animal? I mean, it's a good question because I'm not sure what the outcome will be. In one could predict it might work harder because it understands the hunger in quotes more. I love working order.
Would be. Of course, it's not going to 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 it. Are you more likely to behave in a generous or compassionate way, if you grew up with that Mouse, you know, in the way they are, mice, grow up in academic environments and if it's a
Ranger, how will you behave? How will you behave? If you had a fight with that Mouse previously? And what if you had an and it also matters. Did you win the fight or did you lose the fight? Write your product? You know, intuitively is we probably would all guess I'm more likely to help somebody I defeated in a fight previously because I'm the Supreme, you know, and the hierarchy, I'm the dominant one, I'm probably less likely if that person beat me up.
All these are great questions. I think we can study them. I also think there are ways we can study these kinds of interactions and uman subjects, not that I am going to do that myself, someone in Stanford. Well yeah so I think there's also an opportunity and I'm happy to discuss how neuromodulators like in particular serotonin but also perhaps dopamine and oxytocin May influence the brain, the circuitry in the brain mechanisms that are mediating.
What? I term empathic behaviors.
Let's return to autism. All right.
Does autism involve a lack of empathy. Does autism involve a restructuring of the reward system around? Social interactions may be considering the second question first. I could imagine, for instance, that there are variations in brain wiring that would make it such that a kid who then becomes an adult gets a tremendous amount of reward from I don't know. Math of Designing mugs.
Any number of activities, but that through some variation in brain wiring, social interaction. Spending time with friends is just not as socially, rewarding, it just doesn't feel good in the, in the moment, doesn't necessarily feel bad but it's not selected for. And is there any evidence that that's the case in children who are classified as Autistic or having
autism? I am I want to be clear. I am not.
A world expert on pathophysiology of individuals with autism spectrum disorder. I have read some of the literature I do study Mouse models of genetically based Autism Spectrum Disorder, so the answer is yes. There there have been Imaging studies and again. So your audience to certain members, your audience, don't get mad. We're remember our earlier conversation. We made
Point that autism spectrum disorder is a highly heterogeneous 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 spectrum. Spectrum Disorder are this or that, but there are studies both in human beings and mice that suggests that the
Enforcing component of a social interaction is much less or lacking in our models of autism structures. Some spectrum disorder and certain individuals and important point is is that just genetically wired was that? Because in their early experiences, they weren't able to get the sensory stimuli that tell them, this is a reinforcing. So,
So experienced unknown are least. Those are topics that I think are worthy of 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 in question, and
It's very likely for some individuals. The answer is. Yes. Meaning they do lack. Some of the neural mechanisms that allow them, but that probably doesn't apply to everybody. I wish I can say in our Mouse models of social interactions on our Mouse models of in quotes, empathy in. These are my on my show deficits and those deficits
Assets can be rescued, meaning improved upon by manipulations of certain neuromodulatory systems. In this case, the serotonin system by giving drugs, including a drug called MDMA or ecstasy. So I hope I'm answering 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 accumbens. We will get into this in a bit more detail when we discuss MDMA. But I've now spent a lot of time with a recent paper of yours that
really, really rich. One of the MGM, a
relative roles of dopamine in the nucleus.
Comments versus serotonin, nucleus accumbens by the way Folks, by time, this episode comes out and episode all about MDMA itself. And it's a modes of action will have already aired and you can find that. But even if you haven't heard that, you know, MDMA is an amazing molecule because it profoundly increases dopamine, and that's why the word methamphetamine is actually in. Yep. MDMA still a surprise to many people to hear that. But it also robustly increase.
Is serotonin transmission and what I love about the paper from your lab that explored, this is that it released by my read of the data. It showed very convincingly that it's serotonin released in the nucleus accumbens that's responsible for the pro social effects of MDMA. Whereas oxytocin this thing we talked about earlier that everyone assumes is the pair bonding molecule the molecule of love both in humans. Now I've there's a study in humans and in the mouse work that you've done doesn't seem to play as prominent.
To role in the social enhancement that MDMA 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 sprays 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 or adult with autism makes them somehow more social or Desiring more. So
Connections. I'm not aware of any, I
don't think the I think it is a, it is a worthwhile. It has been studied. I don't think we can close the door on the potential therapeutic uses of oxytocin 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 with a, you know, a lot of hope that intranasal oxytocin would
Promote more positive pro-social experiences. I don't think the door is shut, yet there may be different ways of administering, it administering. It there may be ways of making a different type of oxytocin that might be beneficial. I have a colleague at Stanford, who's actually looking at a related, neuropeptide called vasopressin and she's finding some potential benefit from that and
Is oppressed in an oxytocin are 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'm aware, is not there yet, in terms of MDMA again, complicated story, as you pointed out MDMA.
It's major molecular targets. Don't want to get too technical. Here are the serotonin vacuum cleaner. The molecule that's vacuums up serotonin and the dopamine vacuum cleaner. The molecule that vacuums up and excuse, my language sucks up dopamine when it's released it, because it's an amphetamine. Derivative
As you point correctly, pointed out, it not only prevents these proteins. We call them these molecules these vacuum cleaners from vacuuming up the dopamine and serotonin. When it's released, it actually causes it. How to I don't want to use the term the terminals to vomit out. Dopamine and
serotonin. That's what I say on the is that a minor release? I'm known for when I had my soul episodes. For when I talk about synaptic release, I'll call say that they
gave us
Ahmad Al. So what amphetamine derivative you work on
synaptic transmission. It's
almost an insult to transport. It actually causes it. Not only prevents the vacuum cleaners from sucking up the dopamine and serotonin and it causes it to spew out, dopamine, and serotonin. So imagine if your vacuum cleaner, started the pressure in your vacuum cleaner reversed and all the dirt, you collected started, being spewed out. Now, the one difference for
EMA and, you know, it's a fascinating topic. I hope we have time to talk about is why does MDMA
Qualitatively for most people give give uman subjects a different experience than cocaine or meth a especially
methamphetamine Zuma bleeds. The fact that there's so much serotonin.
Exactly. And so if you actually get in and this is why for your audience's, this is why hardcore molecular science can actually teach us. Something about complex human behavioral phenomena such as social
Interactions and addiction. At least the hypothesis we proposed and others in the field. It's not just, you know, science is not done in isolation. So I want to give credit where credit is due. We did not Define the following that MDMA affects the serotonin system more than the dopamine system. So it's not equal, it's not fifty-fifty, maybe it's 7030 80/20. And that's because the molecule itself of MDMA.
Again, I'm trying not to use language, has a it binds to. It has a higher Affinity, at likes to bind to an influence. The serotonin vacuum cleaner, more than the dopamine vacuum cleaner. It's still affecting both but it's not fifty-fifty. It's more, whatever, 70, Sarah 70%, serotonin 30%, dopamine and then it does influence oxytocin in very complex ways, which is
Further technical discussion, it was just a nice paper that came out that report it that serotonin release in a hypothalamus structure which again the hypothalamus, you can explain to
your listeners marble ish size structure above the roof of your mouth responsible for sex temperature, control feeding and satiety, and a bunch of other things. Critical and yeah.
And that's a home of oxy neurons that produce.
Thank you. So this paper reported that when serotonin is released in the hypothalamus, it activates and causes the release of oxytocin that's in the hypothalamus, our work in the reward. Circuitry suggested, oxytocin, so that's serotonin Upstream of oxytocin in the hypothalamus. In the, where we were looking in the accumbens. It was the opposite oxytocin, cause the release of Serotonin. So, the point to your listeners is the brains, unfortunately.
Complicated. You know, we, we like the distracted, but we like to come up with General hypotheses and principles, but sometimes the devil's 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 nailed down. Is that MDMA? Because it is an amphetamine. Derivative does influence do?
Dopamine release and dopamine, the dopamine system, and some of my colleagues in the MDMA field, who I respect enormously, don't like me to say this, but I'm going to say it. Anyhow.
Remember earlier, in the podcast, we talked about different substances, having addictive liabilities, does it mean that substances automatically? Addictive doesn't mean it's automatically not, it's a Continuum and I would argue that MDMA does have a, some addictive liability because it is an amphetamine, derivative, it feels good and it feels good. And so there are individuals that, especially as you know, is your listeners. May know,
And the Ma has gotten a lot of attention because it's in a therapeutic trial. That's looks very promising for as an adjunct to Psycho therapy for post-traumatic stress disorder and the FDA the part of our government that
Approves or disapproves the legal distribution of therapeutic drugs may end up reproving MDMA for certain uses. The point being is that once it if it gets approved, my personal feeling, is that we'll have some addictive liability. It also has this very powerful what you and I might term Andrew approach social effect, some people even call it a name pathogen
it's a little controversial, meaning it enhances your capacity for empathy to experience the emotional state of another individual to want to understand that person's experiences and emotional state and are what we've suggested is that the addictive liability is mostly although not solely being mediated by its actions on the dopamine system whereas its positive more pro-social effects and perhaps
It's in pathogenic effects. Are more likely to be mediated by its interactions with the serotonin system in this reward circuitry and we are actually doing a lot of work to test that hypothesis. We're actually testing MDMA in these behavioral models of empathy in mice, and it looks like our hypothesis is being supported the other thing. Just to drive your
A nurse crazy about sorry, listeners. How complex the brain is. If you think it isn't, neither you nor I were
consulted at the design phase and so we don't have to apologize for the brain's
capacity because I don't look, trust me as a scientist. I wish I could keep things as simple as possible. That's what good science is. It turns out the serotonin serotonin is produced by neurons and another part of the brain with this wonderful name called the dorsal raphe nucleus. And it turns out
Out the serotonin neurons. Talk to the dopamine neurons, the and influence the dopamine neurons. And 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
And some of the concepts that have been elucidated 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 in the accumbens actually. Modulates dopamine release. So, it gets crazy complicated. But you can still develop simplistic hypotheses. Like, as I was saying about MDMA where, you know,
Abuse addictive, liability. And some of its reinforcing qualities, which you just mentioned MDMA. A lot of people find it fun to take it is probably mostly the being mediated via the dopamine system and some of its social effects of and are being mediated by the serotonin system. We're actually doing studies to figure out whether the reinforcing component of a social experience requires that dopamine release probably does.
So what I'm most interested in really in the context of MDMA and we should just mention because we do like to mention these caveats. Yes, they and I can say this because I participated in a trial with MDMA. It it is a very pleasant experience. It's certainly not for everybody. It still is a schedule. One drug at this moment. Absolutely. So you can go to jail for possessing. And or selling, in fact, it was a big bust recently in Canada and another one in Brussels, a large amounts of MDMA collected. Those people are probably going to go in
To prison for a long period of time. So you do you don't want to take it or possess it? It's illegal. We're talking about clinical trials here but also the fentanyl issue. There's a lot
of things. I was just going to change into your we'd be remiss
if we didn't mention. A lot of people are dying thinking that they're taking one drug when they're taking another, so we are not encouraging the use of these, but I will say that the subjective experience of MDMA provided. It's done in a the appropriate clinical setting. It's actually MDMA doesn't contain other things.
Dost correctly, Etc. Is a pleasant one for sure. And Maya, my sense is that the dopamine release is reinforcing the experience that the context that serotonin is providing the social context and and the word context there becomes important. When we think about back to the 90s, when there are a lot of raves and people were also, you know, getting I guess positive feedback from the interactions they were having dancing all night partying with friends at
Etc. I mean, I think that returning to the issue of autism and the role of Serotonin, so
In autism. There seems to be less of a reinforcement pathway for certain kinds of social interactions in some individuals with autism, and I'm aware that there are some prescription treatments for autism that capitalize on the serotonergic system and dopamine system. So is it fair to
me to my knowledge? The only FDA approved pharmacologic therapeutic for individuals with autism spectrum disorder is
Actually God, I'm just blanking. It's not a serotonergic drug, I have to look it up. I want to say risperidone for agitation. There is no drug for, for lack of a better term, the social deficits, there's no FDA approved drug, if you look at the literature psychiatrist and individuals with group with good,
Attention have tested the utility of traditional serotonergic. Drugs, like Prozac ssris. There are drugs known as snris drugs, that influence serotonin release and another neuromodulator. That, you know, well, norepinephrine and at least, well done, clinical trials, which in my view, as an academic or very important, none of them have showed efficacy. Having said that there are several companies and
Full disclosure Here. I Am the founder of a small biotech called map, light Therapeutics and I'm not advertising from a flight, I'm just doing a full disclosure. It was found it with Carl Dozier off who you've had on your podcast and an entrepreneur in. San Francisco named Carolyn nikolicic and we have the phase 2 trial phase 2 trial means. It's a safe drug. We've done all the safety
Work and it's a drug that targets, a sub type of receptor for serotonin. Serotonin works on many different. I know what word can I use other than
receptor? No listeners of this podcast. Probably be familiar with receptionist sort of parking spots for four molecules yes that the paper you I was referencing earlier from your lab it talked about serotonin, one be receptors being particularly important.
So, 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 actually have any relevance to uman, sub, human beings in particular. Those who some of which have some sort of sociability deficits other companies are pursuing this to, so MDMA itself, there has been
I don't know if it's ongoing. There's a well-known organization. I know if you've ever had anybody from maps on this, the multidisciplinary association, for psychedelic, studies maps, deserves a lot of credit for being a Pioneer and saying, in particular with MDMA promoting the idea that, you know, this drug deserves rigorous and ethical study that that's at least my view.
And Maps which was founded by individual named. Rick doblin has deserves enormous credit for their 30-year effort to make it
Allowed and legal to actually study MDMA. The point I'm making is no maps and perhaps others have done, some small trials, studying MDMA in individuals, high functioning individuals, with some form of social anxiety, I'm saying this because this is public, there's another company called mine Med, which is one of the publicly traded psychedelic companies, and this is on their website.
Full disclosure, I am on their scientific Advisory Board. They are gearing up to do a trial of a, I don't want to get too technical of a certain form of MDMA. There are two different types of MDMA that they have these horrible names called enantiomers. So, the MDMA that is used for clinical trials, that map's MDMA is a molecule and it has mirror images of it.
Itself and one one has the name our MDMA and one has the name s MDMA and they're called this horrible enantiomers because they're 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 enantiomer.
Is the one that has a higher interaction with the dopamine system and the are enantiomer has a higher interaction with the serotonin system. You're staying, if you look at the the literature on autism spectrum, disorder in human subjects, there's a bunch of papers suggesting serotonergic systems are malfunctioning in
Individuals with autism spectrum disorder. And if you look at
Reviews. I've written or any of my papers, we probably cite some of the
reviews. It's clear that serotonin is playing some role in social interactions, at least in mice, and almost certainly in humans, as well. It's hard to imagine Based on data from everything, from ssris, to neurotoxic lesions of the human brain etcetera, that it's not also playing at least, a similar role in
humans, and I fully agree with that and and as we were discussing, there's a, there's a modestly extensive clinical literature.
Literature from Human subjects. Suggesting that some aspects of brain systems that utilize serotonin as one of their signaling molecules one of their neuromodulatory mechanisms. May not be functioning in some populations of individuals with autism spectrum disorder. So based on that, based on my labs, work on the role of serotonin in modifying reward circuitry. It's Ro
roll in pro-social behaviors and the biggest clue. Which I think you would agree with Andrew, is this drug MDMA? I mean, this is why I am not a druggie myself, I am a child of the 60s and 70s. So I did, which means I'm 20 years older than you. And you I did experiment like everybody of my generation with psychoactive substances in the 70s. 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 now, I'm talking scientist to scientist with you Andrew. They have molecular targets that we can manipulate and rigorous ways, we can figure out where in the brain they act using the modern tools of Neuroscience, which your audience may not know about I'm saying this to you conditional.
Knockout 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 MDMA for decades is there's a clue there. How does a drug that has molecular Targets in the dopamine? Neuromodulatory system in the serotonin or modular Choice 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 I don't know, for me there's a clue there. There's something really important from that phenomenological observation in the human experiences that we can learn from.
I completely agree about MDMA and you know, we've done a couple of
Podcasts about psilocybin and by extension LSD because even though there are differences there psilocybin Ellis t. As far as we understand, largely work through, you know, activation of the serotonin 2A receptor, broadening the brain network connectivity. So, again, it's serotonin serotonin serotonin, but different receptors very different subjective experience. And I guess the, perhaps, the best way to describe it is that LSD and psilocybin are almost always considered.
In the, in their subjective effects. Whereas MDMA can be in a pathogen and act engine. And so serotonin in acting to through different receptor systems impacting and creating very different subjective experiences. I also agree, I think MDMA is particularly interesting for the neuroscientist, perhaps also because at least to my knowledge, there is no substance in nature. No plant, no mushroom, no error. Got no end, no mold.
Old that creates this increase in dopamine and serotonin simultaneously. MDMA is a synthesized 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 that folks like maps of are now doing such fantastic work on. So I'm very excited about what's happening with the research on MDMA and I'm
So, glad that your laboratory is parsed that some of the relative roles of Serotonin, The receptors involved it, since we mentioned serotonin 2A, for psilocybin and LSD, we'd be remiss if we didn't say that this wonderful paper that we will provide a link to in the show. No captions. By the way, folks, that Rob milenka, here's lab, it's focused on the serotonin 1B receptor. So even just differences in receptor subtypes leading to profoundly differents objective outcomes. I find that to be just
Just one of the most important areas that one could even think about let alone work
on, thank you. I appreciate the compliment. I will also say unlike everything we're finding it's not all about only serotonin 1V but that's as you know, there are again pointing to the the amazing and Powerful complexity of the human brain or the mammalian brain. There are 16 different serotonin.
Spots or receptors that are distributed in different brain areas and complex ways. And so that's daunting. But it also offers possibilities for developing very novel, therapeutic agents, that, that activate or inhibit, these and complex ways. Hopefully, for therapeutic
benefit
so, before we conclude, I'm very curious to get your opinion on what you see, as the landscape of the work on psychedelics and MDMA, which isn't really a classic psychedelic, but all these drugs that as you pointed out during your youth were used recreationally and for mind, exploration and expansion and now being probed as potential Therapeutics for various mental health challenges, as well as potentially expanding Consciousness, empathy, and all
All of that. I mean, not getting into the details of, you know, the legal issues that have to be overcome, not even necessarily talking about the clinical trials, or the people doing the work in different Laboratories. But just have to imagine this is must amuse. Tickle, surprise, you. I mean, how do you feel about what you're seeing now? Because it is a very exciting time for these compounds. It tickles me and excites me with the appropriate caution. So,
I do think drugs are very powerful probes of brain function. I think this class of drug, which as you correctly pointed out, people use the term psychedelics scientifically when pursuing their understanding their therapeutic potential, their mechanism of action, it's more useful to divide them up into different categories. The classical loosen engines, which are LSD and psilocybin, the intact or and pathogens.
Which is MDMA, which is really a qualitatively different drug. There are other substances which we don't have time to talk about. Like ibogaine an Ayahuasca which are very complex and peyote. But nevertheless, I am tickled and excited as a child of the 60s and 70s. But I am also not Evangelical about their you to use and their therapeutic potential. So as you can imagine what I'm going to say,
I think they should be the subject of rigorous sophisticated and most importantly, ethical research. I think we could learn a lot about how the brain works and it's amazing capabilities. I think we could, I think they may notice, I say may have therapeutic potential, but I do not think they're going to be miracle cures. And I do worry as
As somebody who lived through the 60s and 70s and watched because of the Leary, 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 and I hope that's the case and I want to
Auction your audience that not everybody should take these substances. They are not miracle cures. And while they certainly may be of benefit to certain individuals who are suffering and they certainly may provide unusual. And in quotes mystical experiences for certain individuals, I am very concerned that there are individuals out there that will gain access to these substances.
Aces and have very bad experiences because anybody who grew up in the 60s and 70s knows all about bad trips and truth, be told, I have had a bad trip or two in the 70s and I'm glad I did because it 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 as a bad trip on LSD, and I do have concerns that if you look at the clinical trials that have been done, the welcome to done. Not the anecdotal. I went and saw
some psychedelic therapist that a friend recommended and it did wonders for me, but the well, controlled clinical trials that are being done by certain biotechs, some academic institutions, they have very strict
What are known as inclusionary and exclusionary criteria are about who is allowed to participate in the subject and they 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 pre clinical researchers to study these substances in the way they deserve to be studied. So I hope that articulates my viewpoint. I think that it does and thank you for that Viewpoint. It's 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 42 million dollars from the opioid
Lawsuit settlement with Purdue Pharmaceuticals to the study of ibogaine. So, there's a lot happening, you know?
And I know just be clear, I think there's no problem with that and I actually would support that as long as the studies of ibogaine are done thoughtfully carefully and ethically. I see no problem with testing its efficacy and certain mental illnesses, and addictions.
And and it's actually it's actually a topic. I know a little bit about that, we'll save that for another time. Well first off, I want to 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 as their nose. I certainly hope not but I'm sure the listeners have now
Your picture of the enormous number of contributions in areas, you've worked everywhere from, as I mentioned earlier, neuroplasticity, at the cellular level, and molecular level addiction, work relating, to social cognition, and social interactions, rather as it pertains to autism models, and no psychedelics and empathy and on, and on, and again, train, so many prominent scientists in our field and to take time out of your schedule to come sit here with us and share some of that knowledge and stimulate 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 mentioned, we'd love to have you back again
for another done. All I can say is, I want to thank you for having me. I was a little hesitant or nervous about coming here and now I want to come back. So that was a blast when I just did with you. And I'd be happy to continue this conversation any time. So
You for your very sophisticated and thoughtful questions to be continued to be continued.
Thank you for joining me. For today's discussion all about neuroplasticity reward systems, social connection and empathy with dr. Robert milenka, if you're learning from enter enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition. Please subscribe to the podcast on Spotify and apple and on both Spotify and apple, you can leave us up to a five star
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Anybody thank you, once again for joining me for today's discussion with dr. Robert milenka. And last, but certainly not least, thank you for your interest in science.
